ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Cell and gene therapy comprise a booming avenue in devising novel, emerging healthcare products during the last decade. One such approach with a variety of applications includes CAR-T therapy, which, owing to its innovative and effective approach, has leaped outstandingly fast from idea to clinical practice. Contrary to the prolonged procedure of FDA approval, as observed in case of conventional drugs, the anti-CD-19 CAR-T, KYMRIAH was approved by the FDA within a short span of 4 years in 2017 [1, 2]. This therapeutic was imminently bestowed with the title of the ASCO breakthrough of the year in January 2018 [3]. However, cell and gene therapies such as KYMRIAH are distinct from the "ordinary" drugs in most aspects, and such differences are commonly shared between most cell and gene therapies. In this review, we will focus on some distinct features of such therapies throughout their development, from the R&D bench to the patient bedside, including the regulatory and business aspects of such new therapies which are often overlooked in the reviews on this topic.

The journey of a new drug from labs to shelves is divided into five main areas: R&D, production, regulatory approval, business, and funding. If one of these aspects is missing or is defunct, the drug, irrespective of its efficacy or safety, fails to reach the clinic. The new cell and gene therapies are different from the common drugs in all these areas, as CAR-Ts vividly demonstrate or highlight such differences as well as features that are common to the cell and gene therapies, it is the focus of this review which emphasizes on each of these areas.

Area #1. R&D and emerging technologies

The most distinct feature of CAR-T is that it is based on the concept of personalized medicine which has completely shifted the healthcare ecosystem paradigm from the "one pill fits all" to "every pill made for one patient". The most fascinating aspect of this approach is that it can be effective, not only from a therapeutic but from a business perspective as well. Moreover, these personalized drugs do not disrupt the previous approach, since they can fit well together.

Although the CD-19 CAR-T therapies usher the prospect of long-lasting recovery from advanced stages of cancer which were previously thought incurable [4], its road to approval is fraught with the reports of patient deaths due to cytokine storm [5]. At present, researchers are exposed to new challenges to enable widespread application of this therapy in new areas like infectious diseases, to cure solid tumors, and to enhance its safety, efficacy as well as affordability. To accomplish these goals, the key role is being played by the R&D sector and academic research, which are advancing towards clinical trials with new technology (Table 1).

Table 1. Cell therapy production. Emerging models

Samsonov-tab01.jpg

Firstly, the process of development of personalized drugs shares numerous features with those of the new product development strategies from information technology (IT), or agile processes [6], involving 3 three-step cycle testing ideas like:
– Producing minimal viable product (MVP) as fast as possible.
– Measuring the performance with real-life patients (customers) and gaining knowledge about the improvements needed.
– Repeating [7], and application of agile development methodology.

In this process, every iteration adds some additional features, and fast testing with real-life data shows whether the ideas are right or wrong. One important feature of such products is that they must be very flexible, allowing changes in parts, but maintain the basic functional concept. The software-based products are the best fit for this since they usually utilize the same platform which is used to design the product. This is the case with platforms in biologics, cell, and gene therapies; it allows the use of a platform-based approach for development. Every drug that is based on introducing changes in the DNA or RNA is a kind of "reprogramming" or "genetic software development" suggesting that some effective approaches from IT can be transferred to drug development. This includes all gene and cell-based therapies such as CAR-Ts, or plasmid DNA, or several mRNA-based COVID vaccines, CRISPR-based therapies, etc.

Although there are differences in time frames and regulatory pathways, the approach utilized for personalized drug-development appears to be more similar to this iteration-based development strategy than the standard one-at-a-time perfect drug development strategy used in pharmaceutical industry in the previous as well as present times. Indeed, if we look at the most splendid example- how CAR-T technology developed into its present and future, we can see many similarities.

The first-generation CAR-T therapies were a breakthrough technology in the 1980s [9]; however, despite big hopes, its design was too simple to generate reliable outcomes in clinical trials [8, 10]. Technologically, the first generation of CARs included only the CD3ζ signaling endodomain fused to the extracellular scFv to act as an activator of the T cells. In terms of IT development, it fell exactly in the "minimal viable product" (MVP) category, the product that has the absolute minimum set of features to function. However, despite promising preclinical results, the clinical trials demonstrated caveats such as poor anti-tumor efficacy in patients, caused by low-level CAR-T cell activation. Therefore, the next 2nd generation was introduced, which included co-stimulatory domains for additional activation. This design was highly successful in the clinical trials in treating hematological malignancies, such as acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). This success was confirmed by the FDA approval of two CD-19 CAR-T drugs, KYMRIAH (Tisagenlecleucel) for r/r ALL and r/r large B cell lymphoma and YESCARTA (Axicabtagene ciloleucel) for r/r extent CLL.

In the process of successful clinical trials for both of these drugs, the core of the "agile development approach" was used to adapt for its clinical features and limitations. Additionally, various CAR-T cell-mediated toxicities were reported, such as tumor lysis syndrome [11], cytokine release syndrome (CRS), neurotoxicity [12], and on-target off-tumor toxicity [13], leading to a few patient deaths during the clinical trials.

The most frequent and dangerous feature of CAR-T therapy is cytokine release syndrome (CRS) [14], which leads to some lethal cases during the trials. The iteration product development cycle, which was at this point enabled by the FDA regulations for adaptive clinical trial design, allowed the identification of strategies to avert this risk by introducing several therapeutic options for CRS, such as anti-IL-6 therapy in case of CRS development, and tools to observe the patient, such as hospitalization for a week after CAR-T infusion to closely monitor for adverse reactions [12, 15].

However, the second CAR-T generation failed to show promising results in the case of solid tumors and had several limitations in treating hematological malignancies, such as antigen loss and consequent tumor escape. Such peculiarities of the second generation CAR-T limited the long-term success of CAR-T cell therapy for a quite large group of patients, leading to relapses or lack of tumor response [15, 16]. With further studies, new ideas emerged, leading to the third and fourth generation of CAR-T cells, comprising more receptor domains with different functions added to the chimeric receptor (Fig. 1).

Samsonov-fig01.jpg

Figure 1. Agile Development process and CAR-T (adapted from [7, 8])

The third-generation CAR-T cells combined the signaling potential of two costimulatory domains (CD28 and 4-1BB). To overcome the limitations of the third generation, the fourth generation of CAR-T assimilated various improvements in different parts of the chimeric construct, mostly linked with solid tumor therapies. The antitumor activity of the fourth-generation CAR-T cells was enhanced by features such as additional transgenes for cytokine secretion (e.g., IL-12) or additional costimulatory ligands. Based on the same principle, armored CAR-T cells and TRUCKs (T cells redirected for universal cytokine killing) are constructed i.e., they were modified to express not only CAR but also the inducible cytokine genes. The cytokine expression occurs only when antigen-binding activates the CAR-T cells [17, 18]. Other CAR-T approaches include the dual-receptor CAR-T cells, which are activated only in the presence of dual antigen tumor cells [19], and bi-epitope CARs [20], which fight antigen escape and loss.

With the increasing potency of CAR-T cells, more caution must be taken to ensure their safety. For solid tumors, the off-target activity becomes a limiting factor, since the target antigens are still expressed on some normal cells, and the cytotoxic activity toward these is not desirable. The first potential action is to adjust antibody affinity, thus mitigating on-target off-tumor toxicities related to low-level antigen expression in the normal tissues. The chimeric antibodies with middle or even low affinity to target can have sufficient potential to eradicate the antigen-overexpressing malignant cells, but not to damage normal tissues with low-level antigen expression [21]. Such situation is possible in case of solid tumors, which can even cause death during CAR-T therapy [22].

Another approach for reducing off-target activity is to fabricate short-lived CAR-T cells. This can be achieved via mRNA delivery with a chimeric construct instead of DNA incorporation into the T-cells. In this case, the T-cells express a CAR for up to several days at high efficiencies; however, the drawback of this approach is rapid loss of the transgenic construct and the T-cell activity associated with it, and a need for several dosages to obtain clinically relevant results [23]. This approach not only allows temporal control over the CAR-T pharmacokinetics but can also be applied with gene-editing tools such as TALEN, disrupting TCR and CD52 expression in the CAR-T cells, thus creating off-the-shelf CAR-Ts. In addition, this approach can expand the scope of therapy to treat hematological tumors. In this context, previous studies reported that by using mRNA-transduced anti-CD19 CAR-T cells targeted against the tumor microenvironment, promising results were obtained in the treatment of Hodgkin’s lymphoma [24]. The transient CAR-T production with mRNA delivery can be a potential option for future in vivo CAR-T therapy wherein, mRNA-loaded particles can be injected into specific T-cells within the patients [25].

Yet another approach to increase safety is via the on-off control of CAR-T cells. The most clinically advanced technology is the inducible suicide caspase-9 gene based on a modified human caspase-9 fused to the human FK506 binding protein (FKBP). This fusion protein, expressed in the T-cells, can form dimers when a chemical inducer of dimerization (AP1903 or Rimiducid) is administered to the patient. A single dose of the inducer drug causes rapid elimination of 85-90% of iC9-transduced T cells [26, 27]. Caspase-9-transduced T cells were used in the clinic as a tool to control graft-versus-host disease (GVHD) after haploidentical stem cell transplantation, and the GVHD-associated symptoms could be also quickly eliminated following the caspase switch activation [28].

With more than 600 ongoing clinical trials [29], there are a lot of features emerging continuously in the CAR-T field, similar to the software "add-ons", aimed to solve particular tasks within a particular setting (or overcome particular difficulties) with a combination of different targets and approaches to improve safety and efficacy, some of which were discussed above. Another important limitation concerns the costs and timing of production. Being completely personalized, the currently approved CAR-T relies solely on the patient’s T-cells for the CAR-T production. Therefore, apart from difficulties in logistics and lead times for therapy, the cost of such therapies becomes a huge burden to the patient and acts as a barrier to the widespread use of CAR-T therapies [30].

This issue has been addressed by off-the-shelf CAR-T and CAR-NK products in development. There are several approaches to treat GVHD which is the main challenge for off-the-shelf CAR–based therapies. One approach to solve this problem is to use other cells with the cytotoxic ability and not αβ T-cells. The NK cells fit this approach and have been used in phase 2 clinical trials. However, such off-the-shelf therapy seems to require fourth-generation CAR constructs including death switches and expression of stimulatory molecules to generate stable CAR-NK cell populations [31]. Gene-editing methods such as CRISPR/Cas9 and TALENs are used to disrupt genes encoding the endogenous TCR as well as human leukocyte antigen (HLA), thus creating universal CAR-T therapy. Apart from deleting human histocompatibility loci in CAR-introduced T-lymphocytes, gene editing and CRISPR-like technologies can be used to insert CAR constructs precisely into particular genome regions, instead of just delivering CAR-programming viral plasmids, which can improve the survival of modified T-cells [32, 33, 34]. Yet another promising option is that gene editing allows the deletion of T-cell suppressive receptors, thereby rendering the T-cells less susceptible to tumor-mediated immunosuppression [35].

The efficacy and safety of CAR-T cell therapy still have broad space for improvement, since not only increased safety but also higher efficacy is required. Notably, disease relapse can occur in up to 50% of patients within a year of therapy. Specific tumor biomarkers are widely used to choose and direct therapy with a growing variety of anti-cancer drugs [36]; therefore, the same approach is expected to benefit more complex CAR-T treatments, introducing the idea of individualized disease management as well as personalized therapy [37]. Safety is the first concern that can be managed with the help of biomarkers as cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) which cause up to 60% of life-threatening toxicities [38]. Response rate is also an important aspect that can be determined by biomarkers, especially the primary indications: if up to 90% response can be seen in ALL, according to a meta-analysis by Hou et al. [39], this figure drops to 9% (10-fold lower) in solid tumors.

CRS is caused by activation of T-cells after engagement of their CAR targets. Activated T-cells release various cytokines and chemokines, including interleukin (IL)-6, interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), and soluble IL-2Rα [40]. These cytokines activate monocytes, macrophages, and other immune cells, which in turn release inflammatory cytokines. However, only a few biomarkers have been identified as predictors in clinical trials: serum levels of IL-6 and IFN-γ in the first 24 h after CAR-T-cell infusion in B-ALL patients have been reported as robust biomarkers of severe CRS and CRES [41]. In NHL patients, increased serum IL-8, IL-10, and IL-15 levels, as well as decrease of transforming growth factor (TGF)-β could also predict severe CRS and potential neurotoxicity [42].

CAR-T efficacy prediction is still a challenging issue [43, 44]. Hence, there is a need to identify new biomarkers, especially with growing insights from the new genomic and transcriptomic analysis methods powered by next-generation sequencing, enabling TCR repertoire and lentiviral integration site analysis that allows for clone evolution of the CAR-T cells in the patient and its interaction with immune system [45].

We can see from the above discussion that the technical part of CAR-T development is open to a huge number of options and features, which can be combined into an optimal product to deliver the best possible combination of safety and efficacy for a wide variety of cancers in a personalized therapeutic manner. It is also clear that the diversity of combinations that is possible with CAR-T cells is huge and growing, along with the complexity and uncertainty of the result. This is similar to the current state of software development; thus, the transfer of effective approaches from this field into CAR-T’s development may benefit research and clinical development.

Area #2 Regulatory

As noted in the Harvard Business Review publication "Embracing Agile" [6], the type of innovation that will favor agile methodology is when "Problems are complex, solutions are unknown, and the scope is not clearly defined. Product specifications may change. Creative breakthroughs and the time to market are important. Cross-functional collaboration is vital".

The experience of drug regulation was just about the opposite: regulatory agencies and financial reimbursement bodies that set bottlenecks for fast drug development processes [46]. However, in recent decades, the most influential regulatory agencies, such as the FDA and EMA, have made huge steps toward flexibility, dialog, and increasing speed for innovations, especially in the field of gene and cell therapies. If we look at the history of changes in FDA regulations, the Orphan Drug Act, which loosens regulations for drugs aimed at conditions affecting less than 200,000 people in the USA (and personalized medicines can fit very well in that) was followed by the Accelerated Approval program that allows approval based on surrogate endpoints (with completion of post-approval Phase 4 trials to maintain approval) [47]. Next, the Fast Track designation allowed more frequent reviews with the FDA and expedited rolling reviews, allowing tighter contact between the regulator and developer [48]. The breakthrough therapy program added on top of it by the FDA allows drugs that fall within it to be approved based on clinical studies with alternative clinical designs that could be smaller in the number of subjects and use surrogate endpoints or biomarkers to determine efficacy [49]. The 21st Century Cures Act [50] has driven the FDA to maximize the use of these programs and supports the use of biomarkers as determinants of therapeutic efficacy rather than clinical outcomes alone. And most importantly for Gene and Cell therapies this act set a new Regenerative Medicine Advanced Therapies (RMAT) designation, that includes cell therapies, therapeutic tissue engineering products, human cell, and tissue products as well as certain human gene therapies and xenogeneic cell products aimed to treat serious disease.

It is important to note that drugs carrying an "orphan drug" designation can access the accelerated pathways mentioned above, requiring smaller trials (on average 3 times smaller vs common diseases), avoiding the need for randomization or double-blinding, and obtaining approval based on surrogate endpoints rather than stricter mortality or survival clinical endpoints.

Similar approaches are used by the European Medicinal Agency (EMA) and set in the number of directives [51, 52], which defines the special types of products-advanced therapy medicinal products. Such ATMPs can also be subject to orphan designation, which is different in the EU vs the USA- prevalence is not more than 5 in 10,000 [53]. Most of the activities and benefits that the developer obtains under ATMP, PRIME, and other expedited regimes are based first on extensive communication and obtaining advice and guidance from regulator experts on the development plans and regulatory strategies, including preclinical and clinical aspects. Again, the conditional approval option on the limited data of safety and efficacy (Phase II) is also possible.

The expedited reviews of new product development, readily available for gene and cell therapies, now provide unique opportunities for implementing the agile approach and increasing the efficiency of development for new therapeutics in this very demanding field. This is especially true when combined with therapy personalization, based not only on clinical diagnosis but also on specific biomarkers that enable particular therapeutic interventions. Since this itself opens the orphan pathway to approval, which is more frequently used, up to 25% of new approvals got an orphan designation [46].

New drugs are not only products to be developed for patients but are also products to be developed as regulators. The fate of the same drug candidate can differ dramatically with differences in clinical and pre-clinical data generation and presentation, in manufacturing and quality control processes and documentation [54], as well as the financial, organizational, and even behavioral characteristics of patients in clinical trials [55]. In this case, the ability to create a set of documents and approaches for approval as an "MVP for regulator" and test it during a face-to-face discussion in the iteration process can provide substantial benefits for the developer to make things faster and cheaper. Importantly, most advanced regulators such as FDA understand the uncertainty in development, which is reflected in recent and important for cell and gene therapy products CMC guidance [56] that of states about critical quality attributes (CQA). "We further acknowledge that understanding and defining product characteristics that are relevant to the clinical performance of the gene therapy may be challenging during early stages of product development, when product safety and quality may not be sufficiently understood".

Accelerated approval options (which not only allow approval of the drug based on the Phase II data but also requires tight communication with the regulator) according to some analysis may decrease R&D costs by up to 500 M$ and shorten the time to market for two years on average [57].

However, accelerated approval or conditioned approval in EMA forces developers to follow additional risk mitigation strategies, such as risk evaluation and mitigation strategies (REMS). The REMS program empowers the FDA to regulate post-market activities in exchange for pre-market approval. Under REMS, providers must continue to monitor and report patients with side effects. The CAR-T treatment sites needed to comply with REMS, approved by the FDA, for 15 years.

REMS for CAR-T includes a set of requirements before the site can start CAR-T treatments (such as having two doses of tocilizumab to prevent CRS and neurological toxicities per patient, requirements for medical staff training, and a system to report adverse effects). Fulfillment of the REMS (FDA) or risk management plan (EMA) requirements should be covered and controlled by the pharmaceutical company in partnership with the practicing clinicians.

Since the regulators understand well that cell and gene therapies are much different even from biologics, they are working intensively to create guidelines for this area. Currently, some guidelines cover areas from preclinical, manufacturing, clinical development, and follow-up [56, 58-65]. It is important to highlight new guidance for devices used in regenerative medicine advanced therapies in which CAR-T therapies are commonly included since it clearly defines the requirements for auxiliary devices used in the CAR-T production process [66].

CAR-T regulatory landscape in Russia

CAR-T in Russia falls into the category of biomedical cell products, which are regulated by the federal law # 180-FZ and all linked documents [67]. A full set of regulatory documents was completed in 2020, and real-life application for this law is in the early stage, there are no approved products and only one completely certified production site for cell therapy. Importantly, this law allows for written and even face-to-face consultations directly with experts of the regulator (Federal State Budgetary Institution "SCEEMP"), which is an important step to support the development of complex cell therapies.

Area #3. Production

The next step involved in making the therapy available to the patient is production. Since we are transitioning from the one-pill-fits-all to the one-pill-for-one patient model, the industry understands that big plants are not of much use in this new reality. CAR-T development not only opens issues that are specific to this field, but also provides some solutions to it [68]. New models of production start to emerge (see Table 1 "Cell therapy production. Emerging models", [69-71]). One of the most common strategies to produce in-house CAR-T cells is small-scale production volume, which is just fit to the number of patients in the clinic using cell-modifying equipment such as the CliniMACS Prodigy® system [67], which allows for the small-scale process of cell transformation and sorting for clinical applications.

The overall "agile-like" approach we have discussed above is used in personalized therapies like CAR-Ts such that the therapies are more effective and shorten the development cycle. If we can reduce the production duration and bring the product closer to the patient, it will bring several benefits to the entire system:
1. Benefits to the patient by shortening the duration of manufacturing and transportation. Better adjustment of therapy options due to faster response if the production site is in the clinics, enabling flexibility of regimes and targets.
2. The benefit to pharma companies – big investments in large production facilities are not needed.
3. The benefit to the regulator-better control of safety.

Such close-to-patient therapy production opens new possibilities for treatment adjustments, such as biomarker-assistant cell dosage, relapse, and tumor escape treatment with CARs aimed at different targets.

Academia in business

One feature of the agile approach towards product development is the non-hierarchical horizontal structure of teams of interdisciplinary experts. CAR-T is a product which requires tight collaboration between the pharmaceutical industry and clinics, that are most frequently vertically oriented; however, there are several examples of academia being an active part of the business. Some examples are:

Joint ventures | Startups
In 2013, the Fred Hutchinson Cancer Research Center (FHCRC), Memorial Sloan Kettering Cancer Center (MSKCC), and Seattle Children's Research initiated Juno Therapeutics company as a result of previous long collaboration in CAR-T development, and further started joint ventures with Juno Therapeutics for more than four clinical trials [73].

Academic institution networks, that unite researchers, developers, clinical centers, and companies for developing new therapy
The BioCanRx network (Canada immunotherapy network) is a pan-Canadian network of expertise and infrastructure for the development, manufacturing, and clinical testing of new immunotherapies. It was established in 2016 to boost infrastructure and manufacturing capacity to support bench-to-bedside research and to ultimately increase the access to CAR-T by increasing the number of clinical trials available to Canadian patients, as well as to empower innovations in the engineered T-cell area. It survived government financing cuts and delivered two CAR-T candidates in several clinical trials, including closed-cycle point-of-care CAR-T devices [74].

Multi-country consortia between the academic institutions and small companies allow bypassing big pharmaceutical companies or large investments in CAR-T development
The EURE-CART Alliance involved six academic centers from five countries, and three small and one medium-sized enterprise to conduct clinical trials of CAR-T candidates and to clinically develop CAR-T platforms. In 2020, the alliance started the first clinical trial of a CAR-T, CD44v6 candidate [75].

Crowdfunding consortia
The rare disease consortia started in 2008, uniting patients, charity, and academic research to develop a treatment for the Rett syndrome. In total, more than 60 M$ were collected to finance research or attract research teams in gene therapy and cell therapy dedicated towards curing this syndrome. Multiple collaborations of scientists covered different steps in therapy development. Enabling collaboration with AveXis made this company focus on Rett syndrome, develop AVXS-201 gene replacement therapy up to the preclinical phase, and even managed to keep it in the Novartis pipeline with a fixed date for IND application in 2021 [76]. The same community advanced other gene therapy candidates TSHA-102 with Taysha Therapeutics [77].

As we can see from these examples, forming [6] consortia can indeed deliver therapeutic products in this very complex and challenging field of gene and cell therapy due to advancements in collaboration and working in cross-functional teams, even though it lacks the power and experience of big pharmaceutical companies. However, this can be addressed by skillful application of agile processes technology giants.

Gene and cell technologies and new technology giants
An important point for the future of the healthcare sector, which was boosted in recent years, is the increased support from regulators, such as the US FDA, emerging and more effective technologies, decreasing time to market for them. Big data, genome-based personalization of treatments, and gene-editing are all included in the new focus of attention of regulators, which can possibly reduce the costs of treatment and drugs, and overall decrease the healthcare expenses [78, 79].

Since IT-born agile ideology can be applied to the development of personal therapeutics, they are sweet points of entry into the pharmaceutical market for tech giants who are experts in this development methodology.

One interesting example is the story of Jeff Bezos, Amazon, and Juno Therapeutics, which initiated a possible entry of Amazon into the CAR-T business with 7 years of approval, and possible changes in the US healthcare industry [80].

• 2013 – Juno Therapeutics spin-off from the Fred Hutchinson Cancer Research Center.
• 2014 – Bezos invests Juno 20M$ in 140M$ round.
• 2014 – Bezos family gifted the Fred Hutchinson Cancer Research Center 30M$ to create 1 in the USA clinic for immunotherapy treatment (Bezos Family immunotherapy clinic).
• 2018 – Celgene Juno was sold to Celgene, later to BMS.
• 2018 – Bezos (Amazon) enter the US drug market.
• 2019 – Juno ex-executives started company Sana, dedicated to the development of cell-based treatments ("ultimate next-gen cell engineering company with gene therapy and cell therapy").
• 2019 – Bezos (Amazon) enter the telemedicine and medical insurance markets.
• 2020 – Bezos and other VC invest 700M$ in Sana.
• 2020 – Seattle Cancer Care Alliance, including Bezos Family immunotherapy clinic, hosts 33 clinical trials of immunotherapies.
• 02.2021 – Approval of Juno CAR-T JCAR017 (BMS’ Liso-cel).

One interesting story to tell is Jeff Bezos's investments in the gene and cell therapies company, Juno back in 2014. From that time, Juno went through a series of M&As, starting from $6 billion ended up with $67 billion to BMS. Last year, Bezos again invested in the same Juno team, now gathered under the name Sana, to develop next-generation gene and cell therapies [81]. During these times, Amazon entered the drug delivery and medical insurance markets [82]. Some might infer that it was just smart investments, and it can be seen that Amazon now understands and is building a technology-oriented healthcare infrastructure, opening the existing bottlenecks for new, high-tech, and more efficient healthcare solutions. When the technology giants enter the field of healthcare, the market is destined to change dramatically.

Conclusion

When we look at the gene and cellular therapies, and, in particular, the CAR-T therapies as its most developed and effective segment, it vividly shows general approaches and challenges of this field, as well as features that are particular to the personal therapeutics. We can see that on the technological side, despite the common CAR-T platform, a variety of diseases and corresponding molecular targets, combined with the particularities of patient population groups, will require a diverse set of properties for such drugs, possibly with some features of opposite functions. In turn, to make the most of such flexible and programmable therapeutic platforms as CAR-T, an agile, iteration-based approach of product development can be used, and in fact, has already been used to bring the current flagship therapeutics like KYMRIAH to the market. Moreover, the current regulation for the cell- and gene-based therapeutics, new production technologies, methods of research, development, and clinical collaboration for such products can empower the agile approach, decreasing the costs and time to market such therapies, as well as bringing in new players from the IT and high technology industries to the pharmaceutical market.

Conflict of interest

No potential conflict of interest is reported.

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Introduction

Cell and gene therapy comprise a booming avenue in devising novel, emerging healthcare products during the last decade. One such approach with a variety of applications includes CAR-T therapy, which, owing to its innovative and effective approach, has leaped outstandingly fast from idea to clinical practice. Contrary to the prolonged procedure of FDA approval, as observed in case of conventional drugs, the anti-CD-19 CAR-T, KYMRIAH was approved by the FDA within a short span of 4 years in 2017 [1, 2]. This therapeutic was imminently bestowed with the title of the ASCO breakthrough of the year in January 2018 [3]. However, cell and gene therapies such as KYMRIAH are distinct from the "ordinary" drugs in most aspects, and such differences are commonly shared between most cell and gene therapies. In this review, we will focus on some distinct features of such therapies throughout their development, from the R&D bench to the patient bedside, including the regulatory and business aspects of such new therapies which are often overlooked in the reviews on this topic.

The journey of a new drug from labs to shelves is divided into five main areas: R&D, production, regulatory approval, business, and funding. If one of these aspects is missing or is defunct, the drug, irrespective of its efficacy or safety, fails to reach the clinic. The new cell and gene therapies are different from the common drugs in all these areas, as CAR-Ts vividly demonstrate or highlight such differences as well as features that are common to the cell and gene therapies, it is the focus of this review which emphasizes on each of these areas.

Area #1. R&D and emerging technologies

The most distinct feature of CAR-T is that it is based on the concept of personalized medicine which has completely shifted the healthcare ecosystem paradigm from the "one pill fits all" to "every pill made for one patient". The most fascinating aspect of this approach is that it can be effective, not only from a therapeutic but from a business perspective as well. Moreover, these personalized drugs do not disrupt the previous approach, since they can fit well together.

Although the CD-19 CAR-T therapies usher the prospect of long-lasting recovery from advanced stages of cancer which were previously thought incurable [4], its road to approval is fraught with the reports of patient deaths due to cytokine storm [5]. At present, researchers are exposed to new challenges to enable widespread application of this therapy in new areas like infectious diseases, to cure solid tumors, and to enhance its safety, efficacy as well as affordability. To accomplish these goals, the key role is being played by the R&D sector and academic research, which are advancing towards clinical trials with new technology (Table 1).

Table 1. Cell therapy production. Emerging models

Samsonov-tab01.jpg

Firstly, the process of development of personalized drugs shares numerous features with those of the new product development strategies from information technology (IT), or agile processes [6], involving 3 three-step cycle testing ideas like:
– Producing minimal viable product (MVP) as fast as possible.
– Measuring the performance with real-life patients (customers) and gaining knowledge about the improvements needed.
– Repeating [7], and application of agile development methodology.

In this process, every iteration adds some additional features, and fast testing with real-life data shows whether the ideas are right or wrong. One important feature of such products is that they must be very flexible, allowing changes in parts, but maintain the basic functional concept. The software-based products are the best fit for this since they usually utilize the same platform which is used to design the product. This is the case with platforms in biologics, cell, and gene therapies; it allows the use of a platform-based approach for development. Every drug that is based on introducing changes in the DNA or RNA is a kind of "reprogramming" or "genetic software development" suggesting that some effective approaches from IT can be transferred to drug development. This includes all gene and cell-based therapies such as CAR-Ts, or plasmid DNA, or several mRNA-based COVID vaccines, CRISPR-based therapies, etc.

Although there are differences in time frames and regulatory pathways, the approach utilized for personalized drug-development appears to be more similar to this iteration-based development strategy than the standard one-at-a-time perfect drug development strategy used in pharmaceutical industry in the previous as well as present times. Indeed, if we look at the most splendid example- how CAR-T technology developed into its present and future, we can see many similarities.

The first-generation CAR-T therapies were a breakthrough technology in the 1980s [9]; however, despite big hopes, its design was too simple to generate reliable outcomes in clinical trials [8, 10]. Technologically, the first generation of CARs included only the CD3ζ signaling endodomain fused to the extracellular scFv to act as an activator of the T cells. In terms of IT development, it fell exactly in the "minimal viable product" (MVP) category, the product that has the absolute minimum set of features to function. However, despite promising preclinical results, the clinical trials demonstrated caveats such as poor anti-tumor efficacy in patients, caused by low-level CAR-T cell activation. Therefore, the next 2nd generation was introduced, which included co-stimulatory domains for additional activation. This design was highly successful in the clinical trials in treating hematological malignancies, such as acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). This success was confirmed by the FDA approval of two CD-19 CAR-T drugs, KYMRIAH (Tisagenlecleucel) for r/r ALL and r/r large B cell lymphoma and YESCARTA (Axicabtagene ciloleucel) for r/r extent CLL.

In the process of successful clinical trials for both of these drugs, the core of the "agile development approach" was used to adapt for its clinical features and limitations. Additionally, various CAR-T cell-mediated toxicities were reported, such as tumor lysis syndrome [11], cytokine release syndrome (CRS), neurotoxicity [12], and on-target off-tumor toxicity [13], leading to a few patient deaths during the clinical trials.

The most frequent and dangerous feature of CAR-T therapy is cytokine release syndrome (CRS) [14], which leads to some lethal cases during the trials. The iteration product development cycle, which was at this point enabled by the FDA regulations for adaptive clinical trial design, allowed the identification of strategies to avert this risk by introducing several therapeutic options for CRS, such as anti-IL-6 therapy in case of CRS development, and tools to observe the patient, such as hospitalization for a week after CAR-T infusion to closely monitor for adverse reactions [12, 15].

However, the second CAR-T generation failed to show promising results in the case of solid tumors and had several limitations in treating hematological malignancies, such as antigen loss and consequent tumor escape. Such peculiarities of the second generation CAR-T limited the long-term success of CAR-T cell therapy for a quite large group of patients, leading to relapses or lack of tumor response [15, 16]. With further studies, new ideas emerged, leading to the third and fourth generation of CAR-T cells, comprising more receptor domains with different functions added to the chimeric receptor (Fig. 1).

Samsonov-fig01.jpg

Figure 1. Agile Development process and CAR-T (adapted from [7, 8])

The third-generation CAR-T cells combined the signaling potential of two costimulatory domains (CD28 and 4-1BB). To overcome the limitations of the third generation, the fourth generation of CAR-T assimilated various improvements in different parts of the chimeric construct, mostly linked with solid tumor therapies. The antitumor activity of the fourth-generation CAR-T cells was enhanced by features such as additional transgenes for cytokine secretion (e.g., IL-12) or additional costimulatory ligands. Based on the same principle, armored CAR-T cells and TRUCKs (T cells redirected for universal cytokine killing) are constructed i.e., they were modified to express not only CAR but also the inducible cytokine genes. The cytokine expression occurs only when antigen-binding activates the CAR-T cells [17, 18]. Other CAR-T approaches include the dual-receptor CAR-T cells, which are activated only in the presence of dual antigen tumor cells [19], and bi-epitope CARs [20], which fight antigen escape and loss.

With the increasing potency of CAR-T cells, more caution must be taken to ensure their safety. For solid tumors, the off-target activity becomes a limiting factor, since the target antigens are still expressed on some normal cells, and the cytotoxic activity toward these is not desirable. The first potential action is to adjust antibody affinity, thus mitigating on-target off-tumor toxicities related to low-level antigen expression in the normal tissues. The chimeric antibodies with middle or even low affinity to target can have sufficient potential to eradicate the antigen-overexpressing malignant cells, but not to damage normal tissues with low-level antigen expression [21]. Such situation is possible in case of solid tumors, which can even cause death during CAR-T therapy [22].

Another approach for reducing off-target activity is to fabricate short-lived CAR-T cells. This can be achieved via mRNA delivery with a chimeric construct instead of DNA incorporation into the T-cells. In this case, the T-cells express a CAR for up to several days at high efficiencies; however, the drawback of this approach is rapid loss of the transgenic construct and the T-cell activity associated with it, and a need for several dosages to obtain clinically relevant results [23]. This approach not only allows temporal control over the CAR-T pharmacokinetics but can also be applied with gene-editing tools such as TALEN, disrupting TCR and CD52 expression in the CAR-T cells, thus creating off-the-shelf CAR-Ts. In addition, this approach can expand the scope of therapy to treat hematological tumors. In this context, previous studies reported that by using mRNA-transduced anti-CD19 CAR-T cells targeted against the tumor microenvironment, promising results were obtained in the treatment of Hodgkin’s lymphoma [24]. The transient CAR-T production with mRNA delivery can be a potential option for future in vivo CAR-T therapy wherein, mRNA-loaded particles can be injected into specific T-cells within the patients [25].

Yet another approach to increase safety is via the on-off control of CAR-T cells. The most clinically advanced technology is the inducible suicide caspase-9 gene based on a modified human caspase-9 fused to the human FK506 binding protein (FKBP). This fusion protein, expressed in the T-cells, can form dimers when a chemical inducer of dimerization (AP1903 or Rimiducid) is administered to the patient. A single dose of the inducer drug causes rapid elimination of 85-90% of iC9-transduced T cells [26, 27]. Caspase-9-transduced T cells were used in the clinic as a tool to control graft-versus-host disease (GVHD) after haploidentical stem cell transplantation, and the GVHD-associated symptoms could be also quickly eliminated following the caspase switch activation [28].

With more than 600 ongoing clinical trials [29], there are a lot of features emerging continuously in the CAR-T field, similar to the software "add-ons", aimed to solve particular tasks within a particular setting (or overcome particular difficulties) with a combination of different targets and approaches to improve safety and efficacy, some of which were discussed above. Another important limitation concerns the costs and timing of production. Being completely personalized, the currently approved CAR-T relies solely on the patient’s T-cells for the CAR-T production. Therefore, apart from difficulties in logistics and lead times for therapy, the cost of such therapies becomes a huge burden to the patient and acts as a barrier to the widespread use of CAR-T therapies [30].

This issue has been addressed by off-the-shelf CAR-T and CAR-NK products in development. There are several approaches to treat GVHD which is the main challenge for off-the-shelf CAR–based therapies. One approach to solve this problem is to use other cells with the cytotoxic ability and not αβ T-cells. The NK cells fit this approach and have been used in phase 2 clinical trials. However, such off-the-shelf therapy seems to require fourth-generation CAR constructs including death switches and expression of stimulatory molecules to generate stable CAR-NK cell populations [31]. Gene-editing methods such as CRISPR/Cas9 and TALENs are used to disrupt genes encoding the endogenous TCR as well as human leukocyte antigen (HLA), thus creating universal CAR-T therapy. Apart from deleting human histocompatibility loci in CAR-introduced T-lymphocytes, gene editing and CRISPR-like technologies can be used to insert CAR constructs precisely into particular genome regions, instead of just delivering CAR-programming viral plasmids, which can improve the survival of modified T-cells [32, 33, 34]. Yet another promising option is that gene editing allows the deletion of T-cell suppressive receptors, thereby rendering the T-cells less susceptible to tumor-mediated immunosuppression [35].

The efficacy and safety of CAR-T cell therapy still have broad space for improvement, since not only increased safety but also higher efficacy is required. Notably, disease relapse can occur in up to 50% of patients within a year of therapy. Specific tumor biomarkers are widely used to choose and direct therapy with a growing variety of anti-cancer drugs [36]; therefore, the same approach is expected to benefit more complex CAR-T treatments, introducing the idea of individualized disease management as well as personalized therapy [37]. Safety is the first concern that can be managed with the help of biomarkers as cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) which cause up to 60% of life-threatening toxicities [38]. Response rate is also an important aspect that can be determined by biomarkers, especially the primary indications: if up to 90% response can be seen in ALL, according to a meta-analysis by Hou et al. [39], this figure drops to 9% (10-fold lower) in solid tumors.

CRS is caused by activation of T-cells after engagement of their CAR targets. Activated T-cells release various cytokines and chemokines, including interleukin (IL)-6, interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), and soluble IL-2Rα [40]. These cytokines activate monocytes, macrophages, and other immune cells, which in turn release inflammatory cytokines. However, only a few biomarkers have been identified as predictors in clinical trials: serum levels of IL-6 and IFN-γ in the first 24 h after CAR-T-cell infusion in B-ALL patients have been reported as robust biomarkers of severe CRS and CRES [41]. In NHL patients, increased serum IL-8, IL-10, and IL-15 levels, as well as decrease of transforming growth factor (TGF)-β could also predict severe CRS and potential neurotoxicity [42].

CAR-T efficacy prediction is still a challenging issue [43, 44]. Hence, there is a need to identify new biomarkers, especially with growing insights from the new genomic and transcriptomic analysis methods powered by next-generation sequencing, enabling TCR repertoire and lentiviral integration site analysis that allows for clone evolution of the CAR-T cells in the patient and its interaction with immune system [45].

We can see from the above discussion that the technical part of CAR-T development is open to a huge number of options and features, which can be combined into an optimal product to deliver the best possible combination of safety and efficacy for a wide variety of cancers in a personalized therapeutic manner. It is also clear that the diversity of combinations that is possible with CAR-T cells is huge and growing, along with the complexity and uncertainty of the result. This is similar to the current state of software development; thus, the transfer of effective approaches from this field into CAR-T’s development may benefit research and clinical development.

Area #2 Regulatory

As noted in the Harvard Business Review publication "Embracing Agile" [6], the type of innovation that will favor agile methodology is when "Problems are complex, solutions are unknown, and the scope is not clearly defined. Product specifications may change. Creative breakthroughs and the time to market are important. Cross-functional collaboration is vital".

The experience of drug regulation was just about the opposite: regulatory agencies and financial reimbursement bodies that set bottlenecks for fast drug development processes [46]. However, in recent decades, the most influential regulatory agencies, such as the FDA and EMA, have made huge steps toward flexibility, dialog, and increasing speed for innovations, especially in the field of gene and cell therapies. If we look at the history of changes in FDA regulations, the Orphan Drug Act, which loosens regulations for drugs aimed at conditions affecting less than 200,000 people in the USA (and personalized medicines can fit very well in that) was followed by the Accelerated Approval program that allows approval based on surrogate endpoints (with completion of post-approval Phase 4 trials to maintain approval) [47]. Next, the Fast Track designation allowed more frequent reviews with the FDA and expedited rolling reviews, allowing tighter contact between the regulator and developer [48]. The breakthrough therapy program added on top of it by the FDA allows drugs that fall within it to be approved based on clinical studies with alternative clinical designs that could be smaller in the number of subjects and use surrogate endpoints or biomarkers to determine efficacy [49]. The 21st Century Cures Act [50] has driven the FDA to maximize the use of these programs and supports the use of biomarkers as determinants of therapeutic efficacy rather than clinical outcomes alone. And most importantly for Gene and Cell therapies this act set a new Regenerative Medicine Advanced Therapies (RMAT) designation, that includes cell therapies, therapeutic tissue engineering products, human cell, and tissue products as well as certain human gene therapies and xenogeneic cell products aimed to treat serious disease.

It is important to note that drugs carrying an "orphan drug" designation can access the accelerated pathways mentioned above, requiring smaller trials (on average 3 times smaller vs common diseases), avoiding the need for randomization or double-blinding, and obtaining approval based on surrogate endpoints rather than stricter mortality or survival clinical endpoints.

Similar approaches are used by the European Medicinal Agency (EMA) and set in the number of directives [51, 52], which defines the special types of products-advanced therapy medicinal products. Such ATMPs can also be subject to orphan designation, which is different in the EU vs the USA- prevalence is not more than 5 in 10,000 [53]. Most of the activities and benefits that the developer obtains under ATMP, PRIME, and other expedited regimes are based first on extensive communication and obtaining advice and guidance from regulator experts on the development plans and regulatory strategies, including preclinical and clinical aspects. Again, the conditional approval option on the limited data of safety and efficacy (Phase II) is also possible.

The expedited reviews of new product development, readily available for gene and cell therapies, now provide unique opportunities for implementing the agile approach and increasing the efficiency of development for new therapeutics in this very demanding field. This is especially true when combined with therapy personalization, based not only on clinical diagnosis but also on specific biomarkers that enable particular therapeutic interventions. Since this itself opens the orphan pathway to approval, which is more frequently used, up to 25% of new approvals got an orphan designation [46].

New drugs are not only products to be developed for patients but are also products to be developed as regulators. The fate of the same drug candidate can differ dramatically with differences in clinical and pre-clinical data generation and presentation, in manufacturing and quality control processes and documentation [54], as well as the financial, organizational, and even behavioral characteristics of patients in clinical trials [55]. In this case, the ability to create a set of documents and approaches for approval as an "MVP for regulator" and test it during a face-to-face discussion in the iteration process can provide substantial benefits for the developer to make things faster and cheaper. Importantly, most advanced regulators such as FDA understand the uncertainty in development, which is reflected in recent and important for cell and gene therapy products CMC guidance [56] that of states about critical quality attributes (CQA). "We further acknowledge that understanding and defining product characteristics that are relevant to the clinical performance of the gene therapy may be challenging during early stages of product development, when product safety and quality may not be sufficiently understood".

Accelerated approval options (which not only allow approval of the drug based on the Phase II data but also requires tight communication with the regulator) according to some analysis may decrease R&D costs by up to 500 M$ and shorten the time to market for two years on average [57].

However, accelerated approval or conditioned approval in EMA forces developers to follow additional risk mitigation strategies, such as risk evaluation and mitigation strategies (REMS). The REMS program empowers the FDA to regulate post-market activities in exchange for pre-market approval. Under REMS, providers must continue to monitor and report patients with side effects. The CAR-T treatment sites needed to comply with REMS, approved by the FDA, for 15 years.

REMS for CAR-T includes a set of requirements before the site can start CAR-T treatments (such as having two doses of tocilizumab to prevent CRS and neurological toxicities per patient, requirements for medical staff training, and a system to report adverse effects). Fulfillment of the REMS (FDA) or risk management plan (EMA) requirements should be covered and controlled by the pharmaceutical company in partnership with the practicing clinicians.

Since the regulators understand well that cell and gene therapies are much different even from biologics, they are working intensively to create guidelines for this area. Currently, some guidelines cover areas from preclinical, manufacturing, clinical development, and follow-up [56, 58-65]. It is important to highlight new guidance for devices used in regenerative medicine advanced therapies in which CAR-T therapies are commonly included since it clearly defines the requirements for auxiliary devices used in the CAR-T production process [66].

CAR-T regulatory landscape in Russia

CAR-T in Russia falls into the category of biomedical cell products, which are regulated by the federal law # 180-FZ and all linked documents [67]. A full set of regulatory documents was completed in 2020, and real-life application for this law is in the early stage, there are no approved products and only one completely certified production site for cell therapy. Importantly, this law allows for written and even face-to-face consultations directly with experts of the regulator (Federal State Budgetary Institution "SCEEMP"), which is an important step to support the development of complex cell therapies.

Area #3. Production

The next step involved in making the therapy available to the patient is production. Since we are transitioning from the one-pill-fits-all to the one-pill-for-one patient model, the industry understands that big plants are not of much use in this new reality. CAR-T development not only opens issues that are specific to this field, but also provides some solutions to it [68]. New models of production start to emerge (see Table 1 "Cell therapy production. Emerging models", [69-71]). One of the most common strategies to produce in-house CAR-T cells is small-scale production volume, which is just fit to the number of patients in the clinic using cell-modifying equipment such as the CliniMACS Prodigy® system [67], which allows for the small-scale process of cell transformation and sorting for clinical applications.

The overall "agile-like" approach we have discussed above is used in personalized therapies like CAR-Ts such that the therapies are more effective and shorten the development cycle. If we can reduce the production duration and bring the product closer to the patient, it will bring several benefits to the entire system:
1. Benefits to the patient by shortening the duration of manufacturing and transportation. Better adjustment of therapy options due to faster response if the production site is in the clinics, enabling flexibility of regimes and targets.
2. The benefit to pharma companies – big investments in large production facilities are not needed.
3. The benefit to the regulator-better control of safety.

Such close-to-patient therapy production opens new possibilities for treatment adjustments, such as biomarker-assistant cell dosage, relapse, and tumor escape treatment with CARs aimed at different targets.

Academia in business

One feature of the agile approach towards product development is the non-hierarchical horizontal structure of teams of interdisciplinary experts. CAR-T is a product which requires tight collaboration between the pharmaceutical industry and clinics, that are most frequently vertically oriented; however, there are several examples of academia being an active part of the business. Some examples are:

Joint ventures | Startups
In 2013, the Fred Hutchinson Cancer Research Center (FHCRC), Memorial Sloan Kettering Cancer Center (MSKCC), and Seattle Children's Research initiated Juno Therapeutics company as a result of previous long collaboration in CAR-T development, and further started joint ventures with Juno Therapeutics for more than four clinical trials [73].

Academic institution networks, that unite researchers, developers, clinical centers, and companies for developing new therapy
The BioCanRx network (Canada immunotherapy network) is a pan-Canadian network of expertise and infrastructure for the development, manufacturing, and clinical testing of new immunotherapies. It was established in 2016 to boost infrastructure and manufacturing capacity to support bench-to-bedside research and to ultimately increase the access to CAR-T by increasing the number of clinical trials available to Canadian patients, as well as to empower innovations in the engineered T-cell area. It survived government financing cuts and delivered two CAR-T candidates in several clinical trials, including closed-cycle point-of-care CAR-T devices [74].

Multi-country consortia between the academic institutions and small companies allow bypassing big pharmaceutical companies or large investments in CAR-T development
The EURE-CART Alliance involved six academic centers from five countries, and three small and one medium-sized enterprise to conduct clinical trials of CAR-T candidates and to clinically develop CAR-T platforms. In 2020, the alliance started the first clinical trial of a CAR-T, CD44v6 candidate [75].

Crowdfunding consortia
The rare disease consortia started in 2008, uniting patients, charity, and academic research to develop a treatment for the Rett syndrome. In total, more than 60 M$ were collected to finance research or attract research teams in gene therapy and cell therapy dedicated towards curing this syndrome. Multiple collaborations of scientists covered different steps in therapy development. Enabling collaboration with AveXis made this company focus on Rett syndrome, develop AVXS-201 gene replacement therapy up to the preclinical phase, and even managed to keep it in the Novartis pipeline with a fixed date for IND application in 2021 [76]. The same community advanced other gene therapy candidates TSHA-102 with Taysha Therapeutics [77].

As we can see from these examples, forming [6] consortia can indeed deliver therapeutic products in this very complex and challenging field of gene and cell therapy due to advancements in collaboration and working in cross-functional teams, even though it lacks the power and experience of big pharmaceutical companies. However, this can be addressed by skillful application of agile processes technology giants.

Gene and cell technologies and new technology giants
An important point for the future of the healthcare sector, which was boosted in recent years, is the increased support from regulators, such as the US FDA, emerging and more effective technologies, decreasing time to market for them. Big data, genome-based personalization of treatments, and gene-editing are all included in the new focus of attention of regulators, which can possibly reduce the costs of treatment and drugs, and overall decrease the healthcare expenses [78, 79].

Since IT-born agile ideology can be applied to the development of personal therapeutics, they are sweet points of entry into the pharmaceutical market for tech giants who are experts in this development methodology.

One interesting example is the story of Jeff Bezos, Amazon, and Juno Therapeutics, which initiated a possible entry of Amazon into the CAR-T business with 7 years of approval, and possible changes in the US healthcare industry [80].

• 2013 – Juno Therapeutics spin-off from the Fred Hutchinson Cancer Research Center.
• 2014 – Bezos invests Juno 20M$ in 140M$ round.
• 2014 – Bezos family gifted the Fred Hutchinson Cancer Research Center 30M$ to create 1 in the USA clinic for immunotherapy treatment (Bezos Family immunotherapy clinic).
• 2018 – Celgene Juno was sold to Celgene, later to BMS.
• 2018 – Bezos (Amazon) enter the US drug market.
• 2019 – Juno ex-executives started company Sana, dedicated to the development of cell-based treatments ("ultimate next-gen cell engineering company with gene therapy and cell therapy").
• 2019 – Bezos (Amazon) enter the telemedicine and medical insurance markets.
• 2020 – Bezos and other VC invest 700M$ in Sana.
• 2020 – Seattle Cancer Care Alliance, including Bezos Family immunotherapy clinic, hosts 33 clinical trials of immunotherapies.
• 02.2021 – Approval of Juno CAR-T JCAR017 (BMS’ Liso-cel).

One interesting story to tell is Jeff Bezos's investments in the gene and cell therapies company, Juno back in 2014. From that time, Juno went through a series of M&As, starting from $6 billion ended up with $67 billion to BMS. Last year, Bezos again invested in the same Juno team, now gathered under the name Sana, to develop next-generation gene and cell therapies [81]. During these times, Amazon entered the drug delivery and medical insurance markets [82]. Some might infer that it was just smart investments, and it can be seen that Amazon now understands and is building a technology-oriented healthcare infrastructure, opening the existing bottlenecks for new, high-tech, and more efficient healthcare solutions. When the technology giants enter the field of healthcare, the market is destined to change dramatically.

Conclusion

When we look at the gene and cellular therapies, and, in particular, the CAR-T therapies as its most developed and effective segment, it vividly shows general approaches and challenges of this field, as well as features that are particular to the personal therapeutics. We can see that on the technological side, despite the common CAR-T platform, a variety of diseases and corresponding molecular targets, combined with the particularities of patient population groups, will require a diverse set of properties for such drugs, possibly with some features of opposite functions. In turn, to make the most of such flexible and programmable therapeutic platforms as CAR-T, an agile, iteration-based approach of product development can be used, and in fact, has already been used to bring the current flagship therapeutics like KYMRIAH to the market. Moreover, the current regulation for the cell- and gene-based therapeutics, new production technologies, methods of research, development, and clinical collaboration for such products can empower the agile approach, decreasing the costs and time to market such therapies, as well as bringing in new players from the IT and high technology industries to the pharmaceutical market.

Conflict of interest

No potential conflict of interest is reported.

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Самсонов<sup>1</sup>, Андрей М. Ломоносов<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(101) "

Михаил Ю. Самсонов1, Андрей М. Ломоносов2

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1 ООО Р-Фарм; Отдел фармакологии, институт фармации, Первый Московский государственный медицинский университет
им. И. Сеченова, Москва, Россия
2 Рабочая группа Хелснет Национальной технологической инициативы, Москва, Россия

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За последнее десятилетие достигнуты значительные успехи в медицинской науке и прикладных технологиях. Клеточная и генная терапия позволили добиться выдающихся результатов этих разработок в течение очень коротких сроков. С начала первой волны заболеваемости, пандемия COVID-19 создала препятствия для пациентов в плане доступа к диагностике и лечению в госпитальных условиях. С другой стороны, этот годичный период был ознаменован беспрецедентными технологическими достижениями, особенно – в аспекте терапии, основанной на применении мРНК и ее законодательного регулирования. В настоящей обзорной статье обращается особое внимание на CAR-T-клетки в качестве клинической модели со всеми ключевыми атрибутами их внедрения в рамках сложных цепочек – от первичных научных исследований к многообразию моделей и тенденций их применения в клинической практике.

Ключевые слова

Клеточная и генная терапия, CAR-T–клеточная терапия, планирование управлением рисками, гибкое развитие.

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Mikhail Yu. Samsonov1, Andrey M. Lomonosov2

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1 RPharm JSC; Department of Pharmacology, Institute for Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 Healthnet Working Group of National Technology Initiative, Moscow, Russia


Correspondence
Dr. Mikhail Yu. Samsonov MD, PhD, RPharm. Leninsky prospect 111, Moscow, Russia
E-mail: samsonov@rpharm.ru

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The last decade has witnessed a significant advancement in medical science and technologies. The cell and gene therapies represent remarkable outcomes of such progress achieved in a very short timeframe. The COVID-19 pandemic has created roadblocks for patients to access hospitals for diagnosis and treatments since the onset of its first-wave. On the contrary, this one-year leap has witnessed unprecedented technological advances, especially in terms of mRNA-based therapies and their regulations. The present review focuses on CAR-T as a model with all key attributes and implications in complicated chains from early science to a variety of models and trends in clinical practice.

Keywords

Cell and gene therapy, CAR-T therapy, risk management plan, agile development approach.

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["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27586" ["VALUE"]=> array(2) { ["TEXT"]=> string(108) "<p>Mikhail Yu. Samsonov<sup>1</sup>, Andrey M. Lomonosov<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(72) "

Mikhail Yu. Samsonov1, Andrey M. Lomonosov2

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Mikhail Yu. Samsonov1, Andrey M. Lomonosov2

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The last decade has witnessed a significant advancement in medical science and technologies. The cell and gene therapies represent remarkable outcomes of such progress achieved in a very short timeframe. The COVID-19 pandemic has created roadblocks for patients to access hospitals for diagnosis and treatments since the onset of its first-wave. On the contrary, this one-year leap has witnessed unprecedented technological advances, especially in terms of mRNA-based therapies and their regulations. The present review focuses on CAR-T as a model with all key attributes and implications in complicated chains from early science to a variety of models and trends in clinical practice.

Keywords

Cell and gene therapy, CAR-T therapy, risk management plan, agile development approach.

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The last decade has witnessed a significant advancement in medical science and technologies. The cell and gene therapies represent remarkable outcomes of such progress achieved in a very short timeframe. The COVID-19 pandemic has created roadblocks for patients to access hospitals for diagnosis and treatments since the onset of its first-wave. On the contrary, this one-year leap has witnessed unprecedented technological advances, especially in terms of mRNA-based therapies and their regulations. The present review focuses on CAR-T as a model with all key attributes and implications in complicated chains from early science to a variety of models and trends in clinical practice.

Keywords

Cell and gene therapy, CAR-T therapy, risk management plan, agile development approach.

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1 RPharm JSC; Department of Pharmacology, Institute for Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 Healthnet Working Group of National Technology Initiative, Moscow, Russia


Correspondence
Dr. Mikhail Yu. Samsonov MD, PhD, RPharm. Leninsky prospect 111, Moscow, Russia
E-mail: samsonov@rpharm.ru

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1 RPharm JSC; Department of Pharmacology, Institute for Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 Healthnet Working Group of National Technology Initiative, Moscow, Russia


Correspondence
Dr. Mikhail Yu. Samsonov MD, PhD, RPharm. Leninsky prospect 111, Moscow, Russia
E-mail: samsonov@rpharm.ru

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Михаил Ю. Самсонов1, Андрей М. Ломоносов2

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Михаил Ю. Самсонов1, Андрей М. Ломоносов2

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За последнее десятилетие достигнуты значительные успехи в медицинской науке и прикладных технологиях. Клеточная и генная терапия позволили добиться выдающихся результатов этих разработок в течение очень коротких сроков. С начала первой волны заболеваемости, пандемия COVID-19 создала препятствия для пациентов в плане доступа к диагностике и лечению в госпитальных условиях. С другой стороны, этот годичный период был ознаменован беспрецедентными технологическими достижениями, особенно – в аспекте терапии, основанной на применении мРНК и ее законодательного регулирования. В настоящей обзорной статье обращается особое внимание на CAR-T-клетки в качестве клинической модели со всеми ключевыми атрибутами их внедрения в рамках сложных цепочек – от первичных научных исследований к многообразию моделей и тенденций их применения в клинической практике.

Ключевые слова

Клеточная и генная терапия, CAR-T–клеточная терапия, планирование управлением рисками, гибкое развитие.

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За последнее десятилетие достигнуты значительные успехи в медицинской науке и прикладных технологиях. Клеточная и генная терапия позволили добиться выдающихся результатов этих разработок в течение очень коротких сроков. С начала первой волны заболеваемости, пандемия COVID-19 создала препятствия для пациентов в плане доступа к диагностике и лечению в госпитальных условиях. С другой стороны, этот годичный период был ознаменован беспрецедентными технологическими достижениями, особенно – в аспекте терапии, основанной на применении мРНК и ее законодательного регулирования. В настоящей обзорной статье обращается особое внимание на CAR-T-клетки в качестве клинической модели со всеми ключевыми атрибутами их внедрения в рамках сложных цепочек – от первичных научных исследований к многообразию моделей и тенденций их применения в клинической практике.

Ключевые слова

Клеточная и генная терапия, CAR-T–клеточная терапия, планирование управлением рисками, гибкое развитие.

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1 ООО Р-Фарм; Отдел фармакологии, институт фармации, Первый Московский государственный медицинский университет
им. И. Сеченова, Москва, Россия
2 Рабочая группа Хелснет Национальной технологической инициативы, Москва, Россия

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1 ООО Р-Фарм; Отдел фармакологии, институт фармации, Первый Московский государственный медицинский университет
им. И. Сеченова, Москва, Россия
2 Рабочая группа Хелснет Национальной технологической инициативы, Москва, Россия

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Introduction

Transplant-associated thrombotic microangiopathy (TA-TMA) was initially identified as a complication of allogeneic hematopoietic stem cell transplantation (HSCT) in the late 1980-s, primary as a complication of a graft-versus-host disease (GVHD) prophylaxis with cyclosporine [1, 2]. However, subsequently it was demonstrated that cyclosporine is not the only predisposing factor, and TA-TMA may be observed even after autologous HSCT [3] or high-dose chemotherapy [4]. Absence of diagnostic criteria for almost two decades precluded the appearance of any solid epidemiological data on the incidence of this complication. The reported incidence varied from 0.1% to 29%. Mean incidence across studies was 8.2%. Mortality in the majority of case series exceeded 50% [5-9]. In the modern era, the incidence varies from 3% in the registry studies in predominantly adult population [10] to 16% in the pediatric prospective studies [11]. This difference might represent identification and inclusion of mild TA-TMA cases in the prospective studies. In these recent studies TA-TMA was associated with additional 15% mortality when compared to patients without TA-TMA, also reflecting the spectrum of TA-TMA severity [9, 11].

Diagnostics of TA-TMA

Part of the diagnosis is assessment of TA-TMA probability in the particular HSCT patient. The major risk factors are transplantation from alternative donors, HLA-mismatched donors, non-myeloablative conditioning or intensified myeloablative conditioning, use of anti-lymphocyte globulin, GVHD prophylaxis with combination of calcineurin and mTOR inhibitors and prior HSCT [9,12,13]. Genetic predisposition include polymorphism in the complement pathway genes, including CFH, CFHR, CFI, CFB, C3 and several others. Certain HLA alleles in recipients were also reported to predispose to TA-TMA. Usually presence of several genetic variants and a triggering factor is required for development of TA-TMA [14]. Although TA-TMA may be not associated with additional complications of HSCT common, major clinical triggers are acute GVHD, particularly steroid-refractory form, viral reactivations, high concentrations of calcineurin inhibitors, or severe bacterial infections [15-17].

It should be admitted that currently there are no uniform criteria for TA-TMA. Primary TA-TMA was identified by the presence of microangiopatic hemolysis, fragmented cells (schistocytes), elevation of lactate dehydrogenase (LDH), thrombocytopenia, and organ damage due to microangiopathy, including renal failure or neurologic dysfunction [5, 6].

In 2005-2007, two consensus diagnostic criteria were developed, including Blood and Marrow Transplant Clinical Trials Network (BMT CTN) by Ho et al. [19] and International Working Group (IWG) by Ruutu T. et al. [20]. Analysis of the overlap between these criteria by Cho et al. has shown that twice less patients are diagnosed with TA-TMA using IWG criteria, while less than 10% of patients diagnosed with IWG criteria do not fall into the frame of BMT CTN criteria [21]. The "overall TMA" criteria were proposed on the basis on this analysis, i.e., ≥2% of schistocytes, elevation of LDH, decrease of hemoglobin and platelets. These "overall TMA" criteria are the most commonly used in the studies of novel agents (Table 1). Besides the differences with diagnostic criteria there is a technical problem with the key laboratory index of TA-TMA: schistocyte quantification, which is not standardized. Therefore, its morphological evaluation can provide various results from one laboratory to another [22].

Table 1. Overview of different diagnostic TA-TMA criteria

Moiseev-tab01.jpg

There are several reasons for the non-uniformity of accepted criteria. First, TA-TMA is a syndrome with endothelial dysfunction as the key pathogenetic feature. However, some degree of endothelial injury is present in all HSCT recipients [23]. Of note, the median level of schistocytes after allogeneic HSCT is around 1%, which is very close to the diagnostic level of BMT CTN criteria [24]. This difference could be easily alleviated by the differences in the morphological practices between transplantation centers. An autopsy study demonstrated 10% of patients who died from various causes had evidence of renal microangiopathy [25]. Other complications of HSCT that are also associated with significant endothelial injury can mimic TA-TMA. These are steroid-refractory GVHD, hemorrhagic viral enterocolitis, sepsis and hemorrhagic cystitis [25, 27, 28]. Thus, there is a spectrum of patients with various degrees of endothelial injury and complement activation after HSCT. In the absence of proven effective interventions it is hard to draw the border, where we can say that this degree of endothelial injury is TA-TMA. Emergence of novel therapies will drive the development of novel diagnostic criteria and this set of criteria will define the group of patients that will benefit from certain therapies.

On the other hand, TA-TMA is not only a syndrome with variable severity, but also a syndrome emerging due to a variety of etiological factors. In children, a clear relationship may exist between mutations in the complement – related genes, alterations in the complement pathway and evidence of complement activation that correlates with the clinical presentation. In pediatric cohort, the level of serum soluble membrane attack complex (C5b-9) was elevated in around 70% of TA-TMA patients. These patients had a more fulminate disease course and higher risk of mortality [29]. There are ethnic differences in the incidence of complement-associated TA-TMA. Hence, the exact percentage of this clinical entity may vary across countries [11]. However, in the adult population there is only limited data on complement activation after unmanipulated haploidentical transplantation [30], and In the general population of adult patients several relatively different entities can be distinguished: GVHD-related, drug-induced (primarily, calcineurin and mTOR inhibitors), infection-related (cytomegalovirus and herpes type 6 are most frequently reported viruses), and those associated with other HSCT toxicities. The same entity as in children with overt multiorgan failure and complement activation comprises only a minor subgroup of adult patients [13]. Vice versa 30% of children without complement activation, likely, have similar pathogenetic mechanisms to the adult population.

The large proportion of pediatric patients with complement activation led to the development of a diagnostic algorithm by Jodele S et al. [31]. It involves screening with serial measurement of LDH, proteinuria and blood pressure. If any of these parameters become abnormal, ADAMTS13-related TTP should be excluded and laboratory workout for TA-TMA should be performed. To confirm the diagnosis of TA-TMA, histological evidence of the organ involvement is sufficient. Alternatively, increased LDH, schistocytes on blood smear, de novo thrombocytopenia, or platelet transfusion dependence, arterial hypertension, proteinuria ≥30 mg/dL and elevation of soluble C5b-9 should be documented.

In clinical practice, local standards of TA-TMA diagnosis vary significantly due to above mentioned difficulties [9, 22], and it is hard to recommend one or another strategy. Before using certain diagnostic approach one should decide what will be an application of this approach.

Identification of patients with endothelial injury in the prospective clinical studies is one thing, selecting patients who will benefit from clinical interventions represents another task. However, several practical suggestions can be made to avoid under- and overdiagnosis of this complication. Regular screening of LDH and creatinine levels, proteinuria and blood pressure will identify potential patients at risk for TA-TMA. Further laboratory evaluation is required for the patients who have de novo grade 3-4 anemia or thrombocytopenia, never became transfusion-independent, or those who had acute kidney injury or neurologic dysfunction on the top of positive screening results. Other groups of patients without these key features are unlikely to require any interventions, even if TA-TMA evidence could be obtained from laboratory testing. Schistocyte evaluation is required to confirm the diagnosis, and Coombs test is required to rule out immune hemolytic anemia. When applying morphological criteria of TA-TMA, several rules were formulated for schistocyte quantification that allow to capture TMA-specific changes in the blood smears (Table 2) [22]. The patients with ≥2% schistocytes can be clinically considered having TA-TMA. Rising schistocyte and LDH levels on serial measurement additionally support the diagnosis. Although ADAMTS13 activity is included in the Jodele S et al. algorithm [31], but the incidence of this TMA mechanism in HSCT recipients is limited to single observations [32, 33]. Elevation of sC5b9 >300 ng/mL and angiopoietin-2 to >3 ng/mL can also provide evidence in favor of TMA diagnosis [33].

Table 2. Laboratory approach to the schistocyte quantification in TA-TMA

Moiseev-tab02.jpg

There is no well-established system for assessment of TA-TMA severity. Certain clinical features associated with higher mortality were reported, e.g., presence of neurological signs, acute kidney injury, LDH≥2 upper limits of normal (ULN), a need for ≥2 medications to control hypertension [29, 34]. The BMT CTN consensus proposed common toxicity criteria of severity, where grade 1 corresponded to absence of clinical consequences; grade 2 is assessed at elevated creatinine levels of ≤3 ULN; grade 3 corresponded to creatinine levels of >3 ULN not requiring dialysis, and grade 4 was characterized as renal failure requiring dialysis, and/or encephalopathy. Nonetheless, this severity system was not validated to predict survival of patients with TA-TMA and is rarely used during application of novel therapies.

Treatment of transplant-associated thrombotic microangiopathy

Currently, there are no established treatments of TA-TMA. Historically, therapeutic plasma exchange (TPE) was used, by analogy of thrombotic thrombocytopenic purpura, with a common standard of care. Despite early reports on its efficacy [35], the latest consensus established that average response rate, mostly defined by the subsided laboratory criteria, was 37% for 121 TPE-treated patients. Average mortality across all the patients was 79%, and the consensus stated that plasma exchange should not be considered a standard of care for TA-TMA [36]. The controversial results of TPE treatment may be related to very low frequency of ADAMTS-13-associated mechanism in TA-TMA [33].

Several other treatments were used outside clinical trials in TA-TMA. These included rituximab [37, 38, 39], defibrotide [40, 41, 42], and eculizumab [43, 44, 45, 46]. Clinical efficacy and mechanisms of rituximab in TA-TMA can be hardly assessed with only seven patients reported in the literature. On the other hand, 165 patients were treated with either defibrotide or eculizumab with a very comparable response rate of 73% and 58%, respectively. Nonetheless, overall mortality remained high with both treatments and was 40% across the studies. Particularly favorable results were reported by Jodele et al. with eculizumab in the pediatric cohort where large proportion of patients had mutations in complement-related genes and clear laboratory signs of complement activation [11, 12]. In this cohort, evaluation of eculizumab concentrations demonstrated higher drug clearance than in paroxysmal nocturnal hemoglobinuria as one of the mechanisms behind the lack of efficacy. Thus, Jodele et al. proposed the algorithm of weekly induction doses and additional induction doses based on daily CH50 activity [47]. Two small clinical trials also evaluated narsoplimab, a mannan-binding lectin-associated serine protease-2 inhibitor, also targeting complement pathway. Improvement of laboratory signs was observed in a proportion of patients and overall survival was 50% [48, 49] (Table 3). Looking at the response and survival rate of all these pharmacological treatments, it is clear that, if compared to PTE, they have merit in a proportion of patients. However, their administration was based on various indications and various diagnostic criteria. In the absence of severity criteria, it is also impossible to compare the groups of patients in these studies. Thus, it is difficult to recommend either approach as the first-line treatment. On the other hand, currently published data on the pharmacological treatments rather postulates the necessity for common criteria for severity and response based on empirical data.

Table 3. Results of clinical studies in transplant-associated thrombotic microangiopathy

Moiseev-tab03.jpg

Common first-line intervention for TA-TMA is to manipulate with immunosuppression regimens. The idea comes from early observations that inclusion of cyclosporine A in the prophylaxis regimens was associated with first documented TA-TMA cases [1, 2]. Further evidence for toxicity of calcineurin inhibitors (CNIs) towards endothelium [50] created the basis for tapering or discontinuation of CNIs in patients with TA-TMA [51]. Due to essential needs for GVHD control in the majority of these patients, glucocorticosteroids were historically administered in the most patients after CNIs discontinuation. Recent Blood and Marrow Transplant Clinical Trials Network Toxicity Committee consensus supported discontinuation of CNIs as the primary intervention based on expert opinion [36]. Nonetheless, the large single-center analysis by Li et al. did not show any benefit in terms of overall survival, when tapering or discontinuing CNIs vs their continuation in all subgroups of TMA patients, irrespective of type of GVHD prophylaxis [52]. It seems that, like all other interventions in TMA, sole discontinuation of CNIs does not lead to resolution of symptoms in all the patients, but the time to resolution might be quicker. Also, the different centers are testing other type of agents for GVHD prophylaxis instead of CNIs, with effects on survival outcomes. In our single-center analysis, substitution of CNIs by sirolimus in severe GVHD proved to be superior to steroids [53]. Novel agents, like JAK inhibitors, might also facilitate sufficient GVHD control instead of CNIs without additional endothelial damage [54]. Further investigation of different substitution strategies are warranted. Even in continuation strategies, a pause before obtaining CNI concentration is a rational approach, because the majority of patients show a transitory reduction of CNIs clearance, and high concentrations are common at TMA diagnosis.

Conclusion

Along with clinical criteria, diagnostics of TA-TMA involves several laboratory tests, of which erythrocyte shistocytosis remain a less standardized criterion [22, 55]. Screening of LDH and creatinine levels, proteinuria and blood pressure, exclusion of autoimmune haemolysis should discern potential patients at risk for TA-TMA.

Further improvement of care in TA-TMA requires harmonization of definitions for mortality risk, response, outcome measures and indications for treatment. Since this is a relatively rare entity and even large centers rarely has information on more than 50-100 cases, cooperative effort to gather empirical data is crucial to formulate these definitions, only after that existing and novel therapies can be compared without bias in the multicenter studies. For current clinical practice, internal institutional guidelines should select one of the diagnostic criteria and adhere to them. Reduction or discontinuation of calcineurin inhibitors should be considered in all patients, but internal guidelines for substitution with active immunosuppressive agents should be developed for GVHD control. Novel treatments should be implemented in case of organ failure, or in patients not responding to immunosuppression manipulation.

Conflicts of interest

None reported.

References

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Introduction

Transplant-associated thrombotic microangiopathy (TA-TMA) was initially identified as a complication of allogeneic hematopoietic stem cell transplantation (HSCT) in the late 1980-s, primary as a complication of a graft-versus-host disease (GVHD) prophylaxis with cyclosporine [1, 2]. However, subsequently it was demonstrated that cyclosporine is not the only predisposing factor, and TA-TMA may be observed even after autologous HSCT [3] or high-dose chemotherapy [4]. Absence of diagnostic criteria for almost two decades precluded the appearance of any solid epidemiological data on the incidence of this complication. The reported incidence varied from 0.1% to 29%. Mean incidence across studies was 8.2%. Mortality in the majority of case series exceeded 50% [5-9]. In the modern era, the incidence varies from 3% in the registry studies in predominantly adult population [10] to 16% in the pediatric prospective studies [11]. This difference might represent identification and inclusion of mild TA-TMA cases in the prospective studies. In these recent studies TA-TMA was associated with additional 15% mortality when compared to patients without TA-TMA, also reflecting the spectrum of TA-TMA severity [9, 11].

Diagnostics of TA-TMA

Part of the diagnosis is assessment of TA-TMA probability in the particular HSCT patient. The major risk factors are transplantation from alternative donors, HLA-mismatched donors, non-myeloablative conditioning or intensified myeloablative conditioning, use of anti-lymphocyte globulin, GVHD prophylaxis with combination of calcineurin and mTOR inhibitors and prior HSCT [9,12,13]. Genetic predisposition include polymorphism in the complement pathway genes, including CFH, CFHR, CFI, CFB, C3 and several others. Certain HLA alleles in recipients were also reported to predispose to TA-TMA. Usually presence of several genetic variants and a triggering factor is required for development of TA-TMA [14]. Although TA-TMA may be not associated with additional complications of HSCT common, major clinical triggers are acute GVHD, particularly steroid-refractory form, viral reactivations, high concentrations of calcineurin inhibitors, or severe bacterial infections [15-17].

It should be admitted that currently there are no uniform criteria for TA-TMA. Primary TA-TMA was identified by the presence of microangiopatic hemolysis, fragmented cells (schistocytes), elevation of lactate dehydrogenase (LDH), thrombocytopenia, and organ damage due to microangiopathy, including renal failure or neurologic dysfunction [5, 6].

In 2005-2007, two consensus diagnostic criteria were developed, including Blood and Marrow Transplant Clinical Trials Network (BMT CTN) by Ho et al. [19] and International Working Group (IWG) by Ruutu T. et al. [20]. Analysis of the overlap between these criteria by Cho et al. has shown that twice less patients are diagnosed with TA-TMA using IWG criteria, while less than 10% of patients diagnosed with IWG criteria do not fall into the frame of BMT CTN criteria [21]. The "overall TMA" criteria were proposed on the basis on this analysis, i.e., ≥2% of schistocytes, elevation of LDH, decrease of hemoglobin and platelets. These "overall TMA" criteria are the most commonly used in the studies of novel agents (Table 1). Besides the differences with diagnostic criteria there is a technical problem with the key laboratory index of TA-TMA: schistocyte quantification, which is not standardized. Therefore, its morphological evaluation can provide various results from one laboratory to another [22].

Table 1. Overview of different diagnostic TA-TMA criteria

Moiseev-tab01.jpg

There are several reasons for the non-uniformity of accepted criteria. First, TA-TMA is a syndrome with endothelial dysfunction as the key pathogenetic feature. However, some degree of endothelial injury is present in all HSCT recipients [23]. Of note, the median level of schistocytes after allogeneic HSCT is around 1%, which is very close to the diagnostic level of BMT CTN criteria [24]. This difference could be easily alleviated by the differences in the morphological practices between transplantation centers. An autopsy study demonstrated 10% of patients who died from various causes had evidence of renal microangiopathy [25]. Other complications of HSCT that are also associated with significant endothelial injury can mimic TA-TMA. These are steroid-refractory GVHD, hemorrhagic viral enterocolitis, sepsis and hemorrhagic cystitis [25, 27, 28]. Thus, there is a spectrum of patients with various degrees of endothelial injury and complement activation after HSCT. In the absence of proven effective interventions it is hard to draw the border, where we can say that this degree of endothelial injury is TA-TMA. Emergence of novel therapies will drive the development of novel diagnostic criteria and this set of criteria will define the group of patients that will benefit from certain therapies.

On the other hand, TA-TMA is not only a syndrome with variable severity, but also a syndrome emerging due to a variety of etiological factors. In children, a clear relationship may exist between mutations in the complement – related genes, alterations in the complement pathway and evidence of complement activation that correlates with the clinical presentation. In pediatric cohort, the level of serum soluble membrane attack complex (C5b-9) was elevated in around 70% of TA-TMA patients. These patients had a more fulminate disease course and higher risk of mortality [29]. There are ethnic differences in the incidence of complement-associated TA-TMA. Hence, the exact percentage of this clinical entity may vary across countries [11]. However, in the adult population there is only limited data on complement activation after unmanipulated haploidentical transplantation [30], and In the general population of adult patients several relatively different entities can be distinguished: GVHD-related, drug-induced (primarily, calcineurin and mTOR inhibitors), infection-related (cytomegalovirus and herpes type 6 are most frequently reported viruses), and those associated with other HSCT toxicities. The same entity as in children with overt multiorgan failure and complement activation comprises only a minor subgroup of adult patients [13]. Vice versa 30% of children without complement activation, likely, have similar pathogenetic mechanisms to the adult population.

The large proportion of pediatric patients with complement activation led to the development of a diagnostic algorithm by Jodele S et al. [31]. It involves screening with serial measurement of LDH, proteinuria and blood pressure. If any of these parameters become abnormal, ADAMTS13-related TTP should be excluded and laboratory workout for TA-TMA should be performed. To confirm the diagnosis of TA-TMA, histological evidence of the organ involvement is sufficient. Alternatively, increased LDH, schistocytes on blood smear, de novo thrombocytopenia, or platelet transfusion dependence, arterial hypertension, proteinuria ≥30 mg/dL and elevation of soluble C5b-9 should be documented.

In clinical practice, local standards of TA-TMA diagnosis vary significantly due to above mentioned difficulties [9, 22], and it is hard to recommend one or another strategy. Before using certain diagnostic approach one should decide what will be an application of this approach.

Identification of patients with endothelial injury in the prospective clinical studies is one thing, selecting patients who will benefit from clinical interventions represents another task. However, several practical suggestions can be made to avoid under- and overdiagnosis of this complication. Regular screening of LDH and creatinine levels, proteinuria and blood pressure will identify potential patients at risk for TA-TMA. Further laboratory evaluation is required for the patients who have de novo grade 3-4 anemia or thrombocytopenia, never became transfusion-independent, or those who had acute kidney injury or neurologic dysfunction on the top of positive screening results. Other groups of patients without these key features are unlikely to require any interventions, even if TA-TMA evidence could be obtained from laboratory testing. Schistocyte evaluation is required to confirm the diagnosis, and Coombs test is required to rule out immune hemolytic anemia. When applying morphological criteria of TA-TMA, several rules were formulated for schistocyte quantification that allow to capture TMA-specific changes in the blood smears (Table 2) [22]. The patients with ≥2% schistocytes can be clinically considered having TA-TMA. Rising schistocyte and LDH levels on serial measurement additionally support the diagnosis. Although ADAMTS13 activity is included in the Jodele S et al. algorithm [31], but the incidence of this TMA mechanism in HSCT recipients is limited to single observations [32, 33]. Elevation of sC5b9 >300 ng/mL and angiopoietin-2 to >3 ng/mL can also provide evidence in favor of TMA diagnosis [33].

Table 2. Laboratory approach to the schistocyte quantification in TA-TMA

Moiseev-tab02.jpg

There is no well-established system for assessment of TA-TMA severity. Certain clinical features associated with higher mortality were reported, e.g., presence of neurological signs, acute kidney injury, LDH≥2 upper limits of normal (ULN), a need for ≥2 medications to control hypertension [29, 34]. The BMT CTN consensus proposed common toxicity criteria of severity, where grade 1 corresponded to absence of clinical consequences; grade 2 is assessed at elevated creatinine levels of ≤3 ULN; grade 3 corresponded to creatinine levels of >3 ULN not requiring dialysis, and grade 4 was characterized as renal failure requiring dialysis, and/or encephalopathy. Nonetheless, this severity system was not validated to predict survival of patients with TA-TMA and is rarely used during application of novel therapies.

Treatment of transplant-associated thrombotic microangiopathy

Currently, there are no established treatments of TA-TMA. Historically, therapeutic plasma exchange (TPE) was used, by analogy of thrombotic thrombocytopenic purpura, with a common standard of care. Despite early reports on its efficacy [35], the latest consensus established that average response rate, mostly defined by the subsided laboratory criteria, was 37% for 121 TPE-treated patients. Average mortality across all the patients was 79%, and the consensus stated that plasma exchange should not be considered a standard of care for TA-TMA [36]. The controversial results of TPE treatment may be related to very low frequency of ADAMTS-13-associated mechanism in TA-TMA [33].

Several other treatments were used outside clinical trials in TA-TMA. These included rituximab [37, 38, 39], defibrotide [40, 41, 42], and eculizumab [43, 44, 45, 46]. Clinical efficacy and mechanisms of rituximab in TA-TMA can be hardly assessed with only seven patients reported in the literature. On the other hand, 165 patients were treated with either defibrotide or eculizumab with a very comparable response rate of 73% and 58%, respectively. Nonetheless, overall mortality remained high with both treatments and was 40% across the studies. Particularly favorable results were reported by Jodele et al. with eculizumab in the pediatric cohort where large proportion of patients had mutations in complement-related genes and clear laboratory signs of complement activation [11, 12]. In this cohort, evaluation of eculizumab concentrations demonstrated higher drug clearance than in paroxysmal nocturnal hemoglobinuria as one of the mechanisms behind the lack of efficacy. Thus, Jodele et al. proposed the algorithm of weekly induction doses and additional induction doses based on daily CH50 activity [47]. Two small clinical trials also evaluated narsoplimab, a mannan-binding lectin-associated serine protease-2 inhibitor, also targeting complement pathway. Improvement of laboratory signs was observed in a proportion of patients and overall survival was 50% [48, 49] (Table 3). Looking at the response and survival rate of all these pharmacological treatments, it is clear that, if compared to PTE, they have merit in a proportion of patients. However, their administration was based on various indications and various diagnostic criteria. In the absence of severity criteria, it is also impossible to compare the groups of patients in these studies. Thus, it is difficult to recommend either approach as the first-line treatment. On the other hand, currently published data on the pharmacological treatments rather postulates the necessity for common criteria for severity and response based on empirical data.

Table 3. Results of clinical studies in transplant-associated thrombotic microangiopathy

Moiseev-tab03.jpg

Common first-line intervention for TA-TMA is to manipulate with immunosuppression regimens. The idea comes from early observations that inclusion of cyclosporine A in the prophylaxis regimens was associated with first documented TA-TMA cases [1, 2]. Further evidence for toxicity of calcineurin inhibitors (CNIs) towards endothelium [50] created the basis for tapering or discontinuation of CNIs in patients with TA-TMA [51]. Due to essential needs for GVHD control in the majority of these patients, glucocorticosteroids were historically administered in the most patients after CNIs discontinuation. Recent Blood and Marrow Transplant Clinical Trials Network Toxicity Committee consensus supported discontinuation of CNIs as the primary intervention based on expert opinion [36]. Nonetheless, the large single-center analysis by Li et al. did not show any benefit in terms of overall survival, when tapering or discontinuing CNIs vs their continuation in all subgroups of TMA patients, irrespective of type of GVHD prophylaxis [52]. It seems that, like all other interventions in TMA, sole discontinuation of CNIs does not lead to resolution of symptoms in all the patients, but the time to resolution might be quicker. Also, the different centers are testing other type of agents for GVHD prophylaxis instead of CNIs, with effects on survival outcomes. In our single-center analysis, substitution of CNIs by sirolimus in severe GVHD proved to be superior to steroids [53]. Novel agents, like JAK inhibitors, might also facilitate sufficient GVHD control instead of CNIs without additional endothelial damage [54]. Further investigation of different substitution strategies are warranted. Even in continuation strategies, a pause before obtaining CNI concentration is a rational approach, because the majority of patients show a transitory reduction of CNIs clearance, and high concentrations are common at TMA diagnosis.

Conclusion

Along with clinical criteria, diagnostics of TA-TMA involves several laboratory tests, of which erythrocyte shistocytosis remain a less standardized criterion [22, 55]. Screening of LDH and creatinine levels, proteinuria and blood pressure, exclusion of autoimmune haemolysis should discern potential patients at risk for TA-TMA.

Further improvement of care in TA-TMA requires harmonization of definitions for mortality risk, response, outcome measures and indications for treatment. Since this is a relatively rare entity and even large centers rarely has information on more than 50-100 cases, cooperative effort to gather empirical data is crucial to formulate these definitions, only after that existing and novel therapies can be compared without bias in the multicenter studies. For current clinical practice, internal institutional guidelines should select one of the diagnostic criteria and adhere to them. Reduction or discontinuation of calcineurin inhibitors should be considered in all patients, but internal guidelines for substitution with active immunosuppressive agents should be developed for GVHD control. Novel treatments should be implemented in case of organ failure, or in patients not responding to immunosuppression manipulation.

Conflicts of interest

None reported.

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Моисеев<sup>1</sup>, Татьяна Г. Цветкова<sup>2</sup>, Тапани Рууту<sup>3</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(132) "

Иван С. Моисеев1, Татьяна Г. Цветкова2, Тапани Рууту3

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Всероссийский центр экстренной и радиационной медицины имени А. М. Никифорова, Санкт-Петербург, Россия
3 Клинический Исследовательский Институт, Клиника Университета Хельсинки, Хельсинки, Финляндия

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Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.

Ключевые слова

Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.

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Ivan S. Moiseev1, Tatyana G. Tsvetkova2, Tapani Ruutu3

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
3 Clinical Research Institute, Helsinki University Hospital, Helsinki, Finland


Correspondence
Ivan S. Moiseev, PhD, MD, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients. Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Keywords

Thrombotic microangiopathy, hematopoietic stem cell transplantation, diagnostic criteria, calcineurin inhibitors, defibrotide, eculizumab.

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Moiseev<sup>1</sup>, Tatyana G. Tsvetkova<sup>2</sup>, Tapani Ruutu<sup>3</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(94) "

Ivan S. Moiseev1, Tatyana G. Tsvetkova2, Tapani Ruutu3

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Ivan S. Moiseev1, Tatyana G. Tsvetkova2, Tapani Ruutu3

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients. Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Keywords

Thrombotic microangiopathy, hematopoietic stem cell transplantation, diagnostic criteria, calcineurin inhibitors, defibrotide, eculizumab.

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients. Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Keywords

Thrombotic microangiopathy, hematopoietic stem cell transplantation, diagnostic criteria, calcineurin inhibitors, defibrotide, eculizumab.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
3 Clinical Research Institute, Helsinki University Hospital, Helsinki, Finland


Correspondence
Ivan S. Moiseev, PhD, MD, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
3 Clinical Research Institute, Helsinki University Hospital, Helsinki, Finland


Correspondence
Ivan S. Moiseev, PhD, MD, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia

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Иван С. Моисеев1, Татьяна Г. Цветкова2, Тапани Рууту3

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Иван С. Моисеев1, Татьяна Г. Цветкова2, Тапани Рууту3

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В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3129) "

Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.

Ключевые слова

Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.

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Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.

Ключевые слова

Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Всероссийский центр экстренной и радиационной медицины имени А. М. Никифорова, Санкт-Петербург, Россия
3 Клинический Исследовательский Институт, Клиника Университета Хельсинки, Хельсинки, Финляндия

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Всероссийский центр экстренной и радиационной медицины имени А. М. Никифорова, Санкт-Петербург, Россия
3 Клинический Исследовательский Институт, Клиника Университета Хельсинки, Хельсинки, Финляндия

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Introduction

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell (HSC) disorder characterised by ineffective hematopoiesis accompanied by blood cytopenia and by common progression to acute myeloid leukemia (AML). MDS is mostly observed in the elderly persons [1-4]. The main clinical features of MDS are as follows:

Clonal hematopoietic stem-cell disease(s);
Abnormal differentiation, maturation, impaired apoptosis;
• Genetic (Immune) basis;
• Median age: 74 years;
• Incidence increases with age;
• 40-50 per 100 000 in > 70 yr;
Anemia (90%); Pancytopenia (50%);
AML Transformation (20%-60%).

The cytomorphological examination in MDS is based on detection of bi- or tri-lineage dysplasia in different hematopoietic lineages in the bone marrow and/or peripheral blood, and enumeration of blast cells in the samples (Fig. 1A, B).

Mittelman-fig01.jpg

Figure 1. General pattern of bone marrow in healthy person (A) and MDS patient (B). BM of MDS patients is characterized by altered (hyper or hypo-) cellularity, numerical (hyper or hypo-) changes, morphological abnormalities in one or more hematological lineages, and potential increased % of blasts

Classification

MDS patients are classified by International Prognostic Scoring System (IPSS):

Prognostic Parameters:
– FAB subtype: BM morphology – % blasts;
Cytogenetics;
– "good" vs "bad" types;
# Lineages affected.

IPSS:
– Low-risk; Intermediate-1 – Lower risk disease;
– Intermediate-2; High – Higher risk disease.

IPSS-R:
Very low; Low; Intermediate; High; Very high [5, 6].

Evaluation of Treatment Response – Not Blac & White:Thus, standard response criteria were proposed:

• International Working Group (IWG) 2000/2006 [5, 6]:
– Complete response (CR);
– Marrow CR (mCR); (Partial R);
– Cytogenetic response (Cyt R);
– Hematologic improvement (HI);
    - Erythroid (HI-E); Neutrophil (HI-N); Platelet (HI-P).

IWG 2018: HI-E – Erythroid response [7]:
Transfusion burden:
    - Non (0/16 wk), Low (3-7); High > 8;
    - Response: minor (50% less) or major (TI).

MDS treatment

General Strategy of MDS Treatment depends on the disease status (IPSS/R), by discerning lower-risk cases (IPSS: Low risk; Intermediate-I), and higher-risk MDS (IPSS: Intermediate-II; High risk cases).

Patient factors should be taken into account:
• Age; co-morbidities; functional status;
• Quality of life (QoL); Pt reported outcomes (PRO).

MDS treatment is often consistent with a general ‘Rule of Thumb’:
• Response of about 50%;
• Response duration about 2 yr.

This is true for the following therapeutic approaches:
• RBC Transfusions;
• Erythroid stimulating agents (ESAs);
• Lenalidomide;
• Hypomethylating agents (HMA);
• Stem Cell Transplant (SCT).

The remaining challenges include: increasing response rate and duration of response and, finally, achieving cure of this disorder.

Mittelman-fig02.jpg

Figure 2. Hematology research team at the George-Washington University (I am sitting, second on the right)

My experience with MDS could be traced from the Hematology-Oncology Fellowship – GW-NIH (USA) 1986-1989 at George Washington University Medical Center – Department of Hematology-Oncology (Fig. 2).

Recently, the European MDS Registry (EUMDS) is a prospective multicentre European registry for myelodysplastic syndromes (MDS), being the first international prospective, observational registry for newly diagnosed IPSS low- and intermediate-1 risk MDS patients. 18 countries participate in EUMDS activities, i.e., Austria, Chech Republic, France, Germany, Greece, Italy, Netherlands, Romania, Spain, Sweden, UK, Denmark, Portugal, Poland, Israel, Serbia, Croatia, Switzerland.

Appropriate Guidelines were issued by EUMDS (2019) (see MDS-Europe in the net).

Managing lower risk MDS

80% of MDS patients have a hemoglobin <10 g/dl at diagnosis, the majority become transfusion-dependent. Therefore, MDS treatment for anemia still includes multiple RBC transfusions. Most of these patients received MDS-specific supportive care, including RBC transfusions in 50% of the cases [8].

RBC Transfusions in MDS (I)

RBC transfusions are the mostly used (50%) in low-risk MDS. For those patients who were transfusion-independent at diagnosis, the mean interval between diagnosis and the first transfusion was 249 days [9]. For symptomatic anemia, however, limited evidence was shown.

Complications of RBC transfusions in MDS patients include the following events:
• Volume-related; TRALI (Transfusion-Related Acute Lung Injury); ABO incompatibility;
• RBC allo-immunization in 30% of cases [10]. Having MDS is suggested to be an independent risk factor contributing to production of RBC alloantibodies.

Iron overload due to multiple RBC transfusions is among complication of supportive therapy in MDS [11-12]. E.g., the transfusion dose density is associated with shorter progression-free survival (PFS) and worse quality of life. It showed an inverse correlation with PFS (P<1×10-4): the dose density had an increasing effect until 3 units/16 weeks [13].

RBC Transfusions in MDS (II): ELN-EUMDS 2019 Guidelines

The questions arising:
• Hb threshold for starting the transfusions?
– < 7 g/dl (most centers will transfuse if and when Hb < 7g/dl);
– Individualize (Grade B, level 1).
• Hb target levels?
– No target (Grade C, level 2) – recommendation – activate local policy.
• Transfusion frequency?
– Individualize (C-2).
• Prophylactic RBC Ag matching ? No (C-2)
• Symptomatic benefit vs toxicity?
– Individualize (C-2).

For reference see [14]: Bowen D, Mittelman M, ELN-EUMDS Guidelines (2019; online).

Effects of erythrocyte-stimulating agents (ESA) in low-risk MDS anemia were summarized for 2020. ESA were applied as first-line therapy (without RBC transfusions) and proved to be effective in a series of studies, as shown by Hb rise, fewer RBC transfused, improved QoL, with documented safety for the patients [15-19]. Hematological response was observed in a sufficient group of MDS patients (Table 1).

Table 1. Initial results on recombinant human Epo (rHuEPO) in MDS. The responding patients are shown in bold [20].

Mittelman-tab01.jpg

Therapeutic efficiency and safety of different erythrocyte-stimulating agents (ESAs) in LR-MDS was proven over 3 decades. E,g, darbopoietin A was tested in phase 3 trial (n=147), with ORR of 59% [21]. A randomized study of Epoetin-α (phase 3 trial) enrolled 130 cases, with 46% overall response rate [22]. A meta-analysis of different ESA in LR-MDS has shown an ORR of 45-73%, and, possibly, longer overall survival of MDS patients, with 50% response [23]. Finally, a large study by EUMDS included a cohort of LR-MDS patients, at median duration of ESA therapy for 27.5 months, delayed RBC transfusions (by 6 to 23 months), lower risk of death; similar risk of progression to AML, along with safety of such treatment [24].

A team from Denmark found only marginal effects (RR 1.1-1.9) of ESA upon risk of venous thromboembolism (VTE) and strokes in a cohort of 2114 patients [25]. In general, the response rate to ESA in MDS was 50% at the 2-year terms, and proven safety.

Mittelman-fig03.jpg

Figure 3. Comparative IL-6 levels in blood serum of heathy persons, in MM patients, and in Epo-treated MM patients [31]

EPO non-erythroid (immunologic) effects

Therapeutic efficiency of rhEPO was documented in myeloma-associated anemia [26]. Moreover, probable anti-neoplastic effects of erythropoietin were shown in experimental murine myeloma [27, 28].

Other events associated with erythropoietin therapy in patients with hematological disorders include a decreased glucose level [29], probable bone loss by targeting monocytes and osteoclastic activity in murine model [30], as well as decrease in serum IL-6 upon the EPO therapy [31], as seen in Fig. 3. In myelodysplastic syndrome, improvement of T cell immune functions was an additional positive effect observed after erythropoietin treatment [32].

ESA treatment may fail in sufficient part of MDS patients. Clinical outcomes in LR-MDS in the non-responsive cohort were studied by Park et al. [33].

The study represented a retrospective analysis of LR-MDS patients without 5q chromosome deletion. Of them, 653 experienced primary failure and 494 experienced relapse after a response. Median OS among ESA non-responders was 4.2 years in relapsing patients versus 3.7 years in primary failure. Second-line treatment was performed in 39% of them. Hypomethylating agents (HMA) were used in 336 patients, with 46% response, and lenalidomide, in 88 patients with 39% response rates. However, the five-year OS for patients receiving HMA, lenalidomide, or other therapies was 36.5%, 41.7%, and 51%, respectively (P = .21). In a multivariable analysis, there was no significant OS difference among the three groups. Yes, we need to do better…

Lenalidomide therapy

Several studies demonstrated efficiency of Lenalidomide in LR-MDS, either with or without 5q deletion. List et al. [34] have shown that transfusion demands were reduced in 76% of the treated patients with 5q chromosome deletion, and some of them did not longer require transfusions, regardless of the karyotype complexity. The response to lenalidomide occurred at the median time of 4.6 weeks and retained for a median of 2 years. In the meta-analysis by Lian et al. [35], overall rate of hematological erythrocyte response was 58%. The patients with 5q deletion had significantly higher rate of response, significantly prolonged overall survival and lower risk of AML progression. The drug showed a predictable and manageable safety profile in LR-MDS in terms of adverse effects [36]. P53 mutations with higher TP53 protein expression in BM progenitors of lenalidomide-treated patients proved to be associated with higher AML risk and shorter OS [37-39].

Below are main results of the MDS-004 study in Del (5q) MDS patients [38]:
– RRBC TI 56%; Cytogenetic response was observed in 50% at 10mg of Len daily
– Adverse effects: cytopenia, rash, gastrointestinal, thrombosis
– No effect on leukemic transformation
• Results with non-del (5q) patients: MDS-005 [39]
– Among a group of 239 pts (lenalidomide or placebo), transfusion independence was achieved in 27% (vs 2.5% with placebo) at 8 weeks of Len therapy.

Other therapeutic targets

TGF-binding drugs
Hence, anemia remains a sufficient problem in some LR-MDS patients. What can we offer when ESA, or Lenalidomide treatment fail? Newer drugs, e.g., activin analogues, may potentially improve erythropoiesis, by TGF-b binding, or Smad2/3 inhibition. E.g., Luspatercept was tested in a PACE-MDS Trial (ACE-536) at the Phase II, (s/c injections, every 3 wk; 58 pts; post ESA), as reported by Platzbecker et al. [40]. The drug caused a significant dose-dependent increase in blood Hb contents, and, after 4-mo treatment at a dose of 0.75-1.75 mg/kg, reduced demands for RBC transfusions.

The MEDALIST study was a phase 3, randomized, double-blind, placebo-controlled trial with transfusion-dependent MDS. Luspatercept therapy led to RBC transfusion independence in lower-risk MDS patients resistant to ESA [41]. Of the 229 patients, 153 were randomly assigned to receive luspatercept or placebo, s/c every 3 weeks, for ≥ 24 weeks. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in Luspatercept group versus 13% in the placebo group (P<0.001).

Sotatercept (ACE-011), a drug with similar action, was recently subject to phase 2 study carried out by Komrokji et al. [42]. 74 patients enrolled were ineligible for, or refractory to ESA therapy. Clinical response was documented in 40-50% (better outcomes in those with lower transfusion burden). Adverse effects manifested as diarrhea, bone pain, fatigue, GI, edema, lipase increase.

A special COMMANDS Trial aimed to compare Luspatercept versus erythropoietin is launched now [43].

Low Dose/Oral hypomethylating agents (HMA) in LR-MDS
A prospective trial (Phase 2) was performed using Azacitidine versus best supportive care (BSC). The primary endpoint was erythroid hematologic improvement which was achieved in 44.4% of cases after 9 treatment rounds, versus 5.5% of patients treated with BSC, as well as transfusion independence in all the drug responders for a median of 1 year [44].

Low-dose decitabine versus low-dose azacitidine (Aza) were applied in the phase II study [45]. A total of 113 patients were treated: 35% with Aza and 65% with Dec. The ORRs were 70% and 49% for Dec and Aza, respectively. Transfusion independence was achieved in 32 % of decitabine-trea-ted patients, and the treatment was well tolerated.

A meta-analysis performed by Komrokji et al. (2018) [46] concerning efficiency of Aza in a total sample of 233 patients with, mostly, non-del(5q) LR-MDS has shown that the RBC transfusion independence was achieved in 39% of the cases, at ≥6 azacitidine treatment cycles.

Several years ago, a report on clinical effects of peroral Aza (cc-486) in LR-MDS was published [47]. The study included 216 MDS patients. The disease status was assessed after cycle 6. The ORR was 40%, including hematologic improvement in 28% of patients, and transfusion independence lasted for 56 days in 47% of initially transfusion-dependent cases.

Therefore, QUAZAR study (AZA-MDS-003) was continued as randomized controlled trial (RCT), Phase 3, in LR-MDS patients with anemia and thrombocytopenia [48]. The patients received CC-486 or placebo. 31% and 11% of patients, respectively, achieved RBC-TI in the main and placebo group, which lasted, for, respectively, 11.1 and 5.0 months. Platelet improvement rate was also higher in the CC-486 arm (24.3% vs 6.5%).

Roxadustat (FG-4592)
Usage of oral prolyl hydroxylase (PH) inhibitors may be a promising tool of anemia treatment, since the PH inhibition may stabilize hypoxia-inducible factor (HIF). This factor induces erythropoietin production and decreases hepcidin, thus promoting iron mobilization [49]. Recently, this drug was shown to be safe and efficient in the patients with anemia caused by chronic renal failure – CRF [50].

Roxadustat is another PH inhibitor(Fibrogen) undergoes a clinical FGCL-4592-082 trial which is an open label study including 24 pts, achieving 38% TI if used at a dose of 2.5 mg/kg, ×3/wk [51]. Now this drug is under phase 3, randomized controlled trial, with 156 patients.

Telomerase inhibitors
Clinical trials with Imetelstat, a telomerase inhibitor, were performed in the patients with LR-MDS anemia [52-54]. Phase 2 trial is an open, single arm study, with the drug dose of 7.5 mg/kg I/V q 4 wk. A subgroup of 38 LR-MDS patients were selected with transfusion dependence, ESA relapse/resistance, non-del(5q), being hypomethylating agent and lenalidomide naïve. Of them, 16 patients (42%) achieved transfusion independence. This effect was durable (a median of 21 mo) and accompanied by reduced telomerase activit. Phase 3 (a placebo-controlled study) is ongoing.

Treatment of thrombocytopenia in MDS

Platelet transfusions (PLT) are made in MDS patients. However, there is no evidence on their efficiency. This procedure is indicated in cases of active bleeding and should be performed per local guidelines [14, 55]. In absence of active bleeding, the platelet transfusion cannot be routinely recommended!. One may consider "thrombostatics", e.g., Tranexamic acid, or Anti-fibrinolytic solutions, (Hexakapron).

Romiplostim in MDS
For the last decade, several groups study safety and efficacy of romiplostim, a synthetic protein, an analogue of thrombopoietin which increases platelet production, for treatment of MDS patients with thrombocytopenia. The phase I/II study by Kantarjan et al. [56] in 44 patients have shown a durable platelet response in 46% cases. After achieving platelet response (4 weeks) the patients were treated with romiplostim for up to 1 year. Serious adverse effects were registered in 11% of the cases, and 2 patients progressed to AML.

The Phase II study was arranged as a randomized, placebo-controlled trial which included a total of 250 LR-MDS patients randomized 2:1, to receive romiplostim or placebo weekly for 58 weeks [57]. The incidence of bleeding events was reduced in the romiplostim group, and platelet response rates proved to be higher in the patients who received romiplostim. However, study drug was stopped because of excess blasts and potential AML risk following this treatment. Later on, upon 5-year of this cohort, the percentages of patients with AML (12%) in romiplostim group were similar (11%) to those in placebo group, as shown by Kantarjian et al. [58]. In a special commentary, I emphasized that these long-term results were indeed reassuring, however, one has to bear in mind that treatment had been discontinued [59]. Thus, the long-term data reflect the outcome of a long-term follow up, while the drug exposure was relatively short.

Eltrombopag in MDS
Eltrombopag is an agonist of thrombopoietin receptor which promotes growth and differentiation of megakaryocytes. Since 2014, it was approved by FDA for treatment of aplastic anemia, stimulating production of platelets, RBC and leukocytes. In LR-MDS patients with thrombocytopenia, it has shown efficiency of 47% in terms of platelet responses, versus 3% in the placebo group (Oliva et al., 2017) [60].

The ASPIRE study (Part I) was an open-label, double-blind study of patients with advanced MDS treated for 8 weeks with Eltrombopag, and randomised at later terms [61]. Four patients of 17 achieved increased platelet counts following treatment, and ten had reduced platelet transfusion requirements. Serious adverse events were reported in 58% of eltrombopag-treated, and in 68% placebo-treated patients. In ASPIRE II, fewer adverse events were registered.

Combined effects of Eltrombopag and Azacytidin (AZA) were addressed in the SUPPORT Study [62]. The intermediate-1, intermediate-2, or high-risk MDS patients with low platelet counts were randomized 1:1 to eltrombopag, or placebo, plus azacitidine. The development of this study was, however, stopped due to efficacy outcomes, and for safety problems.

The French MDS group (GFM) have recently presented their experience using long-term eltrombopag, with encouraging clinical efficacy. These promising data might assist in lifting the embargo on thrombomimetic agnets [63].

Immunosuppressive therapy

Despite broad arsenal of novel therapeutic agents for MDS therapy, there are many LR-MDS patients with anemia who are resistant or have lost their response to such drugs. Therefore, immunosuppressive treatment (IST) in these cases is well justified, on the basis of similarity between severe aplastic anemia and hypoplastic MDS. Some experience in this field exists with ATG and/or cyclosporine treatment [64]. Clinical response, however, is dependent on the MDS patient’s age, transfusion history, and karyotype pattern, with erythroid response rate of 25-40%.

A large study published by Stahl et al. reported results of IST results obtained for cohort from 15 centers in Europe and USA, including 207 pts with MDS receiving IST [65].

The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). The overall response rate ORR 48.8%, with 11% reaching complete remission, and transfusion independence (RBC-TI) in 30% of the cases. Median overall survival (OS) was 47.4 mo, being longer for the patients with transfusion independence. The RBC-TI was associated with a bone marrow hypocellularity (<20%). Age, HLA-DR15 positivity did not predict clinical response to IST.

Iron Overload

Iron deposition in the patients occurs due to intrinsic mechanisms of MDS, and as a result of multiple RBC transfusion, causing damage of liver and other organs.

Iron chelator therapy is effective in these cases. A retrospective study based on the European MDS Registry data was recently published by Hoeks et al. [66]. The results of chelator treatment in MDS were compared with non-chelated patients. The propensity-score analysis has revealed improved OS for chelated patients, with erythroid response in up to 39% of the treated cohort. A similar TELESTO study (the only prospective) included 225 patients with high serum ferritin levels after multiple RBC transfusions treated with Deferasirox [67]. Following continuous treatment (0.5 to 3 years), median EFS was prolonged by ca. 1 year (1440 d vs 1091 d) with deferasirox vs placebo, at 36% reduction of events.

Several eligibility criteria are proposed for initiating the chelator therapy [14, 68] (Mittelman et al., 2008, current Guidelines 2019; MDS-EUROPE online [14]: 1. Patients classified as low or Int1, according to the International Prognostic Scoring System; 2. Patients with serum ferritin levels >1000 μg/Ll and those who received a total of 20-25 RBC units; 3. Patients whose blood transfusion requirement has increased significantly; 4. Patients with sufficient organ damage.

Summary and future prospects

Current treatment of the low-risk MDS includes the following:
• ESA +/- RBC transfusions;
• Lenalidomide (del 5q);
• 2nd Line:
  – Luspatercept; Roxadustat; Imetelstat; HMA (?)
Future prospectives:
• Combinations: ESA + other hematopoiesis-stimulating drugs;
• Novel agents;
• Low platelet counts in MDS patients:
  – Therapeutic approaches are still challenging.

Conflict of interest

Disclosures: Research funding: Celgene; Johnson & Johnson; Roche; Novartis; Gilead. Speakers’ bureau: Celgene; Johnson & Johnson; Novartis. Advisory boards (non-paid): Pfizer; Amgen; Roche; Novartis.

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  43. Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Finelli C, M Cazzola, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. New Engl J Med. 2020; 382:140-151. doi: 10.1056/NEJMoa1908892
  44. Sanchez-Garcia J, Falantes J, Medina Perez A, Hernandez-Mohedo F, Hermosin L, Torres-Sabariego A, Bailen A, Hernandez-Sanchez JM, Solé Rodriguez M, Casaño FJ, et al. Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. Leuk Lymphoma. 2018;59(5):1095-1104. doi: 10.1080/10428194.2017.1366998
  45. Jabbour E, Short NJ, Montalban-Bravo G, Huang X, Bueso-Ramos C, Qiao W, Yang H, Zhao C, Kadia T, Borthakur G, et al. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood. 2017;130(13):1514-1522. doi: 10.1182/blood-2017-06-788497
  46. Komrokji R, Swern AS, Grinblatt D, Lyons RM, Tobiasson M, Silverman LR, Sayar H, Vij R, Fliss A, Tu N, Sugrue MM. Azacitidine in lower-risk myelodysplastic syndromes: A meta-analysis of data from prospective studies. Oncologist. 2018; 23(2):159-170. doi: 10.1634/theoncologist.2017-0215
  47. Garcia-Manero G, Almeida A, Giagounidis A, Platzbecker U, Garcia R, Voso MT, Larsen SR, Valcarcel D, Silverman LR, Skikne B, Santini V. Design and rationale of the QUAZAR Lower-Risk MDS (AZA-MDS-003) trial: a randomized phase 3 study of CC-486 (oral azacitidine) plus best supportive care vs placebo plus best supportive care in patients with IPSS lower-risk myelodysplastic syndromes and poor prognosis due to red blood cell transfusion-dependent anemia and thrombocytopenia. BMC Hematol. 2016;16:12. doi: 10.1186/s12878-016-0049-5
  48. Garcia-Manero G, Santini V, Almeida A, Platzbecker U, Jonasova A, Silverman LR, Falantes J, Reda G, Buccisano F, Fenaux P et al. Phase III, Randomized, placebo-controlled trial of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2021: JCO2002619. doi: 10.1200/JCO.20.02619
  49. Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR. Prolyl hydroxylase inhibitors: a breakthrough in the therapy of anemia associated with chronic diseases. J Med. Chem. 2018, 61 (16): 6964-6982. doi: 10.1021/acs.jmedchem.7b01686
  50. Del Vecchio L, Locatelli F. Roxadustat in the treatment of anaemia in chronic kidney disease. Expert Opin Investig Drugs. 2018; 27(1):125-133. doi: 10.1080/13543784.2018.1417386
  51. Henry DH; Glaspy J, Harrup RA, Mittelman M, Zhou A, Carraway HE, Bradley C, Saha G, Bartels P, Leong R, et al. Oral Roxadustat demonstrates efficacy in anemia secondary to lower-risk myelodysplastic syndrome irrespective of ring sideroblasts and baseline erythropoietin levels. Blood. 2020,136, 29-30. ASH Meeting Abstract #1277, Dec 5, 2020.
  52. Fenaux P et al. Imetelstat provides durable transfusion independence in heavily transfused non-del(5q) LR-MDS R/R to ESAS. EHA 2019.
  53. Platzbecker U, Fenaux P, Steensma DP, Van Eygen K, Raza A, Germing U, Font P, Diez-Campelo M, Thepot S, Vellenga E, et al. Treatment with Imetelstat provides durable transfusion independence (TI) in heavily transfused non-del(5q) lower risk MDS (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). 2019. EHA Library. Platzbecker U. 06/12/20; 295003; S183.
  54. Steensma DP, Fenaux P, Van Eygen K, Raza A, Santini V, Germing U, Font P, Diez-Campelo M, Thepot S, Vellenga E, et al. Imetelstat achieves meaningful and durable transfusion independence in high transfusion-burden patients with lower-risk myelodysplastic syndromes in a Phase II Study. J Clin Oncol. 2021; 39(1):48-56. doi: 10.1200/JCO.20.01895
  55. Malouf R, Ashraf A, Hadjinicolaou AV, Doree C, Hopewell S, Estcourt LJ. In people with bone marrow disorders, a comparison of giving platelet transfusions only when bleeding occurs to also giving them to prevent bleeding. Cochrane Database Syst Rev 2018 May 14; issue 5, art. CD012342.
  56. Kantarjian H, Fenaux P, Sekeres MA, Becker PS, Boruchov A, Bowen D, Hellstrom-Lindberg E, Larson RA, Lyons RM, Muus P, Shammo J, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010; 28(3):437-444. doi: 10.1200/JCO.2009.24.7999
  57. Giagounidis A, Mufti GJ, Fenaux P, Sekeres MA, Szer J, Platzbecker U, Kuendgen A, Gaidano G, Wiktor-Jedrzejczak W, Hu K, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014; 120(12): 1838-1846. doi: 10.1002/cncr.28663
  58. Kantarjian HM, Fenaux P, Sekeres MA, Szer J, Platzbecker U, Kuendgen A, Gaidano G, Wiktor-Jedrzejczak W, Carpenter N, Mehta B, et al. Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. Lancet Haematol. 2018; 5(3):e117-e126. doi: 10.1016/S2352-3026(18)30016-4
  59. Mittelman M. Good news for patients with myelodysplastic syndromes and thrombocytopenia. Lancet Haematol. 2018 Mar;5(3):e100-101. doi: 10.1016/S2352-3026(18)30017-6
  60. Oliva EN, Alati C, Santini V, Poloni A, Molteni A, Niscola P, Salvi F, Sanpaolo G, Balleari E, Germing U, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4(3):e127-e136. doi: 10.1016/S2352-3026(17)30012-1
  61. Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong R, Anagnostopoulos A, Brenner B, et al. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): A randomised, placebo-controlled, phase 2 trial. Lancet Haematology. 2018; 5(1); e34-e43. abstr 3822. doi: 10.1016/S2352-3026(17)30228-4
  62. Dickinson M, Cherif H, Fenaux P, Mittelman M, Verma A, Portella MSO, Burgess P, Ramos PM, Choi J, Platzbecker U, et al. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood. 2018;132(25):2629-2638. doi: 10.1182/blood-2018-06-855221
  63. Mittelman M, Oster HS. Thrombocytopenia in myelodysplastic syndromes: time to lift the embargo on thrombomimetics? Br J Haematol 2021;194(2):231-233. doi: 10.1111/bjh.17538
  64. Mittelman M, Oster HS. Immunosuppressive therapy in myelodysplastic syndromes is still alive. Acta Haematol2015; 134:135-137. doi: 10.1159/000371833
  65. Stahl M, DeVeaux M, de Witte T, Neukirchen J, Sekeres MA, Brunner AM, Roboz GJ, Steensma DP, Bhatt VR, Platzbecker U, et al. The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort. Blood Adv. 2018; 2(14):1765-1772. doi: 10.1182/bloodadvances.2018019414
  66. Hoeks M, Yu G, Langemeijer S, Crouch S, de Swart L, Fenaux P, Symeonidis A, Čermák J, Hellström-Lindberg E, Sanz G, et al. Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry. Haematologica. 2020;105(3): 640-651. doi: 10.3324/haematol.2018.212332
  67. Angelucci E, Li J, Greenberg P, Wu D, Hou M, Montano Figueroa EH, Rodriguez MG, Dong X, Ghosh J, Izquierdo M, Garcia-Manero G; TELESTO study investigators. iron chelation in transfusion-dependent patients with low- to intermediate-1-risk myelodysplastic syndromes: A randomized trial. Ann Intern Med. 2020;172(8):513-522. doi: 10.7326/M19-0916
  68. Mittelman M, Lugassy G, Merkel D, Tamary H, Sarid N, Rachmilewitz E, Hershko C; MDS Israel Group; Israel Society of Hematology. Iron chelation therapy in patients with myelodysplastic syndromes: consensus conference guidelines. Isr Med Assoc J. 2008;10: 374–376. PMID:18605364
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Introduction

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell (HSC) disorder characterised by ineffective hematopoiesis accompanied by blood cytopenia and by common progression to acute myeloid leukemia (AML). MDS is mostly observed in the elderly persons [1-4]. The main clinical features of MDS are as follows:

Clonal hematopoietic stem-cell disease(s);
Abnormal differentiation, maturation, impaired apoptosis;
• Genetic (Immune) basis;
• Median age: 74 years;
• Incidence increases with age;
• 40-50 per 100 000 in > 70 yr;
Anemia (90%); Pancytopenia (50%);
AML Transformation (20%-60%).

The cytomorphological examination in MDS is based on detection of bi- or tri-lineage dysplasia in different hematopoietic lineages in the bone marrow and/or peripheral blood, and enumeration of blast cells in the samples (Fig. 1A, B).

Mittelman-fig01.jpg

Figure 1. General pattern of bone marrow in healthy person (A) and MDS patient (B). BM of MDS patients is characterized by altered (hyper or hypo-) cellularity, numerical (hyper or hypo-) changes, morphological abnormalities in one or more hematological lineages, and potential increased % of blasts

Classification

MDS patients are classified by International Prognostic Scoring System (IPSS):

Prognostic Parameters:
– FAB subtype: BM morphology – % blasts;
Cytogenetics;
– "good" vs "bad" types;
# Lineages affected.

IPSS:
– Low-risk; Intermediate-1 – Lower risk disease;
– Intermediate-2; High – Higher risk disease.

IPSS-R:
Very low; Low; Intermediate; High; Very high [5, 6].

Evaluation of Treatment Response – Not Blac & White:Thus, standard response criteria were proposed:

• International Working Group (IWG) 2000/2006 [5, 6]:
– Complete response (CR);
– Marrow CR (mCR); (Partial R);
– Cytogenetic response (Cyt R);
– Hematologic improvement (HI);
    - Erythroid (HI-E); Neutrophil (HI-N); Platelet (HI-P).

IWG 2018: HI-E – Erythroid response [7]:
Transfusion burden:
    - Non (0/16 wk), Low (3-7); High > 8;
    - Response: minor (50% less) or major (TI).

MDS treatment

General Strategy of MDS Treatment depends on the disease status (IPSS/R), by discerning lower-risk cases (IPSS: Low risk; Intermediate-I), and higher-risk MDS (IPSS: Intermediate-II; High risk cases).

Patient factors should be taken into account:
• Age; co-morbidities; functional status;
• Quality of life (QoL); Pt reported outcomes (PRO).

MDS treatment is often consistent with a general ‘Rule of Thumb’:
• Response of about 50%;
• Response duration about 2 yr.

This is true for the following therapeutic approaches:
• RBC Transfusions;
• Erythroid stimulating agents (ESAs);
• Lenalidomide;
• Hypomethylating agents (HMA);
• Stem Cell Transplant (SCT).

The remaining challenges include: increasing response rate and duration of response and, finally, achieving cure of this disorder.

Mittelman-fig02.jpg

Figure 2. Hematology research team at the George-Washington University (I am sitting, second on the right)

My experience with MDS could be traced from the Hematology-Oncology Fellowship – GW-NIH (USA) 1986-1989 at George Washington University Medical Center – Department of Hematology-Oncology (Fig. 2).

Recently, the European MDS Registry (EUMDS) is a prospective multicentre European registry for myelodysplastic syndromes (MDS), being the first international prospective, observational registry for newly diagnosed IPSS low- and intermediate-1 risk MDS patients. 18 countries participate in EUMDS activities, i.e., Austria, Chech Republic, France, Germany, Greece, Italy, Netherlands, Romania, Spain, Sweden, UK, Denmark, Portugal, Poland, Israel, Serbia, Croatia, Switzerland.

Appropriate Guidelines were issued by EUMDS (2019) (see MDS-Europe in the net).

Managing lower risk MDS

80% of MDS patients have a hemoglobin <10 g/dl at diagnosis, the majority become transfusion-dependent. Therefore, MDS treatment for anemia still includes multiple RBC transfusions. Most of these patients received MDS-specific supportive care, including RBC transfusions in 50% of the cases [8].

RBC Transfusions in MDS (I)

RBC transfusions are the mostly used (50%) in low-risk MDS. For those patients who were transfusion-independent at diagnosis, the mean interval between diagnosis and the first transfusion was 249 days [9]. For symptomatic anemia, however, limited evidence was shown.

Complications of RBC transfusions in MDS patients include the following events:
• Volume-related; TRALI (Transfusion-Related Acute Lung Injury); ABO incompatibility;
• RBC allo-immunization in 30% of cases [10]. Having MDS is suggested to be an independent risk factor contributing to production of RBC alloantibodies.

Iron overload due to multiple RBC transfusions is among complication of supportive therapy in MDS [11-12]. E.g., the transfusion dose density is associated with shorter progression-free survival (PFS) and worse quality of life. It showed an inverse correlation with PFS (P<1×10-4): the dose density had an increasing effect until 3 units/16 weeks [13].

RBC Transfusions in MDS (II): ELN-EUMDS 2019 Guidelines

The questions arising:
• Hb threshold for starting the transfusions?
– < 7 g/dl (most centers will transfuse if and when Hb < 7g/dl);
– Individualize (Grade B, level 1).
• Hb target levels?
– No target (Grade C, level 2) – recommendation – activate local policy.
• Transfusion frequency?
– Individualize (C-2).
• Prophylactic RBC Ag matching ? No (C-2)
• Symptomatic benefit vs toxicity?
– Individualize (C-2).

For reference see [14]: Bowen D, Mittelman M, ELN-EUMDS Guidelines (2019; online).

Effects of erythrocyte-stimulating agents (ESA) in low-risk MDS anemia were summarized for 2020. ESA were applied as first-line therapy (without RBC transfusions) and proved to be effective in a series of studies, as shown by Hb rise, fewer RBC transfused, improved QoL, with documented safety for the patients [15-19]. Hematological response was observed in a sufficient group of MDS patients (Table 1).

Table 1. Initial results on recombinant human Epo (rHuEPO) in MDS. The responding patients are shown in bold [20].

Mittelman-tab01.jpg

Therapeutic efficiency and safety of different erythrocyte-stimulating agents (ESAs) in LR-MDS was proven over 3 decades. E,g, darbopoietin A was tested in phase 3 trial (n=147), with ORR of 59% [21]. A randomized study of Epoetin-α (phase 3 trial) enrolled 130 cases, with 46% overall response rate [22]. A meta-analysis of different ESA in LR-MDS has shown an ORR of 45-73%, and, possibly, longer overall survival of MDS patients, with 50% response [23]. Finally, a large study by EUMDS included a cohort of LR-MDS patients, at median duration of ESA therapy for 27.5 months, delayed RBC transfusions (by 6 to 23 months), lower risk of death; similar risk of progression to AML, along with safety of such treatment [24].

A team from Denmark found only marginal effects (RR 1.1-1.9) of ESA upon risk of venous thromboembolism (VTE) and strokes in a cohort of 2114 patients [25]. In general, the response rate to ESA in MDS was 50% at the 2-year terms, and proven safety.

Mittelman-fig03.jpg

Figure 3. Comparative IL-6 levels in blood serum of heathy persons, in MM patients, and in Epo-treated MM patients [31]

EPO non-erythroid (immunologic) effects

Therapeutic efficiency of rhEPO was documented in myeloma-associated anemia [26]. Moreover, probable anti-neoplastic effects of erythropoietin were shown in experimental murine myeloma [27, 28].

Other events associated with erythropoietin therapy in patients with hematological disorders include a decreased glucose level [29], probable bone loss by targeting monocytes and osteoclastic activity in murine model [30], as well as decrease in serum IL-6 upon the EPO therapy [31], as seen in Fig. 3. In myelodysplastic syndrome, improvement of T cell immune functions was an additional positive effect observed after erythropoietin treatment [32].

ESA treatment may fail in sufficient part of MDS patients. Clinical outcomes in LR-MDS in the non-responsive cohort were studied by Park et al. [33].

The study represented a retrospective analysis of LR-MDS patients without 5q chromosome deletion. Of them, 653 experienced primary failure and 494 experienced relapse after a response. Median OS among ESA non-responders was 4.2 years in relapsing patients versus 3.7 years in primary failure. Second-line treatment was performed in 39% of them. Hypomethylating agents (HMA) were used in 336 patients, with 46% response, and lenalidomide, in 88 patients with 39% response rates. However, the five-year OS for patients receiving HMA, lenalidomide, or other therapies was 36.5%, 41.7%, and 51%, respectively (P = .21). In a multivariable analysis, there was no significant OS difference among the three groups. Yes, we need to do better…

Lenalidomide therapy

Several studies demonstrated efficiency of Lenalidomide in LR-MDS, either with or without 5q deletion. List et al. [34] have shown that transfusion demands were reduced in 76% of the treated patients with 5q chromosome deletion, and some of them did not longer require transfusions, regardless of the karyotype complexity. The response to lenalidomide occurred at the median time of 4.6 weeks and retained for a median of 2 years. In the meta-analysis by Lian et al. [35], overall rate of hematological erythrocyte response was 58%. The patients with 5q deletion had significantly higher rate of response, significantly prolonged overall survival and lower risk of AML progression. The drug showed a predictable and manageable safety profile in LR-MDS in terms of adverse effects [36]. P53 mutations with higher TP53 protein expression in BM progenitors of lenalidomide-treated patients proved to be associated with higher AML risk and shorter OS [37-39].

Below are main results of the MDS-004 study in Del (5q) MDS patients [38]:
– RRBC TI 56%; Cytogenetic response was observed in 50% at 10mg of Len daily
– Adverse effects: cytopenia, rash, gastrointestinal, thrombosis
– No effect on leukemic transformation
• Results with non-del (5q) patients: MDS-005 [39]
– Among a group of 239 pts (lenalidomide or placebo), transfusion independence was achieved in 27% (vs 2.5% with placebo) at 8 weeks of Len therapy.

Other therapeutic targets

TGF-binding drugs
Hence, anemia remains a sufficient problem in some LR-MDS patients. What can we offer when ESA, or Lenalidomide treatment fail? Newer drugs, e.g., activin analogues, may potentially improve erythropoiesis, by TGF-b binding, or Smad2/3 inhibition. E.g., Luspatercept was tested in a PACE-MDS Trial (ACE-536) at the Phase II, (s/c injections, every 3 wk; 58 pts; post ESA), as reported by Platzbecker et al. [40]. The drug caused a significant dose-dependent increase in blood Hb contents, and, after 4-mo treatment at a dose of 0.75-1.75 mg/kg, reduced demands for RBC transfusions.

The MEDALIST study was a phase 3, randomized, double-blind, placebo-controlled trial with transfusion-dependent MDS. Luspatercept therapy led to RBC transfusion independence in lower-risk MDS patients resistant to ESA [41]. Of the 229 patients, 153 were randomly assigned to receive luspatercept or placebo, s/c every 3 weeks, for ≥ 24 weeks. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in Luspatercept group versus 13% in the placebo group (P<0.001).

Sotatercept (ACE-011), a drug with similar action, was recently subject to phase 2 study carried out by Komrokji et al. [42]. 74 patients enrolled were ineligible for, or refractory to ESA therapy. Clinical response was documented in 40-50% (better outcomes in those with lower transfusion burden). Adverse effects manifested as diarrhea, bone pain, fatigue, GI, edema, lipase increase.

A special COMMANDS Trial aimed to compare Luspatercept versus erythropoietin is launched now [43].

Low Dose/Oral hypomethylating agents (HMA) in LR-MDS
A prospective trial (Phase 2) was performed using Azacitidine versus best supportive care (BSC). The primary endpoint was erythroid hematologic improvement which was achieved in 44.4% of cases after 9 treatment rounds, versus 5.5% of patients treated with BSC, as well as transfusion independence in all the drug responders for a median of 1 year [44].

Low-dose decitabine versus low-dose azacitidine (Aza) were applied in the phase II study [45]. A total of 113 patients were treated: 35% with Aza and 65% with Dec. The ORRs were 70% and 49% for Dec and Aza, respectively. Transfusion independence was achieved in 32 % of decitabine-trea-ted patients, and the treatment was well tolerated.

A meta-analysis performed by Komrokji et al. (2018) [46] concerning efficiency of Aza in a total sample of 233 patients with, mostly, non-del(5q) LR-MDS has shown that the RBC transfusion independence was achieved in 39% of the cases, at ≥6 azacitidine treatment cycles.

Several years ago, a report on clinical effects of peroral Aza (cc-486) in LR-MDS was published [47]. The study included 216 MDS patients. The disease status was assessed after cycle 6. The ORR was 40%, including hematologic improvement in 28% of patients, and transfusion independence lasted for 56 days in 47% of initially transfusion-dependent cases.

Therefore, QUAZAR study (AZA-MDS-003) was continued as randomized controlled trial (RCT), Phase 3, in LR-MDS patients with anemia and thrombocytopenia [48]. The patients received CC-486 or placebo. 31% and 11% of patients, respectively, achieved RBC-TI in the main and placebo group, which lasted, for, respectively, 11.1 and 5.0 months. Platelet improvement rate was also higher in the CC-486 arm (24.3% vs 6.5%).

Roxadustat (FG-4592)
Usage of oral prolyl hydroxylase (PH) inhibitors may be a promising tool of anemia treatment, since the PH inhibition may stabilize hypoxia-inducible factor (HIF). This factor induces erythropoietin production and decreases hepcidin, thus promoting iron mobilization [49]. Recently, this drug was shown to be safe and efficient in the patients with anemia caused by chronic renal failure – CRF [50].

Roxadustat is another PH inhibitor(Fibrogen) undergoes a clinical FGCL-4592-082 trial which is an open label study including 24 pts, achieving 38% TI if used at a dose of 2.5 mg/kg, ×3/wk [51]. Now this drug is under phase 3, randomized controlled trial, with 156 patients.

Telomerase inhibitors
Clinical trials with Imetelstat, a telomerase inhibitor, were performed in the patients with LR-MDS anemia [52-54]. Phase 2 trial is an open, single arm study, with the drug dose of 7.5 mg/kg I/V q 4 wk. A subgroup of 38 LR-MDS patients were selected with transfusion dependence, ESA relapse/resistance, non-del(5q), being hypomethylating agent and lenalidomide naïve. Of them, 16 patients (42%) achieved transfusion independence. This effect was durable (a median of 21 mo) and accompanied by reduced telomerase activit. Phase 3 (a placebo-controlled study) is ongoing.

Treatment of thrombocytopenia in MDS

Platelet transfusions (PLT) are made in MDS patients. However, there is no evidence on their efficiency. This procedure is indicated in cases of active bleeding and should be performed per local guidelines [14, 55]. In absence of active bleeding, the platelet transfusion cannot be routinely recommended!. One may consider "thrombostatics", e.g., Tranexamic acid, or Anti-fibrinolytic solutions, (Hexakapron).

Romiplostim in MDS
For the last decade, several groups study safety and efficacy of romiplostim, a synthetic protein, an analogue of thrombopoietin which increases platelet production, for treatment of MDS patients with thrombocytopenia. The phase I/II study by Kantarjan et al. [56] in 44 patients have shown a durable platelet response in 46% cases. After achieving platelet response (4 weeks) the patients were treated with romiplostim for up to 1 year. Serious adverse effects were registered in 11% of the cases, and 2 patients progressed to AML.

The Phase II study was arranged as a randomized, placebo-controlled trial which included a total of 250 LR-MDS patients randomized 2:1, to receive romiplostim or placebo weekly for 58 weeks [57]. The incidence of bleeding events was reduced in the romiplostim group, and platelet response rates proved to be higher in the patients who received romiplostim. However, study drug was stopped because of excess blasts and potential AML risk following this treatment. Later on, upon 5-year of this cohort, the percentages of patients with AML (12%) in romiplostim group were similar (11%) to those in placebo group, as shown by Kantarjian et al. [58]. In a special commentary, I emphasized that these long-term results were indeed reassuring, however, one has to bear in mind that treatment had been discontinued [59]. Thus, the long-term data reflect the outcome of a long-term follow up, while the drug exposure was relatively short.

Eltrombopag in MDS
Eltrombopag is an agonist of thrombopoietin receptor which promotes growth and differentiation of megakaryocytes. Since 2014, it was approved by FDA for treatment of aplastic anemia, stimulating production of platelets, RBC and leukocytes. In LR-MDS patients with thrombocytopenia, it has shown efficiency of 47% in terms of platelet responses, versus 3% in the placebo group (Oliva et al., 2017) [60].

The ASPIRE study (Part I) was an open-label, double-blind study of patients with advanced MDS treated for 8 weeks with Eltrombopag, and randomised at later terms [61]. Four patients of 17 achieved increased platelet counts following treatment, and ten had reduced platelet transfusion requirements. Serious adverse events were reported in 58% of eltrombopag-treated, and in 68% placebo-treated patients. In ASPIRE II, fewer adverse events were registered.

Combined effects of Eltrombopag and Azacytidin (AZA) were addressed in the SUPPORT Study [62]. The intermediate-1, intermediate-2, or high-risk MDS patients with low platelet counts were randomized 1:1 to eltrombopag, or placebo, plus azacitidine. The development of this study was, however, stopped due to efficacy outcomes, and for safety problems.

The French MDS group (GFM) have recently presented their experience using long-term eltrombopag, with encouraging clinical efficacy. These promising data might assist in lifting the embargo on thrombomimetic agnets [63].

Immunosuppressive therapy

Despite broad arsenal of novel therapeutic agents for MDS therapy, there are many LR-MDS patients with anemia who are resistant or have lost their response to such drugs. Therefore, immunosuppressive treatment (IST) in these cases is well justified, on the basis of similarity between severe aplastic anemia and hypoplastic MDS. Some experience in this field exists with ATG and/or cyclosporine treatment [64]. Clinical response, however, is dependent on the MDS patient’s age, transfusion history, and karyotype pattern, with erythroid response rate of 25-40%.

A large study published by Stahl et al. reported results of IST results obtained for cohort from 15 centers in Europe and USA, including 207 pts with MDS receiving IST [65].

The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). The overall response rate ORR 48.8%, with 11% reaching complete remission, and transfusion independence (RBC-TI) in 30% of the cases. Median overall survival (OS) was 47.4 mo, being longer for the patients with transfusion independence. The RBC-TI was associated with a bone marrow hypocellularity (<20%). Age, HLA-DR15 positivity did not predict clinical response to IST.

Iron Overload

Iron deposition in the patients occurs due to intrinsic mechanisms of MDS, and as a result of multiple RBC transfusion, causing damage of liver and other organs.

Iron chelator therapy is effective in these cases. A retrospective study based on the European MDS Registry data was recently published by Hoeks et al. [66]. The results of chelator treatment in MDS were compared with non-chelated patients. The propensity-score analysis has revealed improved OS for chelated patients, with erythroid response in up to 39% of the treated cohort. A similar TELESTO study (the only prospective) included 225 patients with high serum ferritin levels after multiple RBC transfusions treated with Deferasirox [67]. Following continuous treatment (0.5 to 3 years), median EFS was prolonged by ca. 1 year (1440 d vs 1091 d) with deferasirox vs placebo, at 36% reduction of events.

Several eligibility criteria are proposed for initiating the chelator therapy [14, 68] (Mittelman et al., 2008, current Guidelines 2019; MDS-EUROPE online [14]: 1. Patients classified as low or Int1, according to the International Prognostic Scoring System; 2. Patients with serum ferritin levels >1000 μg/Ll and those who received a total of 20-25 RBC units; 3. Patients whose blood transfusion requirement has increased significantly; 4. Patients with sufficient organ damage.

Summary and future prospects

Current treatment of the low-risk MDS includes the following:
• ESA +/- RBC transfusions;
• Lenalidomide (del 5q);
• 2nd Line:
  – Luspatercept; Roxadustat; Imetelstat; HMA (?)
Future prospectives:
• Combinations: ESA + other hematopoiesis-stimulating drugs;
• Novel agents;
• Low platelet counts in MDS patients:
  – Therapeutic approaches are still challenging.

Conflict of interest

Disclosures: Research funding: Celgene; Johnson & Johnson; Roche; Novartis; Gilead. Speakers’ bureau: Celgene; Johnson & Johnson; Novartis. Advisory boards (non-paid): Pfizer; Amgen; Roche; Novartis.

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На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. 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Моше Миттельман

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27563" ["VALUE"]=> array(2) { ["TEXT"]=> string(149) "<p> , Медицинский центр Сураски, Университ Тель-Авива, Тель-Авив, Израиль </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(137) "

, Медицинский центр Сураски, Университ Тель-Авива, Тель-Авив, Израиль

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27555" ["VALUE"]=> array(2) { ["TEXT"]=> string(1967) "<p style="text-align: justify;">За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1911) "

За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.

Ключевые слова

Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.

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Moshe Mittelman            

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Tel Aviv Sourasky Medical Center; Tel Aviv University, Israel


Correspondence
Prof. Dr. Moshe Mittelman, Professor of Internal Medicine and Hematology; Past Chairman, Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University; Past President, Israel Society of Hematology and Transfusion Medicine.
Tel Aviv Sourasky (Ichilov) Medical Center, 6 Weizmann St, 64239, Israel.
E-mail: moshemt@gmail.com


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A significant progress has been made over the last couple of decades in understanding the biology and treatment of myelodysplastic syndromes. Based on several parameters (% blasts, cytogenteics, number of affected lineages) the patients are classified as having a lower-risk (LR) or higher risk disease. Here, we will focus on LR-MDS.

The patients with LR-MDS are treated with RBC transfusions as needed, with or without erythroid stimulating agents. Luspatercept, an activin analogue, is a reasonable second line agent. Among the investigational agents in this field we can mention ruxodustat (a HIF inhibitor) and imetelstat, a telomerase inhibitor. Treatment of thrombocytopenia remain challenging and an open question.

Keywords

Myelodysplastic syndrome, low-risk, diagnostics, management, targeted therapy.

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Moshe Mittelman            

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Moshe Mittelman            

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A significant progress has been made over the last couple of decades in understanding the biology and treatment of myelodysplastic syndromes. Based on several parameters (% blasts, cytogenteics, number of affected lineages) the patients are classified as having a lower-risk (LR) or higher risk disease. Here, we will focus on LR-MDS.

The patients with LR-MDS are treated with RBC transfusions as needed, with or without erythroid stimulating agents. Luspatercept, an activin analogue, is a reasonable second line agent. Among the investigational agents in this field we can mention ruxodustat (a HIF inhibitor) and imetelstat, a telomerase inhibitor. Treatment of thrombocytopenia remain challenging and an open question.

Keywords

Myelodysplastic syndrome, low-risk, diagnostics, management, targeted therapy.

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A significant progress has been made over the last couple of decades in understanding the biology and treatment of myelodysplastic syndromes. Based on several parameters (% blasts, cytogenteics, number of affected lineages) the patients are classified as having a lower-risk (LR) or higher risk disease. Here, we will focus on LR-MDS.

The patients with LR-MDS are treated with RBC transfusions as needed, with or without erythroid stimulating agents. Luspatercept, an activin analogue, is a reasonable second line agent. Among the investigational agents in this field we can mention ruxodustat (a HIF inhibitor) and imetelstat, a telomerase inhibitor. Treatment of thrombocytopenia remain challenging and an open question.

Keywords

Myelodysplastic syndrome, low-risk, diagnostics, management, targeted therapy.

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Tel Aviv Sourasky Medical Center; Tel Aviv University, Israel


Correspondence
Prof. Dr. Moshe Mittelman, Professor of Internal Medicine and Hematology; Past Chairman, Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University; Past President, Israel Society of Hematology and Transfusion Medicine.
Tel Aviv Sourasky (Ichilov) Medical Center, 6 Weizmann St, 64239, Israel.
E-mail: moshemt@gmail.com


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Tel Aviv Sourasky Medical Center; Tel Aviv University, Israel


Correspondence
Prof. Dr. Moshe Mittelman, Professor of Internal Medicine and Hematology; Past Chairman, Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University; Past President, Israel Society of Hematology and Transfusion Medicine.
Tel Aviv Sourasky (Ichilov) Medical Center, 6 Weizmann St, 64239, Israel.
E-mail: moshemt@gmail.com


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Моше Миттельман

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Моше Миттельман

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За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.

Ключевые слова

Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.

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За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.

Ключевые слова

Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.

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, Медицинский центр Сураски, Университ Тель-Авива, Тель-Авив, Израиль

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, Медицинский центр Сураски, Университ Тель-Авива, Тель-Авив, Израиль

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Review articles

Low-risk MDS: non-transplant therapeutic approach

Moshe Mittelman            

Review articles

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Михаил Ю. Самсонов1, Андрей М. Ломоносов2

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1 ООО Р-Фарм; Отдел фармакологии, институт фармации, Первый Московский государственный медицинский университет
им. И. Сеченова, Москва, Россия
2 Рабочая группа Хелснет Национальной технологической инициативы, Москва, Россия

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За последнее десятилетие достигнуты значительные успехи в медицинской науке и прикладных технологиях. Клеточная и генная терапия позволили добиться выдающихся результатов этих разработок в течение очень коротких сроков. С начала первой волны заболеваемости, пандемия COVID-19 создала препятствия для пациентов в плане доступа к диагностике и лечению в госпитальных условиях. С другой стороны, этот годичный период был ознаменован беспрецедентными технологическими достижениями, особенно – в аспекте терапии, основанной на применении мРНК и ее законодательного регулирования. В настоящей обзорной статье обращается особое внимание на CAR-T-клетки в качестве клинической модели со всеми ключевыми атрибутами их внедрения в рамках сложных цепочек – от первичных научных исследований к многообразию моделей и тенденций их применения в клинической практике.

Ключевые слова

Клеточная и генная терапия, CAR-T–клеточная терапия, планирование управлением рисками, гибкое развитие.

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Mikhail Yu. Samsonov1, Andrey M. Lomonosov2

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1 RPharm JSC; Department of Pharmacology, Institute for Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 Healthnet Working Group of National Technology Initiative, Moscow, Russia


Correspondence
Dr. Mikhail Yu. Samsonov MD, PhD, RPharm. Leninsky prospect 111, Moscow, Russia
E-mail: samsonov@rpharm.ru

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The last decade has witnessed a significant advancement in medical science and technologies. The cell and gene therapies represent remarkable outcomes of such progress achieved in a very short timeframe. The COVID-19 pandemic has created roadblocks for patients to access hospitals for diagnosis and treatments since the onset of its first-wave. On the contrary, this one-year leap has witnessed unprecedented technological advances, especially in terms of mRNA-based therapies and their regulations. The present review focuses on CAR-T as a model with all key attributes and implications in complicated chains from early science to a variety of models and trends in clinical practice.

Keywords

Cell and gene therapy, CAR-T therapy, risk management plan, agile development approach.

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What we are learning from CAR-T implementation: development, regulatory and clinical practices

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Mikhail Yu. Samsonov1, Andrey M. Lomonosov2

1 RPharm JSC; Department of Pharmacology, Institute for Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 Healthnet Working Group of National Technology Initiative, Moscow, Russia


Correspondence
Dr. Mikhail Yu. Samsonov MD, PhD, RPharm. Leninsky prospect 111, Moscow, Russia
E-mail: samsonov@rpharm.ru

The last decade has witnessed a significant advancement in medical science and technologies. The cell and gene therapies represent remarkable outcomes of such progress achieved in a very short timeframe. The COVID-19 pandemic has created roadblocks for patients to access hospitals for diagnosis and treatments since the onset of its first-wave. On the contrary, this one-year leap has witnessed unprecedented technological advances, especially in terms of mRNA-based therapies and their regulations. The present review focuses on CAR-T as a model with all key attributes and implications in complicated chains from early science to a variety of models and trends in clinical practice.

Keywords

Cell and gene therapy, CAR-T therapy, risk management plan, agile development approach.

Review articles

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Иван С. Моисеев1, Татьяна Г. Цветкова2, Тапани Рууту3

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Всероссийский центр экстренной и радиационной медицины имени А. М. Никифорова, Санкт-Петербург, Россия
3 Клинический Исследовательский Институт, Клиника Университета Хельсинки, Хельсинки, Финляндия

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 27570 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;">Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.

Ключевые слова

Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.

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Ivan S. Moiseev1, Tatyana G. Tsvetkova2, Tapani Ruutu3

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
3 Clinical Research Institute, Helsinki University Hospital, Helsinki, Finland


Correspondence
Ivan S. Moiseev, PhD, MD, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients. Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Keywords

Thrombotic microangiopathy, hematopoietic stem cell transplantation, diagnostic criteria, calcineurin inhibitors, defibrotide, eculizumab.

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Practical review of current approaches to diagnosis and treatment of transplant-associated thrombotic microangiopathy

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Ivan S. Moiseev1, Tatyana G. Tsvetkova2, Tapani Ruutu3

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
3 Clinical Research Institute, Helsinki University Hospital, Helsinki, Finland


Correspondence
Ivan S. Moiseev, PhD, MD, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia

Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients. Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Keywords

Thrombotic microangiopathy, hematopoietic stem cell transplantation, diagnostic criteria, calcineurin inhibitors, defibrotide, eculizumab.

Review articles

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[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 27563 [VALUE] => Array ( [TEXT] => <p> , Медицинский центр Сураски, Университ Тель-Авива, Тель-Авив, Израиль </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

, Медицинский центр Сураски, Университ Тель-Авива, Тель-Авив, Израиль

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 27555 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;">За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.

Ключевые слова

Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.

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Moshe Mittelman            

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Tel Aviv Sourasky Medical Center; Tel Aviv University, Israel


Correspondence
Prof. Dr. Moshe Mittelman, Professor of Internal Medicine and Hematology; Past Chairman, Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University; Past President, Israel Society of Hematology and Transfusion Medicine.
Tel Aviv Sourasky (Ichilov) Medical Center, 6 Weizmann St, 64239, Israel.
E-mail: moshemt@gmail.com


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A significant progress has been made over the last couple of decades in understanding the biology and treatment of myelodysplastic syndromes. Based on several parameters (% blasts, cytogenteics, number of affected lineages) the patients are classified as having a lower-risk (LR) or higher risk disease. Here, we will focus on LR-MDS.

The patients with LR-MDS are treated with RBC transfusions as needed, with or without erythroid stimulating agents. Luspatercept, an activin analogue, is a reasonable second line agent. Among the investigational agents in this field we can mention ruxodustat (a HIF inhibitor) and imetelstat, a telomerase inhibitor. Treatment of thrombocytopenia remain challenging and an open question.

Keywords

Myelodysplastic syndrome, low-risk, diagnostics, management, targeted therapy.

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Low-risk MDS: non-transplant therapeutic approach

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Moshe Mittelman            

Tel Aviv Sourasky Medical Center; Tel Aviv University, Israel


Correspondence
Prof. Dr. Moshe Mittelman, Professor of Internal Medicine and Hematology; Past Chairman, Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University; Past President, Israel Society of Hematology and Transfusion Medicine.
Tel Aviv Sourasky (Ichilov) Medical Center, 6 Weizmann St, 64239, Israel.
E-mail: moshemt@gmail.com


A significant progress has been made over the last couple of decades in understanding the biology and treatment of myelodysplastic syndromes. Based on several parameters (% blasts, cytogenteics, number of affected lineages) the patients are classified as having a lower-risk (LR) or higher risk disease. Here, we will focus on LR-MDS.

The patients with LR-MDS are treated with RBC transfusions as needed, with or without erythroid stimulating agents. Luspatercept, an activin analogue, is a reasonable second line agent. Among the investigational agents in this field we can mention ruxodustat (a HIF inhibitor) and imetelstat, a telomerase inhibitor. Treatment of thrombocytopenia remain challenging and an open question.

Keywords

Myelodysplastic syndrome, low-risk, diagnostics, management, targeted therapy.