Pavlov University lost a charismatic leader who built in St. Petersburg an internationally visible center of excellence in leukemia research and hematopoietic stem cell transplantation. We sadly inform our readers of the untimely death of the Editor-in-Chief of CTT. Professor Boris V. Afanasyev, Director of Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at Pavlov First Saint Petersburg State Medical University, passed away on Monday, March 16, 2020. Over the last three decades he was the major inspirator for the development of hematopoietic stem cell transplantation, as well as chemotherapy, immunotherapy and targeted therapy of malignant and non-malignant blood disorders in Russia. He was broadly known both in Russia and worldwide.

Boris V. Afanasyev graduated from Pavlov First Medical Institute in Leningrad with honors (1971). Till 1973, he was a resident at the Faculty Therapy (Internal Medicine). As a post-graduate student (1974-1976), he was one of the pioneers in basic hematopoietic stem cell research. His PhD Thesis (1977) was dedicated to growth regulation of normal and leukemic precursor cells observed in agar drop test system: Cloning of hematopoietic stem cells, studies of colony-forming ability of bone marrow and blood cells from healthy persons and patients with different neutropenic conditions. His most prominent studies of cultured stem cells included description of terminal differentiation of leukemic stem cells. Boris Afanasyev has also performed a number of pioneering works in stromal regulation of hematopoiesis by mesenchymal stem cells which proved to exert both stimulatory and modulatory effects upon granulocyte precursors that were performed by him in an original ‘agar drop-liquid culture’ system.

From 1976 to 1979, Prof. Boris V. Afanasyev headed the Department of Hematology at the Faculty of Internal Medicine. In 1982 based on the in vitro growth pattern of hematopoietic stem cells he was the first to describe myelodysplastic syndrome in children. His Habilitation Thesis (1983) was entitled: Granulomonocytopoiesis in acute leukemia and in blast crisis. He was one of the first to describe the cellular mechanisms of myeloid and lymphoid types of blast crisis in chronic myeloid leukemia. In 1985, he has published the well-known monograph Ancestral Human Hematopoietic Cells in co-authorship with Prof. V. A. Almazov. Over next 8 years, Boris Afanasyev was a Senior Research Associate at the Faculty of Internal Medicine in the First Leningrad Pavlov Medical Institute, studying biological mechanisms of malignant cells in acute and chronic leukemia, and in severe neutropenic conditions.

In 1986, Boris V. Afanasyev underwent clinical training at the famous Fred Hutchinson Cancer Center in Seattle under supervision of Nobel Laureate, Professor Donnall Thomas. In 1987, Boris V. Afanasyev organized the first Bone Marrow Transplantation (BMT) Department in the Soviet Union at the N. N. Petrov Research Institute of Oncology. In 1991 he performed the first pediatric allogeneic bone marrow transplantation in Russia.

In 2000 Prof. Boris V. Afanasyev organized the first university based BMT Department in Russia at the First St. Petersburg State I. Pavlov Medical University. In 2003, he established the Faculty of Hematology, Transfusiology and Transplantation for postgraduate education at the Pavlov University.

By 2007, based on the initiative of Prof. Boris V. Afanasyev and Pavlov University, with the support of Gorbachev Foundation and National Reserve Bank, the Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation was built and inaugurated in Pavlov University, which he since led as Founding Director of this Institute.

Over the last decade, his interests were focused on developing protocols for patients with relapsed and refractory malignant diseases. Under his supervision, novel protocols of bridging and posttransplant therapy with target agents and monoclonal antibodies were developed. He also was focused on long-term complications of BMT in children and adults and was one of the pioneers of reduced conditioning regimens in children that resulted in reduced long-term toxicity. The scientific heritage by Prof. Boris V. Afanasyev includes over 300 research papers and 6 monographs. This clinical research allowed to significantly expand the transplantation programs, which became the largest in Russia and are among the largest in Europe.

Since 1990, Prof. Afanasyev put effort into the development of unrelated bone marrow donor registry in Russia. These efforts in 2013 succeeded into the collaborative database which now helps recruiting about half of the unrelated donors in Russia. The governmental plan for expanding the database into a national unrelated bone marrow donor program has been approved, creating another legacy to Prof. Boris V. Afanasyev.

During the years that led to the success of BMT program organized by Prof. Afanasyev, he deeply acknowledged the support of his colleagues and friends from abroad: Rolf Neth, Klaus Winkler, Axel Zander, Nicolaus Kroeger, Boris Fehse (Hamburg, Germany), Thomas Buchner (Muenster, Germany), Dieter Hoelzer (Frankfurt, Germany), Hans-Jochem Kolb (Muenchen, Germany), Ruediger Hehlmann (Mannheim, Germany), Gerard Wagemaker (Rotterdam, Netherlands), Robert Gale (London, UK), Andrea Bacigalupo (Rome, Italy), Magne Børset (Trondheim, Norway), Arnon Nagler (Tel Aviv, Israel), Tapani Ruutu (Helsinki, Finland) and many others who facilitated the education of more than 70 Russian hematologists in the European centers.

Starting in 2007, the Annual Raisa Gorbacheva Memorial Meetings at Pavlov University has become the central event to russian and the international leukemia community focused on education, collaboration, exchanging opinions and sharing novel research data, and on spreading excellence in the field of stem cell transplantation.

Prof. Afanasyev was a Member of the Editorial Boards in many Russian and international journals. As Editor-in-Chief, he played a key role in starting and developing the bilingual Cellular Therapy and Transplantation journal, in which Russian and international authors in oncology, hematology and related fields could present their research to the international community. We, his colleagues and friends, but also the whole community of hematologists and stem cell transplanters, will strongly miss his huge enthusiasm, creativity and friendliness.

Boris Afanasyev served life-long the general interest and passed away as he lived, completing a task of vital importance to the Institute, to the University, to hematology, and to the society. He was awarded the Clinical Achievement Award from the EBMT at the Lisbon meeting in 2018. Boris Afanasiev was elected to be honored with an ELN Keynote Lecture this year on the topic: "The Raisa Gorbacheva Memorial Institute in St. Petersburg: Building a Center of Excellence in Russia" in recognition of his international visibility and esteem. He is survived by his wife Olga, daughter Anastasia and grandchildren Emil-Boris and Antonia.

Sergey F. Bagnenko,
Prof. Dr. Med., RAS Full Member, Rector, Pavlov University, Saint Petersburg, Russia
Axel R. Zander,
Prof. Dr. Dr. h.c., University Medical Center Hamburg-Eppendorf, Germany
Gerard Wagemaker,
Prof. Dr. Dr.h.c. Erasmus University, The Netherlands
Rudiger Hehlmann,
Prof. Dr., Dr.h.c. Med. Fakultät Mannheim, Heidelberg University, Germany
Boris Fehse,
Prof. Dr., Hamburg University, Germany 
Alexander D. Kulagin, Prof. Dr.,
Ludmila S. Zubarovskaya, Prof. Dr.,
Ivan S. Moiseev, PhD, MD
Inna V. Markova, PhD
and Alexei B. Chukhlovin, Prof. Dr.
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, Saint Petersburg, Russia

There is a huge number of studies concerning metabolic, immunological and other differences between males and females caused by their differential hormonal and physiological background. However, only few studies are dedicated to sex-dependent differences in amounts of donor hematopoietic cells used for stem cell transplantation (HSCT), kinetics of cytostatic drugs used for conditioning treatment and immunosuppressors for GvHD prophylaxis, as well as differences in common posttransplant complications. The following differences significant for evaluation of HSCT results may be derived from previous studies: (1) Higher counts of CD34+ cells in hematopoietic grafts from males compared to female donors; (2) Metabolism of cytostatic drug in females suggest a tendency for decreased clearance and higher modification rates due to increased CYP3A activities, along with decreased drug efflux from target cells, thus suggesting higher accumulation of active cytostatic metabolites in female patients; (3) More effective and stable humoral immune response in females compared to males could be translated into better anti-infectious response, along with higher risk of chronic GvHD in females after allo-HSCT; (4) Male patients with some hematological malignancies subjected to allo-HSCT are more prone to posttransplant relapses, however, conflicting data are reported; (5) Increased risk of acute GvHD in males exists in cases of allo-HSCT from female donors. The issue of graft-versus-leukemia effect in this setting still remains open. In sum, estrogen hormones seem to be to the most probable cause of gender differences in HSCT-associated risks. However, modifying role of sex steroids is not well studied, and it should vary, depending on the age of patients. Therefore, real significance of sex differences in HSCT deserves further extensive studies in large databases.

Keywords

Hematopoietic stem cell transplantation, sex differences, drug kinetics, immune response, GvHD, relapses, survival, estrogens, outcomes.

Corticosteroids have an established role as the first-line treatment of graft-versus-host disease (GvHD), but their role in the prophylaxis of GvHD is less clear. At present, corticosteroids are included in the prophylaxis regimens only rarely. Studies of adding corticosteroid to the most widely used prophylactic regimen, cyclosporine A and a short course of methotrexate, have yielded conflicting results, possibly due to differences in the treatment schedule. In our earlier published randomized prospective study, the addition of methylprednisolone (MP) to cyclosporine and methotrexate resulted in a markedly reduced incidence of acute GvHD. No difference was seen in the survival. In long-term follow-up of this study, after a median follow-up of 24.5 years in living patients, we observed a marked late non-relapse mortality among the patients not given prophylactic MP, probably due to higher incidence of chronic GvHD in this study arm. At the end of the follow-up, 55% of the patients given MP in the prophylaxis were alive, compared with 20% in the control arm. These findings suggest that the role of corticosteroids in GvHD prophylaxis should be reevaluated.

Keywords

Graft-versus-host disease, acute, chronic, prophylaxis, corticosteroids, glucocorticoids, favorable effect.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of aggressive lymphomas comprising more than 20 different entities and representing about 10% of all non-Hodgkin lymphomas diagnosed in the Western World. Given their heterogeneity, there is no consensus regarding the best first-line treatment and the role of autologous/allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation is controversial. To examine the real-world outcomes for patients with PTCL submitted to HSCT in our institution we retrospectively reviewed the clinical outcomes of 26 patients who were given a transplant either as first-line consolidation or in relapse between January 2000 and July 2018. The median follow-up is 6.3 years; 19 patients had an autologous HSCT, 16 as upfront consolidation and 3, for relapsed disease. Overall survival (OS) and relapse free survival (RFS) were, respectively, 62% and 59%. Seven patients had an allograft, 4 as upfront consolidation and 3 after relapse; 6 are alive and 1 died due to transplant-related mortality (TRM). TRM was 3.7% for the entire population and the 6-year OS and PFS were 74% and 69%, respectively. Our results suggest that autologous/allogeneic HSCT is an effective and safe option for the consolidation of adverse-risk profile patients with PTCL, but they need to be validated in prospective studies including a larger number of patients.

Keywords

Peripheral T-cell lymphomas, first-line therapy, CHOP, Brentuximab vedotin, hematopoietic stem cell transplantation, allogeneic, autologous.

T-cell lymphomas (TCL) comprise a group of aggressive non-Hodgkin lymphomas, which do not have successful treatment standards. Almost 70% of patients undergoing first-line therapy develop a relapse or refractory (r/r) disease. A number of novel therapy approaches are aimed for improvement of outcomes in patients with r/r TCL. This report summarizes clinical experience of Pavlov Medical University in the treatment of T cell lymphomas. We analyzed data of 47 patients with TCL treated from 2005 to 2019. Of them, 44 had r/r TCL, and 3 patients were in complete response after first line therapy. The median age was 45 years (range 1-72 years). These were predominantly patients with peripheral T-cell lymphomas not otherwise specified (TCL-NOS, 41%). 26 patients (55% of total) had a primary chemoresistant disease, while the remaining 18 patients (38% of total) had a relapse after initial treatment.

Our center has implemented new treatment options for r/r TCL, i.e., anti CD30 monoclonal antibody brentuximab, ALK inhibitor crizotinib, immunotherapy with checkpoint inhibitors nivolumab, and hematopoietic stem cell transplantation (HSCT). A total of 24 patients underwent: high-dose chemotherapy with autologous HSCT (auto-HSCT) was performed in 16 cases, 13 patients were subjected to allogeneic HSCT (allo-HSCT), including 5 relapsed patients after auto-HSCT. At the time of analysis, 35 patients remained alive. The median follow-up of surviving patients was 35 months (6-122 mo). The median overall survival (OS) was not reached, 5-year survival rate was 81%, and 8-year survival rate was 78%. Complete remission (CR) at the last follow-up was diagnosed in 22 patients; partial response (PR), in 4 cases, and progression of the disease (PD) was revealed in 21 patients. Among factors significantly associated with adverse prognosis were lower ECOG performance status and B-symptoms at the time of diagnosis (p=0.06). The patients who underwent HSCT showed significantly better disease status at the moment of last follow up: 17/19 (89%) were in CR, versus 5/16 (31%) among the patients not subjected to HSCT. 5-year overall survival rates after auto-HSCT and allo-HSCT were 87% and 77%, respectively. The results show that implementation of novel therapeutic agents, as well as consolidation with high-dose chemotherapy and auto- or allo-HSCT in selected cases improve outcomes in patients with r/r TCL. Brentuximab vedotin and nivolumab-based regimens may be successfully used as a bridge therapy before HSCT.

Keywords

T-cell lymphoma, autologous hematopoietic stem cells transplantation, allogeneic hematopoietic stem cells transplantation, brentuximab vedotin, nivolumab.

Bispecific monoclonal antibody blinatumomab is targeting CD19, being applied for treatment of acute lymphoblastic leukemia (ALL). Several additional targets could be used for combined chemo-free treatment with thyrosine kinase inhibitors: BCR-ABL, FLT3 and IKZF1 deletions are amongst them. In the following study, we aimed to assess toxicity and clinical effectiveness of the combination of blinatumomab and several thyrosine kinase inhibitors.

Patients and methods

From October 2015 to October 2018, we treated 11 relapsed/refractory (R/R) ALL patients (pts). The blinatumomab treatment consisted of 4-5 cycles with 2-week intervals (28 mcg/day by continuous infusion during 28 days per cycle with 9 mcg/day during the first week of the first cycle). Seven BCR-ABL-positive and 2 IKZF1-deleted pts received initially dasatinib at 140 mg/day, one case, with FLT3-ITD received sorafenib (800 mg/day). One BCR-ABL-positive pt with T315I mutation was administered ponatinib (45 mg/day). Pts with IKZF1 deletions received ATRA (45 mg/m²/day for 4 weeks) of the 1^st blinatumomab cycle and during first 2 weeks of subsequent blinatumomab cycles.

Results

In the patients responding to blinatumomab treatment, we observed a statistically significant increment of absolute values in T-helper (p=0.0034), T-cytotoxic (p<0.0001) and NK (p=0.0006) cell subpopulations in peripheral blood over the entire treatment period. T-regulatory and double-negative T-cells as potentially inhibitors of T cell response to blinatumomab remained within low values of normal ranges. Hypogammaglobulinemia was observed in 8 of 11 pts. CR was achieved in 10 pts after 1st cycle of blinatumomab, progressive disease was detected in 1 pt. Nine cases of complete molecular remissions (MolCR) and one cytogenetic complete remission were achieved in ten CR pts. Nine allo-BMT and one auto-BMT were performed in 10 CR pts. Three CNS relapses after allo-BMT and one molecular relapse after auto-BMT were diagnosed. One pt died from septic shock after allo-BMT.

Conclusion

Blinatumomab combined with TKI has high therapeutic potential as induction remission treatment in targeted ALL population without conventional chemotherapy. High rate of potential CNS relapses could be decreased with more intensive intrathecal prophylaxis.

Keywords

Acute lymphoblastic leukemia, blinatumomab, tyrosine kinase inhibitors.

Hemorrhagic cystitis (HC) is a frequent complication in allogeneic hematopoietic stem cell transplantation (allo- HSCT). Human BK-polyomavirus (BKPyV) may be one of the main agents found in late HC developing after allo-HSCT. In previous studies, intravenous immunoglobulin (IVIG) preparations were shown to neutralize BKPyV in mice cell cultures and to reduce BK virus nephropathy in kidney transplantation. The aim of current study was to evaluate efficiency of HC treatment with IVIG in allo-HSCT recipients, with respect to conditioning regimen intensity and presence of graft-versus-host disease (GvHD).

Patients and methods

A total of 1037 allo-HSCT recipients transplanted in R. M. Gorbacheva Memorial institute for Pediatric Oncology, Hematology and Transplantation in 2013-2018 were included into retrospective open single-center cohort study. HC was registered in 118 (11.4%) cases. According to inclusion criteria, only 90 patients were enrolled to the final analysis. This cohort was divided into two groups based on HC therapy used: the intervention group (n=42) included patients with standard HC treatment with addition of IVIG; the control group (n=48) – with standard HC therapy only.

Results

The median HC duration in common group (IVIG and control) was 21 days. There was no statistically significant difference in HC duration between the two groups, with the median of 24 days (16, 32; 95% CI) in the intervention group (standard therapy + IVIG), and 24 days (2, 46; 95% CI) in control group, respectively (p=0.39). The median HC duration in MAC and RIC was 35 days (18, 52; 95% CI) versus 17 days (14, 20; 95% CI), respectively (p<0.01). The presence of GvHD I-IV at the time of HC symptoms manifestation was also characterized by positive correlation with HC duration. It was 36 days (22, 50; 95% CI) in patients with GvHD and 18 days (15, 21; 95% CI) in patients without GvHD (p=0.013).

Conclusions

Our data didn’t show any clinical efficiency of 1.2 g/kg IVIG (Immunovenin® 5%, 50mg/mL by Microgen) effectiveness in post allo-HSCT HC patients. Conditioning regimen intensity and GvHD I-IV are the risk factors for HC longer duration. The further prospective study is needed to make final conclusions on method’s effectiveness.

Keywords

Allogeneic hematopoietic stem cell transplantation, hemorrhagic cystitis, intravenous immunoglobulin, IVIG, risk factors, graft-versus-host disease (GvHD).

Despite growing evidence on the use of posttransplantation cyclophosphamide (PTCY) in matched unrelated transplantation in acute leukemia patients, prospective evidence to support this type of prophylaxis in myelodysplastic syndrome (MDS), chronic myeloproliferative neoplasms and chronic myeloid leukemia (CML) patients is lacking. In this patient population we conducted a prospective randomized study of PTCY vs thymoglobulin for graft-versus-host disease (GvHD) prophylaxis in the setting of 10/10 HLA-matched unrelated transplantation (NCT02627573, clinicaltrials.gov). The strata for randomization was pretransplant assessment of mortality score. The study was terminated prematurely due to poor recruitment, but 33 patients were enrolled, 17 in the PTCY and 16 in the thymoglobulin group. Median follow up was 29 months. There was no difference between groups in the incidence primary graft failure (12.50% vs 11.8%, p=0.9), acute GvHD grade II-IV (23% vs 6%, p=0.2), moderate and severe chronic GvHD (25% vs 23%, p=0.4) in the thymoglobulin and PTCY arms, respectively. However there was a significantly higher overall survival (82% vs 30%, p=0.0126), event-free survival (61% vs 26%, p=0.0335), and GvHD-relapse free survival (61% vs 16%, p=0.0072) in the PTCY group due to reduced late infection-related mortality. No differences was observed in terms of toxicity. In conclusion, despite incomplete recruitment, the study created the basis for the use of PTCY in unrelated transplantations from fully matched unrelated donors in CML and MDS. Future studies are required to confirm if there is a benefit of PTCY-based prophylaxis over thymoglobulin.

Keywords

Posttransplant cyclophosphamide, myelodysplastic syndrome, chronic myeloid leukemia, chronic myeloproliferative neoplasm, matched unrelated donor.

Allogeneic hematopoietic stem cell transplantation is an effective method to cure patients with relapse/refractory (r/r) B-cell acute lymphoblastic leukemia, and deep remission without minimal residual disease is the key factor for the favorable outcome. Monoclonal antibodies (bispecific T-cells engager and conjugates) are the promising option to achieve complete remission in these patients. Our aim was to summarize the results of a single-center non-randomized study in order to investigate in real clinical practice the results of treatment with blinatumomab and inotuzumab ozogamicin in children and adults in heterogeneous cohort of r/r B- ALL.

Results of the single-center non-randomized pilot study in real clinical practice showed high response rate in heterogeneous cohort of r/r B- ALL. The study group included 182 patients with r/r B-ALL, their age was from one to 72 years old. 128 patients were treated with blinatumomab, 54 patients received inotuzumab ozogamicin. Overall response was high in both groups, 96 (75%) and 44 (82%). The major predictors of response were adult age (OR= 3.819; 95% CI, 1.744-8.223; p=0.001) and clinical indications, i.e., active disease or measurable residual disease (OR= 0.018; 95% CI, 0.153-0.841; p=0.01). The other clinical or disease parameters had no significant impact on response.

Keywords

B-cell acute lymphoblastic leukemia, relapse/refractory, monoclonal antibodies, blinatumomab, inotuzumab ozogamicin, overall response.

In compliance with most observations, the multipotent stromal cells (MSC) remain at the site of implantation after local application, whereas intravenously administrated MSC first appear in lungs followed by distribution to different tissues and organs, however, at much smaller quantities. Moreover, there are data on predominant migration of systemically infused MSC into liver, and not into the lungs. Destruction and elimination of introduced MSC, according to published data, occurs in the spleen, kidneys and liver. Due to controversial results on MSC distribution and elimination from the body, the aims of our study were as follows: to investigate the fate of tissue-injected autologous bone marrow-derived multipotent mesenchymal stromal cells (MMSC) entering liver, kidneys and lungs, as well as to obtain new evidence for their elimination from the body via these organs.

Materials and methods

The work is based on morphological evaluation of lungs, liver and kidneys from 6-mo old male rats (Wag inbred strain) at different terms after subcutaneous injection of MMSC labeled with membrane-binding Vybrant® CM-Dil dye. Morphological patterns and distribution of labeled objects in these organs were investigated using visible and luminescent microscopy.

Results

The first luminescent macrophages observed with rhodamine colour-filter were initially revealed in the lungs one week after MMSC injections. The number of luminescent cells and intensity of their fluorescence increased gradually over successive 2-4 weeks. By 2-3 weeks, this red tint was revealed in the inclusions of epithelial cells in some bronchioles. The Vybrant® CM-Dil-labeled objects were sometimes detected at the very edge of alveoli, and even partially located in alveolar lumen. The objects stained by Vybrant® CM-Dil were not found in liver and kidneys at any observation terms.

Conclusion>/h3>

Following subcutaneous injection, MMSCs and their fragments seem to enter bloodstream and migrate to the lungs, where these cells are phagocytized by macrophages. Only after filtration in lungs, the MMSC debris can further disseminate throughout the body. Elimination of detritus from injected MMSC is possible in lung alveoli and further, via bronchial system, to the ambient. Vybrant® CM-Dil-labeled MMSC fragments were not found in liver and kidneys, thus disagreeing the literature data on potential role of these organs in the destruction or removal of injected autologous or foreign MSC.

Keywords

Multipotent stromal cells, elimination, lungs, macrophages, alveoli, liver, kidneys.