Is there a Future for Haematopoietic Cell Transplants?
Robert P. Gale
Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK
Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK
Accepted 23 October 2020
Recent advances in anti-cancer chemotherapy and in targeted and immune therapies raise the question whether there is a future for haematopoietic cell transplants. I discuss their importance but in the end the magnitude of these improvements is modest. I point out the efficacy of immune therapy is predominately restricted to B-cell cancers and that many if not most successful immune therapy recipients eventually receive an allogeneic haematopoietic cell transplant, especially those with acute lymphoblastic leukaemia (ALL).
I also discuss most allotransplants are done for cancers not treated with current immune therapy. Randomized trials show an autotransplant is better than new drugs in young persons with plasma cell myeloma. Considerable data indicate much of the efficacy of allotransplants results from a non-cancer-specific allogeneic effect not expected to operate with current immune therapies. Lastly, I discuss a role for donor-derived chimeric antigen receptor (CAR)-T-cells in persons relapsing after an allotransplant for B-cell cancers. The sum of these considerations suggest an ongoing role for haematopoietic cell transplants in diverse settings.
Hematopoietic stem cell transplantation, targeted drugs, immune therapy, (CAR)-T cells, efficiency.
This paper is based on the lecture held at the R. Gorbacheva Memorial Meeting in Hematopoietic Stem Cell Transplantation and Gene Therapy (Sept 19, 2020, St. Petersburg, Russia)
Table 1. Indications for haematopoietic cell transplants in the US 2018 (https://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/index.aspx)
Table 2. Some new drugs for blood and bone marrow cancers
Figure 1. Results of a randomized trial of azacitidine with or without venetoclax in persons with newly diagnosed AML judged inappropriate to receive intensive chemotherapy 
Haematopoietic cell transplants are increasingly done to treat blood and bone marrow cancers, bone marrow failure and genetic disorders. In the US there were about 14,000 autotransplants and 9,000 allotransplants in 2018. Global autotransplants in 2019 were about 28,000 and allotransplants, about 17,000 with a total of about 45,000. These rates are expected to increase. In the US most autotransplants are for plasma cell myeloma (PCM) and non-Hodgkin lymphoma (NHL) whereas most allotransplants are for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Relatively few allotransplants were done for acute lymphoblastic leukaemia (ALL) or myelo-proliferative neoplasms (MPNs; Table 1). This distribution is important as most immune therapies are for cancers not currently treated with haematopoietic cell transplants as I discuss below.
Recent interventions which might compete with haematopoietic cell transplants include new anti-cancer chemotherapy and targeted and immune therapies. Several new drugs used to treat blood and bone marrow cancers are listed in Table 2.
Although progress in developing new drugs is encouraging the magnitude of benefit with several of these drugs is modest. An example of the impact of azacitidine and venetoclax in newly diagnosed persons with AML judged inappropriate to receive intensive chemotherapy is shown in Figure 1. Although adding venetoclax to azacitidine significantly improved survival, 65% of subjects died by 2.5 years.
Table 3 shows the 5-year survivals of persons with AML and PCM treated in 1999-2003, and treated 2010-2016. These data indicate only a modest improvement with about 70 percent of persons with AML and 45 percent of those with PCM dying before 5 years.
Examples of targeted therapies for myeloid cancers, especially AML are shown in Table 4 along with the target gene.
An example of the impact of targeted FLT3 mutation therapy in AML is shown in Fig. 2 . Although adding midostaurin to cytarabine and daunorubicin improves survival, 55 percent of subjects died by 5 years and many survivors also received an allotransplant in 1st remission. These data indicate a modest impact of targeted therapy in AML.
Fig. 3 displays the estimated impact of targeted therapies on survival of persons with acute myeloblastic leukemia (AML) . It seems only about 10 percent of people will benefit.
Table 5. Some examples of immune therapies in blood and bone marrow cancers
Immune therapy is another new therapy of blood and bone marrow cancers. Some examples are displayed in Table 5.
However, these therapies are effective only in B-cell cancers and are lineage- but not cancer-specific (Fig. 4). Other than gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody, there is no proved safe and effective therapy of myeloid cancers.
CAR-T-cells are an important advance in therapy of lymphoid cancers with high response rates. However, often responses are not sustained unless a subsequent allogeneic haematopoietic cell transplant is done. An example of event-free survival (EFS) in children and young adults with advanced ALL is shown in Figure 5 with a failure rate of 40 percent at 1.5 years in complete responders .
Similarly, there are high rates of therapy-failure after successful CAR-T-cell therapy of diffuse large B-cell (DLBCL; Figure 6), follicular (FL) and marginal zone lymphomas (MZL; Fig. 7).  (https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.8008).
The argument CAR-T-cell therapy serves predominately as a bridge to an allotransplant is unconvincing as there are no strong data survival of persons with ALL transplanted in 2nd remission are better than those transplanted in relapse when all subjects are accounted for. Consequently, the best approach to someone responding to CAR-T-cell therapy is controversial. It may be reasonable to consider an allotransplant in persons with ALL and in those with MZL after responding to CAR-T-cell therapy, but wait for therapy failure in those with DLBCL and FL (Fig. 8).
It is also important to recall much of the efficacy of allotransplants results from an allogeneic anti-cancer effect so far difficult to distinguish from graft-versus-host disease (GvHD) . These data are displayed in Fig. 9. For example, whether there is a specific anti-leukaemia effect is controversial, as reviewed in .
Some data suggest the potential use of donor-derived CAR-T-cells in persons relapsing after an allotransplant for B-cell cancers .
Advances in treating ALL, AML, lymphomas and PCM are important and exciting but the magnitude of benefit is modest and few people are cured. Many persons with immune therapy successes go on to receive an allotransplant. Most cancers where immune therapy is effective are B-cell cancers whereas most allotransplants are done for myeloid cancers. Moreover, these immune therapies are lineage-, not cancer-specific and lack the allogeneic anti-cancer effect associated with allotransplants. In young persons with PCM, autotransplants are better than new drugs in randomized clinical trials. CAR-T-cell therapy of B-cell cancers is effective but mostly not a cure. Donor CAR-T-cells are a promising in persons relapsing after an allogeneic haematopoietic cell transplant. Transplants will remain an important therapy in the immediate future. Put in terms of food, although there is nouvelle cuisine Boef Stroganoff remains a classic and my 1st dinner choice at Chekhov restaurant in Petersburg.
Supported by the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. Prof. Elena Parovichnikova and Drs. Kristina Zakurdaeva and Saida Kadyrova provided expert advice on Boef Stroganoff and Dr. Ivan Moiseev and the late Prof. Boris Afanasyev introduced me to Chekhov restaurant. My preference is for Boef Stroganoff with kasha. Bon Appetit.
Conflict of interest
RPG is a consultant to BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Parmaceuticals Inc. and CStone Pharmaceuticals; advisor to Antegene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.
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Accepted 23 October 2020