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Blood and Bone Marrow Transplantation in India: Past, Present, and Future

CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2020; 41(03): 308-311

DOI: DOI: 10.4103/ijmpo.ijmpo_159_20

Author : Tapan K Saikia

Prologue – The Global Scenario

Interest in the field of bone marrow transplantation was kindled in the early 1950s when laboratory and clinical experiments had begun in the US and France, triggered by the injury caused by nuclear warfare, during and post-WWII.[1] Animal and laboratory experiments provided proof of the principle.[2] As many patients with marrow aplasia and advanced leukemia had no curative treatment, clinical transplants were done as experimental procedures; however, due to lack of adequate knowledge in transplantation immunology and inadequate supportive care, most of them died either due to relapse, infection, or severe graft-versus-host disease (GVHD).[1],[3]

It took conviction of Thomas, first at Cooperstown, then at Fred Hutchison Cancer Research Center (FHCRC), Seattle, to pursue the procedure; better understanding of transplantation immunology through the works of many biologists, specially by Peter Medawar and dog experiments at Seattle, helped to find effective conditioning regimens and GVHD prophylaxis and soon led to a series of successful human allogeneic bone marrow transplants in acute leukemia and severe aplastic anemia.[4] By the late 1970s and early 1980s, the field exploded with many centers performing the procedure across the world.[5] In subsequent years, the indications expanded with autologous transplants for chemosensitive diseases such as lymphomas, myeloma, and some childhood tumors; dearth of matched sibling donors made it necessary to explore matched unrelated donors (MUDs) and umbilical cord blood as sources of hematopoietic stem cells.[6],[7] In recent years, the use of haploidentical transplants has shown exponential increment.

Publication History

Received: 15 April 2020
Accepted: 14 May 2020
Article published online:
28 June 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

Prologue – The Global Scenario

Interest in the field of bone marrow transplantation was kindled in the early 1950s when laboratory and clinical experiments had begun in the US and France, triggered by the injury caused by nuclear warfare, during and post-WWII.[1] Animal and laboratory experiments provided proof of the principle.[2] As many patients with marrow aplasia and advanced leukemia had no curative treatment, clinical transplants were done as experimental procedures; however, due to lack of adequate knowledge in transplantation immunology and inadequate supportive care, most of them died either due to relapse, infection, or severe graft-versus-host disease (GVHD).[1],[3]

It took conviction of Thomas, first at Cooperstown, then at Fred Hutchison Cancer Research Center (FHCRC), Seattle, to pursue the procedure; better understanding of transplantation immunology through the works of many biologists, specially by Peter Medawar and dog experiments at Seattle, helped to find effective conditioning regimens and GVHD prophylaxis and soon led to a series of successful human allogeneic bone marrow transplants in acute leukemia and severe aplastic anemia.[4] By the late 1970s and early 1980s, the field exploded with many centers performing the procedure across the world.[5] In subsequent years, the indications expanded with autologous transplants for chemosensitive diseases such as lymphomas, myeloma, and some childhood tumors; dearth of matched sibling donors made it necessary to explore matched unrelated donors (MUDs) and umbilical cord blood as sources of hematopoietic stem cells.[6],[7] In recent years, the use of haploidentical transplants has shown exponential increment.

Bone Marrow and Blood Stem Cell Transplantation in India

The past (1983–1999)

Keeping in view the international progress and its urgent need in the country, Tata Memorial Centre/Tata Memorial Hospital (TMH) took the lead by sending two young medical oncologists, Dr. S. H. Advani and Dr. R. Gopal in 1981–1982 to FHCRC for training. In March 1983, the first allogeneic bone marrow transplant (BMT) was carried out in a 9-year-old girl with acute myeloid leukemia (AML) in CR1, the donor being a serologically 6/6 antigen-matched younger brother.[8] It was a successful transplant – the recipient survived 22 years without a relapse (GVHD and relapse free), but unfortunately succumbed to uncontrolled diabetes mellitus and tuberculosis. This sad outcome emphasizes the need for awareness, identification, and effective management of long-term complications of the procedure. CMCH, Vellore, soon followed a team ably led by Dr. Mammen Chandy; the hospital began allogeneic BMT in 1986 and in a decade became a center of repute, particularly in the area of thalassemia major and aplastic anemia.[9],[10],[11] The Medical Oncology Department at IRCH/AIIMS, New Delhi, led by Dr. Vinod Kochupillai, was the third center to initiate the procedure. It took nearly two decades for the establishment of a few more centers across the country, Indian Stem Cell Transplant Registry/Indian Society for Blood and Marrow Transplantation (ISCTR/ISBMT).

The CMCH team explored the pros and cons of the commonly used BuCy regimens, investigating laboratory parameters of cyclophosphamide and oral busulfan and also clinical toxicities of rejection and hepatotoxicity. Subsequently, they were able to identify a subgroup of very high-risk Stage 3 thalassemia patients.[10] Inclusion of treosulfan in the conditioning regimen appears to have improved outcome in these patients.[12] The TMH team focused on chronic myeloid leukemia until advent of imatinib;[13] we even explored the feasibility of reduced intensity transplants.[14]

An oft-repeated question is, why it took so long for India to expand its transplant program? There are many factors in initial days: (i) lack of trained transplant physicians, (ii) financial, a general hurdle in the field of health care in the country, (iii) lack of support from government agencies, and (iv) private sector health care expanded only toward the later part of last century. Government support is crucial – for countries such as South Korea, Iran, Saudi Arabia, Taiwan, and China; such support played a significant role. Even here, CMCH could develop the program to a higher level after a proposal was approved by the Indian Council of Medical Research.

The present (2000–2020)

The premier institutes mentioned above and a few more in the country were able to train sufficient number of young physicians in the field of BMT/stem cell transplantation (SCT) who went on to start programs in both government and private hospitals, with significant opportunities in the private sector (ISCTR/ISBMT data, personal communication, unpublished). Currently, 97 transplant centers are reporting to the ISBMT (Registry). Only a few have not joined the registry yet. The most recent report from the registry show approximately 19,000 transplants reported as activity data in various indications: allogeneic transplants being preferred by major centers. The main indications are thalassemia major, severe aplastic anemia, acute myeloid leukemia, and acute lymphoblastic leukemia (ALL). In the area of autologous, main indications are multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma in adults, and neuroblastoma in children. As family size has shrunken in India too, demand for MUD increased and currently a number of centers are recognized by the National Marrow Donor Program, DKMS (Deutsche KnochenMarkSpenderdatei or German Bone Marrow Donor File), and others. The DATRI registry is doing an excellent job of finding Indian donors. In addition, the Marrow Donor Registry India, based in Mumbai, is an active registry. However, such donor search is time-consuming, costly, and at times donor attrition leads to heartbreaks. Such events can lead to legal issues. The safety and success of posttransplant cyclophosphamide (PTCy), pioneered by the Johns Hopkins group, has opened up the field of haploidentical transplants for Indian patients. Anyone in the family could be a potential donor.

Repurposing drugs, with a sound rationale, is an important endeavor in treating an autoimmune condition like chronic GVHD. TMH group has taken a lead in this regard by showing effectiveness of leflunomide in certain subsets of patients.[15]

A few words on pediatric population in India who are candidates for BMT will not be out of place; in fact, it needs a special mention. Majority of thalassemia patients are young, usually, below 10 years of age; the number is massive who needs an allogeneic transplants until we find an alternative methods of effective management. The wait list is long in major centers. In recent years, a set of pediatric transplant physicians have taken the onus of looking after these children – a laudable sign. In addition, these physicians along with the nursing team are equipped to perform transplants for immune deficiency diseases.[16] Transplanted children need special care – before, during the procedure, and certainly long-term follow-up. They need a guided rehabilitation program.

The future (2020 to eternity)

It is never easy to see a future – look what happened to Vision 2020! Nonetheless, we notice that the hematopoietic stem cell transplantation (HSCT) activities are peaking in the country. We expect there will be more number of centers becoming active. One region where HSCT has not been initiated yet is North-East India. Patients need to travel outside or continue with nontransplant options within these states. There is little doubt about further expansion of haploidentical transplant program, thus reducing the MUD and umbilical cord transplant numbers. It is difficult to be sure if it is a good direction, but logistic constraints have led to this situation. A word of caution about haploidentical transplants – as a similar strategy utilizing PTCy is being explored in matched sibling donor transplants as well, there is a reduction in GVHD but definitely at the cost of increased risk of opportunistic infections, most noticeably, cytomegalovirus reactivation and possibility of increased relapse.[16] Recent laboratory data point toward multifunctional effects of PTCy on the prevention of alloreactive T cells dysfunction and suppression.[17] Well-designed randomized trials will provide answers.

Application of tyrosine kinase inhibitors (TKIs) and other novel targeted agents is beginning to bring changes in transplant approach.[18] Assessment of measurable minimal residual disease (MRD) has become widely used in ALL, AML, multiple myeloma, and chronic lymphocytic leukemia. MRD negativity following standard therapy appears to be a prerequisite for a better outcome. Hence, use of novel bispecific T cell engager monoclonal antibody like blinatumomab is being increasingly used for achieving MRD negativity before transplantation for B cell ALL.[19] Chimeric antigen receptor (CAR) T cells are helping to treat high-risk or relapsed ALL, thus acting as a bridge, enabling more cases to undergo allogeneic transplants.[20] These modalities are not yet available in the country, but as we have always noted, with passage of time, facilities become available.

Many attempts are being made to improve transplant outcomes in AML. FLT3-positive patients receive upfront FLT 3 inhibitors and continue maintenance.[21] Similarly, hypomethylating agents are being incorporated to maintenance therapy.[22]

In the autologous transplant front, despite advent of novel agents, eligible myeloma cases appear to derive benefit from high-dose melphalan; however, wider applicability of newer monoclonal antibodies and and CAR-T cell therapy might change the algorithm. The practical challenge here will be the unrealistic cost of novel drugs. Following the wider use of rituximab in aggressive lymphomas, outcome of autologous SCT has fallen significantly. These cases are highly chemoresistant, even to myeloablative doses. Recently approved CAR-T cell therapy seems to be highly efficacious, both from response and durability of response point of view.[23],[24] Nevertheless, more recent data presented at the transcatheter cardiovascular therapeutics (TCT) 2020 meeting emphasized that CAR-T responses were not durable, thus raising further challenges in managing poor-risk and relapsed/refractory lymphomas.

Will HSCT become redundant one day? A very difficult question to answer in 2020. Nevertheless, as we continue to notice beneficial role of allogeneic transplants for TKI resistant CML, added benefit of high-dose melphalan in multiple myeloma, and its curative role in relapsed ALL following blinatumomab or CAR-T cell therapy, there is no imminent possibility of HSCT becoming a forgotten modality. Regardless, one wishes that a treatment modality that causes a number of uncalled for iatrogenic conditions becomes redundant one day – time will tell.

Epilogue

As I mentioned, prediction is hazardous; while working on this editorial with procrastination, the pandemic of COVID-19 has appeared and brought the world down. The arena of HSCT has gone for a scramble. Transplant community has been compelled to make many an urgent changes – deferring collection of stem cells, postponing new cases to be admitted unless very high-risk ones, facing serious delay in transportation of MUD cells, not to mention the extra burden of testing cases for possible infections, and finding ways to manage when there are no specific medicines to treat.[25] The economic hardship for patients and health-care institutions and risk of primary disease progression will be realized only in coming days. Prayers are in plenty, in the meanwhile. So much for predictions! But the human resilience and skill shall overcome this hurdle too. A new order will emerge from the ongoing calamity.

Conflict of Interest

There are no conflicts of interest.

References

  1. de la Morena MT, Gatti RA. A history of bone marrow transplantation. Hematol Oncol Clin North Am 2011; 25: 1-5
  2. Barnes DW, Corp MJ, Loutit JF, Neal FE. Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. Br Med J 1956; 2: 626-7
  3. Thomas ED, Lochte HLJr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med 1957; 257: 491-6
  4. Thomas ED. A history of haemopoietic cell transplantation. Br J Haematol 1999; 105: 330-9
  5. Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med 2007; 357: 1472-5
  6. Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood 2012; 119: 3908-16
  7. Gluckman E, Ruggeri A, Volt F, Cunha R, Boudjedir K, Rocha V. Milestones in umbilical cord blood transplantation. Br J Haematol 2011; 154: 441-7
  8. Advani SH, Saikia TK. Bone marrow transplant in India. Bone Marrow Transplant ation 1994; 13: 731-2
  9. Chandy M. Innovative supportive care practices for stem cell transplantation in India. Biol Blood Marrow Transplant 2009; 15: 95-8
  10. Mathews V, Srivastava A, Chandy M. Allogeneic stem cell transplantation in thalassemia major. Hematol Oncol N Am 2014; 28: 1187-2000
  11. George B, Mathews V, Melinkeri S, Lakshmi KM, Sharma A, Viswabandya A. et al. The use of a fludarabine-based conditioning regimen in patients with severe aplastic anemia-a retrospective analysis from three Indian centers. Clin Transplant 2013; 27: 923-9
  12. Mathews V, George B, Viswabandya A, Abraham A, Ahmed R, Ganapule A. et al Improved clinical outcomes of high risk B thalassemia major patients undergoing a HLA matched related alloegeneic stem cell transplant with s treosulfan based conditioning regimen and peripheral blood stem cell grafts. PLoS One 2013; 8: e61637
  13. Saikia TK, Parikh PM, Tawde S, Amare-Kadam PS, Rajadhyaksha S, Chhaya S. Allogeneic blood stem cell transplantation in chronic myeloid leukaemia-chronic phase following conditioning with busulphan and cyclophosphamide: A follow up report. Natl Med J India 2004; 17: 71-3
  14. Das M, Saikia TK, Advani SH, Parikh PM, Tawde S. Use of a reduced-intensity conditioning regimen for allogeneic transplantation in patients with chronic myeloid leukemia. Bone Marrow Transplant 2003; 32: 125-9
  15. Punatar S, Mohite A, Gokarn A, Nayak L, Bonda A, Shanmugam K. et al. Leflunomide for chronic musculoskeletal graft versus host disease following allogeneic hematopoietic stem cell transplant. Bone Marrow Transplant 2020; 55: 467-9
  16. Yadav SP. Bone marrow transplantation for primary immune deficiency disorders in India: Past, Present and Future. Indian Pediatr 2018; 55: 657-8
  17. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M. et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose posttransplant cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641-650
  18. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, Kanakry CG. Posttransplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest 2019; 129: 2357-73
  19. Radich J. Stem cell transplant for chronic myeloid leukemia in the imatinib era. Semin Hematol 2010; 47: 354-61
  20. Gokbuget N, Dombert H, Bonifacio M, Reichle A, Graux C, Faul C. et al. Blinatumomab for MRD in adults with B-cell precursor acute lymphoblastic leukemia. Blood 2018; 131: 1522-31
  21. Jacoby E. The role of allogeneic HSCT after CAR T cells for acute lymphoblastic leukemia. Bone Marrow Transplant 2019; 54: 810-4
  22. Bazarbachi AH, Al HamedR, Malard F, Mohty M, Bazarbachi A. Allogeneic transplant for FLT3 ITD mutated AML: A focus on FLT3 inhibitors before, during, and after transplant. Ther Adv Hematol 2019; 10: 2040620719882666
  23. Schroeder T, Rautenberg C, Haas R, Germing U, Kobbe G. Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation. Int J Hematol 2018; 107: 138-50
  24. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017; 377: 2531-44
  25. Szer J, Weisdorf D, Querol S, Foeken L, Madrigal A. The impact of COVID-19 on the provision of donor hematopoietic stem cell products worldwide: Collateral damage. Bone Marrow Transplant 2020; 23: 1-2 DOI: 10.1038/s41409-020-0873-x. Online ahead of print

Address for correspondence

Dr. Tapan K Saikia
Prince Aly Khan Hospital
Mumbai, Maharashtra
India   

Publication History

Received: 15 April 2020
Accepted: 14 May 2020
Article published online:
28 June 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

References

  1. de la Morena MT, Gatti RA. A history of bone marrow transplantation. Hematol Oncol Clin North Am 2011; 25: 1-5
  2. Barnes DW, Corp MJ, Loutit JF, Neal FE. Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. Br Med J 1956; 2: 626-7
  3. Thomas ED, Lochte HLJr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med 1957; 257: 491-6
  4. Thomas ED. A history of haemopoietic cell transplantation. Br J Haematol 1999; 105: 330-9
  5. Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med 2007; 357: 1472-5
  6. Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood 2012; 119: 3908-16
  7. Gluckman E, Ruggeri A, Volt F, Cunha R, Boudjedir K, Rocha V. Milestones in umbilical cord blood transplantation. Br J Haematol 2011; 154: 441-7
  8. Advani SH, Saikia TK. Bone marrow transplant in India. Bone Marrow Transplant ation 1994; 13: 731-2
  9. Chandy M. Innovative supportive care practices for stem cell transplantation in India. Biol Blood Marrow Transplant 2009; 15: 95-8
  10. Mathews V, Srivastava A, Chandy M. Allogeneic stem cell transplantation in thalassemia major. Hematol Oncol N Am 2014; 28: 1187-2000
  11. George B, Mathews V, Melinkeri S, Lakshmi KM, Sharma A, Viswabandya A. et al. The use of a fludarabine-based conditioning regimen in patients with severe aplastic anemia-a retrospective analysis from three Indian centers. Clin Transplant 2013; 27: 923-9
  12. Mathews V, George B, Viswabandya A, Abraham A, Ahmed R, Ganapule A. et al Improved clinical outcomes of high risk B thalassemia major patients undergoing a HLA matched related alloegeneic stem cell transplant with s treosulfan based conditioning regimen and peripheral blood stem cell grafts. PLoS One 2013; 8: e61637
  13. Saikia TK, Parikh PM, Tawde S, Amare-Kadam PS, Rajadhyaksha S, Chhaya S. Allogeneic blood stem cell transplantation in chronic myeloid leukaemia-chronic phase following conditioning with busulphan and cyclophosphamide: A follow up report. Natl Med J India 2004; 17: 71-3
  14. Das M, Saikia TK, Advani SH, Parikh PM, Tawde S. Use of a reduced-intensity conditioning regimen for allogeneic transplantation in patients with chronic myeloid leukemia. Bone Marrow Transplant 2003; 32: 125-9
  15. Punatar S, Mohite A, Gokarn A, Nayak L, Bonda A, Shanmugam K. et al. Leflunomide for chronic musculoskeletal graft versus host disease following allogeneic hematopoietic stem cell transplant. Bone Marrow Transplant 2020; 55: 467-9
  16. Yadav SP. Bone marrow transplantation for primary immune deficiency disorders in India: Past, Present and Future. Indian Pediatr 2018; 55: 657-8
  17. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M. et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose posttransplant cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641-650
  18. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, Kanakry CG. Posttransplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest 2019; 129: 2357-73
  19. Radich J. Stem cell transplant for chronic myeloid leukemia in the imatinib era. Semin Hematol 2010; 47: 354-61
  20. Gokbuget N, Dombert H, Bonifacio M, Reichle A, Graux C, Faul C. et al. Blinatumomab for MRD in adults with B-cell precursor acute lymphoblastic leukemia. Blood 2018; 131: 1522-31
  21. Jacoby E. The role of allogeneic HSCT after CAR T cells for acute lymphoblastic leukemia. Bone Marrow Transplant 2019; 54: 810-4
  22. Bazarbachi AH, Al HamedR, Malard F, Mohty M, Bazarbachi A. Allogeneic transplant for FLT3 ITD mutated AML: A focus on FLT3 inhibitors before, during, and after transplant. Ther Adv Hematol 2019; 10: 2040620719882666
  23. Schroeder T, Rautenberg C, Haas R, Germing U, Kobbe G. Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation. Int J Hematol 2018; 107: 138-50
  24. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017; 377: 2531-44
  25. Szer J, Weisdorf D, Querol S, Foeken L, Madrigal A. The impact of COVID-19 on the provision of donor hematopoietic stem cell products worldwide: Collateral damage. Bone Marrow Transplant 2020; 23: 1-2 DOI: 10.1038/s41409-020-0873-x. Online ahead of print

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