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.
