|Year : 2015 | Volume
| Issue : 3 | Page : 115-117
Preparing for a “Haplo” Tsunami in India
Professor of Medicine, Section of Stem Cell Transplant and Leukemia, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA
|Date of Web Publication||30-Sep-2015|
Professor of Medicine, Section of Stem Cell Transplant and Leukemia, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO
Source of Support: Nil., Conflict of Interest: There are no conflicts of interest.
|How to cite this article:|
Vij R. Preparing for a “Haplo” Tsunami in India. MAMC J Med Sci 2015;1:115-7
| The Rise of Allogeneic Stem Cell Transplantation|| |
The field of allogeneic stem cell transplantation (ASCT) has come a long way since the first successful ASCT performed in the late 1960s. It is now estimated that more than 50,000 ASCT are performed worldwide each year with the rate of growth in the number of transplants increasing yearly. ASCT provides a curative option for individuals with a variety of hematologic malignancies and nonmalignant hematopoietic disorders including, thalassemia and aplastic anemia, where cure rates now approach in excess of 80%.
The growth in ASCT has been driven by a variety of factors. These include successive advances in the fields of transplantation immunology to reduce risks for graft rejection and graft-versus-host disease (GVHD) and supportive care to reduce infections and other causes of treatment-related mortality. Also, starting in the 1990s, an increasing use of reduced intensity conditioning regimen shifted focus from toxic strategies seeking to establish myeloablation to a focus on harnessing the power of the immune system to eradicate the neoplastic cells. This permitted the advantages of this modality of therapy to be extended to individuals deemed too old and frail to undergo allogeneic transplantation in the past.
One of the major impediments to the growth of stem cell transplants worldwide has been the lack of suitable donors for individuals in need of the procedure. Only about a third of patients who require ASCT have a human leukocyte antigen (HLA)-matched sibling donor available. In the developed world, the establishment of donor registries has allowed for an appropriate matched unrelated donor (MUD) to be identified for a majority of the Caucasian population who lack a matched related donor (MRD). The National Marrow Donor Program (NMDP) established in 1986 and its cooperative international registries have over 16 million volunteer donors. In the last decade, the results of matched MRD and MUD grafts with HLA allelic identity at the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci (8/8 matched) have grown more similar. However, for ethnic groups other than Caucasians, the lack of suitable donor has been a barrier to the availability of a curative allogeneic procedure for a majority of patients as they are poorly represented in the volunteer donor pool. This has driven the quest to identify alternative donor sources.
One such alternative donor source is cord blood. Since the first cord blood transplant (CBT) was performed in 1989, cord blood transplantation as a field grew rapidly and by 2011 more than 25,000 CBTs had been performed worldwide. CBT has potential advantages including ease of collection, prompt availability, less stringency for HLA-matching, and a relatively low risk of GVHD. However, in the adult population, the utility of CBT has been somewhat limited by the number of stem cells available in the graft. Despite the use of dual cord blood transplants and attempts at ex vivo expansion of stem cell progenitors, a higher risk for graft failure, opportunistic infections and lack of option for obtaining additional hematopoietic stem and immune cells for those requiring additional donor cells for adoptive therapy post-transplant has been a major drawback to use CBT in adults.
More recently, the increasing success of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has opened the possibility of becoming an alternative donor source with the potential to benefit thousands of individuals who have lacked availability of a suitable donor. Haploidentical donors-parents, siblings, and half matched siblings are available for over 95% of individuals needing a stem cell transplant. What lies behind this development that has the potential to open the floodgates of allogeneic transplantation in developing countries like India?
| The Rise of Haplo-Hematopoietic Stem Cell Transplantation|| |
The first successful haplo-HSCT was reported in 1981. For successful haplo-HSCT, the immune cells in the patient and infused graft have to be manipulated to prevent graft failure and GVHD. In light of the evidence that T-cells are responsible for causing GVHD, initially attempts were made to improve the results of haplo-HSCT by removing T-cells from the donor graft. The early strategies to achieve the required immune-suppression were based on utilizing ex vivo T-cell-depleted grafts but this resulted in high rates of graft failure. To overcome the problem of graft failure, in the 1990s, investigators in Perugia, Italy, pioneered transplants utilizing infusion of a "megadose" of stem cells highly depleted of T-cell ex vivo after myeloablative chemotherapy. Though this seemed to overcome the problem of graft failure to a large extent, it was associated with a high rate of fatal infections. Also, ex vivo T-cell depletion is expensive and requires investment in magnetic selection devices and special facilities for ex vivo manipulation of the stem cell product. This initial investment cost and expertise to run such facilities is often a constraint on the adoption of this technology for the developing world.
More recently, investigators have met with success in utilizing T-cell replete grafts and in vivo T-cell depletion, which is much more economical and amenable to widespread adoption. Chinese researchers at Peking University chose to intensify the chemotherapy regimen/immunosuppression and prime the stem cell graft with granulocyte-colony stimulating factor and achieved a measure of success with this strategy. However, it was the use of T-cell replete bone marrow grafts using reduced intensity chemotherapy regimen coupled with post stem cell transplantation (SCT) cyclophosphamide (Cy) pioneered by the group at John Hopkins in Maryland, USA that has now led to a dramatic increase in the number of haplo-HSCTs being performed. This approach is based on the ability of post-transplant Cy at the correct time following infusion of haploidentical cells to eliminate highly active and proliferative T-cells responsible for severe GVHD and graft rejection while sparing quiescent memory T-cells responsible for immunity to infections. Stem cells in the graft contain high levels of aldehyde dehydrogenase, which makes them resistant to the effects of Cy. Though still plagued with relatively high rates of disease relapse, the rates of serious GVHD with this regimen have been low. Now investigators are attempting to reduce the risk of disease relapse by utilizing a variety of strategies. Bashey and Solomon have reported on using a myeloablative chemotherapy regimen and our group at Washington University has been studying the use of stem cells obtained from peripheral blood in place of bone marrow in this regard.,
To date, there have been no prospective randomized comparisons of haplo-HSCT with post-transplant Cy. However, recently, several retrospective studies have been reported which seem to suggest similar intermediate-term outcomes when haplo-HSCT is compared with MRD and unrelated donor (URD) transplants. If the results of these studies are confirmed, it is possible that the role of MUD transplants in patients who lack a MRD may even be questioned, especially since a haplo-donor can be identified much quicker than a URD, thereby reducing the risk for disease relapse in case of aggressive hematopoietic malignancies where a shorter time to transplant is often the difference between life and death.
| The Potential for a Haplo-Hematopoietic Stem Cell Transplantation Tsunami to Hit Indian Shores|| |
With a population of over 1.2 billion people, India has over 1,00,000 cases of leukemia and lymphoma, 10,000 children born with thalassemia major each year, and 6000 cases of aplastic anemia diagnosed each year. India's first successful ASCT was done at Tata Memorial Hospital, Mumbai in 1983. A publication from the Christian Medical College, Vellore, reported that by 2005 data on only 881 patients who had undergone ASCT at six transplant centers in India had been collected.
Now, India has a rising middle class, and the median cost of allogeneic transplantation in India has been reported to be <$20,000. This compares to a cost of $2,00,000 or more for an allogeneic transplant in the United States (US, with charges often exceeding $1 million/transplant). The number of centers performing SCTs in India is increasing. However, a major impediment to SCT in India has been the lack of a suitable stem cell donor. With <30% of patients having an HLA-matched sibling donor and few volunteer donors in Indian registries, the majority of patients in need of SCT in India have been unable to get this life-saving procedure.
However, now with nearly every individual in need of ASCT having a haploidentical parent, sibling or child as a potential stem cell donor, haplo-HSCT is set to boom in India. Already several centers in India have started performing haplo-HSCT.,
| Need for Safeguards|| |
In the US, Canada, Europe, and Australia, the Foundation for the Accreditation of Cellular Therapy (FACT) founded in 1996, has played a pivotal role in establishing standards for high quality medical and laboratory practice in cellular therapies. FACT is a nonprofit corporation co-founded by the International Society for Cellular Therapy and the American Society of Blood and Marrow Transplantation for the purposes of voluntary inspection and accreditation in the field of cellular therapy. It is based in the University of Nebraska. This voluntary accreditation program is founded upon a network of peers helping each other to improve cellular therapy practices. Rigorous and comprehensive inspections are balanced with a collegial approach that encourages organizations to reach minimum standards for the benefit of patients. Inspectors are volunteers, who are international experts in their field with current and practical knowledge of the intent of the requirements. Multiple levels of review and oversight ensure accreditation is awarded consistently, thoroughly, and objectively based upon the international standards. No center in India is currently FACT accredited, and it lacks such an indigenous authority with oversight over transplant facilities.
In addition, the Center for International Blood and Marrow Transplant Research ® (CIBMTR) operates the Stem Cell Therapeutic Outcomes Database. The CIBMTR was created in 2004 as a partnership between the International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry of the Medical College of Wisconsin and the research arm of the NMDP ®. These organizations have more than 30 years of experience in collecting, managing, and analyzing data about bone marrow and umbilical cord blood transplantation. The CIBMTR collects data on every allogeneic transplant performed in the US (as required by US law). US transplant centers also voluntarily submit autologous transplantation data, and transplant centers worldwide voluntarily provide both autologous and allogeneic transplantation data. As a result, their clinical database now contains information on more than 3,30,000 transplant recipients. Every year, a variety of resources are developed from CIBMTR data, including publications, slide sets, and web resources. Investigators, physicians, patients, and others interested in hematopoietic cell transplantation can access outcomes data. The data are available on a public portal and is used by insurance companies and patients to make decisions about their care. Only a handful of transplant centers in India currently submit their data to the CIBMTR.
With haplo-HSCT likely to propel the number of ASCT in India, it is important that Indian institutions too sign up to institutions such as FACT and CIBMTR or develop its own quality assurance mechanisms to ensure an orderly and ethical growth of this technology that has the potential to benefit thousands of individuals. Certainly, there are both monitory and time constraints that pose a challenge to setting up and ensuring compliance with such a regulatory framework. However, with world-class institutions in India already holding Joint Commission International Accreditation, this is certainly achievable.
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Conflicts of interest
There are no conflicts of interest.
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