When matched family donor is not available for blood and marrow transplantation-the Indian dilemma

Apollo Medicine 2012 MarchReview Article

Volume 9, Number 1; pp. 62–67

© 2012, Indraprastha Medical Corporation Ltd

When matched family donor is not available for blood and marrow transplantation—the Indian dilemma

Suparno Chakrabarti**Program Director, Department of Blood and Marrow Transplantation, Apollo Gleneagles Cancer Hospital, Kolkata, West Bengal, India.

ABSTRACT

Only 20–30% of patients requiring a blood and marrow transplantation (BMT) have a matched family donor. For the rest, alternative sources of graft are necessary to provide this curative procedure. Over the past 25 years, BMT from volunteer unrelated donors has undergone immense developments to be at par with matched family donor trans-plants. Similar developments have been witnessed in the field of unrelated cord blood transplantation. Thus, 90% of patients requiring a BMT in the developed worlds receive one from either of the two alternative graft sources. However, >11 million volunteer unrelated donors and 25,000 cord blood units worldwide do not solve the problem for patients from developing countries, due to lack of compatible human leukocyte antigen (HLA) match and enormous financial burden. Thus, Asian countries such as China and Korea have developed Haploidentical or mismatched family donor transplantation for their population with great success. In the light of these developments, this article discusses the options and opportunities for alternative donor BMT in the Indian scenario.

Keywords: Alternative donor, blood and marrow transplantation, cord blood, haploidentical

Correspondence: Dr. Suparno Chakrabarti, E-mail: supchak@gmail.comdoi: 10.1016/S0976-0016(12)60126-4

INTRODUCTION

Allogeneic blood and marrow transplantation (Allo-BMT), which employs the use of hematopoietic progenitor cells (HPCs) from a donor to replace the diseased or defective hematopoietic as well as the immune system, has evolved radically over the past three decades. The indications for Allo-BMT are no longer limited to end-stage leukemias. This is deemed curative, and often the only option for many nonmalignant conditions as well. These advances have been possible through better understanding and management of post transplant complications, both infectious and nonin-fectious. The key to this success is perhaps related to the optimum selection of donors for Allo-BMT.

Human leukocyte antigen (HLA) system is pivotal to the outcome of Allo-BMT unlike solid organ transplanta-tion. In an elegant set of canine experiments which led to the successful inception of clinical Allo-BMT, Thomas et al demonstrated the importance of match in the HLA system between the donor and the recipient to achieve engraftment as well as reduce the incidence of graft-versus-host disease (GVHD).1 Human leukocyte antigen-matched family member was and still is considered the donor of choice for Allo-BMT

for all indications; a paradigm which remains unchanged despite tremendous advancements in this field.

Based on Mendelian laws of inheritance, the chances of siblings being matched to eachother at class I and II HLA locus are only 20–30%. Thus, 70–80% of patients eligible for an Allo-BMT would be unlikely to find a donor within the family. Consanguinity between parents increases the chances of finding an HLA match within the family and even with parents. Thus, certain communities with a high incidence of consanguineous marriage are likely to have a higher fre-quency of certain common haplotypes, and thus a greater likelihood of finding a match within the family. Nevertheless, the large majority of patients does not find a matched fam-ily donor and are candidates for an alternative donor BMT.

UNRELATED DONORS AS A SOURCE OF

CELLS FOR ALLOGENEIC BLOOD AND

MARROW TRANSPLANTATION

The options for alternative donor were limited by the initial studies demonstrating the primacy of HLA matching in

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dictating the outcome of BMT. The chances of finding an HLA match within the extended family are remote and even more so from an unrelated donor. However, in 1973, ran-dom searches through Blood Bank Database in Denmark led to the identification of an HLA-matched donor for a patient in the USA with immunodeficiency.

In 1979, Laura Graves, a patient with leukemia, was referred to the Fred Hutchinson Cancer Center. Laura did not have a matched donor in her family, so center staff searched through their database of platelet donors in an attempt to find a match. Luckily, one of the laboratory staff turned out to be a good match. Laura’s transplant was suc-cessful, and she did not develop GVHD. Although, Laura died 2 years later of recurrent leukemia, the Graves family continued to lead an effort to establish a national registry of people volunteering to be bone marrow donors.1 The National Bone Marrow Donor Registry was federally funded in 1986, and in 1987 the first donor match was made. In 1988, the name was changed to the National Marrow Donor Registry (NMDP). The NMDP now includes a network of donor registries in 30 countries. Its database contains >5.5 million donors and facilitates an average of 200 transplants each month. Several such registries are operational in all developed countries accounting for over 10 million donors worldwide.2,3

Outcome of Unrelated Donor Blood and

Marrow Transplantation

At the inception, unrelated cord blood and marrow trans-plantation (UDBMT) was an extremely high-risk procedure with a transplant-related mortality (TRM) of nearly 50%.3–5 The major causes of mortality were GVHD and infections. Large registry-based studies demonstrated the adverse impact of even single allele mismatch at HLA A, B, C, or DRB1 on the outcome of UDBMT.6 This is more apparent in early stage disease and the adverse impact was balanced by a more pronounced graft versus leukemia (GVL) effect in advanced leukemia.

With improvement in supportive care and advancing knowledge in GVHD and post transplant infections, TRM has reduced from 30% to < 10% in HLA-matched sibling trans-plants. The same is reflected in UDBMT as well with TRM being reduced to < 30%. In the latter, this is largely attributable to improved HLA typing resulting in more perfect match.3–5

The source of HPC is furthermore no longer limited to bone marrow. The use of growth factor mobilized periph-eral blood HPC (PBHPC) contributes to the majority of transplants in 2011. In the past 3 years, 50% of all BMT undertaken worldwide employed the latter as the source of

unrelated grafts. Donor as well as recipient issues have been instrumental in this shift in the source of grafts, both related and unrelated. Peripheral blood HPC donation does not involve general anesthesia as in bone marrow harvest and rarely requires hospitalization. There was an initial concern and ethical dilemma regarding the use of hematopoietic growth factors in unrelated donors. However, cumulative experience in related donors was reassuring enough to initiate the use of mobilized PBHPC from unrelated donors. As regards the recipient, engraftment is definitely more rapid with PBHPC with probably a superior outcome in advanced leukemia.3

Several observational studies over the last decade showed near equivalent outcome for both related and unre-lated donors.7 This has resulted in a paradigm shift in the position of UDBMT in the treatment algorithm for hemato-logical malignancies. From being the final resort for patients with advanced leukemia with no related donor to the treat-ment of choice for early stage diseases, both malignant and nonmalignant, UDBMT has come a long way since the bat-tle launched by Laura Greaves.3–5

Unrelated Cord Blood Transplantation

A decade after the first UDBMT, Gluckman and Broxmeyer carried out the first successful related cord blood transplan-tation (CBT) in a patient with Fanconi’s anemia. This was a result of several years of research establishing the survival and repopulating potential of cord blood both fresh and fro-zen. It was established subsequently that compared with bone marrow, one log less mononuclear cells are sufficient for engraftment in CBT.8

While cord blood provided a unique source of HPC, engraftment was uniformly delayed for neutrophils and more so for platelets. On the other hand, the incidence and severity of GVHD seemed to be low in HLA-matched-related transplants, compared with bone marrow (BM) grafts.8 This brought forward an opportunity for an alterna-tive source of HPC for those lacking a matched-related or -unrelated donors.

In two large registry-based studies from Eurocord and NMDP,8–10 mismatched unrelated cord blood transplanta-tion (UCBT) was shown to be associated with delayed engraftment and a higher TRM without any increase in acute or chronic GVHD, compared with UDBMT in chil-dren. Despite a higher TRM, the disease-free survival (DFS) and overall survival (OS) were comparable, which was attributable to lower rate of relapse among UCBT recipi-ents. Since then, several studies have confirmed these find-ings, both in children and in adults. However, the major

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limitation of UCBT in adults has been the cell dose. With a minimum target cell dose of 3 × 107/Kg, only a minority of adults are likely to find a suitably matched unit. Wagner and colleagues from Minnesota came up with an innovative solution by combining two cord blood unit (CBUs) which are matched to the patient and each other at four of six HLA loci. Over 90% patients engrafted with this approach.11 More GVHD was noted. Interestingly enough, the risk of relapse was significantly less with double UCBT compared with transplant with single CBU.12

Since the first CBT, > 20,000 CBTs have been reported worldwide and > 400,000 CBUs have been stored in > 100 cord blood banks (Source: Bone Marrow Donors Worldwide [BMDW], January 2009). The main practical advantages of using cord blood as an alternative source of stem cells are the relative ease of procurement, the absence of risks for mothers and donors, the reduced likelihood of transmitting infections, particularly cytomegalovirus, and the ability to store fully tested and HLA-typed transplants in the frozen state, available for immediate use.8

The Donor Who is Always There—the

Haploidentical Family Donor

Based on Mendelian laws of inheritance, HLA alleles are inherited as haplotypes from each parent. Thus, parents are matched at least one haplotype with the patient. In addition, 90% of the siblings are expected to be matched at one hap-lotypes. Initial attempts at transplantation with haploidenti-cal donors within the family were met with universal failure as a result of very high incidence of graft rejection or severe GVHD. With the developments in UDBMT and UCBT, this donor source was ignored completely in the mainstream of Allo-BMT.

A group of researchers led by Martelli and Reisner pro-posed a modality of haploidentical BMT wherein infusion of very high-dose of CD34+ cells depleted of T-cells would be infused following intensive myeloablative as well as immunoablative conditioning. It would take several years to optimize the procedure and in its final form, CD34+ cells would be purified using immunomagnetic methods for posi-tive selection and the final product would contain < 2 × 104/Kg T-cells and >10 × 106/Kg CD34+ cells. Initially, only patients with high-risk acute leukemia were treated. All 43 patients achieved full donor chimerism without any GVHD. There was a prominent GVL effect in patients with acute myeloid leukemia (AML) as compared to those with acute lympho-blastic leukemia (ALL). Transplant-related mortality was 40% with infections accounting for most deaths due to poor immune reconstitution.13

Natural Killer-cell Alloreactivity

On further exploration, the same group uncovered a unique phenomenon related to superior survival of patients with AML. Pioneering work by Ruggeri et al14 demonstrated that, in the setting of haploidentical transplantation, natural killer (NK)-cell alloreactivity is the key to the antileukemia effect. Human NK-cells possess killer Ig-like receptor (KIR) genes which recognize allotypic determinants (KIR ligands) shared by cer-tain HLA-class I allele groups (HLA-C group 2 alleles; HLA-C group 1 alleles; HLA-B alleles sharing the Bw4 specificity). Upon interaction with self-HLA KIR ligands, NK-cells become trained to express alloreactivity against cells not expressing self-HLA KIR ligands. Thus, in full haplotype-mismatched hematopoietic stem cell transplantation (HSCT), donor-versus-recipient NK-cell alloreactivity is effected by NK-cells of donor origin missing the self-ligand in the recipient.

Those patients who were mismatched at KIR genes of the NK-cells with the donor had a significantly superior survival without any increase in GVHD. This was the first time GVHD and GVL could be dissected at a clinical level. In 112 patients with high-risk AML, the Perugia group demonstrated a relapse risk of only 3% in those with NK alloreactivity transplanted in first remission, compared with 37% in those without. The same was documented in relapsed AML as well as in children with ALL.14

Haploidentical Blood and Marrow

Transplantation without T-cell Depletion

Since the success of the Perugia group, several groups across the world tried to replicate the results with mixed success only. The Tubingen group used a negative selection modality with depletion of CD3 and CD19+ cells with similar results.15 The rest were less impressive. Major clinical research evolved in two different continents employing different approaches at employing T-replete grafts for haploidentical BMT.

Standard Graft-versus-host Disease Prophylaxis

The researchers in China adopted an intensive conditioning schedule with aggressive GVHD prophylaxis along with granulocyte-colony stimulating factor primed marrow or PBHPC. The results from Peking University were particularly impressive. One hundred percent engraftment was achieved in 250 patients with acute leukemia. The cumulative incidence of grade 3–4 GVHD was only 13.4% and that of chronic GVHD 22.6%. The probability of DFS at 3 years was 70% for standard risk AML and 50% for high-risk ones. The same

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for ALL was 60% and 25%, respectively.16 In addition, hap-loidentical donor graft conferred a survival advantage over matched donors in advanced leukemia due to a superior GVL effect.

The Korean group reported the outcome of haploidenti-cal BMT after reduced intensity conditioning and standard GVHD prophylaxis with cyclosporine and methotrexate on 83 patients with AML or myelodysplastic syndrome (MDS). Donor engraftment was achieved in 92% with grade 2–4 GVHD and chronic GVHD in 20% and 34%, respectively. The TRM was 18% with DFS in AML in remission, refrac-tory and MDS being 45%, 9%, and 53%, respectively.17

Post Transplant High-dose Cyclophosphamide

Cyclophosphamide was one of the first drugs used in con-ditioning for BMT. It was also tried as GVHD prophylaxis in low doses due to its immunosuppressive properties. How-ever, this was not found to be effective at the low weekly doses employed in these studies. Although, the preclinical data confirmed the efficacy of cyclophosphamide in induc-ing transplant tolerance at a much higher dose, the clinical studies employed much lower doses due to the concern over its deleterious effect on progenitor cells. The researchers at the Johns Hopkins and others discovered the unique prop-erty of primitive HPCs of being resistant to the cytotoxicity of cyclophosphamide by dint of very high expression of aldehyde dehydrogenase which metabolizes the drug.18

Several preclinical studies carried out by Luznik et al established the primacy of high-dose cyclophosphamide used post transplant in both reducing graft rejection and GVHD.19 Subsequently, in a pilot study, the Johns Hopkins group employed cyclophosphamide at 100 mg/Kg >2 days, 72 hours after bone marrow infusion in a heterogeneous group of advanced hematological malignancies following reduced intensity conditioning. Graft failure occurred in 13% and grade 3–4 GVHD in 6%. Chronic GVHD occurred in 5% and TRM at 1 year was 15% in this group of heavily pretreated patients.20 In an expanded study on 186 patients, the outcome was very similar to the pilot study with DFS of 35%. This was significantly higher in patients with relapsed Hodgkins disease with 51% DFS.21

The Better Option—Haploidentical Blood and

Marrow Transplantation or Unrelated Cord

Blood Transplantation

While matched UDBMT has established its place as the alternative donor of choice for those lacking a matched

family donor, the jury is still out for the candidates vying for a place alongside. Unrelated cord blood transplantation has been found to be equivalent to UDBMT in several retrospective registry-based studies in both adults and chil-dren, yet the problem of delayed engraftment raised doubts about UCBT being the natural choice. This problem was partly circumvented by the innovative use of double CBUs. Yet, delayed immune reconstitution and viral infections remain unsolved problems. The return of haploidentical BMT to the mainstream, both with and without T-cell deple-tion, has challenged the position of UCBT as the natural choice with or after UDBMT.

The BMT clinical trials network in the USA conducted a parallel study on alternate donor BMT using double CBU or a haploidentical family donor.22 Fifty patients were recruited in each group and received reduced intensity conditioning followed by either double CBU followed by cyclosporine and mycophenolate mofetil or haploidentical bone marrow fol-lowed by high-dose cyclophospamide as per Johns Hopkins protocol. Both had primary engraftment in over 90% of patients. Neutrophil recovery occurred at a median of 15 days with both graft sources, but platelet recovery was quicker in the haploidentical group. Grade 3–4 acute GVHD and chronic GVHD were documented in 21% and 25% of double UCBT and none and 13% in haploidentical BMT. Transplant-related mortality (7% vs 24%) was lower in haploidentical group and but relapse (31% vs 45%) was higher. Disease-free sur-vival was similar in both groups (46% and 48%).

The Indian Scenario

Compared with over 10,000 BMT performed in the USA per year, <500 are performed in India as of 2010 with only 5% being from alternative donors compared with 30% in the USA. There is no public cord blood bank (PCBB) in India and two struggling unrelated donor registries (UDR). The effort at UDBMT was initiated only in the last couple of years with donor search from registries abroad. The chance of obtaining a 10/10 HLA match for an Indian donor from European or American registries is only about 10%. Moreover, the cost of obtaining an UD graft for an Indian patient is about $25,000–30,000. The same is the case with UCBT. Thus, most patients eligible for an allogeneic BMT do not receive a transplant in India.

One must learn from the outcome of African-Americans undergoing UDBMT. The realistic possibility of obtaining a 10/10 matched unrelated donor from a Caucasian domi-nated registry is about 6%.23 Repeated studies have con-firmed poorer outcome after UDBMT in this group which is attributable to less engraftment and more GVHD-related

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to less than full match and transplants across ethnic groups.24 Similar inferior outcomes have been reported fol-lowing mismatched UCBT in African-Americans.

Problems Thwarting Development of

Unrelated Donor Registry in India

The absence of a congruous policy and access to healthcare for all its citizens plague the healthcare system in India. Development of UDR needs education, awareness, and motivation among the people along with a sense of altru-ism. Lack of a national policy regarding cancer and tha-lassemia does not allow further headway regarding more intensive therapy regarding these diseases, such as BMT. Where voluntary blood donation is linked to guaranteed availability of blood products to the donor, volunteer bone marrow donor registry is likely to be a more distant reality. Several attempts have been made by various organizations, but poor recruitment and a faster attrition of donors have hampered the development of a viable registry. In addition, the funding required for infrastructural support and suste-nance is a daunting task for charitable organization.

On the other hand, PCBB requires a lot more capital investment although there is no risk of attrition. Conserva-tively, a UDR requires 1 million donors and a PCBB should have an inventory of at least 20,000 units if > 50% of patients are to find suitable alternative donors. Either of these requires active BMT programs across the country to sustain such alternate donor banks with over 500 UDBMT and UCBT performed per year. Until that becomes a reality or even without it, the need for Indian patients requiring alternative donor BMT is to develop haploidentical BMT programs.

Haploidentical Blood and Marrow

Transplantation in the Indian Context

Although, a few of the centers in India are carrying out UDBMT and UCBT; none have a haploidentical BMT pro-gram. In view of the above consideration, our center has developed a haploidentical BMT program over the past 12 months. In the first phase, we selected only patients with refractory AML. The donor selection was based on the fol-lowing algorithm: (1) NK-KIR mismatched donor, (2) mother if NK alloreactive donor is not available,25 and (3) noninherited maternal antigens-mismatched donor if mother is not available as a donor.26 We detected only one donor–recipient pair to be NK-KIR mismatched among 20 such pairs screened. All patients were transplanted with over 30% marrow blasts and had failed several lines of treatment.

The conditioning protocol employed high-dose cytosine and an anthracycline for 3 days followed by a regimen similar to Johns Hopkins except low-dose total body irradiation being replaced by melphalan. High-dose cyclophosphamide was employed on days 3 and 4 after infusion of the graft which was mobilized PBHPC rather than bone marrow.

All five patients engrafted neutrophils and platelets at a median of 14 and 16 days, respectively. Donor engraftment above 95% was achieved in all at 30 days. None developed acute GVHD de novo. At a median follow-up of 180 days, two patients died in complete remission (CR) due to resistant gram-negative septicemia at 60 and 150 days. Two remain in CR and one alive in relapse. Our study suggests that hap-loidentical BMT is feasible in patients with advanced leuke-mia. The prompt engraftment and lack of GVHD warrants haploidentical BMT to be employed early in the course of the disease. Whether the same approach would be effective in nonmalignant diseases remains to be seen.

CONCLUSION

The enormous progress made in the field of alternative donor BMT has not yet touched the Indian shores. Unrelated cord blood and marrow transplantation from Western regis-tries is unlikely to be a long-term solution due to both the cost involved and a low yield of full HLA-matched donors. The same is true for UCBT. Mismatched UDBMT should be discouraged from ethnically disparate registries if we are to learn from the outcome in African-Americans. Similar to other Asian countries such as China and Korea, haploidenti-cal BMT programs need to be developed in India to cater to the majority of patients requiring a BMT. The challenge in India is not just to develop a haploidentical BMT program for malignant diseases, but to do the same for nonmalignant diseases which account for half of the transplant indications currently.

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