Wanted: Prospective Studies of Alternative Donors

Abstract

Donor availability for allogeneic hematopoietic cell transplantation (HCT) has been an area of intensive research for many years. The aim has been to close the gap in donor availability for those patients who require a potentially curative allogeneic HCT but lack a suitable HLA-matched sibling donor, the “gold standard” of the allogeneic donors. As most hematological malignancies occur in adults in their fifth decade of life and beyond, there was a significant unmet need for alternative donors for this patient population in which an HLA-matched sibling may not be clinically suitable to donate. Until the late 1990s, adult unrelated donors were the main alternative donor type for HCT, with the matched unrelated donor (MUD) becoming the “gold standard of alternative donors.” Currently, Bone Marrow Donors Worldwide has over 25 million potential donors registered (http://www.bmdw.org/). Despite this large number, about one third of Caucasian and a larger proportion of minorities will not find a MUD in the registries [1Gragert L. Eapen M. Williams E. et al.HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry.N Engl J Med. 2014; 371: 339-348Crossref PubMed Scopus (658) Google Scholar]. The ability to find a donor increases if HLA-mismatched unrelated donors are considered. Although a single-locus HLA-mismatched unrelated donor (misMUD) may be well tolerated, greater degrees of HLA mismatch are associated with higher risks of graft-versus-host disease (GVHD) and death. In the late 1990s, cord blood (CB) emerged as yet another potential alternative donor source for HCT [2Gluckman E. Rocha V. Boyer-Chammard A. et al.Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group.N Engl J Med. 1997; 337: 373-381Crossref PubMed Scopus (1180) Google Scholar, 3Rubinstein P. Carrier C. Scaradavou A. et al.Outcomes among 562 recipients of placental-blood transplants from unrelated donors.N Engl J Med. 1998; 339: 1565-1577Crossref PubMed Scopus (1182) Google Scholar, 4Wagner J.E. Barker J.N. DeFor T.E. et al.Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival.Blood. 2002; 100: 1611-1618Crossref PubMed Scopus (47) Google Scholar]. The better tolerance of HLA mismatches and the rapid availability of CB positioned it as a valuable donor type to further close the donor availability gap and allow faster time to transplantation in high-risk patients. Although CB was initially restricted to children because of the limited cell dose in individual units, better understanding of cell dose requirements and technical advances, such as double CB transplantation, broadened its use to adults. In this issue of Biology of Blood and Marrow Transplantation, Malard et al. reported on the outcomes of CB compared with MUD and misMUD after reduced-intensity or nonmyeloablative conditioning [5Malard F. Milpied N. Blaise D. et al.Effect of graft source on unrelated donor hemopoietic stem cell transplantation in adults with acute myeloid leukaemia after reduced-intensity or non myeloablative conditioning: a study from the Société Francaise de Greffe de Moelle et de Thérapie Cellulaire.Biol Blood Marrow Transplant. 2015; 21: 1059-1067Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Although we could be tempted to dissect differences in patient populations to explain their effect, or lack thereof, on the results, the message would not change. The main observation of this study is that despite differences in the risk of complications (eg, such as graft failure and GVHD) and patterns of failure (eg, nonrelapse mortality and relapse), survival was similar for all 3 donor types. This study, which was conducted using more stringent HLA matching for MUD and misMUD (10 alleles), confirms a previous report by the Center for International Blood and Marrow Transplant Research in a similar setting [6Brunstein C.G. Eapen M. Ahn K.W. et al.Reduced-intensity conditioning transplantation in acute leukemia: the effect of source of unrelated donor stem cells on outcomes.Blood. 2012; 119: 5591-5598Crossref PubMed Scopus (101) Google Scholar]. For many years, CB has enjoyed prominence as the go-to alternative donor type for those who lack a MUD. The study of Malard et al. included patients treated between 2002 and 2010, reflecting the era of rapid growth in use of CB [5Malard F. Milpied N. Blaise D. et al.Effect of graft source on unrelated donor hemopoietic stem cell transplantation in adults with acute myeloid leukaemia after reduced-intensity or non myeloablative conditioning: a study from the Société Francaise de Greffe de Moelle et de Thérapie Cellulaire.Biol Blood Marrow Transplant. 2015; 21: 1059-1067Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Along with the growth in utilization, several groups and institutions started studies that have improved the safety and efficacy of CB transplantation, in particular by targeting the slower and lower engraftment rates compared with matched sibling donor and MUD as shown in the Malard et al. data [5Malard F. Milpied N. Blaise D. et al.Effect of graft source on unrelated donor hemopoietic stem cell transplantation in adults with acute myeloid leukaemia after reduced-intensity or non myeloablative conditioning: a study from the Société Francaise de Greffe de Moelle et de Thérapie Cellulaire.Biol Blood Marrow Transplant. 2015; 21: 1059-1067Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. These studies to improve homing or ex vivo expansion of progenitor cells are ongoing. Although a robust new strategy could improve the efficacy of CB transplantation, most are not yet ready for prime time and their technical requirements limit widespread utilization. Not addressed in the study by Malard et al. [5Malard F. Milpied N. Blaise D. et al.Effect of graft source on unrelated donor hemopoietic stem cell transplantation in adults with acute myeloid leukaemia after reduced-intensity or non myeloablative conditioning: a study from the Société Francaise de Greffe de Moelle et de Thérapie Cellulaire.Biol Blood Marrow Transplant. 2015; 21: 1059-1067Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] is the fact that there is a “new kid on the block,” the unmodified partially HLA-matched related donor (haplo-identical) bone marrow with post-transplantation cyclophosphamide (pTCy) as GVHD prophylaxis [7Luznik L. O'Donnell P.V. Symons H.J. et al.HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.Biol Blood Marrow Transplant. 2008; 14: 641-650Abstract Full Text Full Text PDF PubMed Scopus (1200) Google Scholar]. This new strategy for an old donor type has been rapidly growing, especially in regions where access to the unrelated donor or CB pool is limited. Numbers of patients and follow-up in most centers and registries are still limited, but emerging data suggest that results of haplo-identical transplantation with pTCy yield similar survival as MUD [8Ciurea S.O. Zhang M.-J. Bacigalupo A. et al.Survival after T-cell replete haplo-identical related donor transplant using post-transplant cyclophosphamide compared with matched unrelated donor transplant for acute myeloid leukemia.Blood. 2014; 124 (abstract 679)PubMed Google Scholar] and CB [9Brunstein C.G. Fuchs E.J. Carter S.L. et al.Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts.Blood. 2011; 118: 282-288Crossref PubMed Scopus (441) Google Scholar]. In a world where most retrospective studies show similar outcomes between MUD, misMUD, and CB, as in the Malard et al. study [5Malard F. Milpied N. Blaise D. et al.Effect of graft source on unrelated donor hemopoietic stem cell transplantation in adults with acute myeloid leukaemia after reduced-intensity or non myeloablative conditioning: a study from the Société Francaise de Greffe de Moelle et de Thérapie Cellulaire.Biol Blood Marrow Transplant. 2015; 21: 1059-1067Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], and now add haplo-identical donors, how do these data help us move the alternative donor transplantation field forward? Although there is no single answer to this question, the first step is to urge the development of multicenter prospective studies. In phase 2 and phase 3 randomized studies, data collection needs to go beyond the clinical outcome measures and should at least include quality of life, resource utilization, and, when applicable, studies of late effects and immune reconstitution. A good example is the Blood and Marrow Transplant Clinical Trials Network current multicenter phase 3 randomized trial (1101) comparing double CB and haplo-identical donor with pTCy (www.clinicaltrials.gov, NCT01597778) that was built upon 2 parallel prospective phase 2 studies [9Brunstein C.G. Fuchs E.J. Carter S.L. et al.Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts.Blood. 2011; 118: 282-288Crossref PubMed Scopus (441) Google Scholar] that were developed from promising single-center experiences [7Luznik L. O'Donnell P.V. Symons H.J. et al.HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.Biol Blood Marrow Transplant. 2008; 14: 641-650Abstract Full Text Full Text PDF PubMed Scopus (1200) Google Scholar, 10Brunstein C.G. Barker J.N. Weisdorf D.J. et al.Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease.Blood. 2007; 110: 3064-3070Crossref PubMed Scopus (430) Google Scholar]. A second step would include the centers committed and able to test new methodologies to improve all options including not only CB, but MUD, misMUD, and haplo-identical donors in phase 1 and 2 studies. A third step would be to continue large retrospective studies like that by Malard et al. [5Malard F. Milpied N. Blaise D. et al.Effect of graft source on unrelated donor hemopoietic stem cell transplantation in adults with acute myeloid leukaemia after reduced-intensity or non myeloablative conditioning: a study from the Société Francaise de Greffe de Moelle et de Thérapie Cellulaire.Biol Blood Marrow Transplant. 2015; 21: 1059-1067Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], which will highlight areas needing improvement and generate new hypothesis to be tested. The Societé Farncaise de Greffe de Moelle et de Thérapie Cellulaire that sponsored the study by Malard et al. maybe uniquely positioned to conduct such large phase 2 and 3 studies. As patterns of treatment failure differ between donors types, the single payer system in France may allow for unique observations on the early versus late cost effectiveness of the different donor types, as recently published [11Labopin M. Ruggeri A. Gorin N.C. et al.Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France.Haematologica. 2014; 99: 535-540Crossref PubMed Scopus (31) Google Scholar]. Now that we know we can find a donor for virtually every patient who needs an allogeneic HCT, large prospective multicenter studies will help disseminate technology, leading to better care and, ultimately, better outcomes for all our patients. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report.