Search tips
Search criteria 


Logo of bloodadvBlood Advances
Blood Adv. 2017 February 14; 1(6): 397–400.
Published online 2017 February 14. doi:  10.1182/bloodadvances.2016002196
PMCID: PMC5738988

Related haploidentical donors are a better choice than matched unrelated donors: Point

When a person seeks to purchase a product in the marketplace, be it a car or an apple, 2 product characteristics are decisive: price and quality. If a customer perceives 2 varieties of apples to be of equal quality, then the cheaper variety will be preferred and purchased. For patients who lack an HLA-matched sibling donor, bone marrow transplant physicians often must choose between a well-matched unrelated adult donor (MUD) or an HLA-haploidentical (haplo) relative. In the past, the choice was fairly easy: outcomes after transplantation using MUDs approached those from matched sibling donors1-3 and both donor types were easily superior to the poor survivals seen using haplo donors.4 However, haplo transplant outcomes have improved dramatically with modern methods of graft-versus-host disease (GVHD) prophylaxis including the combination of antithymocyte globulin, cyclosporine, methotrexate, and mycophenolate mofetil5 or high-dose, posttransplantation cyclophosphamide.6 It is now possible to say that haplo donors are a better choice than MUDs because grafts from haplo donors offer the same or better quality at a lower price than grafts from MUDs.

Unrelated donor stem cell grafts are more expensive than related donor stem cell grafts because of the costs associated with maintaining unrelated donor registries, performing searches, and providing the logistics to get the donor to a transplant center and the graft to the patient. Fortunately, the cost of acquiring unrelated donor stem cells is not a barrier to transplantation in much of the developed world, and unrelated donor transplants outnumber transplants from related donors in the United States7 and in Europe.8 However, the fact remains that many developing countries have not established registries of unrelated donors because of the associated costs, and these countries benefit substantially from the haplo donor option.

Table 1 lists other practical advantages of haplo over unrelated donors. The most salient advantage of the haplo donor option is donor availability. There is significant ethnic variation in the availability of unrelated donors, ranging from about 19% for African Americans to 80% or more for Caucasians of Northern European origin. In contrast, nearly all patients have an available haplo donor because all biologic parents and children of a patient are haplo and each sibling or half-sibling has a 50% chance of being haplo. The major limitation to the availability of haplo donors is the presence of antidonor HLA antibodies, usually in parous women against paternal HLA antigens present in the children.9 Even if such antibodies are present, they can oftentimes be removed by a desensitization procedure to permit transplantation.10 Haplo donor availability increases further if one considers transplantation from extended family members such as aunts, uncles, nieces, and nephews, who on average have a 50% chance of being haplo, or cousins, who have a 25% chance of being haplo.

Table 1.
Logistical comparison of related haplo vs HLA-matched unrelated donors

Some patients need to get to transplant quickly because their remission is not expected to last or because their health status is precarious and likely to deteriorate. In such circumstances, the transplant is considered urgent and there is a need to obtain and infuse the product as quickly as possible. There has been a dramatic improvement in the speed with which unrelated donor transplantation registries can mobilize donors for transplantation, but delays are unavoidable. We simply do not know how many patients become ineligible for transplantation while waiting for a MUD graft to arrive. In 2008, more than 34 000 patient searches were initiated for a stem cell donor, but only 9747 patients received an unrelated adult donor stem cell transplant.11 It seems reasonable to assume that some of the patients did not make it to transplant because a suitably matched donor could not be identified and mobilized in time. In contrast, haplo donors are readily available and usually are highly motivated to donate to their family member, especially in the case of parent-to-child transplantations. The logistical advantages of related over unrelated donors extend to subsequent cellular therapies, such as donor lymphocyte infusion to treat posttransplantation relapse. Finally, unrelated donor products must be shipped to their destination and can degrade between the time of collection and the time of infusion. The effects of “cold ischemia” time on transplant outcomes are unknown, but are unlikely to weigh in favor of unrelated over haplo grafts.

None of the financial and logistical advantages of related haplo donors over unrelated donors would matter if hematopoietic stem cell transplants from MUDs produced better outcomes. Table 2 shows a number of published, retrospective comparisons of the 2 donor types and, frankly, it is hard to see an advantage of the unrelated donor option. A reasonable interpretation of the data is that haplo stem cell transplantation (SCT) with high-dose, posttransplantation cyclophosphamide (PTCy) is associated with similar overall and progression-free survivals as with MUD SCT, but with perhaps less chronic GVHD. Indeed, a recent study of lymphoma patients receiving either haplo SCT with PTCy or HLA-matched sibling SCT came to the same conclusion.12 It may be argued that the comparison is unfair because the haplo transplants used PTCy, whereas the MUD transplants did not. Support for this argument comes from recent reports showing good survival and low incidence of chronic GVHD after MUD SCT with PTCy.13,14 So, it may turn out that PTCy is the great equalizer of adult stem cell sources by abolishing the detrimental effect of HLA or minor histocompatibility mismatches on the outcome of allogeneic SCT.15

Table 2.
Retrospective comparisons of outcomes of haplo SCT plus posttransplantation cyclophosphamide vs MUD SCT

Concerns have been raised about a higher frequency or worse prognosis of specific complications of haplo SCT or of PTCy, but data so far are reassuring. For example, loss of mismatched HLA occurs in one-third of relapses after haplo SCT, but these relapses have the same prognosis as classical relapse with retention of mismatched HLA.16 Also, donor stem cells are exposed to the potentially mutagenic effects of PTCy, but in 1 report there were only 5 cases of donor-derived malignancy among 790 recipients of allogenic SCT with PTCy.17

Some might say that a prospective, phase 3 trial that randomizes patients to haplo plus PTCy vs MUD is required to establish which donor type is “better.” I would argue that such trials are useful for comparing drugs of fixed chemical composition but are inadequate for comparing specific ingredients (haplo vs MUD) of a recipe (conditioning regimen, donor type, stem cell collection method, GVHD prophylaxis). The loser will always claim that the trial results are obsolete because a better recipe is available. Better to let the market decide.

The foregoing discussion should not be cause for despair among advocates of unrelated donor SCT. If HLA matching is no longer the paramount consideration in donor selection, then perhaps other characteristics, such as non-HLA genes or donor age, may come to the fore. For instance, an HIV-infected patient may benefit from a partially HLA-mismatched SCT from an unrelated donor who lacks the CCR5 receptor. An older patient without children may do better with a young, partially HLA-mismatched unrelated donor than with an older, HLA-haploidentical sibling. Rather than squabble over which is the best donor source, transplant physicians should take pride in having solved the problem of donor availability and move on to bigger and more exciting challenges, such as preventing relapse and curing solid tumors.


This work was supported by the National Institutes of Health, National Cancer Institute (grant P01 CA15396).


Contribution: E.J.F. wrote this manuscript.

Conflict-of-interest disclosure: The author declares no competing financial interests.

Correspondence: Ephraim Joseph Fuchs, Cancer Research Building, 1650 Orleans St, Room 289, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287; e-mail: ude.imhj@peshcuf.


1. 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(17):3908-3916. [PubMed]
2. Yakoub-Agha I, Mesnil F, Kuentz M, et al. ; French Society of Bone Marrow Transplantation and Cell Therapy. Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol. 2006;24(36):5695-5702. [PubMed]
3. Kröger N, Zabelina T, de Wreede L, et al. ; MDS subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia. 2013;27(3):604-609. [PubMed]
4. Szydlo R, Goldman JM, Klein JP, et al. Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol. 1997;15(5):1767-1777. [PubMed]
5. Wang Y, Liu Q-F, Xu L-P, et al. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood. 2015;125(25):3956-3962. [PubMed]
6. McCurdy SR, Kasamon YL, Kanakry CG, et al. Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with posttransplantation cyclophosphamide [published online ahead of print 20 October 2016] Haematologica. [PubMed]
7. Pasquini MC, Zhu X Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR summary slides, 2015. Available at: Accessed 20 January 2017.
8. Passweg JR, Baldomero H, Bader P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786-792. [PMC free article] [PubMed]
9. Gladstone DE, Zachary A, Fuchs EJ, et al. Desensitization for mismatched hematopoietic stem cell transplantation (HSCT) [abstract]. Blood 2011;118(21). Abstract 1955.
10. Leffell MS, Jones RJ, Gladstone DE Donor HLA-specific Abs: to BMT or not to BMT? Bone Marrow Transplant. 2015;50(6):751-758. [PMC free article] [PubMed]
11. Foeken LM, Green A, Hurley CK, Marry E, Wiegand T, Oudshoorn M; Donor Registries Working Group of the World Marrow Donor Association (WMDA). Monitoring the international use of unrelated donors for transplantation: the WMDA annual reports. Bone Marrow Transplant. 2010;45(5):811-818. [PubMed]
12. Ghosh N, Karmali R, Rocha V, et al. Reduced-intensity transplantation for lymphomas using haploidentical related donors versus HLA-matched sibling donors: a center for international blood and marrow transplant research analysis. J Clin Oncol. 2016;34(26):3141-3149. [PMC free article] [PubMed]
13. Moiseev IS, Pirogova OV, Alyanski AL, et al. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Biol Blood Marrow Transplant. 2016;22(6):1037-1042. [PubMed]
14. Mielcarek M, Furlong T, O’Donnell PV, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127(11):1502-1508. [PubMed]
15. Kasamon YL, Luznik L, Leffell MS, et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant. 2010;16(4):482-489. [PMC free article] [PubMed]
16. Crucitti L, Crocchiolo R, Toffalori C, et al. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia. 2015;29(5):1143-1152. [PubMed]
17. Symons HJ, Mogri H, Kanakry JA, et al. Rarity of donor-derived malignancy after allogeneic BMT with high-dose post-transplantation cyclophosphamide. Biol Blood Marrow Transplant. 2014;20(2):S252.
18. Gragert 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(4):339-348. [PubMed]
19. Ciurea SO, Zhang MJ, Bacigalupo AA, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033-1040. [PubMed]
20. Di Stasi A, Milton DR, Poon LM, et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant. 2014;20(12):1975-1981. [PMC free article] [PubMed]
21. Rashidi A, DiPersio JF, Westervelt P, et al. Comparison of outcomes after peripheral blood haploidentical versus matched unrelated donor allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia: a retrospective single-center review. Biol Blood Marrow Transplant. 2016;22(9):1696-1701. [PubMed]
22. Rashidi A, Slade M, DiPersio JF, Westervelt P, Vij R, Romee R Post-transplant high-dose cyclophosphamide after HLA-matched vs haploidentical hematopoietic cell transplantation for AML. Bone Marrow Transplant. 2016;51(12):1561-1564. [PubMed]
23. Burroughs LM, O’Donnell PV, Sandmaier BM, et al. Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2008;14(11):1279-1287. [PMC free article] [PubMed]
24. Kanate AS, Mussetti A, Kharfan-Dabaja MA, et al. Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors. Blood. 2016;127(7):938-947. [PubMed]
25. Garciaz S, Castagna L, Bouabdallah R, et al. Familial haploidentical challenging unrelated donor Allo-SCT in advanced non-Hodgkin lymphomas when matched related donor is not available. Bone Marrow Transplant. 2015;50(6):865-867. [PubMed]
26. Raiola AM, Dominietto A, di Grazia C, et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant. 2014;20(10):1573-1579. [PubMed]
27. Solomon SR, Sizemore CA, Sanacore M, et al. Total body irradiation-based myeloablative haploidentical stem cell transplantation is a safe and effective alternative to unrelated donor transplantation in patients without matched sibling donors. Biol Blood Marrow Transplant. 2015;21(7):1299-1307. [PubMed]
28. Baker M, Wang H, Rowley SD, et al. Comparative outcomes after haploidentical or unrelated donor bone marrow or blood stem cell transplantation in adult patients with hematological malignancies. Biol Blood Marrow Transplant. 2016;22(11):2047-2055. [PubMed]
29. Blaise D, Fürst S, Crocchiolo R, et al. Haploidentical T cell-replete transplantation with post-transplantation cyclophosphamide for patients in or above the sixth decade of age compared with allogeneic hematopoietic stem cell transplantation from an human leukocyte antigen-matched related or unrelated donor. Biol Blood Marrow Transplant. 2016;22(1):119-124. [PubMed]
30. Bashey A, Zhang X, Jackson K, et al. Comparison of outcomes of hematopoietic cell transplants from T-replete haploidentical donors using post-transplantation cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 allele-matched unrelated donors and HLA-identical sibling donors: a multivariable analysis including disease risk index. Biol Blood Marrow Transplant. 2016;22(1):125-133. [PubMed]

Articles from Blood Advances are provided here courtesy of American Society of Hematology