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In conclusion, recent years have witnessed acceptance of and development of diverse approaches to haploidentical transplantation. The original approach, transplantation of high numbers of T celledepleted hematopoietic progenitor cells and no post-transplantation immune suppression has, with over 15 years’ follow-up, provided well-established outcomes in adults and children and continues to offer unique opportunities for innovative immunotherapeutic strategies. All the recent reports of unmanipulated haploidentical transplantation have fostered interest and debate in the field and, most importantly, served to substantially extend its use. The new 2-step approach, as adopted by Grosso et al. [1], provides very interesting results. It is to be hoped they will be confirmed in a longer follow-up and a larger cohort of patients. ACKNOWLEDGMENTS Financial disclosure: The author have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Grosso D, Gaballa S, Alpdogan O, et al. A two-step approach to myeloablative haploidentical transplantation: low nonrelapse mortality and high survival confirmed in patients with earlier stage disease. Biol Blood Marrow Transplant. 2015;21:646-652.
2. Grosso D, Carabasi M, Filicko-O’Hara J, et al. A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing. Blood. 2011;118: 4732-4739. 3. Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998;339:1186-1193. 4. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-2100. 5. Reisner Y, Hagin D, Martelli MF. Haploidentical hematopoietic transplantation: current status and future perspectives. Blood. 2011;118: 6006-6017. 6. Martelli MF, Di Ianni M, Ruggeri L, et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014;124:638-644. 7. Ciceri F, Bregni M, Peccatori J. Innovative platforms for haploidentical stem cell transplantation: the role of unmanipulated donor graft. J Cancer. 2011;2:339-340. 8. Huang X-J, Liu D-H, Liu K-Y, et al. Treatment of acute leukemia with unmanipulated HLA mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2009;15: 257-265. 9. Di Bartolomeo P, Santarone S, De Angelis G, et al. Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation for patients with high-risk hematologic malignancies. Blood. 2013;121:849-857. 10. Fuchs EJ. Human leukocyte antigen-haploidentical stem cell transplantation using T-cell-replete bone marrow grafts. Curr Opin Hematol. 2012;19:440-447. 11. 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: 1573-1579.
HY: Foe or Maybe Friend? Alois Gratwohl* Department of Hematology, University of Basel, Basel, Switzerland
Article history: Received 1 February 2015 Accepted 5 February 2015
Kongtim et al. [1] from the department of stem cell transplantation and cellular therapy at the MD Anderson Cancer Center in Houston report convincing data showing that a female donor for a male recipient can reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia. The positive effects were most pronounced in young patients, under 50 years old, with advanced leukemia. The authors propose considering a female donor as the preferred option in those situations where relapse is of most concern; eg, for younger patients with advanced disease stage or refractory disease. They are optimistic about further studies with novel graftversus-host disease (GVHD) prevention methods. Such new concepts might better exploit this specific advantage of an HY mismatch; hence, leading to improved survival after transplantation.
DOI of original article: http://dx.doi.org/10.1016/j.bbmt.2014.12.018. Financial disclosure: See Acknowledgments on page 581. * Correspondence and reprint requests: Alois Gratwohl, MD, Dittingerstrasse 4, CH-4053 Basel, Switzerland. E-mail address:
[email protected] (A. Gratwohl) 1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2015.02.003
The authors’ carefully conducted single-center study adds to a long series of reports suggesting that minor histocompatibility antigens are as robust transplantation antigens as their major histocompatibility antigen counterparts, the human leukocyte antigens (HLA). HY, a group of Y chromosomeeencoded antigens, are just among the most defined [2,3]. Multiple peptides have been identified. They can be recognized by the host immune system and they can elicit a humoral as well as a cellular immune response. In 1955, Eichwald was the first to describe a higher and faster rejection rate of male skin in female mice compared with those in sex-identical pairs [4]. Twenty years later, Uphoff described increased GVHD in male mice that underwent transplantation with bone marrow from multiparous females compared with those who received bone marrow from male or nulliparous donors [5]. The importance of HY as a relevant clinical entity in the human immune response was clearly described by Goulmy in 1976 [6], followed by a more detailed description of the effects of sex mismatch on rejection and GVHD after transplantation for aplastic anemia [7]. Why then did it take more than 2 decades to establish the role of HY for both GVHD and graft-versus-leukemia (GVL) effects after HSCT [8] and to assess the role of HY in clinical kidney transplantation [9,10]? Why then is gender mismatch not integrated in the kidney donor allocation scheme [11]? Why does the question about best donor selection in HSCT prevail [1]? The answer is, in part, simple. Too frequently, there is just “only 1 donor available.” The slightly higher risk might still
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justify the transplantation, compared with any other nontransplantation strategy in the individual setting. The answer is, in part, complex. There are always advantages and disadvantages; nothing is only black or only white. This is nicely illustrated in the field of kidney transplantation. The disadvantage of a male kidney for a female recipient is equalized by the bigger male kidney with its higher nephron load in the individual setting. The disadvantage of the male recipient “missing” this specific male kidney takes place elsewhere; hence, it is neglected in the decision-making process. In HSCT, the advantage of GVL in preventing relapse after HSCT might be overestimated. GVL and GVHD are influenced by many factors, dependent and independent. For both, the concept originally described by Billingham for GVHD holds true [12]. There must be a recognizable antigenic difference between the donor and recipient, the donor cells must remain in the host (security of tenure), and the donor cells must be able to mount an immune response. GVHD and GVL can, but must not, develop in parallel (Figure 1). None might be present in the absence of an antigenic difference or when no response evolves (no GVHD/no GVL). The target antigen might only be expressed on host tissue but not on leukemic cells (GVHD/no GVL). They might be expressed on both, host tissue and leukemic cells, as is the case for HY (GVH and GVL), or they might be restricted to hematopoietic or leukemic cells only (no GVHD/GVL). Obviously, the latter represents the ideal situation. There are clear indications that it exists, in acute myeloid leukemia especially [13], but it remains scarce. Few true leukemia antigens are identified; in addition, leukemic cells have the capacity to lose their HLA antigens, to escape immune recognition, and to hide [14]. Multiple studies have analyzed the respective role of gender mismatch after HSCT. Results appear conclusive in larger series. There is a higher likelihood of rejection for male donor/female recipient pairs, especially in nonmalignant diseases. There is, vice versa, a higher likelihood of GVHD and transplantation-related mortality (TRM) in female donor/ male recipient pairs and, consistently, an associated lower relapse rate (REL). This has been observed in all disease categories and is independent from donor type, stem cell source, or conditioning intensity [13,15-17]. The relative negative impact on survival of the net difference between TRM and REL on overall survival can vary substantially from disease to disease and can range from less than 5% in acute lymphoblastic leukemia to >20% in chronic myeloid leukemia [15]. So far, it has never been reported to be an advantage for GVL; it becomes to a nonsignificant difference for patients with highly advanced disease, with mismatched transplantations, or with female donors below the age of 20 years. Thus, the report from Kongtim et al. [1] fits the literature. Their tempting conclusions are easily understood, but questions remain. They speculate that for patients younger than 50 years of age but with high-risk disease, the net benefit of GVL might win in overall survival. Today, in young patients with an excellent performance score, a well-matched donor, and no comorbidities, the risk for TRM is indeed low. A reduction of the excessive relapse incidence via GVL appears attractive. This might indeed be the case in the early posttransplantation period, when the reduction of REL might be higher than the modest increase in the low TRM rate. This has been shown by the large European Society for Blood and Marrow Transplantation analysis. Beyond 3 years, however, relapse risk remained similar between the 2 groups, whereas GVHD-associated TRM continued to increase at a higher rate in the female donor/male recipient group. At 5 years, all
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Figure 1. GVHD and GVL after allogeneic HSCT and outcome. The circle depicts the 4 possibilities of GVHD-GVL combinations and their relative role on outcome after an allogeneic HSCT: no GVHD/no GVL (white), GVH/no GVL (yellow), GVHD and GVL (green), and no GVHD/GVL (blue). The graphs illustrate the respective outcome after HSCT: death from relapse (REL, blue), death from transplantation-related mortality (TRM, yellow), and overall survival (OS, white). GVL reduces the proportion of REL and GVHD increases the proportion of TRM. Best OS can, therefore, be obtained in patients experiencing GVL but no GVHD, with worst survival in patients with GVHD but no GVL (see text).
potential benefit was lost [13,15]. It is unlikely, as well, that novel GVHD prevention approaches, as stipulated by the authors, might alter the balance, as long as they cannot separate GVL and GVHD; the same difference between the 2 groups in REL and TRM were observed in T celledepleted as well as in T cellereplete transplantations [13,15]. The authors correctly ask for more studies of new GVHD prevention methods. That’s not enough. There is an urgent need for large multicenter studies on disease mechanisms. Some recipients of HLA-matched transplants never develop GVHD. If they could be identified before transplantation, GVHD prevention could be omitted. Similarly, some male patients with a female donor never get any signs of GVHD. Why is this the case? How could they be identified before transplantation? There are some indications that a disturbed balance in regulatory T cells might be associated with an aberrant strong or absent immune response to HY [18-21] and that application of such specific regulatory T cells might shift the balance to protection from GVHD. With better insight, the rate of recurrent miscarriage in affected pregnant women might be reduced; low-risk female donor/male recipient pairs could be identified. It might then not only justify a female donor/male recipient HSCT in a young patient with advanced leukemia, it might also justify the transplantation early on in the disease course, even for less than high-risk leukemia [22]. Early and low risk transplantations can help to save lives and resources [23]. There are clear prospects for the future. For the time being, it remains wise to stick to the current habit. A bad guy, GVHD, might have a friendly facedGVL; however, he remains a bad guy. HSCT, whatever the indication, should provide a better outcome regarding long-term survival, quality of life, and costs compared with any other nontransplantation strategy. If a choice can be made, a male donor should be preferred for a male recipient. Unrelated donor registries should continue to focus recruitment strategies on young male donors.
ACKNOWLEDGMENTS Financial disclosure: The author has nothing to disclose.
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Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Kongtim P, Di Stasi A, Rondon G, et al. Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation? Biol Blood Marrow Transplant. 2015;21:713-719. 2. Popli R, Sahaf B, Nakasone H, et al. Clinical impact of H-Y alloimmunity. Immunol Res. 2014;58:249-258. 3. Goulmy E, Schipper R, Pool J, et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med. 1996;334:281-285. 4. Eichwald EJ, Silmser CR. Skin. Transplant Bull. 1955;2:148-149. 5. Uphoff DE. Comparative survival of lethally irradiated inbred male mice inoculated with marrow from virgin or multiparous female donors. J Natl Cancer Inst. 1975;54:1343-1348. 6. Goulmy E, Termijtelen A, Bradley BA, van Rood JJ. Alloimmunity to human H-Y. Lancet. 1976;2:1206. 7. Storb R, Prentice RL, Thomas ED. Marrow transplantation for treatment of aplastic anemia. An analysis of factors associated with graft rejection. N Engl J Med. 1977;296:61-66. 8. Gratwohl A, Hermans J, Niederwieser D, et al. Female donors influence transplant-related mortality and relapse incidence in male recipients of sibling blood and marrow transplants. Hematol J. 2001;2:363-370. 9. Tan JC, Kim JP, Chertow GM, et al. Donor-recipient sex mismatch in kidney transplantation. Gend Med. 2012;9:335-347. 10. Gratwohl A, Döhler B, Stern M, Opelz G. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet. 2008;372:49-53. 11. Matching Organs. Available at: http://www.transplantliving.org/beforethe-transplant/about-organ-allocation/matching-organs/. Accessed February 1, 2015.
12. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect. 1968;62:21-78. 13. Stern M, de Wreede LC, Brand R, et al. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia. 2014;28:2235-2240. 14. Vago L, Perna SK, Zanussi M, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361:478-488. 15. Stern M, Brand R, de Witte T, et al. Female-versus-male alloreactivity as a model for minor histocompatibility antigens in hematopoietic stem cell transplantation. Am J Transplant. 2008;8:2149-2157. 16. Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 1998; 352:1087-1092. 17. Gratwohl A, Stern M, Brand R, et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer. 2009;115:4715-4726. 18. Dierselhuis MP, Jankowska-Gan E, Blokland E, et al. HY immune tolerance is common in women without male offspring. PLoS One. 2014;9:e91274. 19. Nielsen HS. Secondary recurrent miscarriage and H-Y immunity. Hum Reprod Update. 2011;17:558-574. 20. Veerapathran A, Pidala J, Beato F, et al. Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease. Blood. 2013;122:2251-2261. 21. Eljaafari A, Yuruker O, Ferrand C, et al. Isolation of human CD4/CD8 double-positive, graft-versus-host disease-protective, minor histocompatibility antigen-specific regulatory T cells and of a novel HLADR7-restricted HY-specific CD4 clone. J Immunol. 2013;190:184-194. 22. van Halteren AG, Dierselhuis MP, Netelenbos T, Fechter M. Donor parity no longer a barrier for female-to-male hematopoietic stem cell transplantation. Chimerism. 2014;5:56-58. 23. Gratwohl A, Brand R, McGrath E, et al. Use of the quality management system “JACIE” and outcome after hematopoietic stem cell transplantation. Haematologica. 2014;99:908-915.
