LAUSR

In this issue, Perales et al. 1 address a controversy in hematopoietic stem cell transplantation: should an HLA-matched unrelated donor or haploidentical transplant be performed for patients who lack a matched sibling? The preferred donor for allogeneic hematopoietic transplantation is an HLA-matched sibling. For several decades, an unrelated donor transplant has been considered the next option if an HLA-matched donor can be identified; survival after matched related and matched unrelated donor transplants has been similar in most studies. A large worldwide network of unrelated donor registries has been established. Patients are most likely to have an HLA-matched donor among individuals with their same racial and ethnic origin. Matches can be found for about 60% of Caucasians, but only 30% for other ethnicities, primarily due to the racial composition of the existing donor registries. Some patients have a common HLA haplotype and have hundreds of matched donors, but at least half have rare or unique haplotypes and a matched unrelated donor cannot be found. Transplant outcomes have been best with younger unrelated donors, and males under the age of 40 are generally considered the preferred donors. The effective development of haploidentical hematopoietic stem cell transplantation (haploHSCT) has been a major therapeutic advance. The use of post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil has reduced the rates of acute and chronic graftversus-host disease (GvHD) with haploHSCT to below the levels reported with matched unrelated donor transplants, and with similar overall survival (OS). Haploidentical transplantation using this approach is now an established treatment option and is provided by transplant centers around the world. The success of haploHSCT has led many to consider use of a haploidentical donor, even if a matched unrelated donor is potentially available. The study reported by Perales et al. is a retrospective analysis conducted by the Center for Blood and Marrow Transplantation Research which compares the results of transplants from a young HLA-matched unrelated donor with haploidentical transplants from a sibling or child, in patients with acute myeloid leukemia (AML) in first or second complete remission. They analyzed 822 patients aged 50-75 years; 192 patients received haploidentical transplants and 631 patients had grafts from matched unrelated donors aged 18-40 years. Patients' and disease characteristics of the two groups were similar except unrelated donor recipients were more likely to have poor risk cytogenetics and to receive a myeloablative conditioning regimens. Post-transplant cyclophosphamide based GvHD prophylaxis was used in all patients receiving haploHSCT but none of the unrelated donor transplants. Five-year OS was 32% and 42% after haploHSCT and unrelated donor transplant, respectively (P=0.04). Multivariable analysis showed improved survival and a lower risk of leukemia relapse after matched unrelated donor transplantation, with a similar risk of non-relapse mortality with either approach. They concluded that matched unrelated donor transplantation with donors younger than 40 years is preferred. Large registry analyses have reported similar outcomes of haploidentical transplants with those from matched unrelated donors, but comparison of haploHSCT and unrelated donor transplants is complicated. Different preparative and GvHD prophylaxis regimens are generally used. Haploidentical transplants are more likely to be rejected than HLA-matched transplants, and most centers have used reduced intensity regimens in older adult patients, but intensified the preparative regimen to include low-dose total body irradiation (TBI) or thiotepa to prevent rejection. The study by Perales et al. has several limitations due to imbalances in the treatment groups. The primary advantage for the unrelated donor group was a reduced rate of leukemia relapse. Myeloablative conditioning produces a lower rate of leukemia relapse than reduced intensity conditioning (RIC) in HLA-matched as well as haploidentical recipients with AML. The unrelated donor group predominantly received myeloablative conditioning, while the haploHSCT group mainly received a reduced intensity regimen with the cyclophosphamide fludarabine low-dose TBI regimen which is associated with a higher relapse rate than has been reported with other, more intensive, RIC regimens. Other retrospective studies have not reported higher relapse rates with haploHSCT compared to unrelated transplants. Use of a more intensive conditioning in the haploHSCT group may have potentially reduced relapse, but may also have increased non-relapse mortality. The haploHSCT group had a lower rate of acute and chronic GvHD compared to the unrelated donor group. This is undoubtedly due to the use of post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil GvHD prophylaxis in the haploHSCT patients; this regimen is now being used for unrelated donor transplants as well, with improvement in control of GvHD. A formal comparison of post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil with tacrolimus methotrexate GvHD prophylaxis for unrelated donor transplants is in progress by the Blood and Marrow Transplant Clinical Trials Network.