Haploidentical transplantation in children

In this issue of Blood, Klingebiel and colleagues present a summary of the outcomes of children and adolescents treated with a T cell–depleted haploidentical HCT for ALL.¹  This paper presents one of the largest experiences to date that describes the outcome of 127 children receiving a haploidentical HCTs using the EBMT registry from 36 pediatric centers.

A constant challenge for pediatric hematopoietic cell transplantation (HCT) centers is finding an acceptable donor for a child with very high-risk acute lymphoblastic leukemia (ALL) in first complete remission (CR1) or relapsed ALL. When no acceptable sibling donor is found, most centers attempt to find an HLA-identical unrelated adult marrow donor or umbilical cord blood (UCB). Unfortunately, initial searches frequently fail to identify acceptable HLA-matched unrelated donors, leading the center to 1 of 2 options. These are either a T cell–depleted haploidentical parent donor or a 4-of-6 HLA–matched unrelated UCB. The chance of finding a parent donor, as long as the parents are in good health, is 100%, and that of a 4-of-6 HLA–matched unrelated umbilical cord blood is as high as 98%.²  Thus, the availability of an acceptable donor from the 2 sources is essentially identical for a pediatric HCT center.

In this study in this issue of Blood, Klingebiel and colleagues found that smaller pediatric centers performing a T cell–depleted haploidentical HCT had a poorer outcome than did larger centers. Significant differences included a higher rate of cytomegalovirus positivity in donor and recipient, greater use of the Isolex T-cell depletion, less total body irradiation, and more antithymocyte globulin or antilymphocyte globulin as part of the conditioning regimen at the smaller centers. Adjustment for these variables still supported the conclusion that the leukemia-free survival was higher and the relapse incidence was lower at larger pediatric transplantation centers.

Although between 20% to 25% of all allogeneic HCT performed worldwide are in the pediatric population, pediatric HCT centers are predominantly smaller centers. The outcomes of a 4-of-6 HLA–matched UCB transplantation have been evaluated in relatively large series by both the CIBMTR and Eurocord. In the CIBMTR study, Eapen et al evaluated 267 children with ALL who received a 4-of-6 HLA–matched UCB transplant.³  The 5-year event-free survival (EFS) for these patients was 33% with a transplantation-related mortality of 46% and relapse rate of 19%. Similarly in Eurocord, Roche et al evaluated 290 children receiving an unrelated UCB transplant for ALL with a 2-year EFS of 65% for CR1, 43% for CR2, and 22% for CR3 patients.⁴  They also compared outcomes with 118 children receiving a haploidentical transplant and found that, although the children receiving a UCB transplant had a higher graft failure rate and acute GVHD rate, they had a lower relapse rate. The transplantation-related mortality and disease survival rates were similar.³  The results from these studies evaluating unrelated UCB transplants is almost identical to the outcomes quoted in a recent review of T cell–depleted haploidentical transplants of 3-year disease-free survival of 22% to 48%.⁵ 

The findings in the Klingebiel paper suggest that medium-sized and small pediatric HCT centers should focus on the use of unrelated UCB transplants rather than attempting the more technologically dependent approach of T cell–depleted haploidentical transplants. One potential option that has not been rigorously evaluated in the pediatric setting is the use of a lower technology–dependent haploidentical donor transplant approach such as post-HCT cyclophosphamide without any ex vivo T-cell depletion.⁶  The additional advantage of this approach is that it could potentially be applied to countries outside of Europe and North America where access to UCB is limited and the parents are immediately available.

The other concern raised by the Klingebiel study is the very poor outcome for ALL in CR1 after receiving a T cell–depleted haploidentical transplantation. Whether there is greater dependence on an early T-cell response or another mechanism, the data suggest that T cell–depleted haploidentical transplantation should be used only for children with ALL at CR2 or higher, no matter the center size.

In summary, this study suggests that for the majority of pediatric HCT centers, UCB transplantation should be the preferred option. T cell–depleted haploidentical transplantation should be used only for children with ALL at CR2 or higher at larger centers that have a high level of experience with T cell–depleted haploidentical transplantation. Less technology-dependent approaches to haploidentical transplantation, such as pharmacologic approaches with cyclophosphamide after transplantation,⁶  potentially should be considered as a future strategy for many pediatric HCT centers, especially those that do not have an easy access to unrelated UCB donors.