Sometimes less might be more, or at least equal

In this issue of Blood, Locatelli et al describe their trial of allogeneic hematopoietic stem cell transplantation (HSCT) using α/β T-cell–depleted grafts in a haploidentical setting. The procedure was performed with very promising results in 80 children with acute leukemia.¹ 

The development of haploidentical HSCT has made great progress in the last 2 decades and is today a viable option when choosing a transplant strategy.²  This is especially true for those patients with an uncommon HLA type or in need of a rapid treatment.

The 2 strategies used today in association with haploidentical HSCT are high-dose, posttransplantation cyclophosphamide or graft manipulation by magnetic enrichment or depletion. Both methods aim to reduce graft-versus-host disease (GVHD) while keeping cells that can facilitate beneficial effects, such as a graft-versus-leukemia (GVL) effect or antimicrobial control.^3,4 

Graft manipulation has evolved from positive selection of CD34⁺ progenitor cells to depletion of CD3⁺ cells to what is described in this paper. Here, α/β T-cell depletion was performed prior to HSCT in combination with rituximab depletion of B cells (see figure). All techniques are associated with different potential problems and benefits.

A retrospective report of α/β T-cell depletion prior to HSCT in children with nonmalignant and malignant disease reported a high rate of engraftment and rapid immune recovery, but clinical long-term effects were unavailable at the time.⁵  Smaller series of patients treated with α/β T-cell–depleted grafts both before and after HSCT as stem cell boosters to treat graft failure have also been reported, with promising results.^6-8  So far, larger studies with greater number of patients have been lacking.

The study by Locatelli et al is in many ways very important for the future development of graft manipulation in combination with not only haploidentical transplantation, but also HSCT as a whole. One important concern with α/β depletion is whether the depleted T cells will reduce not only the risk of GVHD but also the beneficial effect of GVL. Even if both NK and γ/δ T cells have been shown to have antileukemic properties, the question remains whether this is sufficient.

This well-performed study in children with acute leukemia strongly argues that the intrinsic antileukemic effect of NK and γ/δ cells, which remain together with other facilitating cells after depletion, is adequate to create a robust GVL effect. Even if the study is not a randomized trial, the data are greatly strengthened by the fact that 2 control groups of patients were treated at the same hospital during the same time period. In the study, the authors show that haploidentical HSCT after α/β T-cell and B-cell depletion is comparable with regards to both leukemia-free survival and GVHD incidence in children transplanted with HLA-identical sibling donors or matched unrelated donors. In addition, the study has a long-term follow-up for a substantial number of patients included.

This study suggests that all patients, including individuals with acute leukemia, could benefit from haplo-HSCT with α/β T-cell depletion, with an outcome comparable to that obtained with HLA-matched siblings or HLA-matched volunteers. The question mark (see figure) regarding a potentially higher relapse rate might not be erased yet, but the results from this study are encouraging.