Haplo ever after: haplo PTCy for children

In this issue of Blood Advances, Fierro-Pineda et al¹ have successfully performed a prospective multicenter clinical trial through the Pediatric Transplantation and Cellular Therapy Consortium showing the safety and tolerability of myeloablative conditioning with posttransplant cyclophosphamide (PTCy) in pediatric patients receiving haploidentical bone marrow transplant (haploBMT) for hematologic malignancies. Although small single-center studies have been published using this platform, to our knowledge, this is the first prospective, multicenter trial of myeloablative haploBMT with PTCy in pediatric patients with hematologic malignancies, highlighting that the results are generalizable across multiple institutions.

Since the first report by O’Donnell et al in 2002, a multitude of studies have been published showing the success of using PTCy in the haplo-BMT setting.² Although the most robust data are from adult patients, some single-center and retrospective studies using this approach for pediatric hematologic malignancies have also been performed. Symons et al³ reported the results of a single-institution, prospective, phase 2 trial of myeloablative haploBMT using busulfan-based or total body irradiation-based conditioning in 96 children and adults with high-risk hematologic malignancies. This prospective trial was successful but was a mixture of both adults and children. Other groups have reported retrospective^4-6 or single-center data,^4,7-9 with success in pediatrics but no multiinstitutional studies in children have been reported to date.

Fierro-Pineda et al demonstrate no transplant-related mortality at day 180 (0%) and no severe acute graft-versus-host disease (aGVHD) grade 3 to 4 (0%), highlighting that this regimen is safe and well tolerated in children. The overall survival at 1y and 2y is 77% and 73%, respectively. The cumulative incidence (CUI) of aGVHD grade 2 at day 100 was 13% and the CUI of moderate-to-severe chronic GVHD at 1 year was 4%. Although this study included a small number of patients, the results are reassuring and show outcomes comparable with those of other donor sources.

These results have a significant impact on pediatric transplantation in a multitude of ways. First, this approach broadens donor availability and improves access to care for patients of all racial and ethnic backgrounds. The impressively low rates of toxicity (transplant-related and GVHD) with PTCy ensure that the identification of a suitable haploidentical donor can be available in a rapid fashion when patients are ready to undergo transplantation. Second, this approach is easily implemented and can be performed at any transplantation center throughout the globe; this treatment can be offered to our youngest and most vulnerable patients. Third, this study also offers guidance to help optimize the practice of haploBMT in children and young adults.

This approach had an extremely low incidence of GVHD and the duration of tacrolimus was 180 days. However, the CUI of relapse at 1y was 32%, with more relapses noted in patients with pre-BMT minimal residual disease (MRD)+ vs MRD−. Although this incidence is comparable to that of other transplantation approaches, future trials incorporating a shorter duration of tacrolimus (as has been published in the nonmyeloablative setting) may help augment the graft vs leukemia effect and improve the relapse rate.¹⁰ In addition, the addition of newer agents before transplantation to achieve an MRD negative state, such as blinatumomab for acute lymphoblastic leukemia or epigenetic modifiers for acute myeloid leukemia, may improve the relapse rate after transplantation. Moreover, there were higher rates of graft failure than usually seen with myeloablative conditioning conditioning, with 16% (n = 5) of patients not achieving >95% donor engraftment by day 60. However, there was a clear discrepancy in cell dose in patients who failed to meet the engraftment criteria, with all patients receiving a low total nucleated cell count dose of <4 × 10⁸/kg. This highlights that optimizing the cell dose is imperative for successful engraftment.

The results of this trial¹ have set the stage for an open and enrolling Children’s Oncology Group randomized controlled trial of haploidentical transplantation (using PTCy or alpha-beta T-cell–depleted platforms) vs matched unrelated donor (MUD) hematopoietic stem cell transplantation in pediatric patients with high-risk hematologic malignancies. This prospective study will help answer the question of whether the outcomes of a haplo approach are similar or improved compared with a MUD for hematologic malignancies. HaploBMT with PTCy is a well-tolerated transplantation approach for children with hematologic malignancies and can be performed universally at any center performing transplantation. Optimizing this approach to achieve fewer relapses should be the focus of future investigations.

Conflict-of-interest disclosure: The authors declare no competing financial interests.