PTCY keeps on giving!

In this issue of Blood, Battipaglia and colleagues report improved outcomes for patients receiving posttransplant cyclophosphamide (PTCY) vs antithymocyte globulin (ATG) as backbone of their immunosuppression regimen after 1-antigen mismatched unrelated donor (MMUD) allogeneic hematopoietic cell transplantation (alloHCT) for treatment of acute myeloid leukemia (AML).¹ 

AML is the most common indication for an alloHCT, and >3000 patients are transplanted annually in the United States. Because transplant success rates are higher with alloHCT pursued soon after diagnosis, timely identification of a suitable donor used to represent the biggest challenge to optimally timed alloHCT. However, the days of difficult donor searches for an alloHCT patient are behind us. With the use of PTCY, which permits transplantation across human leukocyte antigen (HLA) barriers and promotes tolerance induction, haploidentical donors are a safe, efficacious, and rapid choice.²  Haploidentical transplants are not feasible only for a small fraction of patients for whom an MMUD strategy is a viable option. HLA mismatches have been associated with worse overall outcomes in unrelated donor alloHSCT, particularly in terms of graft-versus-host disease (GVHD) and nonrelapse mortality. Thus, the addition of in vivo T-cell depletion with ATG or alemtuzumab to calcineurin-based immunosuppression has become an immunosuppression backbone in the MMUD setting. Both ATG and PTCY have a well-documented efficacy in GVHD prevention, with greater variability of ATG effects driven by distinct ATG formulations, a continued source of debate in the field. However, with increasing evidence supporting comparable feasibility and efficacy of PTCY- and conventional immunosuppression-based allografting in AML,^3,4  PTCY has become a viable option for MMUD alloHCT. Limited single-center studies have evaluated PTCY use in MMUD mostly through a feasibility prism, and the current report represents the largest real-world body of evidence supporting PTCY use in this setting.

In this matched-pair analysis of 93 PTCY and 179 ATG patients identified in the European Society for Blood and Marrow Transplantation registry, PTCY not only is confirmed as a viable agent in MMUD alloHCT but also hints of its superiority emerge as well. This includes control of grade III to IV acute GVHD, enhanced leukemia-free survival, and composite end point of GVHD/relapse-free survival. Subset analyses further identify patients in whom PTCY might be particularly beneficial, with documentation of improved overall survival in recipients transplanted with their primary disease in complete remission and with peripheral blood stem cells as a source. The former finding is particularly noteworthy, given the majority of PTCY recipients was transplanted beyond the first complete remission, a well-defined risk factor for inferior outcomes.

Caveats regarding long(er)-term benefits of PTCY remain and are primarily driven by the significantly shorter follow-up duration in the PTCY group (median of 14 vs 27 months), an issue likely to be addressed with updated data in the future. A few additional aspects require greater clarification to determine the optimal approach for an individual patient. Increasingly, these reasons are cost driven. Although both platforms allow for safe and permanent discontinuation of long-term immunosuppression in the large majority of patients,^5,6  the immediate peritransplant immunosuppression burden and consequent infection risk remain high. This is particularly pertinent to the ATG recipients, who in this study exhibited a higher rate of lethal infections, possibly contributing to the observed survival differences. In addition, the optimal immunosuppressive agents added to PTCY and duration of their administration remain undefined. Unfortunately, no further insight into these issues was possible due to limitations of registry-based retrospective analyses; however, they should be explored in the future. What mechanisms drive the outcome differences between ATG and PTCY recipients remains unknown as well. Both platforms have long been considered to derive benefits primarily from lymphodepleting effects and increasingly regulatory T-cell modulation.^7,8  Prolonged lymphopenia with ATG doses used in alloHCT, however, is not observed with PTCY use, which is associated with enhanced conversion to donor T-cell chimerism and the early survival advantage for CD4⁺ T cells, regulatory T cells, and α/β T cells.⁹  These phenomena offer a potential biological rationale for favorable PTCY outcome, although they require further investigation.

The work by Battipaglia et al adds to the increasing body of evidence supporting the benefits of PTCY-based allografting across different transplant scenarios and includes indications previously relying on ATG-based regimens.¹⁰  Although a prospective and randomized trial comparing PTCY and ATG outcomes would provide the highest-quality assessment of both strategies, such an endeavor remains highly unlikely given the cost and the diminishing use of MMUD alloHCT with the use of PTCY alternative donor strategies. Results of the upcoming randomized trial of ATG vs PTCY vs standard immunosuppression in MUD setting (#NCT03602898) will define the overall value of each in unrelated alloHCT, with potential applicability to MMUD transplant. Until these are available, the current results provide evidence supporting PTCY feasibility and efficacy and highlight it as a viable alternative to ATG in MMUD alloHCT. Based on trends toward broad improvement of transplant outcomes with PTCY, a discussion between a patient and a physician on the appropriate immunosuppression backbone choice in MMUD alloHCT can now be based on data rather than personal preference.