Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide

Abstract

Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02-11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41-55%) and 53% (95% CI: 46-61%) after myeloablative HLA-matched related, 42% (95% CI: 34-52%) and 52% (95% CI: 44-62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40-50%) and 50% (95% CI: 45-55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.

Figure 1.

Kaplan-Meier curves* for overall survival, disease-free survival, GRFS, and CRFS after post-transplantation cyclophosphamide platforms for myeloablative HLA-matched related, myeloablative HLA-matched unrelated, and non-myeloablative HLA-haploidentical bone marrow transplantation. GRFS: graft-versus-host disease-free, relapse-free survival; CRFS: chronic graft-versus-host disease-free, relapse-free survival; MA: myeloablative; MRD: HLA-matched related donor; MUD: HLA-matched unrelated donor; NMA: non-myeloablative; Haplo: HLA-haploidentical; OS: overall survival; DFS: disease-free survival. *P-values shown in the plots were based on stratified log-rank tests and the curves were truncated at 8 years.

Figure 2.

(A) Kaplan-Meier curves* of GRFS and CRFS and (B) distribution of first event components of GRFS and CRFS following different transplant platforms with post-transplantation cyclophosphamide. GRFS: graft-versus-host disease-free, relapse-free survival; CRFS: chronic graft-versus-host disease-free, relapse-free survival; MA: myeloablative; MRD: HLA-matched related donor; MUD: HLA-matched unrelated donor; NMA: non-myeloablative; Haplo: HLA-haploidentical; aGVHD 3–4: grade 3–4 acute graft-versus-host disease; cGVHD trt: chronic graft-versus-host disease requiring systemic treatment; NRM: non-relapse mortality; cGVHD-modsev: moderate or severe chronic graft-versus-host disease. *P-values shown in the plots were based on stratified log-rank tests and the curves were truncated at 8 years.

Figure 3.

Relapse according to post-transplantation cyclophosphamide bone marrow transplant platform. (A) Cumulative incidence of relapse (P-value in the model is a result of testing the differences of cumulative incidence of relapse among transplant platforms stratified by bone marrow transplant year). (B–D) Kaplan-Meier curves of post-relapse survival by (B) post-transplantation cyclophosphamide bone marrow transplant platform and (C–D) time from transplantation to relapse. MA: myeloablative; MRD, HLA-matched related donor bone marrow transplant; MUD: HLA-matched unrelated donor bone marrow transplant; NMA: non-myeloablative; Haplo: HLA-haploidentical bone marrow transplant; BMT: bone marrow transplant.