Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation

Abstract

Background: High-dose, post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1-antigen human leukocyte antigen (HLA)-mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients.

Methods: A parallel, 2-arm, nonrandomized phase 2 clinical trial was conducted of melphalan-based reduced-intensity conditioning with PTCy, tacrolimus, and mycophenolate mofetil to prevent GVHD in patients with high-risk hematologic malignancies who underwent HAPLO (n = 60) or 9/10 MUD (n = 46) SCT.

Results: The 1-year overall and progression-free survival rates were 70% and 60%, respectively, in the HAPLO arm and 60% and 47%, respectively, in the 9/10 MUD arm. The day +100 cumulative incidence of grade II to IV acute GVHD and grade III to IV acute GVHD was 28% and 3%, respectively, in the HAPLO arm and 33% and 13%, respectively, in the 9/10 MUD arm. The 2-year cumulative incidence of chronic GVHD was 24% in the HAPLO arm and 19% in the 9/10 MUD arm. The 1-year cumulative incidence of nonrelapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, and the 1-year relapse rate was 19% in the HAPLO arm and 25% in the 9/10 MUD arm.

Conclusions: Although this was a nonrandomized study and could not serve as a direct comparison between the 2 groups, the authors conclude that PTCy-based GVHD prophylaxis is effective for both HAPLO and 9/10 MUD SCTs. Prospective randomized trials will be required to compare the efficacies of alternative donor options for patients lacking HLA-matched donors. Cancer 2016;122:3316-3326. © 2016 American Cancer Society.

Keywords: 9/10 matched unrelated donors; graft-versus-host disease; haploidentical transplantation; hematologic malignancies; post-transplantation cyclophosphamide.

Figure 1

(A,B) The incidence of acute graft-versus-host disease (aGVHD) is illustrated in (A) the haploidentical donor arm and (B) the 1-antigen human leukocyte antigen-mismatched unrelated donor (9/10 MUD) arm. (C,D) The incidence of chronic GVHD is illustrated in (C) the haploidentical donor arm and (D) the 9/10 MUD arm.

Figure 2

(A,B) Overall survival (OS) and progression-free survival (PFS) outcomes are illustrated in (A) the haploidentical donor arm and (B) the 1-antigen human leukocyte antigen-mismatched unrelated donor (9/10 MUD) arm. (C,D) PFS is illustrated according to conditioning intensity for those who received FM140 (1 intravenous dose of 140 mg/m² melphalan on day −7, 1 intravenous dose of 5 mg/kg thiotepa on day −6, and 4 intravenous doses of 40 mg/m² fludarabine [1 daily on days −5 through −2]) versus those who received FM100 (the same regimen with a lower melphalan dose of 100 mg/m²) in (C) the haploidentical donor arm and (D) the 9/10 MUD arm. (E,F) Relapse-related mortality (RRM) and nonrelapse-related mortality (NRM) are illustrated in (E) the haploidentical donor arm and (F) the 9/10 MUD arm.

Figure 3

Charts illustrate immune reconstitution of lymphocyte subsets in the haploidentical donor (HAPLO) and 1-antigen human leukocyte antigen-mismatched unrelated donor (9/10 MUD) arms. Median absolute counts of T-lymphocyte subsets, B cells (cluster of differentiation 19-positive [CD19+]), natural killer cells (CD3−/CD56+), and T-regulatory cells (CD4+/CD25+) are shown for each donor type. Horizontal lines in the graphs indicate reference values, and tables below the graphs display median values at different time points. Reference values have not been established for CD4+/CD25+, CD45RA+/CD4+, or CD45RO+/CD4+ cells. D indicates day.