Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide

Abstract

Post-transplant cyclophosphamide (PTCy) can be used as the sole immunosuppression after myeloablative conditioning (MAC) for HLA-matched bone marrow transplantation (BMT). However, the effects of graft-versus-host disease (GVHD) with this platform are undefined. We retrospectively analyzed 298 consecutive adult patients with hematologic malignancies who engrafted after MAC HLA-matched sibling donor (MSD; n = 187) or HLA-matched unrelated donor (MUD; n = 111) T-cell-replete BMT with PTCy 50 mg/kg on days +3 and +4. After MSD and MUD BMT, 35% and 57% of patients, respectively, developed grade II acute GVHD (aGVHD) by 100 days, 11% and 14% grade III to IV aGVHD by 100 days, and 9% and 16% chronic GVHD (cGVHD) by 1 year. In landmark analyses at 100 days after HLA-matched BMT, 4-year overall survival (OS) and progression-free survival (PFS) were 57% (95% confidence interval [CI], .49 to .67) and 40% (95% CI, .31 to .51) in patients without grades II to IV aGVHD, and 68% (95% CI, .59 to .78) and 54% (95% CI, .44 to .65) in patients with grade II aGVHD. In adjusted time-dependent multivariable analyses, grade II aGVHD was associated with improved OS (hazard ratio, .58; 95% CI, .37 to .89; P = .01) and PFS (hazard ratio, .50; 95% CI, .34 to .74; P < .001) after HLA-matched BMT with PTCy. The ability of PTCy to limit grades III to IV aGVHD and cGVHD while maintaining grade II aGVHD may contribute to its effectiveness, and further attempts to reduce aGVHD may be detrimental.

The Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) Score for HLA Class I Graft-versus-Host Disparity Is Associated with Increased Acute Graft-versus-Host Disease in Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

“…Although greater GVH PS was associated with aGVHD, it did not seem to offer any GVT effect, because the class I GVH PS was not associated with decreased relapse. Previous research by McCurdy et al [63,64] has demonstrated a reciprocal relationship between grade II aGVHD and relapse and progression-free survival in both HLA-matched and haploidentical allo-HCT with PTCy. Given these data, our study might not have been adequately powered to detect an association between PS and incidence of relapse.…”

Posttransplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression

“…Importantly, supporting the possible direct clinical relevance of our findings, our results appear fully consistent with clinical outcomes. In human HCT, grade II acute GVHD frequently occurs after PTCy (2,5,(30)(31)(32) and even may be associated with better malignancy control (5,47). Furthermore, high rates of severe acute GVHD are seen when PTCy is used as single-agent GVHD prophylaxis after peripheral blood HLA-matched HCT (48, 49).…”

Graft‐versus‐host disease and graft‐versus‐leukaemia effects in secondary acute myeloid leukaemia: a retrospective, multicentre registry analysis from the Acute Leukaemia Working Party of the EBMT

“…These interventions might include post‐transplant administration of targeted therapies, such as demethylating agents (Goodyear, et al , ; Ehx, et al , ; Huls, et al , ). Another strategy for separating GVL effects from severe GVHD in the HLA‐matched transplantation setting might comprise post‐transplantation administration of cyclophosphamide (PTCy, 50 mg/kg on days +3 and +4) as a single GVHD‐prophylaxis agent (Kanakry, et al , ; McCurdy, et al , ).…”