# Safety of Post-transplant Cyclophosphamide as a Single Agent for Graft-Versus-Host Disease Prophylaxis After Human Leukocyte Antigen (HLA)-Matched Transplantation With the Japanese Population: A Single-Center Phase Ⅰ/Ⅱ Study

## TL;DR

This study examines the safety of using cyclophosphamide alone to prevent graft-versus-host disease in a Japanese population after stem cell transplants.

## Contribution

This is the first single-center phase I/II study in the Japanese population evaluating post-transplant cyclophosphamide as a sole GVHD prophylaxis.

## Key findings

- PTCy monotherapy showed 66.7% GVHD-free, relapse-free survival at six months.
- Two out of three patients required additional cyclosporine for immune complications.
- Overall survival was 100% at six months, but the study was terminated early due to poor recruitment.

## Abstract

Background

Graft-versus-host disease (GVHD) is a severe complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although calcineurin inhibitor (CNI)-containing GVHD prophylaxis is currently standard, it has the disadvantages of nephrotoxicity, a risk for thrombotic microangiopathy, drug interaction, and a requirement for monitoring blood concentration. Therefore, we conducted a prospective trial with the Japanese population undergoing allo-HSCT from an HLA-matched donor to investigate the safety and preliminary efficacy of single-agent post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis.

Methods

This single-center phase I/II trial was a prospective study registered in the UMIN Clinical Trials Registry (UMINID: UMIN000028779) on November 1, 2017, and enrolled patients aged 16-60 years old with hematological malignancies in remission but without a history of previous allo-HSCT. Myeloablative conditioning (fludarabine 120 mg/m2 and total body irradiation 12 Gy) was followed by bone marrow transplantation from an HLA-matched donor. Cyclophosphamide (50 mg/kg) was administered on days 3 and 4. The primary endpoint was GVHD-free, relapse-free survival (GRFS) at six months after transplantation. Secondary endpoints included overall survival, incidences of relapse, non-relapse mortality (NRM), and acute and chronic GVHD (a/cGVHD). The prespecified sample size was 20.

Results

Four patients were enrolled, and one patient withdrew due to medication non-compliance. The GRFS at six months post-transplant was 2 out of 3 evaluable patients (66.7%). Grade 2 aGVHD was observed in 2/3 (66.7%), and neither grade 3-4 aGVHD nor moderate-to-severe cGVHD appeared within six months after transplantation. Two patients required additional cyclosporine administration because of hemophagocytic lymphohistiocytosis and grade 2 skin aGVHD, respectively, which improved promptly after cyclosporine administration. One patient relapsed, and NRM was not observed. Overall survival at six months was 3/3 (100%). The study was terminated early with poor recruitment.

Conclusions

PTCy alone may ensure safety, but PTCy alone may ensure safety. However, in this small cohort, PTCy monotherapy failed to provide adequate immunosuppression, necessitating CNI-based therapy in two of three patients for immune-mediated complications. Consistent with prior studies in HLA-matched settings that have not shown superiority of PTCy monotherapy over PTCy plus CNI, GVHD prophylaxis with single-agent PTCy should be carefully considered.