Optimizing the dosing of post-transplantation cyclophosphamide for peripheral blood stem cell transplantation

The National Cancer Institute awarded a $695,155 Cooperative Agreement to Fred Hutchinson Cancer Center on September 1, 2026, under the Cancer Treatment Research program (CFDA 93.395) to optimize post-transplantation cyclophosphamide (PTCY) dosing for hematopoietic cell transplantation with peripheral blood stem cell grafts.

The award funds a phase I/II clinical trial examining PTCY dose de-escalation in recipients of HLA-matched or HLA-haploidentical donor transplants using reduced-intensity conditioning. Preclinical data and prior phase I/II trials suggest that intermediate PTCY dosing of 25 mg/kg/day, rather than the standard high dose of 50 mg/kg/day, effectively prevents graft-versus-host disease while reducing toxicity, accelerating engraftment and T-cell recovery, and lowering infectious complications. The trial will test PTCY dosing optimization across separate cohorts with related HLA-matched donors, unrelated HLA-matched donors, and HLA-haploidentical donors to identify optimal dosing based on graft source and donor-recipient HLA disparity.

Work is performed in Seattle, Washington. The period of performance runs from September 1, 2026, through August 31, 2031. The Cancer Treatment Research program supports development and evaluation of improved cancer treatment methods through fundamental and applied research, including stem cell and bone marrow transplantation, chemotherapy optimization, and studies to reduce treatment toxicity.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for many malignant and severe nonmalignant hematologic diseases, but its success has been limited by graft-versus-host disease (GVHD) and donor availability. High-dose (50 MG/KG/day) post-transplantation cyclophosphamide (PTCY) reduces the risks of severe GVHD, allowing donors that are not fully human leukocyte antigen (HLA) matched (e.g., HLA-haploidentical) to be used nearly as safely as fully HLA-matched donors. Thus, high-dose PTCY has greatly improved access to HCT. High-dose PTCY also recently became standard-of-care (SOC) for HLA- matched peripheral blood stem cell (PBSC) HCT. Our preclinical data showed that intermediate, rather than high, dosing of PTCY maximally prevents GVHD while leading to less toxicity and better immune recovery. In a phase I/II clinical trial (NCT03983850) for myeloablative HLA-haploidentical bone marrow HCT, we found that 25 MG/KG/day PTCY effectively prevented GVHD and also had clinical benefits including less toxicity, faster engraftment, faster T-cell recovery, and less cytomegalovirus infection and BK virus-associated cystitis compared with high-dose PTCY. Our ongoing phase I/II trial (NCT04959175) of bone marrow HCT with reduced- intensity conditioning (RIC) and PTCY 25 MG/KG/day has shown equally promising results, including low relapse rates. Yet, the optimal PTCY dose has not been defined and likely will vary based on the graft source and donor/recipient HLA disparity. Here, we will optimize PTCY dosing for HCT with PBSC, the graft source used for ~90% of hcts worldwide. In aim 1, we will conduct a PTCY dose DE-escalation phase I/II clinical HCT trial with RIC and PBSC grafts from HLA-matched (related or unrelated) or HLA-haploidentical donors in separate cohorts (NCT05436418). This study will identify the lowest weight-based PTCY dose for each cohort that maintains protection against severe acute and chronic GVHD and graft failure, and also will assess the clinical benefits of the lower doses. In aim 2, we will determine the pharmacokinetic exposures of PTCY and its active metabolites for each patient and assess how they affect risk for GVHD and relapse, recovery of T-cell subsets contributing to or protecting from GVHD occurrence, and longitudinal lymphocyte subset immune reconstitution. In aim 3, we will determine associations between cyclophosphamide metabolite exposure and T-cell receptor (TCR) repertoire diversity and clonal dynamics, anti-viral antibody repertoires, T-cell responses to BK virus and herpes viruses, BK viral levels in blood and urine, and the severity of BK virus-associated cystitis. For aims 2 and 3, differences between HLA-matched and HLA-haploidentical HCT also will be assessed. Our work will leverage the expertise of the three collaborating institutions and associated investigators to optimize the current SOC while deeply probing the impact of PTCY dosing on immune recovery and subsequent GVHD development, relapse risk, and infectious complications. Our results will motivate and inform future randomized studies to definitively identify optimal PTCY dosing according to donor type and stem cell source.