Intermediate Dose Post-Transplant Cyclophosphamide Is Associated with Faster Engraftment and Similar Other Outcomes When Compared with Full Dose Post-Transplant Cyclophosphamide Among Patients Undergoing Allogeneic Transplantation: A Single Center Retrospective Analysis

Introduction: Post-transplant cyclophosphamide given at 50 milligrams per kilogram on days 3 and 4 (full dose or FD-PTCy) is highly effective at preventing graft-versus-host disease (GVHD) but has been potentially associated with higher rates of infection, hemorrhagic cystitis, cardiac toxicity, and other toxicities. Preclinical and early clinical studies have demonstrated that an intermediate dose of PTCy (25 milligrams per kilogram on days 3 and 4) (ID-PTCy) given to patients undergoing HLA-mismatched bone marrow transplantation is feasible and may be associated with similar rates of acute GVHD; faster engraftment; a lower incidence of viral infections; and less severe mucositis. Given this promising data, our center has implemented the use of ID-PTCy in select patients undergoing transplantation that are at higher risk for transplant-related mortality (TRM) and/or PTCy-related toxicity. However, the efficacy and side effect profile of ID-PTCy, particularly in comparison to FD-PTCy, remains unclear.

Methods: We performed a single-center, retrospective review of patients undergoing allogeneic transplantation who received ID-PTCy for GVHD prophylaxis. All patients aged 18 years or older were included for analysis. For comparison, a 1:1 matched cohort undergoing transplantation with FD-PTCy was selected. Patients were matched based on diagnosis; age within 10 years; hematopoietic cell transplant comorbidity index (HCT-CI) within 1; Karnofsky performance status (KPS) within 10; conditioning intensity; and graft source. The primary endpoint was TRM at day 100. Key secondary endpoints include rates of grade III-IV acute GVHD; neutrophil engraftment; platelet engraftment; CMV viremia requiring treatment; and symptomatic BK cystitis. Exploratory endpoints include incidence of moderate-severe chronic GVHD; relapse; relapse-free survival; GVHD-free relapse-free survival; and overall survival. Outcomes were analyzed using Gray’s sub-distribution method to account for competing risk or Cox proportional hazards models as appropriate. This study was approved by our Institutional Review Board and conducted in accordance with the Declaration of Helsinki.

Results: Fifty-four patients were included for analysis, twenty-seven in each group. The median age was 61 (range 22-74) years and 28% of patients were African American. Less patients in the ID group received a haploidentical donor (3 vs 8; p = 0.24). Median duration of follow-up was 211.5 days in the ID-PTCy group and 233 days in the FD-PTCy group. Five patients in the ID group and twelve in the FD group were dead at the time of last follow-up. Patients in the ID group were transplanted in later years compared with patients in the FD group (100% in the ID group were transplanted between 2023-2024; 51.8% in the FD group were transplanted between 2016-2019; p<0.001). All patients received a peripheral blood graft. TRM at 100 days (11% versus 22%; HR 0.32; p = 0.081) and infection-related death (40% versus 58.3%; p = 0.56) were non-significantly lower in the ID group. Day 30 neutrophil engraftment was significantly faster in the ID group (93% vs 78%; HR 2.38; p = 0.004) along with day 100 platelet engraftment (89% versus 78%; HR 1.85; p = 0.039). Rates of grade III-IV acute GVHD were low in both groups (11% for ID versus 3.7% for FD at 180 days; HR 2.97; p = 0.3). In the ID group compared with the FD group, incidence of symptomatic BK cystitis (12 versus 3.7% at 1 year; HR 3.28; p = 0.25) was non-significantly higher, while incidence of CMV viremia requiring treatment (7.4% versus 25% at 1 year; HR 0.33; P=0.17) was non-significantly lower. One-year overall survival was non-significantly higher in the ID group (72.2% versus 52.3%; HR 0.46; p = 0.157).

Conclusions: In this single-center, retrospective review, neutrophil and platelet engraftment were faster among patients receiving ID-PTCy. Faster hematopoietic recovery may have contributed to the lower rate of TRM. Other outcomes were comparable. In this analysis, patients receiving ID-PTCy were transplanted later than those receiving FD-PTCy, and lack of institutional experience with PTCy in earlier years may have affected outcomes in the FD group. This study is limited by its single-center, retrospective nature; limited patient numbers in each group; and a limited duration of follow-up in each group. A propensity score analysis is planned.