Efficacy and Safety of Reduced-Doses of Post-Transplant Cyclophosphamide in Matched Peripheral Blood Stem Cell Transplantation, a Multicenter Study

Introduction: post-transplantation cyclophosphamide (PTCy) 50 mg/kg/day on D3 and D4, firstly introduced in the haploidentical setting, has demonstrated significant efficacy in reducing the incidence of severe acute and chronic GvHD. The aim of this study was to evaluate efficacy and safety of reduced dose of PTCy to 30 mg/kg/day on D3 and D4 in HLA-matched patients from two institutions, encompassing post-HCT toxicity, engraftment, and GvHD.

Methods: this was a multicenter, observational study in two university hospitals in Mexico and Spain from February 2018 to May 2024. Adults with hematological malignancies who received an HLA-matched peripheral blood stem cell (PBSC) hematopoietic cell transplantation (HCT) from siblings (MSD) or unrelated donors (MUD) with low-dose PTCy, 30 mg/kg on D3 and D4, plus calcineurin inhibitors D+90-140 with or without mycophenolate mofetil (MMF) until D+35 as GVHD prophylaxis. Clinical and laboratory data were collected retrospectively from medical records.

Results: we included 56 patients, with a median age of 52 years (IQR, 29-68), 33 (59%) were male, acute leukemia (AL) was the most common diagnosis (n=35, 63%). Thirteen (23%) patients had HCT-CI ≥3 and 20 (36%) had a high or very high DRI. The median CD+34 cells infused were 6.05x10e6/kg (IQR, 4.3-9.6). Most (n=38, 68%) received reduced-intensity conditioning (RIC), and 31 (55%) had MSD, 9 (16%) were female donors to male patients. Twenty-one (38%) patients received additional MMF in the GvHD prophylaxis.

All patients had successful donor engraftment, except 2 (4%) who died during neutropenic phase, due to de novo cardiac and renal failure, respectively. Median time for neutrophil recovery was 17 days (IQR, 13-24). Full donor chimerism was achieved after 30 days in 46 (85%) patients. One patient presented cytokine release syndrome (2%), febrile neutropenia was developed in 27 patients (48%), early-onset hemorrhagic cystitis in 3 (5%) that resolved with supportive care, and 5 (9%) had CMV reactivation. No thrombotic microangiopathy or sinusoidal obstruction syndrome were identified.

Cumulative incidences of overall, grades II-IV and III-IV aGVHD at day 100 were 43% (95% CI, 29-56), 30% (95%, 18-42) and 5% (95% CI, 1-14), respectively. No grade IV aGVHD was observed. Cumulative incidence of cGVHD and moderate/severe cGVHD at 1 year was 8% (95% CI, 2-20) and 5% (95% CI, 0-16), respectively.

At data cutoff, the median follow-up was 6.7 months (IQR, 4-18.1). The cumulative incidence of non-relapse mortality at 1 years was 9% (95% CI, 2-21). Estimated 1-year overall survival, relapse-free survival, and disease-free and GVHD-free relapse-free (GRFS) were 73% (95% CI, 59-91), 64% (95% CI, 49-83) and 58% (95% CI, 43-78), respectively. All outcomes were similar in both participating centers.

Conclusion: our study demonstrated that reduced doses of PTCy, 30 mg/kg on D3 and D4, in adult patients undergoing PBSC HLA-identical HCT, either MSD or MUD, were effective and safe with high engraftment rate, reduced incidence of severe forms of both acute and chronic GvHD and favorable survival outcomes, suggesting that reduced-dose PTCy is a viable option for reducing toxicity. To our knowledge, this is the largest reduced-dose PTCy analysis in an HLA-matched donor population.