Background:

Post-transplant cyclophosphamide (PTCy), mycophenolate mofetil, and tacrolimus have become a standard regimen for graft-versus-host disease (GVHD) prophylaxis in reduced-intensity conditioned (RIC) peripheral blood stem cell transplantation (PBSCT), owing to their demonstrated efficacy in reducing both acute and chronic GVHD (Bolanos-Meade et al.). Conventional practice involves maintaining calcineurin inhibitor (CNI)-based immunosuppression (IS) for approximately 180 days, with tapering initiated around day 100. Recent studies suggest that, in the context of PTCy, a shorter duration of IS (discontinuation by days 90–100) may yield comparable outcomes in preventing acute GVHD (aGVHD) and may theoretically reduce relapse risk. However, available data are limited by short follow-up durations, small sample sizes, and focus on RIC transplantation. The impact of shortened IS (SIS) on chronic GVHD (cGVHD) incidence and subsequent systemic IS requirements remains unclear. To address this gap, we evaluated cGVHD outcomes in patients with extended follow-up after PBSCT using a PTCy platform and SIS approach.

Methods:

Following IRB approval, we retrospectively reviewed all consecutive adult patients (≥18 years) who underwent HLA-matched or mismatched, RIC or myeloablative PBSCT for malignant hematologic indications at the University of Wisconsin between January 2018 and March 2024. Of 353 transplants, 277 patients (78.5%) met inclusion criteria. Exclusions included pediatric patients (n=16), absence of CNI use (n=19), non-malignant transplant indications (n=25), multiple transplants (n=10), absence of PTCy (n=6), and confirmed relapse. Patients were stratified by total IS duration including taper: <120 days (SIS) vs. ≥120 days (traditional IS [TIS]). SIS was primarily physician-directed, based on high-risk disease, declining chimerism, or other clinical factors. Primary outcomes included cumulative incidence (CI) of aGVHD and cGVHD. Secondary outcomes were relapse incidence, non-relapse mortality (NRM), and one-year overall survival. The log-rank test was used for between-group comparisons.

Results:

Baseline characteristics, including mean age (p=0.669) and sex distribution (p=0.564), were similar between groups. The median follow-up was 17.5 months (585 days; range, 36–1910). At last follow-up, 64.6% of patients were alive; 23.5% had died due to relapse, and 11.9% due to other causes. Of the 277 patients, 151 received SIS (mean tacrolimus duration: 76 days; range, 30–119), and 126 received TIS (mean duration: 172 days; range, 120–534) (p<0.001). The CI of aGVHD was 54.3% in the SIS group vs. 59.5% in the TIS group (p=0.383), and the CI of cGVHD was 20.0% vs. 23.0%, respectively (p=0.543). Among patients with cGVHD, 40.0% (12/30) in the SIS group and 41.4% (12/29) in the TIS group experienced severe disease (p=0.896). Systemic steroid therapy was required in 90.0% of SIS patients with cGVHD (80.0% requiring second-line therapy), and in 82.8% of TIS patients (72.4% requiring second-line therapy). Ruxolitinib was the most commonly used second-line agent in both cohorts. Relapse rates were significantly higher in the SIS group (37.1%) compared to the TIS group (19.8%) (p=0.001).

Discussion:

In this large single-center cohort, shortened immunosuppression (SIS) following PBSCT with PTCy resulted in comparable rates of aGVHD and cGVHD compared to traditional IS duration. Notably, no increase in severe cGVHD or need for systemic IS was observed with SIS. The overall incidence of cGVHD in both groups aligns with rates reported in the pivotal CTN 1703 trial. Although we did not observe a relapse risk reduction with SIS, this may reflect selection bias, as patients with high-risk disease were more likely to undergo early IS withdrawal. SIS appears to be a feasible approach, though its benefits and risks should be carefully evaluated and tailored to individual patient needs. We hypothesize that SIS may facilitate earlier initiation of anti-disease maintenance therapies when appropriate, reduce treatment-related toxicities, and lessen the burden of frequent clinic visits and monitoring—all without increasing the risk of GVHD. Prospective, randomized studies are warranted to validate these findings and identify patient populations most likely to benefit from early IS discontinuation.

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2025
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