The Efficacy and Safety of Cyclophosphamide in Treating Refractory Hepatic aGVHD

Background

Post-transplant liver dysfunction affects approximately 50%-80% of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Hepatic acute graft-versus-host disease (aGVHD) is a substantial contributor to this dysfunction and is associated with poor prognosis and reduced survival rates for patients after allo-HSCT. Cyclophosphamide (CTX) is a well-established immunosuppressive and cytotoxic agent commonly used in pretransplant conditioning regimens. However, its potential efficacy in managing refractory hepatic aGVHD remains unexplored.

Methods

We conducted a prospective, single-arm trial to investigate the efficacy and safety of intravenous cyclophosphamide (CTX) at a weekly dose of 100-400 mg in patients with refractory hepatic aGVHD（refractory to second-line therapies） following allo-HSCT. The median cumulative dose of CTX administered was 900 mg (range: 200-2600 mg). The primary endpoint was overall response (complete response or partial response) at day 28 and day 56. Secondary endpoints included overall survival (OS), relapse, and non-relapse mortality.

Results

Between January 2018 and November 2023, 50 patients (median age [range], 34 [10-58] years; 19 [38.0%] women) received CTX treatment and were included in this study. 44 patients (88%) presented with Grade III or IV aGVHD before treatment. A total of 20 patients (40.0%) had a complete remission, and 14 (28.0%) had a partial remission, with an ORR(overall response rate) of 68.0% (34 patients; 95% CI, 53.3%-80.4%) at day 28, and 70% patients(35 patients; 95% CI, 55.4%-82.1%) achieved ORR at day 56. Patients who responded at day 56 received a relatively higher dose CTX (p=0.044). The median follow-up for this cohort was 22.9 months (range, 1.1-60.2) months, with the median OS of 4.7 months (range, 1.1-34.1) months. 5 patients (10%) experienced relapse and the non-relapse mortality rate was 48%. Hepatic-variant of liver aGVHD demonstrated prolonged survival compared to classic liver aGVHD (p=0.045). Prolonged survival was also observed in patients with skin aGVHD(p<0.01), whereas gastrointestinal involved had poorer survival(p<0.01). The most common adverse events up to day 28 were neutropenia (in 34 [68.0%] patients) and cytomegalovirus infection (in 26 [52.0%] patients).

Conclusions

Cyclophosphamide demonstrated a significant response in patients with refractory hepatic aGVHD and a reasonably well-tolerated safety profile. These findings contribute to the evidence supporting CTX as a promising therapeutic choice for refractory hepatic aGVHD.

No relevant conflicts of interest to declare.