Cladribine as an Alternative to Fludarabine in Melphalan and Total Body Irradiation-Based Reduced Intensity...

Drug shortages, such as the fludarabine (FLU) shortage during the COVID-19 pandemic, necessitate finding alternative agents for allogeneic stem cell transplantation (ASCT) conditioning regimens. Cladribine (2-CdA), a purine nucleoside analog with broad antileukemic and potent immunosuppressive activity, emerged as a theoretically viable substitute based on its mechanism of action, wider availability, and lower cost. This prospective cohort study aimed to systematically compare the safety and efficacy of substituting 2-CdA for FLU in a reduced-intensity conditioning (RIC) regimen comprising low-dose melphalan (MEL) and total body irradiation (TBI). Patients with high-risk hematological malignancies undergoing ASCT between November 2019 and December 2022 were included in this prospective single-center non-randomized cohort study. Consecutive enrollment minimized selection bias. Patients received MEL 75 mg/m² on day -2, 200 cGy TBI on day -1, and either 2-CdA 10 mg/m² subcutaneously or FLU 40 mg/m² intravenously on days -5 to -2, with allocation determined by drug availability. Graft-versus-host disease (GvHD) prophylaxis comprised a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) for matched related donors, and post-transplant cyclophosphamide with CNI and MMF for unrelated and haploidentical donors. The primary endpoint was to compare safety, including regimen-related toxicities and transplant-related mortality (TRM). Secondary endpoints included overall survival (OS), progression-free survival (PFS), engraftment kinetics, and GvHD incidence. Statistical analyses included Kaplan-Meier estimates, log-rank tests, and multivariate Cox regression. In a cohort of 70 consecutive patients undergoing ASCT with either 2-CdA (n = 27) or FLU (n = 43) conditioning, baseline characteristics were balanced across groups. The median follow-up was 18.4 mo (range 0.1 to 58.9). FLU was associated with faster neutrophil engraftment (15 versus 19 days, P = .01), but comparable platelet engraftment, engraftment failure rates, duration of hospital stay, and transfusion requirements. Toxicity profiles were comparable, and no grade 3 to 4 non-hematological toxicities were observed in either cohort. Acute GvHD occurred more frequently with FLU (62.8% versus 33.3%, P = .04), but chronic GvHD and other complications were similar. TRM, OS, and PFS did not differ significantly between regimens. However, non-significant trends suggested inferior long-term OS and PFS with 2-CdA, particularly in subgroups with high-risk disease or lymphoma. Multivariate analysis identified Eastern Cooperative Oncology Group performance status ≥1 as a powerful independent predictor of inferior OS (hazard ratio [HR]: 2.84, P = .008) and PFS (HR: 2.89, P = .006). Substituting 2-CdA for FLU in this 2-CdA/MEL75/TBI200 RIC regimen during a drug shortage demonstrated comparable safety profile, survival outcomes, and lower acute GvHD incidence, potentially reflecting enhanced T-cell suppression. These findings support 2-CdA as a viable alternative to maintain transplant access in high-risk populations, though results are specific to this regimen and patient cohort. Further randomized studies with extended follow-up are needed to validate long-term efficacy, optimize dosing, assess quality-of-life outcomes, and elucidate the immunologic mechanisms behind GvHD and survival differences.