Cyclosporine (CSA) and methotrexate (MTX) is a standard, effective regimen for prophylaxis of GVHD following allogeneic BMT. However, MTX increases mucosal injury and delays hematopoietic recovery in myeloablative allografts. We demonstrated in a prospective, randomized trial that CSA and mycophenolate mofetil (MMF) decreased mucositis and permitted more rapid neutrophil engraftment versus CSA/MTX in 40 patients undergoing myeloablative allogeneic BMT from matched sibling donors, with similar rates of acute and chronic GVHD, relapse, and 6-month survival. We subsequently adopted CSA/MMF as our preferred regimen for GVHD prophylaxis in matched sibling donor allografts. The objective of this analysis is to describe peri-transplant and long-term outcomes in an expanded cohort, comparing CSA/MMF with CSA/MTX. Inclusion criteria: adult patients (18 years or older) who underwent allogeneic BMT with myeloablative conditioning from a matched sibling donor with either CSA/MTX (n=76) or CSA/MMF (n=89) for GVHD prophylaxis. Median age was 45 years (range, 18–65).

Diagnoses: AML (50%), CML (15%), ALL (15%), MDS (9%), NHL (6%), other (8%). Only 21% of patients had more than 2 prior regimens, and 9% had prior radiotherapy. Preparative regimens included busulfan (Bu) and cyclophosphamide (Cy) (64%), Bu/Cy + etoposide (19%), TBI-based (13%), or other (4%). All but 1 patient who received Bu/Cy + etoposide also received CSA/MTX. No other baseline characteristic differed between the groups. Median CD34+ cell dose: 1.78 x 10E6/kg overall, no difference between groups; CD3+ cell doses were incomplete for most patients who received CSA/MTX, but median values were equal between CSA/MMF and CSA/MTX patients with available data. Compared with CSA/MMF patients, those who received CSA/MTX had worse mucositis (median score 0.17 versus 1.0, P<0.001) and longer length of hospital stay for transplantation (27 versus 34 days, P<0.001). The risk of mucositis remained elevated for patients who received CSA/MTX versus CSA/MMF after adjusting for the influence of etoposide in the preparative regimens (P<0.001). Patients who received CSA/MMF had more rapid neutrophil engraftment (ANC > 500, median 11 versus 19 days, P<0.001) and platelet engraftment (platelets > 20,000, median 19 versus 24 days, P<0.001) post-transplantation. Median follow-up post allogeneic BMT was shorter for CSA/MMF patients (36 vs. 82 months, P<0.001). The probabilities of acute GVHD (all grades, grades II-IV, grades III-IV) were similar for CSA/MMF (58%, 36%, 18%) and CSA/MTX (66%, 42%, 15%) (P=NS). CSA/MMF patients experienced a lower likelihood of chronic GVHD than CSA/MTX patients (overall 42% vs. 53%, P=0.04; extensive 20% versus 37%, P=0.01). Overall infection rates were similar (P=NS), although CMV reactivation or infection was somewhat more frequent in CSA/MMF patients (58% versus 43% at 1 year, P=0.08). Five-year rates of relapse (36% versus 39%), non-relapse mortality (39% versus 39%), and overall survival (39% versus 37%) also did not differ between CSA/MMF and CSA/MTX patients. In multivariable models, CSA/MTX prophylaxis was the only factor associated with a greater risk of chronic GVHD (overall, HR 1.79, 95%CI 1.06– 3.02, P=0.03; extensive, HR 2.27, 95%CI 1.16–4.44, P=0.02).

CONCLUSION: GVHD prophylaxis with CSA/MMF in matched sibling donor allografts reduces mucositis, time to engraftment, length of stay, and the risk of chronic GVHD compared with CSA/MTX, without adversely influencing rates of relapse, non-relapse mortality, or overall survival. The protective effect of CSA/MMF against chronic GVHD may be related to the fact that MMF is administered for a longer period post-transplantation than MTX, or the reduction in peri-transplant mucosal injury with MMF could result in decreased activation of potentially alloreactive T-cells. CSA/MMF is a safe and effective regimen for prophylaxis against GVHD in matched sibling donor allogeneic BMT with myeloablative conditioning.

Disclosures: No relevant conflicts of interest to declare.

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