Reduced Incidence of Acute Graft Versus Host Disease (GVHD) and Transplant-Related Mortality (TRM) with the Addition of Short-Course Mini-Dose Methotrexate (MTX) to Cyclosporine (CSA) as GVHD Prophylaxis Following Nonmyeloablative Hematopoietic Stem Cell Transplantation (NST).

Acute GVHD is a major cause of morbidity and mortality following NST. A high incidence of aGVHD occurs when CSA alone is used as prophylaxis. We investigated the effect of combining either mycophenolate mofetil (MMF) or an abbreviated course of low dose MTX with CSA on the incidence and severity of aGVHD. Between 11/97 and 07/07, 230 consecutive patients (pts) (solid tumors n=127, hematologic malignancies n=57, non-malignant hematologic disorders n=46) underwent conditioning with fludarabine (125mg/m²) and cyclophosphamide (120mg/kg), followed by a G-CSF mobilized PBSC transplant from an HLA identical (n=222: 96%) or 5/6 HLA-matched (n=8: 4%) related donor. Forty-eight pts with a history of heavy RBC transfusions or those receiving a 5/6 HLA-matched transplant had ATG (40mg/kg/d × 4 days) added to their conditioning. The initial cohort of pts (Group 1, n=66), received CSA alone (dose adjusted to maintain therapeutic serum levels) as GVHD prophylaxis. Due to the high incidence of severe aGVHD in this group, subsequent pts received CSA with either MMF (1 gram po bid; Group 2, n=82) or an abbreviated course of mini-dose MTX (5mg/m² days +1, +3, +6; Group 3, n=82). In all three groups, decisions regarding discontinuation of CSA and MMF were based on donor T cell chimerism, presence of GVHD, and disease status. With a median follow-up of 2963, 2317 and 894 days in the three consecutive cohorts, a comparison was undertaken using competing risk analysis. The incidence of grades II–IV and III–IV GVHD was significantly higher in pts receiving CSA alone or CSA+MMF compared to those receiving CSA+MTX; the cumulative incidence of grades II–IV GVHD in the three groups was 56%, 59%, and 37% (p=0.05) while grades III–IV GVHD occurred in 30%, 34%, and 15% (p=0.019) respectively. The incidence of chronic GVHD (45% vs. 57% vs. 46%, p=0.27) was similar in the three groups. The lower incidence of aGVHD associated with MTX use was accompanied by a significantly improved TRM in group 3 pts; transplant related mortality was 21% in group 1, 21% in group 2 and 5% in group 3 pts (p=0.019). The impact of adding MMF or MTX to CSA on disease-specific outcome in pts with different malignant diseases could not be assessed due to small sample sizes.

Conclusion: The addition of an abbreviated course of mini-dose methotrexate to CSA was associated with a significantly lower incidence of grades II–IV and III–IV aGVHD as well as lower TRM compared with CSA used alone or in combination with MMF in pts undergoing NST. To our knowledge this is the first report demonstrating a benefit of adding mini-dose MTX for GVHD prophylaxis in patients undergoing NST.