Methotrexate alters hematopoietic recovery and engraftment kinetics when added to cyclosporine for acute GVHD prophylaxis after reduced-intensity stem cell transplantation

Abstract

Methotrexate (MTX) is a standard drug for graft-versus-host disease (GVHD) prophylaxis, but its effects on hematopoietic recovery and donor engraftment in the setting of reduced-intensity stem cell transplantation (RIST) are not well described. We compared these parameters and acute GVHD in patients with hematologic malignancies undergoing RIST on 2 consecutive clinical trials using identical reduced-intensity conditioning (fludarabine and cyclophosphamide). Group 1 included 50 patients receiving cyclosporine (CSA) alone for GVHD prophylaxis after RIST. Group 2 included 24 patients receiving CSA+ MTX (5 mg/m2 on days +1, +3, +6, +11) for GVHD prophylaxis. The groups were similar with respect to host immune status before RIST, age, and allograft dose of CD34+ and CD3+ cells. All patients in each group received salvage therapy with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus fludarabine (EPOCH-F) prior to RIST. Fourteen patients in the CSA/MTX group also received rituximab with EPOCH-F. Hematopoietic recovery was delayed in the CSA/MTX group, with median neutrophil recovery (>500/μL) and platelet recovery (>100K/μL) occurring 3 and 6.5 days later, respectively, than in the CSA group. Donor engraftment was rapid and complete for most patients in each group (median total mononuclear cell chimerism 100% at day +28 for both groups), and no patient experienced graft rejection. However, full donor chimerism (>95%) was less common for CSA/MTX (75% at day +28, 71% at day +100) than for CSA (90% at day +28, 97% at day +100). Adding MTX to CSA decreased the incidence and severity of acute GVHD. Grade 2–4 acute GVHD occurred in 33/50 (66%) CSA patients, versus 9/24 (38%) CSA/MTX patients. Grade 3–4 GVHD affected 17/50 (34%) CSA patients, including 6 with grade 4 GVHD and 8 with steroid-refractory disease. In contrast, only 5/24 (21%) of CSA/MTX patients had grade 3 GVHD, while none had grade 4 or steroid-refractory GVHD. No treatment-related deaths occurred in the CSA/MTX group, but 14 CSA patients died of treatment-related complications. Thus, the addition of MTX to CSA markedly attenuates the GVH response post RIST, slowing donor engraftment and delaying hematopoietic recovery. These data illustrate the sensitivity of engraftment kinetics to the intensity of GVHD prophylaxis following RIST. Further studies should determine if CSA/MTX will be associated with an increased risk of disease progression after RIST.