GVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide

GVHD Prophylaxis With Methotrexate and Cyclosporine in Haploidentical Stem Cell Transplantation Using Posttransplant Cyclophosphamide in Hematologic Malignancies: Phase I/II Trial

Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic strategy for many malignant and benign hematologic diseases. Haploidentical HCT has been increasingly used in patients lacking a HLA-matched donor due to its prompt availability, possibly lower cost and results comparable with other donor types. Graft-versus-host disease (GVHD) is the main cause of morbidity and mortality after HSCT, and prophylactic strategies are routinely used. In the context of haploidentical HCT, posttransplant cyclophosphamide plus cyclosporine and mycophenolate mofetil (MMF) is the most common platform used in Brazil. Data comparing MMF and methotrexate (MTX) as GVHD prophylaxes have proved controversial in other donor types, yet some large studies have showed that MTX is associated with lower risk of GVHD and improved long-term outcomes. Moreover, it is known that MMF is a potent inhibitor of natural killer (NK) cells, possibly interfering with the graft-versus-leukemia effect in haploidentical HCT. Given the possible advantages and the absence of consistent evidence regarding safety, efficacy and ideal dosage of MTX as GVHD prophylaxis in this setting, we propose a phase I / II study evaluating this drug in adult patients with hematologic malignancies undergoing haploidentical HCT with posttransplant cyclophosphamide.

Inclusion Criteria:

• Diagnosis of acute myeloid leukemia and chronic myeloid leukemia in complete morphologic remission, myelodysplastic syndrome with less than 10% in bone marrow or peripheral blood, Ph-negative acute lymphoblastic leukemia in complete morphologic remission, chemosensitive Hodgkin lymphoma or non-Hodgkin lymphoma in at least partial remission
• Donor type: haploidentical related donor
• Graft source: bone marrow or peripheral blood
• Recipients of non-myeloblative or myeloablative intensity conditioning
• Left Ventricle Ejection fraction > 40%
• Estimated creatinine clearance > 40 mL/min
• Adjusted DLCO ≥ 40% and FEV1 ≥ 40%
• Total bilirubin < 2x ULN e ALT/AST < 2.5x ULN

Exclusion Criteria:

• Prior allogeneic transplant
• Ex-vivo graft manipulation (T-cell-depleted or CD34-selected grafts)
• Use of alemtuzumab or anti-thymocyte globulin
• KPS < 70%
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
• Pregnant or lactating women
• Patients seropositive for human immunodeficiency virus (HIV) or active hepatitis B or C infection by PCR
• Presence of fluid collection (ascites, pleural or pericardial effusion) that may interfere with methotrexate clearance or make methotrexate use contraindicated
• Patients with a serious medical or psychiatric illness likely to interfere with participation in this study