A Phase I/II Trial of Bortezomib, Tacrolimus and Methotrexate for Prophylaxis of Acute Graft Versus Host Disease after HLA Mismatched Reduced Intensity Transplantation

There remains a need for better control of acute graft versus host disease (GVHD) after HLA mismatched peripheral blood stem cell (PBSC) allogeneic transplantation. Bortezomib is a small molecule proteasome inhibitor with immunomodulatory properties, and preclinical data indicate utility in GVHD control after allogeneic transplantation. We report on Phase I of a Phase I/II trial of bortezomib, tacrolimus and low dose methotrexate for GVHD prophylaxis after HLA mismatched reduced intensity conditioning (RIC) PBSC transplantation for patients with hematologic malignancies. Dose limiting toxicity (DLT) by day 45 after PBSC infusion is the primary endpoint, evaluating both acute bortezomib toxicity (e.g. neuropathy) and impact on stem cell function. Secondary endpoints include incidence of acute and chronic GVHD.

Patients with 1-2 locus antigen/allele mismatch (HLA-A, -B, -C, -DRB1) are eligible. Pretransplant conditioning consists of busulfex (0.8 mg/kg/d) and fludarabine (30 mg/m²/d) each for 4 days. GVHD prophylaxis is bortezomib (dose level cohorts of 1, 1.3 or 1.5 mg/m² on days +1, +4, +7), tacrolimus (days –3 to +180) and low dose methotrexate (5 mg/m² on days +1, +3, +6, +11).

13 patients were enrolled on the bortezomib dose finding Phase I portion of the study. At bortezomib dose level 1, one of 5 patients had a possible DLT, with poor engraftment likely related to progression of underlying MDS/AML. At bortezomib dose level 1.3, none of 3 patients had a DLT. At bortezomib dose level 1.5, two of 5 patients had a possible DLT. One patient failed to engraft in the setting of minimally treated myeloproliferative disease; the other had graft rejection in the setting of persistent CLL post transplant. Bortezomib dose level 1.3 is considered the MTD, and 6 additional patients have been enrolled at this dose on the expanded Phase I/II portion of the study thus far.

Overall, the 19 patients on study have a median follow-up of 12 months. No neurotoxicity has been noted. No platelet or neutrophil nadir was noted in 8 patients. The median time to neutrophil engraftment (ANC >500) was 13 days in 7 patients experiencing a nadir; and the median time to platelet engraftment (Plts >20,000) was 19 days in 8 patients with a nadir. Grade 2-4 acute GVHD has occurred in 2 of 17 evaluable patients (one each at bortezomib dose level 1 and 1.5), for a 180 day cumulative incidence of 14%, with relapse or death as a competing risk. Chronic GVHD has occurred in 6 of 12 evaluable patients, for a 1 year cumulative incidence of 50%. Overall and relapse free survival at 1 year are 73% and 58% respectively.

In summary, GVHD prophylaxis with bortezomib, tacrolimus and low dose methotrexate after busulfex/fludarabine RIC PBSC transplantation is well tolerated. The low rate of acute GVHD in the HLA mismatched context is encouraging, and additional accrual is ongoing.