Feasibility of Low Dose Azacitidine Post T Cell Depleted Allogeneic Hematopoietic Stem Cell Transplants in Patients with Myeloid Malignancies At High Risk for Relapse

Background: Post transplant relapse remains a main cause of transplant failure and mortality in patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).  Azacitidine, a hypomethylating agent, has been reported to reduce post transplant relapse in these patients after unmodified allogeneic hematopoietic stem cell transplantation (HSCT).  There have been no reports of azacitidine use in patients undergoing T cell depleted (TCD) HSCT. Patients: Nine  patients; 4 with high risk MDS, 1 with AML evolved from MDS, 2 with therapy-related AML, and 2 with de-novo AML, who had undergone TCD HSCT, were treated with azacitidine post transplant. The dose of azacitidine, as determined in a phase 1 study, was 32mg/m2 subcutaneously daily for 5 days monthly. All patients had been conditioned with a myeloablative regimen of busulphan, melphalan, fludarabine and rabbit ATG and had received a peripheral blood stem cell graft from a matched or mismatched related or unrelated donor. Results: Seven patients were treated in complete remission as a prophylactic measure, one patient was treated in relapse and one patient received,  in addition to azacitidine, a dose of DLI (0.5x10⁶  CD3 cells/kg) for increasing host chimerism and a new cytogenetic abnormality. Treatment began at a median of 117 days post transplant (range 80-333) and patients received a median of 3 cycles (range 1-7). At a median of 8 months follow-up, 7 patients were alive and 2 had died; one of pulmonary failure, possibly secondary to busulphan and the other patient of relapsed disease. In one patient, treatment was discontinued after development of an EBV-LPD while receiving  budesonide  for upper GI GvHD,  and in another patient therapy was discontinued because of  severe pancytopenia secondary to adenovirus infection. A third patient had treatment interruption after developing dyspnea secondary to heart failure and chronic obstructive lung disease. The patient with relapsed disease had persistent pancytopenia throughout the treatment. In  the 8 remaining patients,  there were 4 with grade I anemia and/or thrombocytopenia. Only one of the 8 patients required G-CSF and azacitidine dose reduction (20%). However, this patient’s neutrophils were noted to decrease prior to initiation of Azacitidine, possibly related to treatment of an EBV-LPD with Rituxan. Two patients had grade I skin GvHD and one patient had grade 1 upper GI GvHD. Therapy with azacitidine did not worsen the severity of GvHD. Conclusions: This review shows that timely administration of low dose azacitidine is feasible after TCD transplant in patients with MDS and AML. The most common toxicity related to azacitidine, myelosuppression, has been reported only in patients who had concomitant viral infections. A phase II trial will be conducted to assess the efficacy of post transplant azacitidine after TCD transplant.