Treatment of Recurrent or Persistent AML/MDS After Allogeneic Hematopoietic Cell Transplantation with Azacitidine.

Abstract 1288

Recurrence or persistence of disease after hematopoietic cell transplantation (HCT) remains a significant obstacle in the treatment of patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndromes (MDS). Standard therapies for relapsed disease include withdrawal of immunosuppression (WIS), donor lymphocyte infusion, induction chemotherapy, and in selected patients, a second HCT. Regardless of the intervention chosen, survival for post-transplant relapse has been dismal. Effective therapies without significant toxicity are needed.

Azacitidine, a DNA demethylating agent, is the only non-HCT therapy shown to prolong survival in patients with MDS. It has also shown efficacy in patients with AML when used alone as induction or consolidation therapy or in combination with the anti CD-33 antibody gemtuzumab. Its use following HCT was inspired by the discovery of the drug's potential to enhance the graft-versus-leukemia effect through demethylation of the KIR regions on donor NK cells and by enhancing HLA-DR2 expression on leukemic blasts. It has also been shown to modulate T-cells post-engraftment and may result in lower rates of GVHD without impairing the GVL effect.

Several small case series have been published evaluating azacitidine as therapy for treatment of relapse following HCT and have demonstrated improvement in disease status. None of these studies have examined azacitidine in the setting of persistent disease, which has become more relevant with the use of lower intensity conditioning regimens and the use of new methods to detect the presence of disease at extremely low levels.

In this retrospective study, we determined the outcomes of patients treated with azacitidine (75 mg/m²/day for 7 days +/− gemtuzumab (3mg/m²) on day 9, every 4 weeks) for post-HCT recurrence or persistence of AML/MDS. Azacitidine treatment was initiated following HCT if there was evidence of recurrent or persistent disease (defined as any recurrent abnormal blasts detected by flow on peripheral blood or marrow or recurrent cytogenetic abnormalities). Seventeen (74%) of the patients had AML while 6 (26%) had MDS. FAB subtypes of the latter included RAEB (3), RA (1), CMML (1) and unclassified (1). Eighteen (78%) patients underwent conventional high dose conditioning, and 5 (22%) patients underwent nonmyeloablative conditioning prior to HCT. Eleven (48%) of patients had low risk cytogenetics, 3 (13%) had intermediate risk, and 9 (39%) had high risk cytogenetics. Seventeen (74%), 0 (0%) and 6 (26%) of patients were diagnosed with persistent or relapsed disease within 100, 100–200 and > 200 days following HCT. Patients began azacitidine 0–242 (median: 17) days from time of relapse and completed a median of 2 azacitidine cycles (range 1–8). Overall 6-month survival from the day of relapse was 57% and from start of azacitidine therapy was 48%. Among the 18 patients who started azacitidine within 2 months of documented relapse the 6-month survival was 50%. Blast count at time of relapse was not significantly associated with survival (> 1% vs ≤ 1%, HR=1.26, p=0.63), nor was survival after initial treatment with azacitidine affected by longer time intervals prior to first administration (> 28 days vs ≤ 28 days, HR=0.85, p=0.76). There were 12 patients who received gemtuzumab with azacitidine, and the addition of gemtuzumab made no difference in survival (HR with gemtuzumab = 0.81 (0.3-2.1), p=0.66). The 6-month survival with azacitidine is superior to that observed with induction chemotherapy (20%) or WIS (10%). Azacitidine therapy may be superior to standard therapies for recurrent/persistent disease following HCT and warrants further study.