Efficacy of Azacytidine (5-AC) Given as Maintenance or Salvage Therapy for Patients (pts) with Acute Leukemia Post Allogeneic Stem Cell Transplantation (HSCT).

Background. Relapse is the most frequent cause of treatment failure in pts with refractory acute leukemia undergoing HSCT. Modifications of the preparative regimen using multiple combinations of chemotherapy and physical agents have failed to reduce the risk of relapse without an increase in non relapse mortality. 5-AC is a DNA hypomethylating agent that may induce leukemic cell differentiation and increased immunogenicity, therefore potentially increasing the graft-versus-leukemia effect. 5-AC, at low doses, through its hypomethylation effect has shown significant activity in pts with myelodysplastic syndromes. Furthermore, low doses are likely to be better tolerated after ASCT. Patients 5-AC was given as salvage therapy for post HSCT relapse in 7 pts with acute myeloid leukemia (AML) and as maintenance therapy in 5 (4 AML, 1 acute lymphocytic leukemia) with high-risk disease. Median age was 52 years (range, 29–67 years). At the time of HSCT, 8 pts were refractory and 4 pts (AML) were in second (n=2) and third complete remission (CR) (n=2). Four pts received and failed previous HSCT following ablative regimen. Donors were HLA-compatible related (n=2), unrelated (n=7; cord blood, n=2), or syngeneic (n=1). Conditioning regimen was gemtuzumab ozogamicin 2 mg/m2, fludarabine and melphalan 140 mg/m2 in 3 pts, fludarabine and melphalan 140 mg/m2 in 6, cyclophosphamide, fludarabine and low dose TBI in 2, and busulfan and cyclophosphamide in 1.GVHD prophylaxis was tacrolimus and mini-methotrexate. ATG was administered to recipients of unrelated donor transplants.

Results. After HSCT all pts were in CR. 5-AC was administered at the time of relapse that occurred at a median of 11 months (range, 5–26), and at a median of 4 months (range, 1–12) post HSCT as a maintenance therapy. 5-AC was given at the dose of 16 mg/m2 daily × 5 repeated every 4 weeks (n=3) and 25 mg/m2 daily × 5 (n=9). A median of 7 cycles (range, 2–18 cycles) were delivered. Among 7 pts with relapsed disease [medullary relapse in 4 (median percentage of blasts, 39), extramedullary relapse in 3], 3 achieved a sustained CR for 7+ months, 2 had sustained partial remission for 3+ months, and 2 pts did not respond. All pts receiving 5 AC as maintenance therapy remain in CR for a median of 14+ months (4–28). There was no significant increase in the rates of GVHD. After a median follow-up of 14 months (range, 3–20 months) from the start of 5-AC therapy,11 out of 12 pts are alive, 9 in CR. The 12-month actuarial survival from HSCT is 91%. There were no extra-medullary toxicities and only grade I/II hematologic toxicities were noted.

Conclusion. Low dose 5-AC may be effective in the post HSCT setting. Further follow-up and larger number of patients will be necessary to confirm these observations.