Phase 2 Study of Decitabine and Gemtuzumab Ozogamicin in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome- Outcome in Previously Untreated Patients.

Ligation of CD33 antigen on acute myelogenous leukemia (AML) cells by CD33 antibodies results in recruitment of docking protein Syk to the intracellular tail of CD33. Syk is a ‘tumor suppressor’ and anti-leukemic activity of gemtuzumab ozogamicin (GO), a CD33 antibody linked to calicheamicin, correlates with expression of Syk in AML cells (Balaian, L and Ball, ED. Leukemia 2006; 20, 2093). Treatment of AML cells with 5-azacitidine, a hypomethylating agent, increases expression of Syk and enhances antileukemia activity of GO. A report from a phase 2 study of 5-azacitidine with GO and hydroxyurea in older patients with untreated AML showed high remission rates (70%) (Nand S et al. Leuk Lymphoma. 2008;49:2141). We are investigating the efficacy and safety of the combination of GO with decitabine, another hypomethylating agent in AML and myelodysplastic sydromes (MDS).

Induction regimen comprises of decitabine 20 mg/m² intravenously (IV) daily for 5 days and GO 3 mg/m² IV X 1 on day 5. Initially an additional GO dose during induction was allowed if patient had circulating blasts on day 14, but the induction regimen was revised to omit mid-cycle GO and add 5 more days of decitabine, starting day 15±2, if day 14 bone marrow shows >5% blasts. Subsequent therapy allows for 5 additional cycles of decitabine administered at 20 mg/m² intravenously (IV) daily for 5 days and GO at 3 mg/m² IV X 1 on day 5 (administered every 4-6 weeks) as in induction without the day 15 ±2 dose of decitabine. Patients showing any response can continue beyond the first 6 cycles with decitabine x 5 days every 4-6 weeks for a total duration of 2 years. Patients with untreated/relapsed/refractory AML and high-risk myelodysplastic syndrome (MDS) (IPSS intermediate 2 or high) are eligible. Eligibility criteria include Serum creatinine </= 2 mg/dL, total bilirubin </= 2 mg/dL, AST (SGOT) and/or ALT (SGPT) </= 2.5 x upper limit of normal IULN) or </= 5 x ULN if related to disease, performance status </= 3.

We report on the 33 patients (AML=23, MDS=10) with previously untreated AML or MDS enrolled in the trial. The median age was 67 years (range, 56-84 years), median ECOG performance status= 1 (range, 0-2), 19 (58%) patients were male and 20 (61%) patients have poor risk cytogenetics. Twenty-one (64%) patients were treated according to the original schedule and 12 (36%) according to the revised schedule.

Responses were seen in 14 (42%) patients (8/12=67% in revised schedule, 6/21=29% in original schedule). Eight patients (24%) (3/21=14% in original schedule, 5/12=42% in revised schedule) achieved complete remission (CR) or CR without platelet recovery (CRp). Five (15%) patients (3/21 in original schedule and 2/12 in revised schedule) had clearance of marrow blasts and 1 patient had hematological improvement-hemoglobin. Toxicities were mostly related to infusion reactions with GO administration. Twelve patients had infectious episodes requiring hospitalization. Grade 3/4 non-hematological toxicities include atrial flutter (1 patient), transient ischemic attack (1 patient). There was 1 death during induction from sepsis and multi-organ failure. Another death occurred from diffuse pulmonary hemorrhage beyond induction cycle. Responding patients have continued therapy for a median duration of 196 days (range, 70-411 days).

The combination of decitabine and GO is an active regimen in patients with untreated AML or high-risk MDS, toxicities are minimal and the regimen can be safely delivered among older patients. The accrual in this study and an analysis of response/survival compared to a similar group of patients treated with decitabine alone or in combination with valproic acid is ongoing and will be updated.

Borthakur:Eisai, Inc.: Research Funding. Kantarjian:Eisai: Research Funding.