Phase 2 Study of Decitabine and Gemtuzumab Ozogamicin in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome- Outcome in Previously Untreated Patients.
Authors: Borthakur Gautam , Garcia-Manero Guillermo , Estrov Zeev , Konopleva Marina , Burger Jan A. , Thomas Deborah A. , Kadia Tapan , Williams Betsy , George Solly , Kantarjian Hagop 
Published: October 2019

Abstract
Abstract 1053
Poster Board I-75

Background:
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).

Patients and Methods:
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.

Results:
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).

Conclusion:
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.

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