Update of a Phase I/II Trial of 5-Azacytidine Prior to Gemtuzumab Ozogamicin (GO) for Patients with Relapsed Acute Myeloid Leukemia with Correlative Biomarker Studies

• Published in: Blood 2010-11, Vol.116 (21), p.3286-3286
• Main Authors: Ball, Edward D., Medeiros, Bruno C., Balaian, Larissa, Roque, Tracy, Corringham, Sue, Rajwanshi, Richa, Coutre, Steven, Gotlib, Jason R, Bashey, Asad, Messer, Karen
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.3286.3286

Abstract 3286 Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that is a down-regulator of cell growth when ligated by a monoclonal antibody in a Syk-dependent manner. The response of AML cells to gemtuzumab ozogamicin (GO) also depends on Syk and SHP-1 expression (Leukemia 20:2093, 2006). The hypomethylating agent 5-azacytidine (5-aza) induced re-expression of Syk in some cases, therefore increasing the sensitivity of originally Syk-negative, non-responsive cells to CD33 ligation to levels of Syk-positive cells. We initiated a phase 1/2 clinical trial examining if treatment with 5-aza prior to GO is safe, efficacious, and whether in vivo responses to GO correlated with Syk expression and induction by 5-aza. Here we update the interim results of this trial (NCI registration number NCT00766116). In Phase I, 14 patients (9 males, 5 females), age range: 39–82 years [median: 66]) were treated with 75mg/m2 5-aza daily and GO in a dose-escalation manner, 4 cohorts total. The first cohort (n=3) received 5-aza for 2 days followed by GO at 3 mg/m2 on days 3 and 17; the second cohort (n=3) received 5-aza for 2 days followed by GO at 6 mg/m2 on days 3 and 17; the third cohort (n=4) received 5-aza for 4 days followed by GO at 6 mg/m2 on days 5 and 19; and the fourth cohort (n=4) at 5-aza for 6 days followed by GO at 6 mg/m2 on days 7 and 21. There were no responses in the first 2 cohorts. One patient in cohort 3 achieved CR, and 2 in cohort 4 achieved CR and CRp. Adverse events (≥ Grade 3) included febrile neutropenia 36%, infection 14%, pancytopenia 7%, dyspnea 7%, and retinopathy 7%. Average length on study (n=14) was 45 days with a mortality rate of 14% (unrelated to treatment). No dose-limiting toxicities were encountered in phase I, therefore the MTD is the dose in cohort 4. The overall response rate in evaluable patients in phase I (n=11) is 27%. Average time to ANC recovery (n=6): 30 days (range 15–42, median 33 days). In Phase II, 10 patients (5 males, 5 females), age range: 29–64 years (median 60) were treated at the MTD: 5-aza for 6 days and GO at 6 mg/m2 on days 7 and 21. 8 patients were in 1st relapse, 1 in 2nd and 1 in 3rd. There were 3 responders (2 CR, 1 CRp) in this phase, all in 1st relapse at baseline. Adverse events (≥ Grade 3) include febrile neutropenia 50%, infection 20%, increased LFTs 10%, thrombocytopenia 10%, dyspnea 10%, wheezing 10%, mucositis 10%, cough 10%, and hypoalbuminemia 10%. The average length on study (n=10