This Phase 1/2 study aimed to determine optimal doses of daunorubicin (DNR; mg/m 2 ) and cytarabine (mg/m 2 ) to be combined with fractionated doses of gemtuzumab ozogamicin (GO, Mylotarg 1 ; 3 mg/m 2 on day 1, 4, and 7) satisfying safety requirements. Three dose levels of DNR/AraC were investigated namely (45, 100), (60, 100), and (60, 200). Patients included were acute myeloid leukemia in first relapse, aged 50-70 years. Hematological recovery was 31 days for neutrophil and 32 days for platelet counts. A documented infectious episode > Grade 2 occurred in 11/20 patients (55%). None of the 20 patients had signs of veno-occlusive disease. Overall, eleven patients reached complete remission (CR), two CR with incomplete platelets recovery. The results showed that combination of fractionated GO doses with DNR at 60 mg/m 2 /d for 3 days and cytarabine at 200 mg/m 2 /d for 7 days is tolerable and could be further investigated in the front-line therapy. Am. J. Hematol. 87:62-65, 2012. V V C 2011 Wiley Periodicals, Inc.
IntroductionThe 7 1 3 combination of anthracycline and cytarabine is the standard induction therapy for patients with acute myeloid leukemia (AML). In patients aged 50-year old or more, this regimen with 45-60 mg/m 2 daunorubicin (DNR) daily for 3 days and 100-200 mg/m 2 cytarabine (AraC) daily for 7 days yields approximately 50-75% complete remission (CR) rate and 15-35% long-term survivors, depending on median age and disease characteristics [1,2]. Gemtuzumag ozogamicin (Mylotarg*; Wyeth Pharmaceuticals, Collegeville, PA) is a humanized anti-CD33 monoclonal antibody linked to a potent antitumor antibiotic chalicheamicin [3]. In a Phase 2 study that included 277 patients with AML in first relapse, single-agent gemtuzumab ozogamicin (GO) administered at a dose of 9 mg/m 2 on day 1 and 14 was associated with a 26% CR rate. However, prolonged myelosuppression and frequent elevations of bilirubin and transaminases levels with some veno-occlusive disease (VOD) reports were observed with this initial dose and schedule [4].In a previous Phase 2 study conducted by our group in relapsing AML patients, we evaluated the safety and efficacy of single-agent GO at the initial dose of 9 mg/m 2 but administered in three fractionated doses (3 mg/m 2 on day 1, 4, and 7) [5]. This fractionated regimen was retained based on the results obtained by Van Dongen and coworkers, who showed a rapid in vitro and ex vivo reexpression of the CD33 antigen on myeloblast cell surface after exposure to GO [6]. We thus hypothesized that a better tolerance and efficacy could be obtained with fractionated doses. Fifty-seven adult patients with AML in first relapse were treated in this first study. Results showed a good efficacy and safety profile with 36% response rate associated with a neutrophil and platelet count recovery of 30 days, without Grade 3 or 4 liver toxicity. These first results prompted us to design the present Phase 1/2 combination study.