A Phase I/II Trial of Gemtuzumab Ozogamicin in Combination with Cytarabine and Anthracyclines (Daunorubicin or Idarubicin) for CD33-Positive Refractory or Relapsed AML Patients Younger Than 65 Years. Results of Phase I Parts of the JALSG-AML206 Study.

Gemtuzumab ozogamicin (GO) is an antibody-targeted chemotherapeutic agent consisted of a humanized anti-CD33 monoclonal antibody conjugated to a calicheamicin. Several trials evaluated the efficacy of GO in combination with cytotoxic chemotherapy for treating refractory/ relapsed acute myeloid leukemia (AML) or as front-line therapy. However, there is a still open question what is optimal dose or timing of GO as well as optimal partner of antileukemic drugs. In order to investigate better molecular-target therapy for AML, we initiated phase I/II trial named JALSG AML206 study.

The primary goal of this study is to evaluate the safety and the antileukemic activity of combination of GO, cytarabine (Ara-C) and either daunorubicin (DNR)[DAG regimen] or idarubicin (IDR)[IAG regimen] in patients with relapsed/refractory CD33-positive AML. Phase I part was dose-finding study for GO, IDR and DNR. Eligibility criteria included age (20-64yrs), AML(except APL) in first relapse more than 6 months from induction therapy or refractory to the first induction therapy, ECOG performance status 0-2, CD33 expression >20%. All registered patients were received standard dose of Ara-C(100 mg/m2/CIV) on days 1-7 combining GO with either DNR or IDR. GO was planned to administer one day after last administration of DNR or IDR. In the DAG regimen, DNR (50 mg/m2/IV) on days 1-3 + GO(3 mg/m2/DIV) on day 4 as level-1, DNR(50 mg/m2/IV on days 1-4 + GO(3mg/m2/DIV) on day 5 as level-2, and DNR(50 mg/m2/IV) on days 1-5 + GO(3mg/m2/DIV) on day 6 as level-3 were administered. In the IAG regimen, IDR(10 mg/m2/IV) on days 1-3 + GO(3mg/m2/DIV) on day 4 as level-1, IDR(12 mg/m2/IV) on days 1-3 + GO(3 mg/m2/DIV) as level-2, and IDR(12 mg/m2/IV) on days 1-3 + GO (5 mg/m2/DIV) on day 4 as level-3 were administered. Dose and schedule level indicated above was increased using a standard 3+3 design.

Nineteen patients (10 patients in the DAG, 9 patients in the IAG) have enrolled: median age was 59 yrs (range 33-64) and 53% were male. Eight patients were refractory and 11 patients were relapsed AML. Cytogenetic risk (according to CALGB): poor 19%, intermediate 63%, and good 19%. The median value of blasts in the bone marrow before treatment was 93%(range 39-100%). No DLT was observed at levels 1 and 2 in both the DAG and the IAG regimens. At level 3 in the DAG, no DLT was observed although one patient had Grade 4 neutropenia for 4 weeks due to progression of AML. In the IAG regimen, 3 of 3 patients had a DLT at level 3; these were Grade 3/4 infection due to severe neutropenia and prolongation of Grade 4 neutropenia independent to progression of leukemia. Two patients had Grade 3 of increase of AST/ALT, but none had VOD/SOS. Among 15 patients assessable for response, 6 patients (4 in DAG, 2 for IAG) (40%) attained CR, and 6 patients had hematologic improvement. One patient died of CNS bleeding within 30-days of therapy due to progression of AML.

The MTD of GO just after administration of anthracycline combining with standard Ara-C was 5 mg/m2. Addition to standard Ara-C, GO (3 mg/m2) on day 6 with dose-dense DNR(50 mg/m2 × 5 days) and GO(3 mg/m2) on day 4 with IDR(12 mg/m2 × 3days) can be safely administered. Antileukemic activity of these level-3s of DAG and IAG regimens will be evaluated in phase 2 part of this study.

No relevant conflicts of interest to declare.