COG AAML03P1: Efficacy and Safety in a Pilot Study of Intensive Chemotherapy Including Gemtuzumab in Children Newly Diagnosed with Acute Myeloid Leukemia (AML)

Childhood AML survival outcomes and treatment related adverse events remain less than optimal despite recent treatment advances. Intensive chemotherapy and hematopoietic stem cell transplant (HSCT), when suitable, are the mainstay of current therapy for newly diagnosed patients. Newer agents, such as gemtuzumab ozogamicin (GMTZ), a calicheamicin coupled anti-CD 33 monoclonal antibody, have been evaluated in adults and in phase 1 studies in children. We report data from a COG open-label pilot of intensive chemotherapy containing GMTZ in selected therapy cycles for pediatric AML patients. The primary objective was to determine the safety of adding single dose GMTZ to an intensive two course induction adapted from the Medical Research Council (MRC) regimen. The complete remission rate of the induction regimen and the safety of adding a single dose of GMTZ to one course of post-remission intensification therapy were also evaluated. Eligible patients were newly diagnosed children (≥1 month old to ≤21 years old) with de novo AML excluding those with Down syndrome and those with acute promyelocytic leukemia. Accrual occurred from December 2003 to November 2005 at COG institutions. Enrollment included 350 patients with 340 patients that were determined to be eligible by protocol guidelines. Treatment consisted of a remission induction phase (induction I and induction II) followed by intensification I, II, and III or intensification I and matched related donor HSCT. Cycle regimens were cytarabine, daunorubicin, etoposide (ADE) 10+3+5 plus GMTZ on day 6 (induction I), ADE 8+3+5 (induction II),high dose cytarabine and etoposide (AE) (intensification I), mitroxantrone, cytarabine (MA) plus GMTZ on day 7 (intensification II), and Capizzi II (intensification III). A busulfan - cyclophosphamide conditioning regimen was used for those children receiving HSCT as part of their consolidation treatment. The median length of each cycle was 36, 35, 35, 48, 48, and 111 (HSCT) days respectively. Median time (in days) for recovery of ANC and platelet counts by cycle was Induction 1: ANC 35, platelets 35, Induction II: ANC: 33, platelets: 33, Int 1: ANC 34, platelets 34, Int II: ANC 51.5, platelets 46, Int III: ANC 49, platelets 48 and HSCT: ANC 110.5, platelets 110. Median follow-up for all eligible patients alive at last contact is 775 days. Overall results show that the induction I complete response (CR) was 83%, refractory disease (RD) with 5 – 20% BM blasts was 8.6%, RD failure with >20% BM blasts was 5.2%, CNS relapse/persistent disease or developed 2^nd malignancy combined represented 1.5%, and death rate was 1.5%. The cumulative induction (induction I and II) CR was 87%, RD 1.6%, RD failure 8.5%, and death 2.6%. 3 year EFS from study entry was 49% ± 7% while OS was 63% ± 6%. Patients in remission after induction I had DFS 56% ± 7% and OS 65% ± 8%. For patients in remission after induction II, the DFS (58 ± 7%) and OS (67% ± 8%) were similar to those patients achieving remission after the 1^st cycle. Treatment related mortality (TRM) for induction I and induction II was 9% and 7% respectively. Children with a matched related donor for transplant had an improved 3 year risk of relapse (RR) when compared to those with no donor: 22% ± 12% compared to 39% ± 9% (p=0.053). The most common non-transplant related adverse events (grade 3 or higher) reported include anorexia, febrile neutropenia, and hypokalemia. Veno-occlusive disease (VOD) was reported in 18 patients (5%): 2 patients during intensification II, 8 patients during HSCT and 8 patients during the follow-up phase. Overall, AAML03P1 therapy shows a continued historical trend for improvement in OS and EFS when compared to the previous COG AML trial (CCG-2961). TRM in this pilot study is similar to that observed in CCG-2961. VOD, a key targeted toxicity, occurs in only a small percentage of patients and is within the published rates observed with other therapies for AML. This study shows that GMTZ can be safely added to this MRC based regimen. The determination of whether GMTZ improves patient outcome is being studied in the ongoing COG Phase III randomized trial, AAML0531.