ORLANDO, Fla.—This phase 3 study was recently completed by Alan S. Gamis, MD, MPH, of the Children’s Mercy Hospitals and Clinics in Kansas City, Mo., and colleagues. The findings from this study were presented at the 52nd American Society of Hematology Annual Meeting and Exposition.
The approach to AML treatment in children has evolved from that of an intensive-timing strategy to a more dose-intensive strategy. This study was based upon the MRC AML 12 dose-intensive regimen study that was conducted by Gibson et al (Blood 2002;100:35a), which resulted in a complete remission (CR) of 93% in their ADE arm. For this study, the survival outcomes remain “blinded” as the last patients complete therapy. However, remission (REM) outcomes can be evaluated with the data available from the June 2010 data cutoff.
A total of 1017 enrolled patients with de novo AML were eligible for evaluation from the data cutoff. Patients were randomized to two arms: 1) standard therapy with or 2) without GO at 3 mg/m2 given on induction (Ind) I day 6 and intensification II day 7. Induction therapy consisted of two courses (Ind I: ADE10 and Ind II: ADE8), intrathecal (IT) cytarabine on day 1, cytarabine 100 mg/m2/dose twice daily (bid) x 10 days (8 days for Ind II), etoposide 100 mg/m2/day on days 1-5, and daunomycin 50 mg/m2/day on days 1, 3, and 5. Patients remained in the study regardless of REM status after Ind I, but those patients not in CR after Ind II were taken off protocol.
Intensification therapy consisted of three courses: intensification I consisted of IT cytarabine on day 1, cytabarine IV on days 1-5, and etoposide IV on days 1-5; intensification II: of IT cytarabine on day 1, cytabarine IV on days 1-4, and mitoxantrone HCl IV on days 3-6; intensification III: cytabarine IV on days 1, 2, 8, 9 and asparaginase intramuscularly on days 2 and 9. Patients in remission proceeded to allogeneic stem cell transplant (SCT) 2-8 weeks after blood counts recover. Patients not in CR were removed from protocol therapy.
There were 1017 patients that began Ind I and 940 patients that began Ind II. As of the March 2010 data cutoff, from Ind I there were 25 withdrawals, 50 who were still in Ind or had not yet submitted data, and 19 deaths. From Ind II, there were 7 withdrawals, 29 who were still in Ind or had not yet submitted data, and 4 deaths. By the end of Ind I, 70% (628/900) of patients achieved CR (defined as <5% blasts and extramedullary disease [EMD] resolved) and 86% (731/854) of patients by the end of Ind II. These results were found to be similar to the intensively timed CCG-2961 after 2 Ind courses. Partial REM (5-15% blasts) was seen in 12% (104/900) of patients after Ind I. Fourteen percent (126/900) of patients had persistent disease (PD) (>15% blasts) at the end of Ind I. Those patients who had PD defined by only residual EMD with marrow in PR or CR, 97% achieved a CR after Ind II. In addition, 42% of those patients who had PD (defined by >15% blasts) achieved a CR after Ind II. There was no difference found in the degree of PD (15-30% blasts vs >30% blasts) and the impact on achieving a CR (52% vs 36%; P=0.234).
Diagnostic characteristics were analyzed for CR rate after Ind II. Please click here for additional study data. Prognostic factors that were found to be statistically significant included the following: initial WBC > 100,000 (OR=2.7; P<0.001), Flt3-ITD mutation (OR=2.9; P<0.001), low-risk cytogenetics (OR=0.2; P<0.001). In a multivariate model in 464 patients who had all three risk factors, the same risk factors were independently predictive of outcome: WBC (OR=2.5; P=0.002), Flt3-ITD (OR=2.0; P=0.034), and low-risk cytogenetics (OR=0.24; P=0.07). Other risk factors that were identified but not found to be statistically significant with regard to CR rates included: age, presence of monosomy 7, WHO pathology (Inv16, t(8;21), M0, M2, M7), and high Flt3-ITD AR.
The rate of mortality due to toxicity by the end of Ind II was 2.4%, which was found to be similar to that reported in the COG pilot trial, AAML03P1, and better than that seen in CCG-2961.
The results from this study will provide background for the next COG phase 3 trial utilizing the same standard Ind. This trial is expected to open soon and will provide a platform for an early comparison between outcomes of the MRC trials and those in COG with identical Ind courses.