A Phase 3 Randomized Trial for Patients with De Novo AML Comparing Standard Therapy Including Gemtuzumab Ozogamicin (GO) to CPX-351 with GO - a Report from the Children's Oncology Group

Introduction: Survival in childhood AML has plateaued and new therapeutic strategies are essential. CPX-351 (Vyxeos) is a liposomal preparation of cytarabine and daunorubicin with superior pharmacokinetic properties when compared to free drug. The Children's Oncology Group (COG) Phase III clinical trial AAML1831 tested the hypothesis that CPX-351 given during Inductions 1 and 2 would improve treatment outcomes and reduce long-term toxicities compared to a standard chemotherapy. Methods: COG AAML1831 randomized patients (pts) <22 years of age with de novo AML to 2 different induction regimens. Pts with FLT3 mutations were offered enrollment onto gilteritinib-containing regimens and are not included in this analysis. Arm A patients received cytarabine, daunorubicin and gemtuzumab ozogamicin (DA+GO) during Induction 1 and DA during Induction 2. Patients on Arm B received, during Induction 1, CPX-351 on days 1, 3 and 5 and GO on day 6; the CPX-351 dosing was repeated in Induction 2. Centralized risk stratification occurred after Induction 1 and was based on cytomolecular findings and end of induction 1 (EOI 1) minimal residual disease (MRD) >0.05% by central multidimensional flow cytometry. Pts were designated as low risk 1 (LR1; favorable genetics and MRD negative), low risk 2(LR2; pts not in LR1 or HR), or high risk (HR; MRD+ without favorable genetics or any high risk genetics) and received 4 (LR1) versus 5 (LR2) cycles of chemotherapy or 2-3 cycles followed by hematopoietic stem cell transplant (HSCT; HR). Results: A total of 721 eligible pts without FLT3 mutations were randomized to Arm A (n=358) or Arm B (n=363). Age, race, ethnicity and sex were similar for the 2 arms; distribution of risk-defining cytomolecular features were also comparable, with exception of higher rates of inv(16)(p13.1q22.1) (Arm A: 10% vs Arm B: 6%; p=0.03) but not t(16;16)(p13.1;q22) CBFB-MYH11 AML. Pts on Arm A were also more likely to be CNS negative at time of initial assessment (Arm A: 86%; Arm B: 79%; p=0.026). EOI 1 MRD was comparable (Arm A: 23%; Arm B: 23%) and elective withdrawal rates at EOI1 did not differ significantly between the 2 arms (Arm A: 9%; Arm B: 11%). However, Induction 2 treatment toxicities [grade 3 infection (Arm A: 7.4%; Arm B: 27.2%), grade 3 sepsis (Arm A: 3.5%; Arm B: 5.1%)] and median cycle length (Arm A: 35 days; Arm B: 44 days) were higher in Arm B though this did not translate into higher Induction 2 treatment related mortality. Protocol-specified interim analyses using data available on 12/31/23 were performed to monitor efficacy and futility of event-free survival (EFS) for Arm A and Arm B patients without FLT3 mutations. Closure of this randomization was recommended given the futility monitoring rule was crossed. Using a 6/30/24 data cutoff, 2-year EFS from study entry for Arm A was 60.9% (95% CI: 54.3-66.8%) vs. 51.2% (95% CI: 44.7-57.4%) for Arm B (p=0.019) though overall survival (OS) was not significantly different [Arm A: 75.5% (95% CI-69.3-80.5%); Arm B: 74.5% (95% CI - 68.4-79.6%]; p=0.782]. Outcomes for HR patients were comparable for both arms whereas EFS was significantly lower and relapse rates (RR) higher for LR patients on Arm B [2-yr EFS from EOI1: Arm A: 71.9% vs. Arm B 57.8% (p=0.006); 2-year RR Arm A: 16.1% vs. Arm B: 25.4%, p=0.018). EFS from EOI1 in the LR1 patients was particularly impacted (Arm A: 78.3%; Arm B: 62.6%, p=0.029) while LR2 EFS from EOI is Arm A: 67.2 % vs. Arm B: 54.6% (p=0.079); most events reported for either group were relapse. Conclusion The primary randomization of the Phase III study COG AAML1831, a comparison between standard induction therapy and CPX-351, was terminated early because the futility boundary was crossed. The difference in EFS observed was driven mainly by events in LR pts, particularly those that received 4 cycles of chemotherapy (LR1). Further analysis is underway to determine additional factors that may have contributed to the inferior outcomes observed for pts enrolled on Arm B.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.