Препарат CPX-351 показал худшие результаты лечения острого миелоидного лейкоза у детей по сравнению со стандартом

Induction with CPX-351, a liposomal formulation of daunorubicin and cytarabine, resulted in inferior event-free survival (EFS) and a higher risk of relapse compared with standard daunorubicin/cytarabine (DA) among children and young adults with newly diagnosed acute myeloid leukemia (AML) without FLT3 mutations, with poorer outcomes driven largely by patients with low-risk disease, according to phase 3 findings published in the Journal of Clinical Oncology. “While anthracyclines are essential for cure, there are significant acute and late toxicities associated with their use, including early cardiotoxicity associated with significantly decreased EFS/OS and substantial late cardiac morbidity/mortality in pediatric AML survivors,” the study authors explained in their report. “Thus, alternative therapeutic strategies that mitigate cardiotoxicity while improving survival are essential.” CPX-351 has demonstrated benefit in selected adult AML populations and previously showed favorable results in children with relapsed AML. The investigators conducted an open-label, multicenter phase 3 AAML1831 trial to evaluate whether CPX-351 during the first 2 induction cycles improved outcomes compared with conventional DA induction in children and young adults with de novo AML (ClinicalTrials.gov Identifier: NCT04293562). The primary analysis included 721 patients aged 21 years or younger with newly diagnosed AML without FLT3 mutations, randomly assigned to DA (n=358) or CPX-351 (n=363). Demographic characteristics were similar between the treatment groups. Both groups received gemtuzumab ozogamicin (GO) during the first induction cycle. Postinduction treatment was based on risk assignment after induction 1, with high-risk patients receiving allogeneic hematopoietic stem-cell transplantation and low-risk patients receiving chemotherapy alone. The primary endpoint was EFS from study entry. Randomization was stopped after a protocol-specified interim analysis crossed the futility boundary. At 2 years, EFS was 62.2% with DA and 51.2% with CPX-351 (hazard ratio [HR], 1.38; 95% CI, 1.08-1.77; P =.011). The 2-year cumulative incidence of relapse (CIR) was also higher with CPX-351 (44.3% vs 31.7%; HR, 1.51; 95% CI, 1.14-2.01; P =.005). However, 2-year OS did not differ significantly between the groups (73.9% vs 75.8%; P =.673). The differences were particularly pronounced among patients with low-risk AML. The 2-year disease-free survival (DFS) was 57.5% with CPX-351 vs 73.8% with DA (HR, 1.85; 95% CI, 1.27-2.70; P =.001), while the 2-year CIR was 39.9% vs 23.6%, respectively (HR, 1.95; 95% CI, 1.31-2.89; P =.001). Among patients with high-risk AML, the 2-year DFS was nearly identical between the CPX-351 and DA groups (43.0% vs 43.1%, respectively; P =.871). CPX-351 was also associated with greater myelosuppression and infectious toxicity. During induction 2, grade 3 or higher infection occurred in 27.2% of patients receiving CPX-351 vs 7.4% receiving DA, and grade 3 sepsis occurred in 13.8% vs 3.2%, respectively (both P <.001). Neutrophil recovery was also slower, and treatment cycles were longer with CPX-351. Cardiac adverse events and toxic death rates did not differ significantly between the treatment groups. The primary random assignment of AAML1831 determined that CPX-351 and GO given as induction chemotherapy is inferior to a daunorubicin, cytarabine, and GO regimen for children with newly diagnosed AML, particularly in low-risk patients. “In conclusion, the primary random assignment of AAML1831 determined that CPX-351 and GO given as induction chemotherapy is inferior to a daunorubicin, cytarabine, and GO regimen for children with newly diagnosed AML, particularly in low-risk patients,” the investigators concluded in their report. “Trial-related factors, including CPX-351 dosing, high rates of withdrawal from protocol therapy, and exclusion of patients with diagnoses for which CPX-351 is approved, might have influenced our results.” The team also noted that subgroup analyses are ongoing and may identify pediatric AML populations that could benefit from CPX-351. AAML1831 was also the first Children’s Oncology Group trial to use centralized next-generation sequencing and measurable residual disease data to automate risk assignment. Ongoing analyses of serial echocardiograms and cardiac biomarkers may further clarify the cardiac effects of liposomal anthracycline therapy and dexrazoxane, while centralized genomic analyses may help identify mutations associated with poorer response to CPX-351 and refine risk stratification for future pediatric AML studies. Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. This article originally appeared on Hematology Advisor