Bacon-Wrapped Chemo: Can Liposomal Cytarabine/Daunomycin Improve Outcomes for Children With Newly Diagnosed AML Versus Conventional Therapy?

Study Title: A Phase 3 Randomized Trial for Patients with De Novo AML Comparing Standard Therapy Including Gemtuzumab Ozogamicin (GO) to CPX-351 with GO, and the Addition of the FLT3 Inhibitor Gilteritinib for Patients with FLT3 Mutations (AAML1831)

ClinicalTrials.Gov Identifier: NCT04293562

Sponsor: Children's Oncology Group (COG)

Participating Centers: 177 institutions in the United States, Canada, Australia, and New Zealand

Accrual Goal: 1,400 children and adolescent/young adults younger than 22 years

Study Design: AAML1831 is a randomized phase III clinical trial comparing the efficacy of standard multi-agent chemotherapy with gemtuzumab ozogamicin (arm A) to that of CPX-351, a liposomal formulation of cytarabine and daunomycin with a fixed 5:1 molar ratio, with gemtuzumab ozogamicin (arm B) and subsequent standard chemotherapy for children and adolescents/ young adults younger than 22 years who have newly diagnosed acute myeloid leukemia (AML; Figure). Patients are risk stratified as high-risk or low-risk based on AML-associated cytogenetic/molecular genetic alterations (Table) and end-induction measurable residual disease (MRD) assessed by centralized multi-dimensional flow cytometry. High-risk patients (identified by unfavorable genetics and/or MRD positivity ≥ 0.05%) are allocated to best-available donor allogeneic hematopoietic stem cell transplantation (HSCT) in first remission after three chemotherapy cycles, while low-risk patients are treated with chemotherapy alone. Low-risk patients with favorable AML-associated genetics and negative MRD receive four chemotherapy cycles (LR1), while low-risk patients with non-prognostic genetics and negative MRD receive five chemotherapy cycles (LR2) without HSCT. The FLT3 inhibitor (FLT3i) gilteritinib is added to standard chemotherapy or CPX-351/chemotherapy cycles for all patients with FLT3-internal tandem duplication (ITD) with an allelic ratio greater than 0.1 (arm C) or clinically-relevant FLT3-activating point mutations (arm D). FLT3-mutant patients also receive gilteritinib maintenance therapy for one year following HSCT or completion of chemotherapy (Figure).

Rationale: Liposomal anthracycline formulations have been reported as pharmacologically advantageous given prolonged time in circulation, altered biodistribution, and circumvention of drug efflux transporters,¹  which may provide clinical benefit. A meta-analysis of nine randomized controlled trials of liposomal anthracyclines in adult patients demonstrated decreased cardiotoxicity, a major and potentially lifelong sequela of intensive AML anthracycline-based chemotherapy.²  The international Berlin-Frankfurt-Münster (iBFM) Study Group Relapsed AML 2001/01 phase III trial (NCT00186966) reported improved early treatment responses in children with first-relapse AML with fludarabine/cytarabine/granulocyte colony-stimulating factor (FLAG) reinduction chemotherapy and liposomal daunorubicin versus FLAG alone,³  though overall survival between the groups did not differ. The nonrandomized COG AAML1421 phase II trial also showed excellent clinical outcomes for children with first-relapsed AML reinduced with CPX-351 (cycle 1) and FLAG (cycle 2).⁴  A multi-center randomized phase III trial reported superior outcomes of CPX-351 versus conventional 7+3 cytarabine/daunomycin chemotherapy in older adults with newly diagnosed poor-risk AML.⁵  These studies provided strong rationale for the evaluation of CPX-351 in pediatric subjects with de novo AML.

Adding FLT3i to chemotherapy has improved outcomes in children and adults with FLT3-ITD AML,^6–9  but studies of earlier-generation inhibitors (e.g., midostaurin, sorafenib) have also been complicated by toxicity due to multi-kinase inhibitory properties and/or development of resistance mutations. The next-generation selective FLT3i gilteritinib was chosen for pediatric investigation in AAML1831 based on clinical efficacy in adults with AML.^10,11  In addition to children with FLT3-ITD AML for whom there are clear data to support FLT3i efficacy, those with FLT3-activating mutations are also treated with gilteritinib in AAML1831 based on potent preclinical activity and clinical safety data.^12–14  However, it is plausible that resistance mutations will develop in gilteritinib-treated children over time, as has been reported in adult patients.^15,16 

Another significant feature of AAML1831 is its implementation of a revised molecular risk classification (Table). This updated classification based on next-generation sequencing analyses of banked COG and iBFM clinical trial specimens facilitated identification of new “boutique” high-risk genetic subsets of childhood AML with poor outcomes with chemotherapy alone.^17–21 

The predecessor COG AAML1031 trial showed that patients with genetically low-risk AML (Table) and negative end-induction MRD could be successfully treated with four instead of five chemotherapy cycles without increasing relapse risk.²²  These favorable outcomes informed the empiric AAML1831 decision to exchange a traditional anthracycline-containing (mitoxantrone/ cytarabine) intensification 2 cycle for a high-dose cytarabine/asparaginase cycle with a goal of cardiotoxicity reduction for this population.

Comment: Survival of children with AML has plateaued despite maximally intensive therapy, and survivors remain at risk for lifelong treatment-related complications. AAML1831 aims both to improve survival and to reduce cardiotoxicity via investigation of liposomal cytarabine/daunomycin chemotherapy in the frontline setting, as well as to credential a selective FLT3 inhibitor in pediatric patients with FLT3-mutant AML. Importantly, this trial uses an evidence-based revised risk classification that will allocate a larger percentage of patients to HSCT in first remission due to high-risk genetics, while also reducing chemotherapy for children with favorable genetics and induction therapy responses to preserve good clinical outcomes while minimizing toxicities.