Chemotherapy

Mitoxantrone.[4]

Fludarabine and idarubicin.[12]

L-asparaginase.[13]

Etoposide.

Liposomal daunorubicin. A study by the International BFM group compared fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) with FLAG plus liposomal daunorubicin. The 4-year OS rate was 38%, with no difference in survival for the total group. However, the addition of liposomal daunorubicin increased the likelihood of obtaining a remission and led to significant improvement in OS in patients with core-binding factor variants (82%, FLAG plus liposomal daunorubicin vs. 58%, FLAG; P = .04).[14][Level of evidence A1]

CPX-351. The liposomal combination agent CPX-351, which uses a fixed combination of daunorubicin and cytarabine, has been evaluated in the phase I/II Children's Oncology Group (COG) AAML1421 (NCT02642965) trial for children with relapsed AML. CPX-351 (135 units/m2/day and containing 60 mg/m2 of daunorubicin) was administered without dexrazoxane in cycle 1 on days 1, 3, and 5 followed by a FLAG cycle. CPX-351 was well tolerated, with no unexpected toxicity, one dose-limiting toxicity (grade 3 ejection fraction decline that resolved), and no toxic mortality. A maculopapular rash occurred in 40% of patients. Among 37 evaluable patients, 75.7% had a CR (including CR with partial recovery of platelet count [CRp] and CR with incomplete blood count recovery [CRi]) after the CPX-351 cycle. Further, 21 of 25 CR/CRp patients had no minimal residual disease (MRD) after cycle 2, and 20 of 25 patients had no MRD before HSCT.[15][Level of evidence B4]

Venetoclax. The St. Jude Children's Research Hospital (SJCRH) VENAML trial (NCT03194932) evaluated venetoclax, a selective inhibitor of BCL-2, in combination with cytarabine with or without idarubicin in pediatric patients with relapsed or refractory AML.[16] The combination was well tolerated. The most common grades 3 and 4 adverse events were febrile neutropenia (66% of patients), blood stream infections (16% of patients), and invasive fungal infections (16% of patients). Among the 20 patients treated at the recommended phase II dose, 14 patients (70%) achieved a complete response with or without complete hematological recovery, and 2 patients (10%) achieved a partial response.

Clofarabine. Regimens built upon clofarabine have been used.[17-19][Level of evidence B4] The COG AAML0523 (NCT00372619) trial evaluated the combination of clofarabine plus high-dose cytarabine in patients with relapsed AML. The response rate was 48% and the OS rate was 46%, with 21 of 23 responders undergoing HSCT. MRD before HSCT was a strong predictor of survival.[20][Level of evidence B4]

Cladribine. Regimens using cladribine plus idarubicin have been used.[21]