Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial

Abstract

Purpose: To identify effective and less toxic therapy for children with acute myeloid leukemia, we introduced clofarabine into the first course of remission induction to reduce exposure to daunorubicin and etoposide.

Patients and methods: From 2008 through 2017, 285 patients were enrolled at eight centers; 262 were randomly assigned to receive clofarabine and cytarabine (Clo+AraC, n = 129) or high-dose cytarabine, daunorubicin, and etoposide (HD-ADE, n = 133) as induction I. Induction II consisted of low-dose ADE given alone or combined with sorafenib or vorinostat. Consolidation therapy comprised two or three additional courses of chemotherapy or hematopoietic cell transplantation. Genetic abnormalities and the level of minimal residual disease (MRD) at day 22 of initial remission induction determined final risk classification. The primary end point was MRD at day 22.

Results: Complete remission was induced after two courses of therapy in 263 (92.3%) of the 285 patients; induction failures included four early deaths and 15 cases of resistant leukemia. Day 22 MRD was positive in 57 of 121 randomly assigned evaluable patients (47%) who received Clo+AraC and 42 of 121 patients (35%) who received HD-ADE (odds ratio, 1.86; 95% CI, 1.03 to 3.41; P = .04). Despite this result, the 3-year event-free survival rate (52.9% [44.6% to 62.8%] for Clo+AraC v 52.4% [44.0% to 62.4%] for HD-ADE, P = .94) and overall survival rate (74.8% [67.1% to 83.3%] for Clo+AraC v 64.6% [56.2% to 74.2%] for HD-ADE, P = .1) did not differ significantly across the two arms.

Conclusion: Our findings suggest that the use of clofarabine with cytarabine during remission induction might reduce the need for anthracycline and etoposide in pediatric patients with acute myeloid leukemia and may reduce rates of cardiomyopathy and treatment-related cancer.

Trial registration: ClinicalTrials.gov NCT00703820.

Figures

FIG 1.

AML08 treatment schema. Patients with adequate organ function were randomly assigned to receive clofarabine and cytarabine (Clo+AraC; clofarabine 52 mg/m2 per day on days 1 to 5 and cytarabine 1 g/m2 per day on days 1 to 5) or high-dose cytarabine, daunorubicin, and etoposide (HD-ADE; cytarabine 3 g/m2 every 12 hours on days 1, 3, and 5, daunorubicin 50 mg/m2 on days 2, 4, and 6, and etoposide 100 mg/m2 per day on days 2 to 6) during induction I. Minimal residual disease (MRD) was assessed at day 22. During induction II, low-dose cytarabine (100 mg/m2 every 12 hours on days 1 to 8), daunorubicin, and etoposide (LD-ADE) were given alone to low-risk (LR) and standard-risk (SR) patients, with sorafenib to patients with FLT3–internal tandem duplication (ITD), and with vorinostat to high-risk patients who lacked FLT3-ITD. Induction II MRD was assessed at the time of count recovery. LR patients then received chemotherapy, SR patients received chemotherapy with or without subsequent natural killer (NK) cell therapy, and high-risk (HR) patients were eligible for hematopoietic cell transplantation (HCT). Postinduction chemotherapy initially included MA (mitoxantrone 12 mg/m2 on days 3 to 5 and cytarabine 1 g/m2 every 12 hours on days 1to 4), AA (cytarabine 3 g/m2 every 12 hours on days 1, 2, 8, 9 and l-asparaginase 6000 Units/m2 3 hours after the fourth and eighth doses of cytarabine), and AE (cytarabine 1 g/m2 every 12 hours on days 1 to 5 and etoposide 150 mg/m2 on days 1 to 5). The protocol was amended to remove AE. KIRmm, killer immunoglobulin–like receptor–human leukocyte antigen-mismatched donors.

FIG 2.

Consort diagram. Clo+AraC, clofarabine 52 mg/m2 per day on days 1 to 5 and cytarabine 1 g/m2 per day on days 1 to 5; CR, complete remission; HCT, hematopoietic cell transplantation; HD-ADE, cytarabine 3 g/m2 every 12 hours on days 1, 3, and 5, daunorubicin 50 mg/m2 on days 2, 4, and 6, and etoposide 100 mg/m2 per day on days 2 to 6; NK, natural killer.

FIG 3.

Outcome according to treatment arm. (A) Probability of event-free survival (EFS) according to treatment. (B) Probability of overall survival (OS) according to treatment.

FIG A1.

Detailed patient flowchart. Clo+AraC, clofarabine and cytarabine; HD-ADE, high-dose cytarabine, daunorubicin, and etoposide; MRD, minimal residual disease; NK, natural killer.

FIG A2.

Outcome according to treatment arm and minimal residual disease positive (MRD+) or negative (MRD−). (A) Probability of event-free survival (EFS) according to induction I MRD and treatment. Patients alive and on study at the time of MRD evaluation were included in this analysis. In addition, date of MRD evaluation was defined as baseline time. (B) Probability of overall survival (OS) according to induction I MRD and treatment. Patients alive and on study at the time of MRD evaluation were included in this analysis. In addition, date of MRD evaluation was defined as baseline time. Clo+AraC, clofarabine and cytarabine; HD-ADE, high-dose cytarabine, daunorubicin, and etoposide.