Outcome for pediatric acute promyelocytic leukemia patients at Children's Oncology Group sites on the Leukemia Intergroup Study CALGB 9710 (Alliance)

Abstract

Background: Acute promyelocytic leukemia (APL) is a unique leukemia subtype requiring specialized treatment including all-trans retinoic acid (ATRA). A prior report demonstrated worse outcome among young children <5 years old compared with older children.

Methods: We evaluated outcomes for pediatric patients (<18 years old; N = 83) with APL treated on North American intergroup study CALGB 9710 at Children's Oncology Group sites. Induction and consolidation included ATRA, cytarabine, and anthracyclines. Patients ≥15 years old were randomized to addition of arsenic trioxide (ATO) consolidation. All patients were randomized to ATRA maintenance with versus without oral chemotherapy.

Results: The estimated 5-year overall survival (OS) rate was 82%, and the event-free survival (EFS) rate was 54%. Seven patients (8.4%) died during induction due to coagulopathy. Maintenance randomization demonstrated that addition of oral chemotherapy to ATRA significantly reduced relapse rate, but difference in EFS did not reach statistical significance (P = 0.12; 5-year rates [95% CI]: 41% [17%-64%] ATRA only vs 72% [56%-88%] ATRA plus chemotherapy). There was no difference (P = 0.93) in EFS for age <5 years versus 5-12.99 years versus 13-17.99 years (5-year rates: 56%, 47%, and 45%, respectively). Among adolescents 15-17.99 years old in the ATO randomization, there was a significantly lower relapse risk at 5 years for those receiving ATO (0% ATO vs 44% no ATO; P = 0.02).

Conclusion: Our data demonstrate that intensified ATRA, cytarabine, and anthracycline chemotherapy is effective for pediatric APL including very young patients, but early deaths and relapses remain barriers to cure. Further improvements are likely with incorporation of ATO into pediatric APL regimens.

Keywords: APL; ATRA; arsenic trioxide; pediatric.

FIGURE 1

CONSORT diagram

FIGURE 2

Survival for all patients <18 years stratified by presenting WBC. Kaplan-Meier plots for overall survival (A), event free survival (B), and disease-free survival (C) demonstrate that high presenting WBC is a risk marker for worse overall survival.

FIGURE 3

Survival and relapse risk for patients <18 years stratified by maintenance therapy. Kaplan-Meier plots for overall survival (A), event free survival (B) and relapse risk (C). For figure 3C, death without relapse curves are not shown because there were none of these events for either group. These demonstrate no significant difference in outcome by maintenance arm, but of interest there were more relapses after 2 years (the end of therapy) in the non-chemotherapy maintenance group. These survival curves represent patients who completed induction and consolidation to be eligible for maintenance randomization and thus survival is higher than in the entire cohort represented in Figure 2.

FIGURE 4

Survival and relapse risk for three age sub-groups among pediatric patients. Kaplan-Meier plots for overall survival (a), event free survival (b) and relapse risk following remission (c) demonstrate that young children have similar survival and relapse rate as older children and adolescents.

FIGURE 5

Survival and relapse risk for patients age 15–17.99 years stratified by ATO consolidation treatment. Kaplan-Meier plots for overall survival (a) and event free survival (b) are not significantly different, but relapse risk (c) was lower among patients who received ATO. In figure 5c, the relapse risk lines for both “ATO, relapse” and “No ATO, death without relapse” are overlapping on the 0% probability line.