Comparative Effectiveness of Reinduction Approaches for Pediatric Relapsed Acute Myeloid Leukemia

Introduction: Intensive frontline chemotherapy achieves initial remission rates above 80% in pediatric acute myeloid leukemia (AML), however, approximately half of patients relapse, and overall survival (OS) after relapse is poor. There is a paucity of comparative effectiveness data on salvage regimens to inform selection of optimal post-relapse therapy. The objective of this analysis was to compare outcomes following relapse by prevalent reinduction regimens in a multi-center real-world dataset.

Methods: Patients 18 years and younger who had received frontline chemotherapy for AML between 2011-2019 at 12 pediatric institutions were eligible for inclusion. Trained personnel completed manual chart abstraction to obtain demographics, diagnosis, treatment, and outcome information.

The analysis included patients who achieved morphologic remission and then experienced disease relapse; patients with primary refractory AML and those who pursued palliative therapy only after relapse were excluded. Prevalent reinduction regimens were classified as (1) intensive without anthracycline [e.g. fludarabine/cytarabine and high-dose cytarabine-containing regimens], (2) intensive with anthracycline (e.g. CPX-351, mitoxantrone/cytarabine and cytarabine/daunorubicin/etoposide), and (3) non-intensive (including azacytidine or decitabine-based regimens). Primary outcomes were OS after relapse and end reinduction disease response defined by morphologic remission (<5% blasts) and measurable residual disease (MRD)-negative remission (<0.1% blasts).

Covariate distributions were compared by reinduction regimen using chi-square tests. Survival analyses used Kaplan-Meier methods and multivariable cox proportional hazards models. End induction response was evaluated using logistic regression. Adjustment was made for covariates found to both differ by reinduction regimen and be associated with outcome, regardless of statistical significance.

Results: Of 530 patients, 157 (29.6%) experienced a relapse at a median of 9.7 months (IQR 6.5-16.3) after initial diagnosis. Median post-relapse follow-up was 2.2 years (IQR 1.1-3.2). One- and 2-year OS rates from relapse were 44.9 ± 4.1% and 38.6 ± 4.1%, respectively.

Of 157 patients with relapse, 129 from 9 institutions had available information on post-relapse treatment and pursued reinduction with curative intent. Patients were 48.8% female, 27.1% Hispanic, 14.7% non-Hispanic Black and had a median age of 7.1 years (IQR 2.70-14.2) at relapse. Most patients (89.2%) relapsed after completion of frontline therapy, and 24% had undergone hematopoietic cell transplantation (HCT) in first clinical remission.

Reinduction regimens were as follows: 79 (61.2%) received intensive reinduction without anthracycline, 34 (26.4%) received intensive reinduction with anthracycline and 16 (12.4%) received non-intensive reinduction. Patients with a non-intensive reinduction were more likely to have relapsed within one year of initial diagnosis (50% versus 34%, p = 0.23) and undergone transplant prior to relapse (75.0% versus 16.8%, p < 0.001). Covariates were balanced across intensive induction regimens. One-year OS was 50.3 ± 4.6%, with 63 (40.1%) achieving morphologic remission and 40 (31.0%) achieving an MRD-negativity after first reinduction cycle. Seventy-three patients (56.9%) underwent HCT after relapse; 11 (15.1%) received a second transplant. OS curves and adjusted outcome comparisons by reinduction regimen are shown in the Figure and Table. One-year OS was 51.1 ± 5.8%, 60.2 ± 9.0% and 26.7 ± 11.4% for intensive therapy without anthracycline, with anthracycline and non-intensive, respectively. However, after adjustment hazard ratios (HRs) were not statistically significant [HR = 0.85 (p = 0.65) and 1.77 (p = 0.23) for intensive with anthracycline and non-intensive, compared to non-intensive without anthracycline, respectively].

Conclusions: After controlling for patient, disease and treatment characteristics, we did not identify a significant difference in remission rates or OS by reinduction approaches for pediatric relapsed AML. Although anthracycline-based reinduction did not improve OS, adjusted point estimates suggest that anthracyclines may improve end reinduction disease response. Ongoing cohort expansion will enable comparative effectiveness analyses of specific reinduction regimens.