DNA Damage Response Pharmacogenomic (DDR_PGx) Score Predicts Response to Chemotherapy Consisting of Gemtuzumab Ozogamicin in Pediatric AML: A Report from the Children's Oncology Group.

Document Type

Article

Publication Date

3-3-2025

Identifier

DOI: 10.1158/1078-0432.CCR-23-2073; PMCID: PMC11233425

Abstract

PURPOSE: Comprehensive pharmacogenomics (PGx) evaluation of calicheamicin pathway to identify predictive PGx markers of response to gemtuzumab ozogamicin (GO) treatment in acute myeloid leukemia (AML).

EXPERIMENTAL DESIGN: SNPs in DNA damage response (DDR) pathway genes were tested for association with event-free survival (EFS), overall survival (OS), and risk of relapse after induction 1 (RR1) in patients treated with standard chemotherapy consisting of Ara-C, daunorubicin, and etoposide (ADE) with or without addition of GO on COG-AAML03P1 and COGAAAML0531 trials (ADE+GO, n = 755; ADE n = 470). SNPs with significant association with any endpoint within ADE+GO arm but not in the ADE arm were tested using multi-SNP modeling to develop DDR_PGx7 score.

RESULTS: Patients with low DDR_PGx7 score ( < 0) had significantly worse EFS [HR = 1.51, 95% confidence interval (CI: 1.21-1.89), P < 0.001], worse OS [HR = 1.59, 95% CI (1.22-2.08), P < 0.001], and higher RR1 [HR = 1.87, 95% CI (1.41-2.47), P < 0.0001] compared with patients with highDDR_PGx7 score ( ≥ 0)when treated withGO (ADE+GO cohort). However, no difference between low and high DDR_PGx7 score groups was observed for EFS, OS, and RR1 (all P > 0.3) in patients treated on ADE arm.

CONCLUSIONS: Our results suggest that DDR pathway-based pharmacogenomic score holds potential to predict outcome in patients treated with GO which consists of DNA damaging cytotoxin, calicheamicin. The potential clinical relevance for this score to personalize GO in AML requires further validation in independent and expanded cohorts.

Journal Title

Clinical cancer research : an official journal of the American Association for Cancer Research

Volume

31

Issue

5

First Page

890

Last Page

898

MeSH Keywords

Humans; Gemtuzumab; Leukemia, Myeloid, Acute; Child; Female; Male; Polymorphism, Single Nucleotide; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; DNA Damage; Adolescent; Infant; Etoposide; Pharmacogenetics; Prognosis; Cytarabine; Daunorubicin

PubMed ID

38197878

Keywords

Gemtuzumab; Myeloid, Acute Leukemia; Single Nucleotide Polymorphism; Antineoplastic Combined Chemotherapy Protocols; DNA Damage; Etoposide; Pharmacogenetics; Prognosis; Cytarabine; Daunorubicin

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