Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2024 Oct 1;30(19):4388-4396.
doi: 10.1158/1078-0432.CCR-24-0863.

Pharmacogenomic Score Effectively Personalizes Treatment of Acute Myeloid Leukemia

Richard J Marrero  1 , Huiyun Wu  2 , Xueyuan Cao  3 , Phani Krishna Parcha  1 , Abdelrahman H Elsayed  1 , Hiroto Inaba  4 , Dennis John Kuo  5 , Barbara A Degar  6 , Kenneth Heym  7 , Jeffrey W Taub  8 , Norman Lacayo  9 , Ching-Hon Pui  4 , Raul C Ribeiro  4 , Jeffrey E Rubnitz  4 , Stanley B Pounds  2 , Jatinder K Lamba  1   10   11
Affiliations
Randomized Controlled Trial

Pharmacogenomic Score Effectively Personalizes Treatment of Acute Myeloid Leukemia

Richard J Marrero et al. Clin Cancer Res. .

Abstract

Purpose: Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for more than five decades. Recent pharmacogenomics-based 10-SNP ara-C (ACS10) scores showed low ACS10 (≤0) to be associated with poor outcomes in patients with AML treated with standard chemotherapy. Here, we evaluated the ACS10 score in the context of three different induction I regimens in patients with pediatric AML.

Experimental design: ACS10 score groups (low, ≤0, or high, >0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose ara-C (LDAC arm, n = 91), AML02 + AML08 high-dose ara-C (HDAC arm, n = 194), and AML08 clofarabine + ara-C (Clo/ara-C arm, n = 105) induction I regimens.

Results: Within the low-ACS10 score (≤0) group, significantly improved EFS and OS were observed among patients treated with Clo/ara-C as compared with LDAC (EFS, HR = 0.45; 95% CI, 0.23-0.88; P = 0.020; OS, HR = 0.44; 95% CI, 0.19-0.99; P = 0.048). In contrast, within the high-ACS10 score group (score >0), augmentation with Clo/ara-C was not favorable as compared with LDAC (Clo/ara-C vs. LDAC, EFS, HR = 1.95; 95% CI, 1.05-3.63; P = 0.035; OS, HR = 2.10; 95% CI, 0.96-4.59; P = 0.063). Personalization models predicted 9% improvement in the outcome in ACS10 score-based tailored induction (Clo/ara-C for low and LDAC for high-ACS10 score groups) as compared with nonpersonalized approaches (P < 0.002).

Conclusions: Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcomes in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests: We declare no competing interests.

Figures

FIG 1.
FIG 1.. Overall study design.
Abbreviations: EFS, event-free survival; LDAC: Low dose ara-C HDAC, high-dose ara-C; EFS: event free Survival; OS, overall survival; ACS10, ara-C pharmacogenomic 10-SNP score.
FIG 2.
FIG 2.. Patient outcomes by composite ACS10 score groups within three treatment arms in patients enrolled on AML02 and AML08 cohorts:
(A) EFS and (B) OS by 3 treatment arms within low ACS10 score group; (C) EFS and (D) OS by treatment arms within High ACS10 score group; EFS, event-free survival; OS, overall survival; HR, hazard ratio; LDAC: Low dose ara-C regimen; HDAC: High dose ara-C regimen; Clo/Ara-C: clofarabine and Ara-C combination regimen.
FIG 3.
FIG 3.. Forest plots of multivariable Cox proportional hazard models within low and high ACS10 groups by the three treatment arms with inclusion of age, risk-group assignment, WBC, ancestry and MRD1.
(A) EFS and (B) OS by LDAC, HDAC and Clo/Ara-C arms within low ACS10 group patients; (C) EFS and (D) OS by LDAC, HDAC and Clo/Ara-C arms within low ACS10 group patients. ACS10, ara-C pharmacogenomic 10-SNP score; EFS, event-free survival; OS, overall survival; HR, hazard ratio; LDAC: Low dose ara-C regimen; HDAC: High dose Ara-C regimen; Clo/Ara-C: clofarabine and Ara-C combination regimen.
FIG 4.
FIG 4.. Impact of interaction between numerical ACS10 scores by treatment arms on 5-year OS and EFS.
(A) Five-year OS and (B) 5-year EFS in AML02 LDAC, HDAC and Clo-Ara-C treatment arms by ACS10 scores. ACS10, ara-C pharmacogenomic 10-SNP; EFS, event-free survival; OS, overall survival; HR, hazard ratio; LDAC: Low dose ara-C regimen; HDAC: High dose Ara-C regimen; Clo/Ara-C: clofarabine and Ara-C combination regimen.
FIG 5.
FIG 5.
Personalization model for 5-year EFS (A) and OS (B) based on ACS10 score groups in pediatric AML.
See this image and copyright information in PMC

References

    1. Bose P, Vachhani P, Cortes JE: Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Curr Treat Options Oncol 18:17, 2017 - PubMed
    1. Dohner H, Weisdorf DJ, Bloomfield CD: Acute Myeloid Leukemia. N Engl J Med 373:1136–52, 2015 - PubMed
    1. Rubnitz JE, Kaspers GJL: How I treat pediatric acute myeloid leukemia. Blood 138:1009–1018, 2021 - PubMed
    1. Chou TC, Arlin Z, Clarkson BD, et al.: Metabolism of 1-beta-D-arabinofuranosylcytosine in human leukemic cells. Cancer Res 37:3561–70, 1977 - PubMed
    1. Grant S: Ara-C: cellular and molecular pharmacology. Adv Cancer Res 72:197–233, 1998 - PubMed

Publication types