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. 2022 Mar 1;40(7):772-783.
doi: 10.1200/JCO.21.01422. Epub 2022 Jan 6.

Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation

Abdelrahman H Elsayed  1 , Xueyuan Cao  2 , Amit K Mitra  3 , Huiyun Wu  4 , Susana Raimondi  5 , Christopher Cogle  6 , Zeina Al-Mansour  6 , Raul C Ribeiro  7 , Alan Gamis  8 , Edward Anders Kolb  9 , Richard Aplenc  10 , Todd A Alonzo  11   12 , Soheil Meshinchi  13 , Jeffrey Rubnitz  7 , Stanley Pounds  4 , Jatinder K Lamba  1   14   15
Affiliations

Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation

Abdelrahman H Elsayed et al. J Clin Oncol. .

Abstract

Purpose: To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment.

Materials and methods: Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial.

Results: In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms).

Conclusion: Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

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Conflict of interest statement

Abdelrahman H. ElsayedPatents, Royalties, Other Intellectual Property: I have a patent pending application T18496 titled Pharmacogenomics Score to Make Decisions on Therapy Augmentation in AML Christopher CogleConsulting or Advisory Role: Bristol Myers Squibb Alan GamisConsulting or Advisory Role: Novartis Edward Anders KolbTravel, Accommodations, Expenses: Roche/Genentech Richard AplencExpert Testimony: Vorys Jeffrey RubnitzConsulting or Advisory Role: Kura Oncology, Biomea, PinotbioResearch Funding: Abbvie (Inst) Stanley PoundsPatents, Royalties, Other Intellectual Property: I have pending patents for the six-gene pediatric leukemia stem cell score (https://pubmed.ncbi.nlm.nih.gov/31645648/) and other omics scores predictive of pediatric AML outcomes Jatinder K. LambaPatents, Royalties, Other Intellectual Property: Title Status Application No Methods for Predicting AML Outcome Published PCT/US2020/051961 Development of Novel CD33 Antibodies Filed 63/078,686 CD33-Targeted Cancer Therapy Nationalized PCT/US2017/026369No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Overall study design. ACS10, ara-C pharmacogenomic 10-SNP; ADE, Ara-C, daunorubicin and etoposide; ara-C, cytarabine; ara-CTP, ara-C triphosphate; BIC, Bayesian information criterion; EFS, event-free survival; GO, gemtuzumab ozogamicin; HDAC, high-dose ara-C; HWE, Hardy-Weinberg Equilibrium; LD, linkage disequilibrium; LDAC, low-dose ara-C; MAF, minor allele frequency; MOI, mode of inheritance; MRD, minimal residual disease; MRD1, minimal residual disease at the end of induction I; OS, overall survival; QC, quality control; SNP, single nucleotide polymorphism; var, variant; wt, wild-type.
FIG 2.
FIG 2.
Patient outcomes by composite ACS10 score groups within standard treatment arms of AML02 and AAML0531 cohorts: (A) EFS in AML02 cohort-LDAC arm; (B) OS in AML02-LDAC arm; (C) EFS in COG AAML0531 ADE arm; and (D) OS in COG AAML0531 ADE arm. ACS10, ara-C pharmacogenomic 10-SNP; ADE, Ara-C, daunorubicin and etoposide; EFS, event-free survival; GO, gemtuzumab ozogamicin; HR, hazard ratio; OS, overall survival.
FIG 3.
FIG 3.
Forest plots of multivariable Cox proportional hazard models that includes ACS10 score groups, risk-group assignment, ethnicity, WBC count at diagnosis, and age for association with patient outcomes in standard treatment arms of the AML02 and AAML0531 cohorts. (A) EFS and (B) OS in the AML02 LDAC arm; (C) EFS and (D) OS in the COG-AAML0531-ADE arm. * indicates P values < 0.05. ACS10, ara-C pharmacogenomic 10-SNP; AIC, Akaike Information Criterion; EFS, event-free survival; HR, hazard ratio; GO, gemtuzumab ozogamicin; ADE, Ara-C, daunorubicin and etoposide; OS, overall survival.
FIG 4.
FIG 4.
Patient outcomes by composite ACS10 score groups with augmented treatment arms: (A) EFS in the AML02 cohort-HDAC arm; (B) OS in the AML02-HDAC arm; (C) EFS in the COG AAML0531 ADE + GO arm; and (D) OS in the COG AAML0531 ADE + GO arm. ACS10, ara-C pharmacogenomic 10-SNP; ADE, Ara-C, daunorubicin and etoposide; EFS, event-free survival; GO, gemtuzumab ozogamicin; HR, hazard ratio; OS, overall survival.
FIG 5.
FIG 5.
Impact of interaction between numerical ACS10 scores and treatment arms on 5-year EFS and OS in AML02 cohort and COG cohorts. (A) Five-year OS and (B) 5-year EFS in AML02 LDAC and HDAC treatment arms by ACS10 scores; (C) 5-year OS and (D) 5-year EFS in AAML0531 ADE and ADE + GO treatment arms by ACS10 scores. ACS10, ara-C pharmacogenomic 10-SNP; ADE, Ara-C, daunorubicin and etoposide; COG, Children's Oncology Group; EFS, event-free survival; GO, gemtuzumab ozogamicin; HDAC, high-dose ara-C; LDAC, low-dose ara-C; OS, overall survival.
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References

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