Introduction: The aldehyde dehydrogenase 2 (ALDH2) gene encodes for an enzyme of the aldehyde dehydrogenase family involved in oxidative alcohol metabolism and protection from hypoxic stress. Using a comparative proteomic approach based on in vivo biotinylation, we have recently identified a marked overexpression of ALDH2 in a rat model of acute myeloid leukemia (AML). In solid tumors, ALDH2 has been described to reduce sensitivity to anthracyclines, a mainstay in the treatment of AML. Here, we analyzed the prognostic impact of ALDH2 expression levels in AML.
Methods: Using oligonucleotide microarrays, we analyzed ALDH2 gene expression in pretherapeutic bone marrow or blood samples from 492 AML patients who received intensive chemotherapy within the AMLCG-1999 trial (GSE37642). Results were validated in an additional cohort of 270 intensively treated younger AML patients from the HOVON group (GSE6891).
Results: When dichotomized at the first quartile, higher transcript levels of ALDH2 predicted poorer overall (5-year OS 20.2% vs 41.7% for high vs low expression, respectively), event-free (5-year EFS 11.9% vs 30.0%) and relapse-free survival (5-year RFS 22.1% vs 45.0%) (log-rank test: P < 0.001 for all variables). Patients with higher ALDH2 levels had significantly lower rates of complete remission on induction chemotherapy (53% vs 63%; P < 0.05). In multivariate Cox regression analyses including age, gender, primary vs secondary AML, ECOG, WBC, LDH, cytogenetic risk and molecular risk, high ALDH2 expression, among others, remained an independent adverse prognostic factor for OS (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.11 to 2.04; P= 0.008), EFS (HR, 1.43; 95% CI, 1.08 to 1.90; P= 0.012) and RFS (HR, 1.82; 95% CI, 1.24 to 2.67; P= 0.002). Finally, the prognostic impact of ALDH2 was confirmed in a second cohort of 270 intensively treated younger AML patients from the HOVON group (GSE6891). Again, when dichotomized at the first quartile, high ALDH2 significantly predicted inferior OS (5-year OS 37.3% vs 59.4%; P= 0.003) and EFS (5-year EFS 28.8% vs 53.0%; P < 0.001).
Conclusion: We identified high ALDH2 expression as an adverse prognostic factor in two large independent cohorts of intensively treated AML patients.
Lenz: Celgene, JJ, Hexal, Roche, BMS, Novartis, Bayer: Consultancy; AstraZeneca, Gilead, JJ, Celgene, Novartis, Bayer: Research Funding. Hiddemann: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Asterisk with author names denotes non-ASH members.