ALDH2 Polymorphism Has a Significant Impact on Transplant Related Mortality after HLA-Matched Bone Marrow Transplantation

Background:

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme known to degrade acetaldehyde metabolized from ethanol, is also involved in critically important biological processes such as drug metabolism and DNA repair in hematopoietic stem cells. Based on its role in these biological processes, we hypothesized that a functional ALDH2Glu504Lys polymorphism, which is highly prevalent in East Asian populations, could affect the outcome of hematopoietic transplant recipients. Here, we investigated the association between recipient and donor ALDH2 polymorphism and the clinical outcomes of bone marrow transplantation (BMT).

Methods.:

We analyzed the Japanese national registry data for 409 patients who underwent allogeneic BMT from an HLA-matched unrelated donor through the Japan Marrow Donor Program. The probability of overall survival (OS) was estimated according to the Kaplan-Meier method. The probabilities of relapse, transplant-related mortality (TRM), engraftment, and graft-versus-host disease (GVHD) were estimated based on cumulative incidence curves. Competing events were death without relapse for relapse, relapse for TRM, death without engraftment for engraftment, and death without GVHD for GVHD. To evaluate the impact of recipient and donor ALDH2 polymorphism on transplant outcomes, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for potential confounders. The Cox proportional hazards model was used to evaluate the effect on OS, whereas Fine and Gray's proportional hazards model was used for the other endpoints.

Results.:

The median follow-up period in survivors was 6.3 years (range, 0.3-13.1 years). The unadjusted 3-year OS rate was 51% (95% CI, 43%-57%) in Glu/Glu genotype recipients, 52% (43%-60%) in Glu/Lys genotype recipients, and 43% (25%-60%) in Lys/Lys genotype recipients. We did not observe a statistically significant association between the recipient ALDH2 polymorphism and OS. The cumulative incidence of unadjusted 3-year TRM was 28% (21%-34%) in Glu/Glu genotype recipients, 25% (18%-33%) in Glu/Lys genotype recipients, and 50% (29%-68%) in Lys/Lys genotype recipients. The recipient ALDH2 Lys/Lys genotype was significantly associated with a higher TRM, with a HR relative to Glu/Glu genotype of 2.45 (95% CI = 1.22-4.90, P = 0.01). Among the causes of TRM, the incidence rate of organ failure in recipients with the Lys/Lys genotype was twice as high as in recipients with the Glu/Glu genotype (5.9 vs. 3.0 per 1,000 person-days). A statistically significant association between the recipient ALDH2 polymorphism and relapse or GVHD was not observed. With regard to engraftment, the cumulative incidence of platelet engraftment at day 50 was 82% (76%-87%) in Glu/Glu genotype recipients, 80% (72%-85%) in Glu/Lys genotype recipients, and 65% (47%-78%) in Lys/Lys genotype recipients. Compared to the recipient Glu/Glu genotype, the recipient Lys/Lys genotype was marginally significantly associated with delayed platelet engraftment (HR = 0.60, 95% CI = 0.43-1.03, P = 0.06). In contrast, donor ALDH2 polymorphism did not show any significant association with transplant outcomes.

Conclusions:

We observed poor TRM and delayed platelet engraftment in HLA-matched unrelated BMT recipients with ALDH2 Lys/Lys genotype. Taken functional significance of this polymorphism, our results might indicate that recipient ALDH2 polymorphism could affect the metabolism of chemotherapeutic agents leading to higher TRM and delayed platelet engraftment.