UGT1A1*28 Genotype Is Associated With Reduced Overall Survival in Intermediate-Risk AML

Patients with intermediate-risk acute myeloid leukemia (AML) who are treated with cytarabine-based chemotherapy have lower overall survival (OS) if they possess the low-activity UGT1A1*28 homozygous genotype, suggests a study published in Leukemia. While these findings are novel, study investigator David Gallardo, MD, of the University of Girona in Spain, told ASH Clinical News that additional confirmation studies are needed before routine UGT1A1 genotyping can be proposed for patients with AML.

The UGT1A1 gene encodes a UDP-glucuronosyltransferase (UGT) enzyme important for inactivation and detoxification of certain chemotherapy metabolites, and variations in UGT1A1 genotype have been shown to influence toxicity of chemotherapy in several clinical settings.

Bone marrow samples from 455 patients with intermediate-risk AML were retrospectively analyzed. All patients had been treated with intensive chemotherapy in the context of previously reported clinical trials.

The investigators examined samples for NPM1, FLT3-ITD, and CEBPA mutations, as well as UGT1A1 genotype. A total of 148 patients (32.5%) were homozygous for the wild-type allele (UGT1A1*1), 258 patients (56.7%) were heterozygous (UGT1A1*1/*28), and 43 patients (9.5%) were homozygous for the variant allele (UGT1A1*28). There were no differences in age, sex, cytogenetic abnormalities, or presence of FLT3 or NPM1 mutations between patients with different UGT1A1 genotypes.

Overall, the complete response (CR) rate following induction therapy was 79.5%. Approximately 10.1% of patients (n=46) were refractory to initial therapy, and 9.9% (n=45) died during induction chemotherapy. The CR rates for each genotype group were not statistically different:

  • homozygous UGT1A1*1: 80.4%
  • heterozygous: 79.4%
  • UGT1A1*28 homozygous: 79.1%

The UGT1A1 genotype also did not affect the duration of neutropenia following induction chemotherapy (p=0.51). The median durations of neutropenia following induction chemotherapy were not different, but patients who were homozygous for the UGT1A1*28 variant had a median duration of neutropenia after consolidation chemotherapy of 25 days, which was significantly longer than heterozygous patients and UGT1A1*1 homozygous patients, who had median durations of 20 days (range = 2-106) and 18 days (range = 4-59), respectively (p=0.040).

There was no difference in the mortality rate during induction chemotherapy between the genetic groups (p=0.55). During consolidation chemotherapy, however, the incidence of mortality was significantly higher in patients with the homozygous UGT1A1*28 variant compared with patients who were heterozygous or wild-type homozygous (14% vs. 1.9% vs. 0.7%, respectively; p<0.001).

The median OS for all patients was 31.7 months. At 5 years, the OS was significantly better for patients who were UGT1A1*1 homozygous (42.3%) and UGT1A1*1/*28 heterozygous (46.5%) compared with patients who were homozygous for the UGT1A1*28 variant (25.8%; p=0.010).

“It would be interesting to determine whether modifying the intensity of consolidation chemotherapy based on UGT1A1 genotype is helpful.”

—David Gallardo, MD

In a multivariate analysis adjusted for age, sex, white blood cell count, FLT3 mutational status, cytogenetics, and NPM1, homozygous UGT1A1*28 genotype was an independent risk factor for lower OS (hazard ratio [HR] = 1.79; 95% CI 1.16-2.76; p=0.008).

In terms of disease-free survival (DFS), the UGT1A1 rs8175347 genotype was found to be an independent risk factor for worse DFS in the multivariate model (HR=1.60; 95% CI 1.04-2.46; p=0.033). Other risk factors for lower DFS included age >60 years, male sex, white blood cell count ≥100 × 109/L, and absence of the NPM1 mutation.

“If our results are confirmed,” said Dr. Gallardo, “it would be interesting to determine whether modifying the intensity of consolidation chemotherapy based on UGT1A1 genotype is helpful.” Ultimately, he noted, this strategy could reduce the chemotherapy-associated toxicity in this group of patients.

Reference

Díaz-Santa J, Rodríguez-Romanos R, Osca G, et al. UGT1A1 genotype influences clinical outcome in patients with intermediate-risk acute myeloid leukemia treated with cytarabine-based chemotherapy. Leukemia. 2020 Mar 9. [Epub ahead of print]