A NUDT15 Genetic Polymorphism Study in Adult Acute Leukemia Patients Integrating Pharmacogenomics and Clinical Practice: A Single Centre Experience from South India
Authors: Babu Thomas , Durairaj Logesh , Sanjeevi Aditya , Subramanian Jeyasankar , Goswami Uddiptya , George Deepak , Stanislasus Cecili , Muralitharan Nirusha , K M Vani , Ratnakumar Sooraj , Easow Jose M 
Published: December 2023

Background: Severe myelosuppression secondary to thiopurines such as 6-Mercaptopurine (6-MP) in patients with acute leukemia undergoing maintenance therapy is frequently attributed to inherited genetic polymorphisms of Thiopurine Methyltransferase (TPMT); however, this is rare in the Asian population. Nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) is also responsible for encoding critical enzymes involved in 6-MP metabolism. We aimed to determine the frequency of genetic polymorphisms of NUDT15 in the South Indian population and the impact of the omission of 6-MP from the treatment protocol of these patients.

Methods: We retrospectively reviewed 17 patients diagnosed with acute leukemia between May 2018 and May 2020 and analyzed the prevalence of NUDT15 genetic polymorphisms in these patients. The NUDT15 mutation study (NUDT15 415C&gt;T) used allele-specific Real-Time PCR in peripheral blood. 6-Mercaptopurine (6-MP) was excluded from the treatment regimen of patients with NUDT15 genetic polymorphisms and the impact of its exclusion was also studied.

Results: Among the 17 patients for whom we cared, 10 were diagnosed with B-cell Acute Lymphoblastic Leukemia (B-ALL), three with T-cell Acute Lymphoblastic Leukemia (T-ALL), one with Mixed Phenotype Acute Leukemia (MPAL), and one with Acute Promyelocytic Leukemia (APML). Treatment records could not be retrieved for 2 patients. NUDT15 mutations were present in six patients (36%) (see fig1), of whom two had homozygous (33%) polymorphisms and four had heterozygous (67%) polymorphisms. In the heterozygous group, 2 were Ph. (Philadelphia chromosome) negative B-ALL; one was treated with BFM and the other with hyper-CVAD, one Ph. positive B-ALL was treated with BFM + Ponatinib, and one High-risk APML was treated with the APML 4 protocol. In the homozygous group, treatment details could not be retrieved for one case, and the other patient had T-ALL, which was treated with hyper-CVAD. 6-MP was omitted from the treatment protocol for all NUDT15 mutation-positive patients, both homozygous and heterozygous. Of these patients, two developed grade 1 myelosuppression, one developed grade 2 myelosuppression, one developed dyselectrolytemia, and one patient did not develop any toxicity. The incidence of severe or grade 3 and 4 myelosuppression in NUDT15 polymorphisms receiving 6MP can be as high as 50% (Khaeso K et.al Front Pharmacol. 2021). In comparison, none of our patients developed grade 3 or 4 myelosuppression. Overall, treatment-related adverse events included grade 1-2 myelosuppression (n=6), grade 1-2 hepatotoxicity (n=1), deep vein thrombosis (n=2), and sepsis (n=2). Five of the 6 patients with NUDT15 mutations achieved complete remission (CR).

Conclusion: The prevalence of NUDT15 polymorphisms was high in our study population. Based on a meta-analysis, the prevalence of NUDT15 in the South Indian population was 16.5%, and in patients with adverse effects, the pooled prevalence of NUDT15 polymorphisms was 49.51% (Anuraag Jena et.al. Expert Review of Clinical Pharmacology 2021). Based on our results, although limited by the small number of cases, we suggest that pre-emptive testing to detect these polymorphisms should be undertaken in all adult acute leukemia patients of South Indian origin, given their high prevalence in this population. The omission of 6-MP from treatment protocols can help prevent severe myelosuppression and treatment interruption or discontinuation, which in turn can improve treatment outcomes.