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Open AccessArticle

Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia

1
College of Pharmacy, University of Tennessee Heath Science Center, Memphis, TN 38163, USA
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Department of Pharmacology, Apollo Institute of Medical Sciences and Research, Hyderabad 500090, India
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Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research, Pondicherry 605006, India
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Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education & Research, Pondicherry 605006, India
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Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education & Research, Pondicherry 605006, India
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Division of Haemato-Oncology, Care Hospitals, Hyderabad 500019, India
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American Oncology Institute, Nallagandla Serilingampalli, Hyderabad 500019, India
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Department of Pharmacology, Kalinga Institute of Medical Sciences, Bhubaneswar 751024, India
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Onco-Hematology Unit, Research Platform of Pediatric Onco-Hematology, Department of Paediatrics, Gynaecology and Obstetrics, University Hospitals of Geneva, University of Geneva, 1205 Geneva, Switzerland
*
Authors to whom correspondence should be addressed.
Genes 2020, 11(6), 594; https://doi.org/10.3390/genes11060594
Received: 21 April 2020 / Revised: 13 May 2020 / Accepted: 25 May 2020 / Published: 28 May 2020
Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3–4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3–4) was seen in 54.9% of patients. The NUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105’T’) carrier status along with NUDT15c.415T allele [HR = 2.7 (1.5–4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT. View Full-Text
Keywords: NUDT15; polymorphism; toxicity; 6-mercaptopurine; relapse; survival; methotrexate; myelosuppression; toxicity; acute lymphoblastic leukemia; children; India NUDT15; polymorphism; toxicity; 6-mercaptopurine; relapse; survival; methotrexate; myelosuppression; toxicity; acute lymphoblastic leukemia; children; India
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MDPI and ACS Style

Kodidela, S.; Dorababu, P.; Thakkar, D.N.; Dubashi, B.; Sundaram, R.; Muralidharan, N.; Nidanapu, R.P.; Aribandi, A.; Pradhan, S.C.; Uppugunduri, C.R.S. Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia. Genes 2020, 11, 594. https://doi.org/10.3390/genes11060594

AMA Style

Kodidela S, Dorababu P, Thakkar DN, Dubashi B, Sundaram R, Muralidharan N, Nidanapu RP, Aribandi A, Pradhan SC, Uppugunduri CRS. Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia. Genes. 2020; 11(6):594. https://doi.org/10.3390/genes11060594

Chicago/Turabian Style

Kodidela, Sunitha; Dorababu, Patchava; Thakkar, Dimpal N.; Dubashi, Biswajit; Sundaram, Rajan; Muralidharan, Niveditha; Nidanapu, Ravi P.; Aribandi, Anil; Pradhan, Suresh C.; Uppugunduri, Chakradhara R.S. 2020. "Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia" Genes 11, no. 6: 594. https://doi.org/10.3390/genes11060594

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