Thiopurine Methyltransferase Intermediate Metabolizer Status and Thiopurine‐Associated Toxicity During Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia

Abstract

Mercaptopurine is a cornerstone of maintenance chemotherapy in childhood acute lymphoblastic leukemia (ALL). Its cytotoxic effects are mediated by 6‐thioguanine nucleotides (TGNs) incorporation into lymphocyte DNA. Thiopurine methyltransferase (TPMT) inactivates mercaptopurine, and deficiency resulting from genetic variants increases TGN exposure and hematopoietic toxicity. Although mercaptopurine‐dose reduction reduces toxicity risk without compromising relapse rate in patients with TPMT deficiency, dosing recommendations for those with moderately reduced activity (intermediate metabolizer (IM)) are less clear and their clinical impacts have yet to be established. This cohort study assessed the effect of TPMT IM status on mercaptopurine‐associated toxicity and TGN blood exposure in pediatric patients with ALL initiated on standard dose mercaptopurine. Of 88 patients studied (mean age 4.8 years), 10 (11.4%) were TPMT IM, and all had undergone ≥ 3 cycles of maintenance therapy (80% completed). A larger proportion of TPMT IM than normal metabolizers (NM) had febrile neutropenia (FN) during the first two cycles of maintenance, reaching significance in the second cycle (57% vs. 15%, respectively; odds ratio = 7.33, P < 0.05). Compared to NM, FN events occurred more frequently and with prolonged duration in IM in cycles 1 and 2 (adjusted P < 0.05). IM had a 2.46‐fold increased hazard ratio for FN, and about twofold higher TGN level than NM (P < 0.05). Myelotoxicity was more common in IM than NM (86% vs. 42%, respectively) during cycle 2 (odds ratio = 8.2, P < 0.05). TPMT IM initiated at a standard mercaptopurine dose are at greater risk for FN during early cycles of maintenance therapy, thus our findings support genotype‐guided dose adjustment to reduce toxicity.

Population-Specific Distribution of TPMT Deficiency Variants and Ancestry Proportions in Ecuadorian Ethnic Groups: Towards Personalized Medicine

“…80 A skewed metabolism of 6-MP can cause gastrointestinal toxicity, including refractory nausea, pancreatitis, and hepatotoxicity, which can significantly limit the tolerable dose. 18,20,[81][82][83] Given the calculated prevalence of TPMT deficiency in the Ecuadorian population and the heterogeneous distribution of genetic factors linked to this condition among the various ethnic groups under examination, it becomes paramount to institute genetic screening measures to mitigate the risk of severe adverse effects stemming from thiopurine toxicity. These screening strategies should encompass the assessment of TPMT*3A, TPMT*3B and TPMT*3C alleles, with a particular emphasis on their application within IND and AFE minority groups, where the probability of their occurrence is higher compared to the MEZ group.…”