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Presenter Status

Fellow

Abstract Type

Research

Primary Mentor

Terrie Flatt, DO

Start Date

6-5-2022 12:45 PM

End Date

6-5-2022 1:00 PM

Presentation Type

Oral Presentation

Description

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Overall survival rate is > 90% in the United States. However, ethnic and racial disparities remain. Hispanic patients have an inferior overall survival compared to non-Hispanics. The reasons for these differences remain unclear. Mercaptopurine (6MP) is a crucial drug in ALL treatment. Variations in the TMPT and NUDT15 genes lead to altered 6MP metabolism and accumulation of toxic metabolites (6TGN or 6MMPN). Each metabolite is associated with specific dose-limiting toxicities. The accumulation of 6TGN causes myelosuppression, and increased 6MMPN causes GI toxicity. While variants in these genes have been identified in the Caucasian population, they are not characterized in Hispanics. Hispanics often experience atypical metabolism, with elevated levels of 6MMPN causing myelosuppression but not GI toxicity.

Objective: Characterize variation in the genes contributing to variation in 6MP metabolism and toxicities in Hispanic children with ALL.

Methods: This is a single institution pilot study. Subjects were identified through the Hematology/Oncology Program and the CMH Cancer Registry. A chart review was performed and included 6MP-related laboratory values, toxicities, and clinical symptoms during maintenance chemotherapy. We are utilizing samples from the CMH Tumor Bank to perform whole genome sequencing.

Results: Thirty-three% of Hispanic patients had atypical 6MP metabolism with an accumulation in 6MMPN resulting in myelosuppression. 6MP was suspended in 23 out of 24 patients and 96% received less than suggested doing. Due to toxicity, 46% of patients required the addition of allopurinol to alter 6MP metabolism. Skin toxicity was correlated with elevated 6MMPN levels, which has not previously been described. Only one patient in our cohort had abnormal TPMT or NUDT15 genes.

Conclusions: Mercaptopurine is a vital component of successful ALL treatment and cure. Hispanic patients have altered 6MP metabolism that leads to toxic side-effects and altered dosing that is not explained by our current body of knowledge. This project is ongoing with the goal to increase understanding of the genetics of mercaptopurine metabolism to improve outcomes and decrease side effects in this patient population. Whole genome sequencing will be performed to search for novel mutations that may be responsible for the metabolic patterns we describe.

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May 6th, 12:45 PM May 6th, 1:00 PM

Variation in Thiopurine Metabolism in Hispanic Children

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Overall survival rate is > 90% in the United States. However, ethnic and racial disparities remain. Hispanic patients have an inferior overall survival compared to non-Hispanics. The reasons for these differences remain unclear. Mercaptopurine (6MP) is a crucial drug in ALL treatment. Variations in the TMPT and NUDT15 genes lead to altered 6MP metabolism and accumulation of toxic metabolites (6TGN or 6MMPN). Each metabolite is associated with specific dose-limiting toxicities. The accumulation of 6TGN causes myelosuppression, and increased 6MMPN causes GI toxicity. While variants in these genes have been identified in the Caucasian population, they are not characterized in Hispanics. Hispanics often experience atypical metabolism, with elevated levels of 6MMPN causing myelosuppression but not GI toxicity.

Objective: Characterize variation in the genes contributing to variation in 6MP metabolism and toxicities in Hispanic children with ALL.

Methods: This is a single institution pilot study. Subjects were identified through the Hematology/Oncology Program and the CMH Cancer Registry. A chart review was performed and included 6MP-related laboratory values, toxicities, and clinical symptoms during maintenance chemotherapy. We are utilizing samples from the CMH Tumor Bank to perform whole genome sequencing.

Results: Thirty-three% of Hispanic patients had atypical 6MP metabolism with an accumulation in 6MMPN resulting in myelosuppression. 6MP was suspended in 23 out of 24 patients and 96% received less than suggested doing. Due to toxicity, 46% of patients required the addition of allopurinol to alter 6MP metabolism. Skin toxicity was correlated with elevated 6MMPN levels, which has not previously been described. Only one patient in our cohort had abnormal TPMT or NUDT15 genes.

Conclusions: Mercaptopurine is a vital component of successful ALL treatment and cure. Hispanic patients have altered 6MP metabolism that leads to toxic side-effects and altered dosing that is not explained by our current body of knowledge. This project is ongoing with the goal to increase understanding of the genetics of mercaptopurine metabolism to improve outcomes and decrease side effects in this patient population. Whole genome sequencing will be performed to search for novel mutations that may be responsible for the metabolic patterns we describe.

 

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