PB1658 RELEVANCE OF TPMT, NUDT15 AND ABCC4 GENOTYPING IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
Authors: Couto E. , Bizarro S. , Oliva T. , Teixeira M. , Pinto A. 
Published: June 2019

Background:

Acute lymphoblastic leukemia/lymphoma (ALL/lymphoma) is the most common pediatric cancer. The approved standard treatment includes a 24‐month maintenance phase with 6‐mercaptopurine (6‐MP) and methotrexate, achieving complete responses in 80% of the cases.

According to the literature, there are genetic polymorphisms in enzymes involved in the thiopurine drugs metabolism (namely, thiopurine methyltransferase or TPMT and nudix hydrolase 15 or NUDT15) and transport (ATP binding cassette subfamily C member or ABCC4) that can influence their therapeutic effect and cause adverse events along this phase (myelosuppression, hepatotoxicity, pancreatitis, among others).

Inherited TPMT deficiency (mainly, variants 2, 3A, 3B and 3C) is the primary genetic cause of thiopurine intolerance in Europeans and Africans, whereas risk alleles in NUDT15 explain most of thiopurine‐related myelosuppression in Asians and Hispanics. Not so well established are the presence of genetic variants in genes coding for drug transport proteins like ABCC4.

The Clinical Pharmacogenetics Implementation Consortium has published recommendations for adjusting starting doses based on TPMT/NUDT15 genotypes but, although relevant to prevent severe adverse effects, these studies are not yet universally implemented.

Aims:

Genotyping pediatric ALL/lymphoma with hematologic toxicity along the maintenance phase of the oncologic treatment.

Methods:

Patients diagnosed with ALL/lymphoma since 2012, presenting hematologic toxicity to 6‐MP and requiring regular dose adjustments along the maintenance phase were studied for TPMT genotype. In case of negative study for TPMT, NUDT15 and ABCC4 genotypes were also explored.

Results:

Eleven patients were identified, median age 8 [1‐14] years, male gender in 6 cases (54.5%). Seven patients had a B‐ALL (63.6%), one had a T‐ALL and three had a lymphoma.

Six patients already finished their maintenance phase. These had a median of 19.5 [7‐35] adjustments for 6‐MP dose along this phase for hematologic toxicity, with a median time of 14 days between adjustments. One of these patients was identified with the genotype TPMT 3A∗ (the most common variant allele in the Caucasian population that confers low enzyme activity), and required 23 adjustments for hematologic toxicity in a median time of 14 days [3‐116] until reaching the adequate dose.

Five patients are still in the maintenance phase (median time of 9 [2‐11] months) and had already a median of 10 [2‐20] adjustments for hematologic toxicity, in a median time of 14 days between adjustments. From these, there are 3 cases identified with an ABCC4 genotype that seem to predispose to adverse hematologic events, requiring closer medical monitoring.

All these 11 patients are alive and have no oncologic disease. Overall survival is 2 [1‐7] years and progression free survival is also 2 [1‐4] years.

Summary/Conclusion:

This study led to the implementation of TPMT genotyping in all Pediatric ALL/lymphoma patients in our center, before the maintenance phase and to a 50% dose reduction of 6‐MP in those with TPMT forms with low activity (TPMT∗2, TPMT∗3B, TPMT∗3C and TPMT∗3A) to reduce hematologic toxicity related to an excessive dose administered. Based on the results obtained for ABCC4 and NUDT15 genotypes and according to the literature, it is still not recommended the study of these additional genes for all patients.