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Letters to the Editor
of death were relapse of leukemia, second malignancy, or complications related to bone marrow transplantation. OS and EFS were 91%± 6% and 82%±7%, respectively (Online Supplementary Figure S4).
This Asian international study showed that most patients with NUDT15 PM required a reduced 6-MP dose to <10 mg/m2 during maintenance therapy. These findings were concordant with the recommendations by the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines.2 NUDT15 c.52G>A and c.36_37insGGAGTC are defined as an uncertain function allele in the CPIC guidelines,2 and a patient with *5/*5 can tolerate as high as 18.3 mg/m2. However, three cases with *3/*5 had intolerance to 6-MP at <10 mg/m2, point- ing to a compound heterozygous effect. Additionally, cases with bi-allelic variant with *6 (only c.36_37insGGAGTC) might be more tolerant to 6-MP than those with c.415C>T. Moriyama et al. defined *3 as low, and *5 and *6 as intermediate activity in vitro.4 Our results demonstrate that diplotypes of intermediate/inter- mediate tolerate moderate intensity, but that intermedi- ate/low is extremely sensitive to 6-MP. These heteroge- neous sensitivities in bi-allelic variants of NUDT15 high- light the importance of precise diplotyping analysis.
Twenty-seven patients started maintenance therapy with the reduced 6-MP dose to less than 30 mg/m2, main- ly because they experienced severe toxicities during con- solidation and their NUDT15 variants had already been genotyped. As shown in the Online Supplementary Figure S1, typical cases with NUDT15 bi-allelic variants showed a sudden crash of the leukocyte count after an approxi- mately 2-week exposure to 6-MP, and required a long time to attain recovery of leukocyte counts. These obser- vations are concordant with the findings of previous reports.8, 9 Accordingly, adjustment of the 6-MP dose is often difficult in most cases as the 6-MP dose fluctuated dramatically and treatment interruption was common. With a reduced starting dose of 6-MP, dose fluctuation was not observed and maintenance therapy could be given continuously. However, some researchers reported that patients with the NUDT15 c.415C>T variant devel- oped thiopurine-induced leukopenia within 2 months from initiation of therapy.7, 10
Regarding tolerability to MTX, some studies reported that the average MTX dose was not different in NUDT15 genotypes.6, 11 However, some cases had reduced MTX dose, probably due to myelosuppression caused by 6-MP and, thus, the optimal MTX dose in NUDT15 bi-allelic cases needs to be established in future studies.
Patients with the NUDT15 variant experienced thiop- urine-induced hematological toxicity for several months regardless of the disease or race.9 The majority of patients with NUDT15 bi-allelic variant experienced grade 4 neu- tropenia. This finding was in line with previous reports that Nudt15–/– mice, which demonstrated significantly decreased neutrophil counts upon thiopurine exposure.12 Neutrophils were more sensitive than other leukocytes to thiopurine with deficient NUDT15. For patients with bi- allelic variants, neutrophil counts should be carefully monitored, as well as total leukocyte counts, during 6- MP treatment. Given the risk of severe infectious compli- cations, pre-emptive NUDT15 genotyping for all patients with ALL should be performed and dose modification in cases with bi-allelic variants must be considered.
This study has some limitations. First, TPMT genotype information is insufficient because routine screening for TPMT variants, another determinant of 6-MP sensitivity, was not performed. However, considering variant distri- bution of NUDT15 and TMPT2, variant allele frequency
Figure 2. Average 6-mercaptopurine dose during maintenance therapy.
of TPMT in those with NUDT15 bi-allelic variant is extremely low as observed in our limited data. Therefore, we can select, according to each racial background, which of the two major genetic determinants of 6-MP should be genotyped. However, considering recent racial mixture and advances in genomic analysis technology, comprehensive genotyping information responsible for drug sensitivity for all cases should be obtained to pro- vide a precise medical approach. Second, most of our cases were identified as having NUDT15 variants because of their intolerance to 6-MP, and , thus, the tol- erable dose of NUDT15 bi-allelic cases may be overesti- mated, which underpins the importance of upfront geno- typing. Third, the number of cases with some haplotypes (such as *6 or *7) were small, and tolerability of those patients with these rare haplotypes still needs to be determined by future studies.
In conclusion, bi-allelic NUDT15 variants conferred extreme intolerance to 6-MP. Pre-emptive NUDT15 genotyping for all patients with ALL should be performed and dose modification in cases with bi-allelic variants must be considered. Precise upfront genotyping and a reduction of the 6-MP dose to less to than 10 mg/m2 is recommended to avoid the risk of severe complications and therapy interruption.
Yoichi Tanaka,1 Allen Eng Juh Yeoh,2 Takaya Moriyama,3
Chi-Kong Li,4 Ko Kudo,5 Yuki Arakawa,6 Jassada
Buaboonnam,7 Hui Zhang,8 Hsi-Che Liu,9 Hany Ariffin,10
Zhiwei Chen,2 Shirley K.Y. Kham,2 Rina Nishii,3 Daisuke
Hasegawa,11 Junya Fujimura,12 Dai Keino,13 Kensuke
Kondoh,13 Atsushi Sato,14 Takahiro Ueda,15 Masaki
Yamamoto,16 Yuichi Taneyama,17 Moeko Hino,18 Masatoshi
Takagi,19 Akira Ohara,20 Etsuro Ito,5 Katsuyoshi Koh,7 Hiroki
Hori,21 Atsushi Manabe,22 Jun J. Yang,3 and Motohiro Kato,23,24,25
1Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki, Japan; 2VIVA-NUS Center of Translational Research in Acute Leukemia (Molecular), Department of Pediatrics,
2028
haematologica | 2021; 106(7)