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Letters to the Editor
An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia
6-mercaptopurine (6-MP) is one of the essential chemotherapeutic agents for treatment of acute lym- phoblastic leukemia (ALL) in children and adults.1 Bone marrow suppression is the main dose-limiting toxicity of 6-MP, and the sensitivity to 6-MP is strongly affected by germline variants in genes regulating thiopurine metabo- lism.2 Recently, the NUDT15 variant c.415C>T has been identified as a genetic cause for 6-MP intolerability,3 which could explain the majority of thiopurine-induced myelosuppression in Asians that are also common in Hispanics.2 So far, multiple NUDT15 haplotypes with various combination of variants are known to exist (Figure 1A). Several researchers have reported that these variants had decreased NUDT15 activity,4, 5 and bi-allelic variants caused extremely intolerance to 6-MP.6 However, individual studies included a limited number of patients with bi-allelic variants, which significantly hin- dered the comprehensive analysis of the exact clinical course of 6-MP toxicity and development of evidence- based recommendations. Therefore, in this international collaborative study, we comprehensively evaluated the actual 6-MP tolerable dose, frequencies of 6-MP-induced toxicity, and outcomes in ALL patients with bi-allelic variants of NUDT15.
We asked collaborators from Japan, Singapore, Malaysia, Taiwan, China, and Thailand, about their experience of cases with NUDT15 bi-allelic variants, which led to the identificationof 37 ALL cases, most of the which were genotyped due to intolerance to 6-MP. Clinical information of the cases was retrospectively col- lected, focusing on 6-MP dosing and toxicity. Patients with NUDT15 bi-allelic variants were enrolled in this study, including some patients in prior case reports or small case series.6, 7 NUDT15 was genotyped by Sanger sequencing4. Thiopurine methyltransferase (TPMT) geno- type information was available for 20 cases, and no case had hypomorphic variants which also confer 6-MP sensi- tivity. The treatment of maintenance therapy typically started with 40 to 60 mg/m2/day of 6-MP (Online
Supplementary Table S1) and 20 to 40 mg/m2/week of methotrexate (MTX); these dosages were adjusted to maintain the target leukocyte count at 1,500 to 3,000/mL. Toxicities were graded by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and those rates were estimated by cumulative incidence. The tolerated dosages of 6-MP and MTX were defined as the average (mean) of the doses per day or per week, respec- tively, during the entire duration of maintenance therapy. The dose for bi-allelic variant was compared with the dose for wild-type and mono-allelic variant in our previ- ous report.6, 7
The average dose in each NUDT15 genotype was esti- mated by the Kruskal-Wallis test. The interruption dura- tion between 6-MP initial doses was estimated by the Mann Whitney U-test. Four-year overall survival (OS) and event-free survival (EFS) from start of maintenance therapy were estimated by the log-rank test. The statisti- cal analysis was conducted using R statistical software (version 3.4.1; http://www.r-project.org/).
Patient characteristics for the 37 cases are shown in Table 1. Patients with bi-allelic variant had intolerance to 6-MP, and reduction was required mainly due to myelo- suppression (Online Supplementary Figure S1). The average 6-MP dose of these patients during maintenance therapy was 5.2 (range, 1.1–25.6) mg/m2/day, and the 6-MP dose by each diplotype is shown in Figure 1B. Comparatively, the average MTX dose was 10.4 (range, 1.9–44.6) mg/m2/week (Online Supplementary Figure S2). This 6-MP dose was significantly lower compared with the average dose for the NUDT15 wild-type (n=138, 41.7 mg/m2, P= 3.9×10–14) and mono-allelic variant (n=47, 33.6 mg/m2, P=2.7×10–13) in Japanese patients reported previously (Figure 2).6, 7 Most of the cases showed intolerance to 6- MP, and 10 mg/m2 or less was sufficient to maintain the target leukocyte range for 32 (86.4%) of the 37 cases. The median 6-MP average dose for *2/*2, *2/*3, and *3/*3 (poor metabolizer [PM]) were 5.2 mg/m2/day, and the average dose was not different among these three diplo- types (P=0.29, Figure 1B). NUDT15 haplotypes other than PM showed heterogeneous sensitivity to 6-MP, although the average 6-MP dose as a group was not sta- tistically different from PM (Online Supplementary Table S2, P=0.53).
Table 1. Patient characteristics
Total,n
Male/Female, n
Median age, years (range) Immunotype (BCP/T), n
Median 6-MP initial dose, mg/m2 (range)
NCI/Rome criteria
Standard/High risk, n
NUDT15 genotype, n *2/*2
*2/*3 *2/*5 *2/*6 *2/*7 *3/*3 *3/*5 *5/*5
Japan Singapore Taiwan China Thailand
20 7 6 3 1
9/11
6 (3-15) 18/2
17.2 (1.9-51.3)
15/5
3/4
6 (3-14) 7/0
10.9 (3.5-17.5)
3/4
5/1
9 (3-16) 5/1 11.4(5.0-39.5)
4/2
1/2 1/0 6 (4-7) 5
2/1 1/0 20.6 (4.3-29.8) 24.4
2/1 1/0
10300 51010 10000 02000 00100 10 4 2 1 1 20010 10000
2026
BCP: B-cell precursor; T: T-cell; 6-MP: 6-mercaptopurine; n: number; 6-MP: 6-mercaptopurine; NCI: National Cancer Institute.
haematologica | 2021; 106(7)