Figure 2

Distribution of the average of the tolerated last-cycle 6-MP DIPs (%) of the CRIM1 rs3821169 and/or IL6 rs13306435 variant carrier vs. non-carrier subgroups among 240 pediatric patients with ALL presenting both NUDT15 and TPMT WT characterization. Of the 320 pediatric patients with ALL, we excluded 80 carriers presenting either NUDT15 or TPMT variants to obtain 240 subjects with both NUDT15 and TPMT WT. Both (a) non-carrier group of CRIM1 rs3821169 or IL6 rs13306435 (N = 115, 47.92%, i.e., “All WTs” in Table 2 and Fig. 3) and (b) carrier group of heterozygous CRIM1 rs3821169 only (N = 94, 39.17%) showed significantly higher thiopurine tolerance than the carrier groups of (d) homozygous CRIM1 rs3821169 (N = 11, 4.38%) (adj. p < 0.05, posthoc Tukey) and of (e) both IL6 rs13306435 and CRIM1 rs3821169 (N = 8, 3.33%) (adj. p < 0.0005, posthoc Tukey) by one-way ANOVA (p = 0.0001). (c) Carrier group of IL6 rs13306435 heterozygous variant only (N = 12, 5.00%) showed significantly higher thiopurine intolerance than (c) that of the hetero/homozygous variant of both IL6 and CRIM1 (adj. p < 0.05, posthoc Tukey). No carrier of homozygous IL6 was detected, and only one subject carried both heterozygous IL6 and homozygous CRIM1 variants (DIP = 9.7%). Thiopurine intolerance was measured by the last-cycle 6-MP DIP (%) among 240 pediatric patients with ALL presenting both NUDT15 and TPMT WT genes to control their effect on thiopurine intolerance. *p < 0.05 and **p < 0.01, posthoc Tukey test after one-way ANOVA. ALL acute lymphoblastic leukemia, WT wild-type, DIP (%) dose intensity percentage, 6-MP 6-mercaptopurine.