Early proactive monitoring of DNA-thioguanine in patients with Crohn’s disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers

Table 1 Baseline characteristics of the 148 patients included in the study

Characteristics	Patients		P value	Odds ratio (95%CI)
	Leucopenia	Nonleucopenia
Number of subjects (%)	42 (28.4)	106 (71.6)
Female, n (%)	14 (33.3)	22 (20.8)	0.11	1.91 (0.86-4.23)
Age (yr)	29 (12-59)	26 (13-61)	0.03	0.96 (0.92-0.99)
Azathioprine, n (%)	37 (26.6)	102 (73.4)	Reference	0.29 (0.07-1.14)
6-mercaptopurine, n (%)	5 (55.6)	4 (44.4)	0.08	1.05 (1.01-1.10)
Thiopurine dose (mg)	87.5 (25-100)	75 (50-150)	0.76	0.99 (0.98-1.01)
Azathioprine	75 (25-100)	75 (50-150)
6-mercaptopurine	50 (37.5-50)	37.5 (25-50)
Weight (kg)	52 (40-69)	55 (37-79)	0.02	1.05 (1.01-1.10)
Hematologic indices
Leukocyte count (109/L)	6.25 (4.09-16.66)	6.92 (4.09-17.60)	0.83	1.31 (0.11-15.71)
Absolute neutrophil count (109/L)	3.98 (1.30-15.55)	4.59 (1.91-14.76)	0.78	0.70 (0.06-8.31)
Absolute lymphocyte count (109/L)	1.64 (0.41-4.45)	1.53 (0.27-4.26)	0.79	0.94 (0.57-1.53)
Monocyte count (109/L)	0.49 (0.22-1.98)	0.57 (0.10-1.72)	0.66	1.29 (0.42-3.91)
Hemoglobin (g/L)	126 (76-165)	130 (66-166)	0.43	1.01 (0.99-1.02)
Platelets (109/L)	287 (122-589)	302 (150-680)	0.10	1.00 (0.99-1.01)
Comedication (%)
Anti-TNF agents	2 (4.76)	16 (15.09)	0.49	0.46 (0.05-4.09)
Corticosteroids	2 (4.76)	5 (4.72)	0.76	1.41 (0.16-12.47)
Genotypes (phenotypes)
NUDT15*1/*1 (NM)	18 (42.86)	93 (87.74)	Reference
NUDT15*1/*3 (IM)	13 (30.95)	8 (7.55)	0.95	0.97 (0.34-2.72)
NUDT15*1/*2 (IM)	9 (21.43)	5 (4.72)	0.61	1.42 (0.37-5.44)
NUDT15*1/*6 (IM)	2 (4.76)	0	0.99
TPMT*1/*1 (NM)	40 (95.24)	105 (99.06)	Reference
TPMT*1/*3C (IM)	2 (4.76)	1 (0.94)	0.19	0.94 (0.47-2.35)

CI: Confidence interval; NM: Normal metabolizer; IM: Intermediate metabolizer; NUDT15: Nudix hydrolase 15; TPMT: Thiopurine methyltransferase.

Table 2 Univariate and multivariate analysis of independent predictors for leucopenia

Characteristics	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Age (yr)	1.04 (1.01-1.08)	0.005	1.06 (1.02-1.09)	0.002
Weight (kg)	0.95 (0.91-0.99)	0.013	0.96 (0.92-1.00)	0.076
DNATG (fmol/μg DNA)	1.004 (1.002-1.005)	< 0.001	1.004 (1.002-1.005)	< 0.001
NUDT15 genotypes		< 0.001
NUDT15*1/*1	Reference		Reference
NUDT15*1/*6	17.99 (3.95-81.90)	< 0.001	11.62 (1.51-89.26)	0.018
NUDT15*1/*3	4.93 (2.41-10.10)	< 0.001	3.21 (1.54-6.71)	0.002
NUDT15*1/*2	4.50 (2.01- 10.03)	< 0.001	3.25 (1.41-7.50)	0.006
6TGN (pmol/8 × 108 RBC)	1.003 (1.001-1.004)	< 0.001	1.000 (0.998-1.002)	0.98
Sex		0.19
Female	Reference
Male	0.64 (0.34-1.22)	0.17
TPMT genotypes		0.31
TPMT*1/*1	Reference
TPMT*1/*3C	2.38 (0.57-9.87)	0.25

HR: Hazard ratio; CI: Confidence interval; NUDT15: Nudix hydrolase 15; TPMT: Thiopurine methyltransferase; 6TGN: 6-thioguanine nucleotides; DNATG: DNA-thioguanine; RBC: Red blood cell.