NUDT15 c.415C>T Polymorphism Predicts 6-MP Induced Early Myelotoxicity in Patients with Acute Lymphoblastic Leukemia Undergoing Maintenance Therapy

Figures & data

Table 1 Baseline Characteristics of Patients

Patient Parameters	Cohort-1 (n=42) N (%)	Cohort-2 (n=133) N (%)
Median Age at Diagnosis (range)	16.5 (2–56)	17 (1–63)
Sex
Male	35 (83.3)	88 (66)
Female	07 (16.7)	45 (34)
BSA (m^2)	1.5 (0.5–2.2)	1.5 (0.4–2.1)
Immunophenotype
B cell	31 (73.8)	111 (83.4)
T cell	09 (21.4)	20 (15)
MP-ALL	–	1 (1)
NA	2 (4.7)	1 (1)
Cytogenetics Risk
Favourable	6 (14.2)	25 (18.7)
Intermediate	25 (59.5)	81 (61)
Poor	7 (16.7)	7 (5.3)
NA	4 (9.6)	20 (15)
ALL Risk
Standard Risk	17 (40.4)	20 (15)
Intermediate Risk	20 (47.6)	70 (52.6)
High Risk	5 (12)	5 (3.8)
NA	–	38 (28.6)
Polymorphisms
TPMT variants
*2A
Homozygous reference	42 (100)	130 (100)
Not available	0	3 (-)
*3A (*3B&C)
Homozygous reference	39 (100)	123 (96.8)
Heterozygous variant	–	4 (3.2)
Not available	3 (-)	6 (-)
ITPA c.94 C > A
Homozygous reference	37 (88)	97 (76.4)
Heterozygous variant	5 (12)	28 (22)
Homozygous variant	–	2 (1.6)
Not available	–	6 (-)
MRP4 c.2269G>A
Homozygous reference	32 (76.2)	107 (80)
Heterozygous variant	9 (21.4)	13 (10)
Homozygous variant	1 (2.4)	2 (2)
Not available	–	11 (8)
NUDT15 c.415C>T
Homozygous reference	23 (54.7)	115 (86)
Heterozygous variant	14 (33.3)	18 (14)
Homozygous variant	5 (12)	–

Figure 1 Study design.

Figure 2 Associations between NUDT15 c.415C>T polymorphism (rs116855232) and % 6-MP dose intensity (A) and therapy interruption (B) in cohort-1 and cohort-2 (C) and (D). *Asterisks indicate the level of the significance (p-value); *Means p< 0.05, **Means p< 0.01, ***Means p< 0.001 and ns-not significant.

Table 2 Association Analysis of Genetic Variants and Clinical Response in Prospective Patients with ALL Undergoing Maintenance Therapy

Clinical Response/Toxicities	Association Analysis*
Covariates	Univariate Linear Regression		Multivariate Regression
	β	p value	β	p value
% MP Dose intensity
Age	−0.195	0.063	−0.044	0.760
ALL risk group	−0.228	0.027	−0.169	0.134
BSA	−0.191	0.028	−0.166	0.265
MRP4 c.2269G>A	−0.178	0.050	−0.029	0.789
NUDT15 c.415C>T	−0.173	0.047	0.138	0.203
ITPA c.94 C > A	0.155	0.081	0.137	0.200
Myelotoxicity
Early
Age	0.162	0.063	−0.062	0.590
BSA	0.245	0.005	0.263	0.024
NUDT15 c.415C>T	−0.328	<0.001	−0.314	<0.001
Late
TPMT*3A	−0.181	0.042	−0.209	0.025
NUDT15 c.415C>T	−0.191	0.028	−0.197	0.018

Notes: *Amongst covariates tested in both univariate and multivariate regression, only significant variables are listed above. Bold values denote statistical significance at the p ≤ 0.05 level.

Figure 3 Associations between NUDT15 c.415C>T polymorphism (rs116855232) and (A) Early, (B) Late Myelotoxicity. *Asterisks indicate the level of the significance (p-value); *Means p< 0.05 and ****Means p<0.0001.

Abbreviation: ANC, absolute neutrophil count.

Table 3 Influence of NUDT15 c.415C>T Polymorphism in Early 6-MP Induced Toxicities (Cohort-2)

Clinical Response	Patients with NUDT15 c.415C>T Polymorphism
	Wild Type, N=/115 (%)	Heterozygous, N=/18 (%)	Odds Ratio (95% CI), p-value*
MP dose reduced (<100%)	99 (86)	18 (100)	1.6 (−0.56–1.46), 0.361
% MP Dose intensity
>80%	66 (57)	11 (61)
50–80%	30 (26)	6 (33)
<50%	3 (3)	1 (6)
Neutropenia (ANC <1500 mm^3)	84 (73)	18 (100)	13.79 (0.57–7.48), 0.005
Severe neutropenia (ANC <500 mm^3)	24 (21)	12 (67)	7.18 (0.95–3.07), 0.0001
Dose interruption	98 (85)	17 (94)	2.07 (−0.75–2.97), 0.373

Notes: *ORs and p-values were calculated using penalized likelihood test-Firth logistic regression method using R. Bold values denote statistical significance at the p ≤ 0.05 level.