Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia

Clinical and demografic characteristics and their association with glucocorticoid (GC) response. The GC response is assesed by absolute number of blasts per mm3 of blood on day 8. Statistically significant associations (p < 0.05) were bolded

Patients characteristics	Group	Entire group	≥1000 blasts	100≤ blasts <1000	1≤ blasts <100	blast negative patients	GC response (cutoff=1000 blasts)0	GC response (cutoff=100 blasts)1	GC response (cutoff=0 blasts)2

		n (%)	n (%)	n (%)	n (%)	n (%)	OR [95%CI], p0	OR [95%CI], p1	OR [95%CI], p2
Age	≥1 and <6 (non-risk)	65 (53.3)	4 (30.8)	17 (54.8)	21 (55.3)	23 (57.5)	reference	reference	reference
Age	<1 or ≥6 (risk)	57 (46.7)	9 (69.2)	14 (45.2)	17 (44.7)	17 (42.5)	2.86 [0.83-9.85], 0.085	1.42 [0.68-2.98], 0.356	1.29 [0.60-2.76], 0.514
Gender	male	66 (54.1)	10 (76.9)	13 (41.9)	20 (52.6)	23 (57.5)	reference	reference	reference
Gender	female	56 (45.9)	3 (23.1)	18 (58.1)	18 (47.4)	17 (42.5)	0.32 [0.083-1.26], 0.081	1.12 [0.54-2.35], 0.761	1.28 [0.57-2.63], 0.598
Initial WBC count^∗	<20,000/microL	64 (53.3)	1 (8.3)	13 (43.3)	21 (55.3)	29 (72.5)	reference	reference	reference
Initial WBC count^∗	≥20,000/microL	56 (46.7)	11 (91.7)	17 (56.7)	17 (44.7)	11 (27.5)	15.40 [1.92-123.6], 0.001	3.57 [1.62-7.88], 0.001	3.39 [1.49-7.72], 0.003
Immunophenotype	B	108 (88.5)	9 (69.2)	27 (87.1)	35 (92.1)	37 (92.5)	reference	reference	reference
Immunophenotype	T	14 (11.5)	4 (30.8)	4 (12.9)	3 (7.9)	3 (7.5)	4.40 [1.15-16.90], 0.043F	2.67 [0.86-8.27], 0.081	1.91 [0.50-7.28], 0.546

OR = Odds ratio between a group with higher number of blasts in comparison with a group with lower number of blasts. The group with lower number of blasts represents reference group.

CI = Confidence interval

0 Association with prednosine response on day 8 according to Berlin-Frankfurt-Munster (BFM) protocol: prednisone poor responder (PPR) group (≥1000 blasts) vs. prednisone good responder (PGR) group (<1000 blasts)

1 Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts

2 Association with blast status on day 8: blast positive vs blast negative patients.

1 Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts

2 Association with blast status on day 8: blast positive vs blast negative patients.

F Fisher exact test

Table 2

Genotype frequencies and association with glucocorticoid (GC) response. The GC response is assesed taking into account absolute number of blasts per mm3 of blood on day 8. For univariate analysis, chi square test was used, unless differently stated. Dominant model was used unless differently stated. Statistically significant associations (p < 0.05) were bolded

Genotype	≥ 1000 blasts	100 ≤ blasts < 1000	1 ≤ blasts < 100	blast negative patients	GC response (cutoff=1000 blasts)0	GC response (cutoff=1000 blasts)0, ADJ	GC response (cutoff=100 blasts)1	GC response (cutoff=100 blasts)1, ADJ	GC response (cutoff=0 blasts)2	GC response (cutoff=0 blasts)2, ADJ

	n (%)	n (%)	n (%)	n (%)	OR[95%CI] P value	OR[95%CI] P value	OR[95%CI] P value	OR[95%CI] P value	OR[95%CI] P value	OR[95%CI] P value
NR3C1 rs33389
CC	10 (76.9)	21 (67.7)	33 (86.8)	32 (80.0)	reference	reference	reference	reference	reference	reference
CT	3 (23.1)	9 (29.0)	4 (10.5)	6 (15.0)	1.12[0.29-4.41] 1F	1.10[0.21-5.92] 0.910	2.1[0.87-5.05] 0.095	1.85[0.73-4.71] 0.195	1.12[0.44-2.86] 0.805	0.89[0.32-2.44] 0.826
TT	0 (0.0)	1 (3.2)	1 (2.6)	2 (5.0)
NR3C1 rs33388
AA	4 (30.8)	11 (35.5)	7 (18.4)	9 (22.5)	reference	reference	reference	reference	reference	reference
AT	4 (30.8)	15 (48.4)	19 (50.0)	19 (47.5)	0.74[0.21-2.60] 0.737F	0.71[0.16-3.13] 0.658	0.5[0.22-1.15] 0.098	0.53[0.28-1.26] 0.148	0.79[0.32-1.92] 0.606	0.83[0.32-2.11] 0.699
TT	5 (38.5)	5 (16.1)	12 (31.6)	12 (30.0)
NR3C1 6198
AA	7 (53.8)	21 (67.7)	28 (73.7)	30 (75.0)	reference	reference	reference	reference	reference	reference
AG	4 (30.8)	10 (32.3)	9 (23.7)	10 (25.0)	reference	reference	reference	reference	reference	reference
GG	2 (15.4)	0 (0.0)	1 (2.6)	0 (0.0)	19.64[1.65-234.32] 0.030R, F	16.76[1.20-234.27] 0.036R	1.66[0.75-3.68] 0.222R	4.01[0.34-47.4] 0.27R	1.04[0.99-1.08] 0.22R	- 1R
GSTP1 rs1695
AA	7 (53.8)	15 (48.4)	16 (42.1)	16 (40.0)	reference	reference	reference	reference	reference	reference
AG	5 (38.5)	13 (41.9)	18 (47.4)	19 (47.5)	0.65[0.21-2.06] 0.46	0.91[0.26-3.25] 0.885	0.70[0.33-1.46] 0.338	0.73[0.34-1.58] 0.423	0.77[0.36-1.66] 0.508	0.84[0.37-1.9] 0.682
GG	1 (7.7)	3 (9.7)	4 (10.5)	5 (12.5)
GSTP1 rs1138272
CC	9 (69.2)	25 (80.6)	31 (81.6)	38 (95.0)	reference	reference	reference	reference	reference	reference
CT	3 (23.1)	6 (19.4)	7 (18.4)	2 (5.0)	2.79[0.76-10.20] 0.119F	3.17[0.76-13.28] 0.115	2.26[0.84-6.07] 0.122	2.23[0.81-6.15] 0.121	4.97[1.09-22.69] 0.024	4.44[0.9-21.08] 0.060
TT	1 (7.7)	0 (0.0)	0 (0.0)	0 (0.0)
GSTM1 homozygous deletion
WT	6 (46.2)	13 (41.9)	18 (47.4)	19 (47.5)	reference	reference	reference	reference	reference	reference
DEL	7 (53.8)	18 (58.1)	20 (52.6)	21 (52.5)	0.99[0.31-3.13] 0.99	0.96[0.25-3.70] 0.953	1.19[0.56-2.50] 0.707	1.03[0.47-2.27] 0.941	1.0[0.51-2.38] 0.805	0.96[0.43-2.18] 0.935
GSTT1 homozygous deletion
WT	8 (61.5)	23 (74.2)	31 (81.6)	35 (87.5)	reference	reference	reference	reference	reference	reference
DEL	5 (38.5)	8 (25.8)	7 (18.4)	5 (12.5)	2.78[0.82-9.09] 0.138F	3.70[0.95-14.08] 0.058	2.33[0.94-5.56] 0.063	2.39[1.03-6.25] 0.044	2.27[0.78-6.67] 0.127	2.06[0.67-6.29] 0.202
ABCB1 rs1128503
CC	5 (38.5)	10 (32.3)	13 (34.2)	13 (32.5)	reference	reference	reference	reference	reference	reference
CT	6 (46.2)	16 (51.6)	21 (55.3)	17 (42.5)	0.79[0.24-2.59] 0.759F	0.74[0.20-2.76] 0.651	0.97[0.44-2.11] 0.932	0.89[0.40-1.99] 0.773	0.92[0.41-2.07] 0.857	0.84[0.36-1.97] 0.691
TT	2 (15.4)	5 (16.1)	4 (10.5)	10 (25.0)
ABCB1 rs2032582
GG	5 (31.3)	9 (24.3)	15 (30.6)	14 (27.5)	reference	reference	reference	reference	reference	reference
GT	4 (25.0)	16 (43.2)	17 (34.7)	16 (31.4)	0.86[0.26-2.80] 0.769F	1.08[0.29-4.05] 0.908	1.27[0.58-2.78] 0.693	1.27[0.56-2.88] 0.57	0.98[0.44-2.17] 0.968	0.9[0.39-2.1] 0.813
TT	3 (18.8)	5 (13.5)	6 (12.2)	9 (17.6)	0.86[0.26-2.80] 0.769F	1.08[0.29-4.05] 0.908	1.27[0.58-2.78] 0.693	1.27[0.56-2.88] 0.57	0.98[0.44-2.17] 0.968	0.9[0.39-2.1] 0.813
GA	1 (6.3)	1 (2.7)	0 (0.0)	1 (2.0)
ABCB1 rs1045642
CC	3 (23.1)	6 (19.4)	11 (28.9)	11 (27.5)	reference	reference	reference	reference	reference	reference
CT	7 (53.8)	16 (51.6)	19 (50.0)	18 (45.0)	1.15[0.30-4.49] 1F	1.47[0.31-6.35] 0.657	1.53[0.63-3.70] 0.393	1.92[0.74-4.98] 0.18	1.17[0.5-2.77] 0.711	1.31[0.52-3.28] 0.559
TT	3 (23.1)	9 (29.0)	8 (21.1)	11 (27.5)

OR = Odds ratio between a group with higher number of blasts in comparison with a group with lower number of blasts. The group with lower number of blasts represents reference group.

CI = Confidence interval

ADJ Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression

1 Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts

ADJ Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression

2 Association with blast status on day 8: blast positive vs blast negative patients.

ADJ Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression

F Fisher exact test

R Recessive model

F Fisher exact test

R Recessive model

F Fisher exact test

Table 3

Haplotype carring status and association with glucocorticoid (GC) response. The GC response is assesed taking into account absolute number of blasts per mm3 of blood on day 8. For univariate analysis, chi square test was used, unless differently stated. Statistically significant associations (p < 0.05) were bolded

Haplotype (estimated frequency)	Carrier status^∗	≥ 1000 blasts	100 ≤ blasts < 1000	1 ≤ blasts < 100	blast negative patients	GC response (cutoff=1000 blasts)2	GC response (cutoff=1000 blasts)2, ADJ	GC response (cutoff=100 blasts)1	GC response (cutoff=100 blasts)1, ADJ	GC response (cutoff=0 blasts)0	GC response (cutoff=0 blasts)0, ADJ

		n (%)	n (%)	n (%)	n (%)	OR [95%CI] p value	OR [95%CI] p value	OR [95%CI] p value	OR [95%CI] p value	OR [95%CI] p value	OR [95%CI] p value
NR3C1 (rs33389-rs33388-rs6198) haplotypes
CTA (51.2%)	absent	4 (30.8)	11 (35.5)	7 (18.4)	9 (22.5)	reference	reference	reference	reference	reference	reference
CTA (51.2%)	present	9 (69.2)	20 (64.5)	31 (81.6)	31 (77.5)	0.71[0.21-2.60] 0.737F	0.72[0.16-3.13] 0.658	0.50[0.22-1.15] 0.098	0.53[0.22-1.26] 0.148	0.79[0.32-1.92] 0.606	0.83[0.32-2.11] 0.699
CAA (20.5%)	absent	12 (92.3)	15 (48.4)	25 (65.8)	25 (62.5)	reference	reference	reference	reference	reference	reference
CAA (20.5%)	present	1 (7.7)	16 (51.6)	13 (34.2)	15 (37.5)	0.12[0.015-0.98] 0.030F	0.12[0.013-1.02] 0.052	1.12[0.52-2.41] 0.763	1.27[0.57-2.80] 0.561	0.96[0.44-2.1] 0.922	1.22[0.53-2.80] 0.643
CAG (16.0%)	absent	7 (53.8)	20 (64.5)	28 (73.7)	29 (72.5)	reference	reference	reference	reference	reference	reference
CAG (16.0%)	present	6 (46.2)	11 (35.5)	10 (26.3)	11 (27.5)	2.06[0.64-6.62] 0.222F	1.82[0.49-6.74] 0.372	1.71[0.78-3.75] 0.18	1.60[0.70-3.65] 0.262	1.29[0.56-2.97] 0.543	1.28[0.53-3.1],0.576
TAA (12.3%)	absent	10 (76.9)	21 (67.7)	33 (86.8)	32 (80.0)	reference	reference	reference	reference	reference	reference
TAA (12.3%)	present	3 (23.1)	10 (32.3)	5 (13.2)	8 (20.0)	1.12[0.29-4.41] 1.000F	1.10[0.21-5.92] 0.91	2.10[0.87-5.05] 0.095	1.85[0.73-4.71] 0.195	1.12[0.44-2.86] 0.805	0.89[0.32-2.44] 0.826
GSTP1 (rs1695-rs1138272) haplotypes
AC (66.4%)	absent	1 (7.7)	3 (9.7)	4 (10.5)	5 (12.5)	reference	reference	reference	reference	reference	reference
AC (66.4%)	present	12 (92.3)	28 (90.3)	34 (89.5)	35 (87.5)	1.49[0.18-12.45] 1.000F	0.99[0.11-9.21] 0.993	1.30[0.38-4.51] 0.768F	1.18[0.33-4.19] 0.797	1.32[0.4-4.33] 0.756	1.15[0.33-3.93] 0.825
GC (25.4%)	absent	11 (84.6)	20 (64.5)	21 (55.3)	18 (45.0)	reference	reference	reference	reference	reference	reference
GC (25.4%)	present	2 (15.4)	11 (35.5)	17 (44.7)	22 (55.0)	0.22[0.045-1.01] 0.036	0.27[0.054-1.38] 0.117	0.42[0.19-9.20] 0.028	0.42[0.19-0.96] 0.041	0.47[0.22-1.02] 0.054	0.55[0.24-1.23] 0.149
GT (7.8%)	absent	9 (69.2)	25 (80.6)	32 (84.2)	38 (95.0)	reference	reference	reference	reference	reference	reference
GT (7.8%)	present	4 (30.8)	6 (19.4)	6 (15.8)	2 (5.0)	3.02[0.82-11.12] 0.101F	3.41[0.81-14.34] 0.094	2.57[0.93-7.11] 0.062	2.61[0.93-7.37] 0.069	4.6[1.00-21.12] 0.034	4.33[0.91-20.62] 0.065
ABCB1 (rs1128503-rs2032582-rs1045642) haplotypes
CGC (45.9%)	absent	4 (30.8)	10 (32.3)	8 (21.1)	12 (30.0)	reference	reference	reference	reference	reference	reference
CGC (45.9%)	present	9 (69.2)	21 (67.7)	30 (78.9)	28 (70.0)	0.85[0.25-2.98] 0.754F	0.74[0.19-2.81] 0.654	0.74[0.33-1.67] 0.465	0.73[0.32-1.69] 0.461	1.17[0.5-2.7] 0.714	1.43[0.58-3.53] 0.432
TTT (36.9%)	absent	6 (46.2)	12 (38.7)	17 (44.7)	16 (40.0)	reference	reference	reference	reference	reference	reference
TTT (36.9%)	present	7 (53.8)	19 (61.3)	21 (55.3)	24 (60.0)	0.82[0.26-2.60] 0.772	0.85[0.24-3.08] 0.805	1.06[0.50-2.24] 0.88	1.13[0.52-2.47] 0.76	0.89[0.41-1.93] 0.778	0.91[0.4-2.05] 0.821
CGT (8.6%)	absent	10 (76.9)	24 (77.4)	30 (78.9)	38 (95.0)	reference	reference	reference	reference	reference	reference
CGT (8.6%)	present	3 (23.1)	7 (22.6)	8 (21.1)	2 (5.0)	1.62[0.40-6.52] 0.446F	2.29[0.50-10.59] 0.289	2.00[0.76-5.27] 0.156	2.34[0.86-6.33] 0.095	5.34[1.17-24.31] 0.018	7.56[1.6-35.82] 0.011

OR = Odds ratio between a group with higher number of blasts in comparison with a group with lower number of blasts. The group with lower number of blasts represents reference group.

CI = Confidence interval

2 Association with blast status on day 8: blast positive vs blast negative patients.

ADJ Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression

1 Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts

ADJ Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression

0 Association with prednosine response on day 8 according to Berlin-Frankfurt-Munster (BFM) protocol: prednisone poor responder (PPR) group (≥ 1000 blasts) vs. prednisone good responder (PGR) group (< 1000 blasts)

ADJ Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression

F Fisher exact test

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DOI: https://doi.org/10.2478/raon-2018-0034 | Journal eISSN: 1581-3207 | Journal ISSN: 1318-2099

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Language: English

Page range: 296 - 306

Submitted on: Feb 19, 2018

Accepted on: Apr 24, 2018

Published on: Sep 11, 2018

Published by: Association of Radiology and Oncology

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

pharmacogenomics,

childhood ALL,

glucocorticoids,

glucocorticoid receptor gene,

glutathione S-transferase genes,

multidrug resistance 1 gene

Related subjects:

Medicine,

Clinical medicine,

Radiology

© 2018 Vladimir Gasic, Branka Zukic, Biljana Stankovic, Dragana Janic, Lidija Dokmanovic, Jelena Lazic, Nada Krstovski, Vita Dolzan, Janez Jazbec, Sonja Pavlovic, Nikola Kotur, published by Association of Radiology and Oncology
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Volume 52 (2018): Issue 3 (September 2018)