Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia
Article Category: Research Article
Published Online: Sep 11, 2018
Page range: 296 - 306
Received: Feb 19, 2018
Accepted: Apr 24, 2018
DOI: https://doi.org/10.2478/raon-2018-0034
© 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 Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
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) 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) | GC response (cutoff=1000 blasts) 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) Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression | GC response (cutoff=100 blasts) Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts | GC response (cutoff=100 blasts) Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression | GC response (cutoff=0 blasts) Association with blast status on day 8: blast positive vs blast negative patients. | GC response (cutoff=0 blasts) Association with blast status on day 8: blast positive vs blast negative patients. Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression |
|---|---|---|---|---|---|---|---|---|---|---|
| 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 | |
| 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] 1 Fisher exact test | 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) | ||||||
| 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] 0.737 Fisher exact test | 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) | ||||||
| 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) | ||||||
| GG | 2 (15.4) | 0 (0.0) | 1 (2.6) | 0 (0.0) | 19.64[1.65-234.32] Recessive model Fisher exact test | 16.76[1.20-234.27] Recessive model | 1.66[0.75-3.68] 0.222 Recessive model | 4.01[0.34-47.4] 0.27 Recessive model | 1.04[0.99-1.08] 0.22 Recessive model | - 1 Recessive model |
| 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) | ||||||
| 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] 0.119 Fisher exact test | 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] | 4.44[0.9-21.08] 0.060 |
| TT | 1 (7.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | ||||||
| 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 |
| 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] 0.138 Fisher exact test | 3.70[0.95-14.08] 0.058 | 2.33[0.94-5.56] 0.063 | 2.39[1.03-6.25] | 2.27[0.78-6.67] 0.127 | 2.06[0.67-6.29] 0.202 |
| 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] 0.759 Fisher exact test | 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) | ||||||
| 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] 0.769 Fisher exact test | 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) | ||||||
| GA | 1 (6.3) | 1 (2.7) | 0 (0.0) | 1 (2.0) | ||||||
| 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] 1 Fisher exact test | 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) | ||||||
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) Association with blast status on day 8: blast positive vs blast negative patients. | GC response (cutoff=1000 blasts) Association with blast status on day 8: blast positive vs blast negative patients. Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression | GC response (cutoff=100 blasts) Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts | GC response (cutoff=100 blasts) Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression | GC response (cutoff=0 blasts) 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) | GC response (cutoff=0 blasts) 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) Adjusted for age, gender and initial white blood cells (WBC) count using logistic regression |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | ||
| CTA (51.2%) | absent | 4 (30.8) | 11 (35.5) | 7 (18.4) | 9 (22.5) | reference | reference | reference | reference | reference | reference |
| present | 9 (69.2) | 20 (64.5) | 31 (81.6) | 31 (77.5) | 0.71[0.21-2.60] 0.737 Fisher exact test | 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 |
| present | 1 (7.7) | 16 (51.6) | 13 (34.2) | 15 (37.5) | 0.12[0.015-0.98] Fisher exact test | 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 |
| present | 6 (46.2) | 11 (35.5) | 10 (26.3) | 11 (27.5) | 2.06[0.64-6.62] 0.222 Fisher exact test | 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 |
| present | 3 (23.1) | 10 (32.3) | 5 (13.2) | 8 (20.0) | 1.12[0.29-4.41] 1.000 Fisher exact test | 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 | |
| AC (66.4%) | absent | 1 (7.7) | 3 (9.7) | 4 (10.5) | 5 (12.5) | reference | reference | reference | reference | reference | reference |
| present | 12 (92.3) | 28 (90.3) | 34 (89.5) | 35 (87.5) | 1.49[0.18-12.45] 1.000 Fisher exact test | 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 |
| present | 2 (15.4) | 11 (35.5) | 17 (44.7) | 22 (55.0) | 0.22[0.045-1.01] | 0.27[0.054-1.38] 0.117 | 0.42[0.19-9.20] | 0.42[0.19-0.96] | 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 |
| present | 4 (30.8) | 6 (19.4) | 6 (15.8) | 2 (5.0) | 3.02[0.82-11.12] 0.101 Fisher exact test | 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] | 4.33[0.91-20.62] 0.065 | |
| CGC (45.9%) | absent | 4 (30.8) | 10 (32.3) | 8 (21.1) | 12 (30.0) | reference | reference | reference | reference | reference | reference |
| present | 9 (69.2) | 21 (67.7) | 30 (78.9) | 28 (70.0) | 0.85[0.25-2.98] 0.754 Fisher exact test | 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 |
| 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 |
| present | 3 (23.1) | 7 (22.6) | 8 (21.1) | 2 (5.0) | 1.62[0.40-6.52] 0.446 Fisher exact test | 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] | 7.56[1.6-35.82] | |
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) 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) | GC response (cutoff=100 blasts) Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts | GC response (cutoff=0 blasts) Association with blast status on day 8: blast positive vs blast negative patients. |
|---|---|---|---|---|---|---|---|---|---|
| n (%) | n (%) | n (%) | n (%) | n (%) | OR [95%CI], p 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) | OR [95%CI], p Association with number of blasts on day 8 with cut-off value of 100: higher (≥ 100 blasts) vs lower (< 100 blasts) number of blasts | OR [95%CI], p Association with blast status on day 8: blast positive vs blast negative patients. | ||
| Age | ≥1 and <6 (non-risk) | 65 (53.3) | 4 (30.8) | 17 (54.8) | 21 (55.3) | 23 (57.5) | reference | reference | reference |
| <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 |
| 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 |
| ≥20,000/microL | 56 (46.7) | 11 (91.7) | 17 (56.7) | 17 (44.7) | 11 (27.5) | 15.40 [1.92-123.6], | 3.57 [1.62-7.88], | 3.39 [1.49-7.72], | |
| Immunophenotype | B | 108 (88.5) | 9 (69.2) | 27 (87.1) | 35 (92.1) | 37 (92.5) | reference | reference | reference |
| T | 14 (11.5) | 4 (30.8) | 4 (12.9) | 3 (7.9) | 3 (7.5) | 4.40 [1.15-16.90], Fisher exact test | 2.67 [0.86-8.27], 0.081 | 1.91 [0.50-7.28], 0.546 | |