Pooled relative risk of second- and third-generation TKIs, in comparison with imatinib by toxicity
| Study . | TKIs ENEST RCT: 300 mg . | TKIs ENEST RCT: 400 mg . | TKIs ENEST RCT: mean values of 300 and 400 mg . | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Outcome toxicity: grade 3-4*,† . | No. of RCTs . | No. of pts . | RR‡ . | 95% CI‡ . | No. of RCTs . | No. of pts . | RR‡ . | 95% CI‡ . | No. of RCTs . | No. of pts . | RR‡ . | 95% CI‡ . |
| Anemia | 7 | 2704 | 1.17 | 0.80-1.72 | 7 | 2702 | 1.20 | 0.86-1.69 | 7 | 2703 | 1.19 | 0.83-1.70 |
| Neutropenia | 7 | 2704 | 0.69 | 0.46-1.02 | 7 | 2702 | 0.68 | 0.45-1.01 | 7 | 2703 | 0.68 | 0.46-1.02 |
| Thrombocytopenia | 7 | 2704 | 1.55 | 1.17-2.05 | 7 | 2702 | 1.58 | 1.22-2.06 | 7 | 2703 | 1.57 | 1.20-2.05 |
| Cardiovascular events | 7 | 2704 | 2.26 | 1.32-3.87 | 7 | 2702 | 2.75 | 1.62-4.67 | 7 | 2703 | 2.54 | 1.49-4.33 |
| Cutaneous effects | 7 | 2704 | 0.73 | 0.21-2.47 | 7 | 2702 | 1.03 | 0.35-2.98 | 7 | 2703 | 0.93 | 0.32-2.75 |
| GI effects | 7 | 2704 | 1.80 | 0.67-4.84 | 7 | 2702 | 2.02 | 0.84-4.86 | 7 | 2703 | 1.94 | 0.77-4.85 |
| Fluid retention§ | 7 | 2704 | 3.21 | 1.09-9.48 | 7 | 2702 | 2.81 | 0.99-7.97 | 7 | 2703 | 3.11 | 1.07-9.00 |
| Infectious events | 7 | 2704 | 1.11 | 0.54-2.28 | 7 | 2702 | 1.12 | 0.49-2.56 | 7 | 2703 | 1.11 | 0.54-2.28 |
| Pancreatic effects | 5 | 2413 | 2.24 | 1.29-3.87 | 5 | 2411 | 2.31 | 1.33-4.02 | 5 | 2412 | 2.29 | 1.32-3.96 |
| Hepatic effects | 6 | 2459 | 3.01 | 1.21-7.51 | 6 | 2457 | 3.89 | 1.81-8.35 | 6 | 2458 | 3.51 | 1.55-7.92 |
| Musculoskeletal disorders | 6 | 2658 | 0.76 | 0.36-1.62 | 6 | 2656 | 0.92 | 0.46-1.83 | 6 | 2657 | 0.85 | 0.42-1.73 |
| QT prolongation | 5 | 2352 | 0.82 | 0.39-1.73 | 5 | 2350 | 0.82 | 0.39-1.74 | 5 | 2351 | 0.82 | 0.39-1.73 |
| Study . | TKIs ENEST RCT: 300 mg . | TKIs ENEST RCT: 400 mg . | TKIs ENEST RCT: mean values of 300 and 400 mg . | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Outcome toxicity: grade 3-4*,† . | No. of RCTs . | No. of pts . | RR‡ . | 95% CI‡ . | No. of RCTs . | No. of pts . | RR‡ . | 95% CI‡ . | No. of RCTs . | No. of pts . | RR‡ . | 95% CI‡ . |
| Anemia | 7 | 2704 | 1.17 | 0.80-1.72 | 7 | 2702 | 1.20 | 0.86-1.69 | 7 | 2703 | 1.19 | 0.83-1.70 |
| Neutropenia | 7 | 2704 | 0.69 | 0.46-1.02 | 7 | 2702 | 0.68 | 0.45-1.01 | 7 | 2703 | 0.68 | 0.46-1.02 |
| Thrombocytopenia | 7 | 2704 | 1.55 | 1.17-2.05 | 7 | 2702 | 1.58 | 1.22-2.06 | 7 | 2703 | 1.57 | 1.20-2.05 |
| Cardiovascular events | 7 | 2704 | 2.26 | 1.32-3.87 | 7 | 2702 | 2.75 | 1.62-4.67 | 7 | 2703 | 2.54 | 1.49-4.33 |
| Cutaneous effects | 7 | 2704 | 0.73 | 0.21-2.47 | 7 | 2702 | 1.03 | 0.35-2.98 | 7 | 2703 | 0.93 | 0.32-2.75 |
| GI effects | 7 | 2704 | 1.80 | 0.67-4.84 | 7 | 2702 | 2.02 | 0.84-4.86 | 7 | 2703 | 1.94 | 0.77-4.85 |
| Fluid retention§ | 7 | 2704 | 3.21 | 1.09-9.48 | 7 | 2702 | 2.81 | 0.99-7.97 | 7 | 2703 | 3.11 | 1.07-9.00 |
| Infectious events | 7 | 2704 | 1.11 | 0.54-2.28 | 7 | 2702 | 1.12 | 0.49-2.56 | 7 | 2703 | 1.11 | 0.54-2.28 |
| Pancreatic effects | 5 | 2413 | 2.24 | 1.29-3.87 | 5 | 2411 | 2.31 | 1.33-4.02 | 5 | 2412 | 2.29 | 1.32-3.96 |
| Hepatic effects | 6 | 2459 | 3.01 | 1.21-7.51 | 6 | 2457 | 3.89 | 1.81-8.35 | 6 | 2458 | 3.51 | 1.55-7.92 |
| Musculoskeletal disorders | 6 | 2658 | 0.76 | 0.36-1.62 | 6 | 2656 | 0.92 | 0.46-1.83 | 6 | 2657 | 0.85 | 0.42-1.73 |
| QT prolongation | 5 | 2352 | 0.82 | 0.39-1.73 | 5 | 2350 | 0.82 | 0.39-1.74 | 5 | 2351 | 0.82 | 0.39-1.73 |
Sensitivity analysis of different nilotinib doses (ENEST RCT: 300 mg, 400 mg, and mean values of 300 mg and 400 mg) (bosutinib BEFORE [NCT02130557], bosutinib BELA [NCT00574873], dasatinib DASISION [NCT00481247], dasatinib [NCT00070499], dasatinib NordCML006 [NCT00852566], nilotinib ENEST [NCT00471497; 300-mg and 400-mg doses], ponatinib EPIC [NCT01650805]). In ENEST RCT, the patients were randomly assigned to receive 300 mg of nilotinib (n = 282), 400 mg of nilotinib (n = 281), 400 mg of imatinib (n = 283); the number of events is presented for the 3 groups (300 mg of nilotinib, 400 mg of nilotinib, 400 mg of imatinib). The sensitivity analysis was made by introducing into the meta-analysis: first, the results of 300 mg of nilotinib; second, the results of 400 mg of nilotinib; and third, the arithmetic mean of the results of the 2 nilotinib doses.
National Cancer Institute Common Terminology Criteria for Adverse Events.
M-H method, random-effects method.
Bold values in these columns are statistically significant.
Pleural and pericardial effusion.