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Meta-Analysis
. 2020 Jun 23;4(12):2723-2735.
doi: 10.1182/bloodadvances.2019001329.

First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis

Claudia Vener  1   2 , Rita Banzi  3 , Federico Ambrogi  4 , Annalisa Ferrero  5 , Giuseppe Saglio  6 , Gabriella Pravettoni  1 , Milena Sant  2
Affiliations
Meta-Analysis

First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis

Claudia Vener et al. Blood Adv. .

Abstract

Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of the optimal first-line TKI for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk [RR], 4.28; 95% confidence interval [CI], 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Flowchart of search strategy.
Figure 2.
Figure 2.
Tables and forest plots of MMR at 3 months. ENEST RCT sensitivity analysis: 300 mg and 400 mg of nilotinib and mean values of 300 mg and 400 mg of nilotinib. Nilotinib ENEST (NCT00471497; 300 mg and 400 mg). 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 (A); second, the results of 400 mg of nilotinib (B); and third, the arithmetic mean of the results of the 2 nilotinib doses (C). df, degrees of freedom.
Figure 3.
Figure 3.
Tables and forest plots of AP and BP transformations during study treatment. ENEST RCT sensitivity analysis: 300 mg of nilotinib, 400 mg of nilotinib, and mean values of 300 mg and 400 mg of nilotinib. Nilotinib ENEST (NCT00471497; 300 mg and 400 mg). 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 (A); second, the results of 400 mg of nilotinib (B); and third, the arithmetic mean of the results of the 2 nilotinib doses (C).
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References

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