The Role of the Newer Tyrosine Kinase Inhibitors As First Line Treatment in Chronic Phase Chronic Myeloid Leukemia – an Updated Meta-Analysis
Authors: Gurion Ronit , Vidal Liat , Leader Avi , Raanani Pia , Gafter-Gvili Anat 
Published: October 2019

Abstract

Background: Imatinib, nilotinib and dasatinib are all considered first line treatment in chronic phase (CP) chronic myeloid leukemia (CML) patients. The choice of the most suitable tyrosine kinase inhibitor (TKI) for an individual patient is influenced by multiple factors including disease characteristics, patient comorbidities and preferences, as well as each TKI's unique profile of adverse events. A meta-analysis of second generation TKIs as first line treatment for patients with CML was published by our group in 2011. In view of the recently published long term results of three of the trials included in the previous meta-analysis and data from two new trials, we decided to update our data.
Objectives: To evaluate the efficacy and toxicity of different TKIs as first line treatment for patients with CML.
Methods: Systematic review and meta-analysis of randomized controlled trials comparing first line treatment with the newer TKIs (nilotinib, dasatinib, bosutinib and ponatinib) to imatinib in patients with CP-CML. The MEDLINE, conference proceedings and references were searched until August 2014. Two reviewers appraised the quality of trials and extracted data. The following outcomes were assessed: complete cytogenetic response (CCyR); major molecular response (MMR); complete molecular response (CMR), defined as a 4.5 log reduction in BCR-ABL transcripts; early molecular response, defined as BCR-ABL transcript levels of 10% or less at 3 months; progression to accelerated phase (AP) / blastic crisis (BC); all-cause mortality (ACM) and toxicity. Relative risks (RR) were estimated and pooled. Random-effect model was used in all analysis.
Results: Our search yielded six trials including 2,426 patients. These trials compared the effects of nilotinib, dasatinib, bosutinib or ponatinib to imatinib. Data from the six trials were available for analysis of MMR. Treatment with the newer TKIs significantly improved MMR at all-time points (3, 12, 18, 24 and 48 months) compared to imatinib (Table 1). Of note, the newer TKIs significantly increased the rate of CMR compared to imatinib at 12 months (RR 2.68, 95% CI 1.64-4.36, 5 trials, figure 1) and at 24 months (RR 2.04, 95% CI 1.62-2.57, 3 trials). Moreover, there was a statistically significant advantage in favor of the newer TKIs as compared to imatinib in terms of early molecular response at 3 months (RR 1.34, 95% CI 1.27-1.41, 5 trials). Importantly, progression rate to AP/BC at 24 months was significantly lower with the newer TKIs in comparison with imatinib (RR 0.35, 95% CI 0.20-0.61, 4 trials). However there was no difference in ACM (RR 0.73, 95% CI 0.46-1.15, 4 trials). We conducted a meta-analysis for specific adverse events according to the distinct toxicity profile of the different TKIs. Severe peripheral arterial occlusive disease occurs more frequently in the newer TKIs arm (i.e. nilotinib and ponatinib) (RR 8.13, 95% CI 1.51-43.83, 2 trials) than in the imatinib arm. In addition, pleural effusion requiring discontinuation occurs at a higher rate in the newer TKIs arm (RR 4.61, 95% CI 1.31-16.23, 4 trials; dasatinib and bosutinib vs. imatinib). Regarding hematologic toxicity including grade 3-4 anemia and neutropenia, there was no difference between the two arms (all newer TKIs vs. imatinib). However, regarding thrombocytopenia grade 3-4, there were more events with thrombocytopenia in the newer TKIs arm compared to imatinib (RR 1.41, 95% CI 1.01-1.97).
Conclusions: With a longer follow-up of 4 years, the newer TKIs remain more potent than imatinib in terms of MMR, CMR and early molecular response. Yet, an effect on overall survival cannot be shown. Since CMR is a prerequisite for treatment discontinuation, the newer TKIs can potentially facilitate cessation of treatment more frequently than imatinib. These data should be taken into consideration in choosing treatment for a newly diagnosed CML patient.
Table 1 – MMR at different time points Time point Relative risk 95% Confidence of interval No. of trials 3 months 6.63 2.31-19.01 5 12 months 1.68 1.48-1.89 6 18 months 1.37 1.18-1.59 4 24 months 1.28 1.06-1.54 4 48 months 1.20 1.05-1.38 3
Figure 1 – CMR at 12 months Figure 1 –. CMR at 12 months

Disclosures
No relevant conflicts of interest to declare.