Garipalli, Archana

Abstract Background: Tyrosine kinase inhibitors (TKI) are associated with marked improvements in molecular response and survival compared with previous therapies for patients with chronic myelogenous leukemia (CML) in chronic phase (CP). We previously reported efficacy and safety of TKI at 12-month follow-up (Firwana et. al.JCO. 2014; 32(15_suppl): 7054). Here, we summarize the evidence of TKI efficacy and safety of TKI, comparing them directly and in-directly, in the mature follow-up for patients with newly diagnosed CP-CML. Methods: We included randomized controlled trials (RCTs) evaluating TKI in adults with newly diagnosed CP-CML. TKI (imatinib, dasatinib and nilotinib) were included if used as an initial treatment. Studies on bosutinib were excluded as it is only approved in the US for the treatment of CP-CML after failure of initial therapy. Studies that included patients with accelerated- or blast-phase CML, intolerant or resistant patients to first-line treatment, those on IFN-α, older agents or stem cell transplantation were excluded. Main outcomes are efficacy, represented by major molecular response (MMR, ≤ 0.1% BCR-ABLIS) and deeper molecular responses (MR4.5, ≤ 0.0032%IS), survival, represented by overall survival (OS) and progression free survival (PFS), and safety represented by medication discontinuation rate due to adverse events. Latest period of reporting outcome data were considered. As available trials provides direct comparison with imatinib, with no head-to-head trials to compare other TKI, we conducted a mixed treatment comparison (MTC) analysis which pools evidence from direct and indirect comparisons to facilitate simultaneous inference regarding all treatments. Bayesian mixed-treatment comparison method was used to rank TKI in terms of effectiveness. Results: Four landmark trials reported in 15 published articles and conference abstracts were identified involving 1647 patients with CP-CML. Follow-up times ranged from 3 months to 6 years. Table-1 depicts the results of MTC for imatinib, dasatinib and nilotinib. MTC analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy and safety. Nilotinib ranked first in efficacy with better improvement in MMR and MR4.5 at 48-month follow-up despite its different regimens, followed by dasatinib. Dasatinib has the highest medication discontinuation rate due to adverse events or drug-related toxicity. Among TKI, nilotinib was found to have the best survival profile; however, it was statistically nonsignificant. Conclusion: Both nilotinib and dasatinib are associated with significantly better efficacy and safety profiles compared to imatinib. At 48-month follow-up period, nilotinib ranked first to achieve MMR and MR4.5, with lower discontinuation rate due to adverse events. This analysis shows that new generation TKI are not only showing faster response, but also maintaining a more potent one through longer follow up period. It is important to note out that MTC is not a substitute for well conducted RCTs investigating direct comparisons. Table-1: Results of mixed treatment comparison for imatinib, dasatinib and nilotinib using fixed-effect Bayesian method. Comparison Mean risk difference (95% CrI) compared to from reference standard (Imatinib) Rank* MMR MR 4.5 PFS OS Discontinuation due to adverse events 48 months 48 months 36 months 48 months 48 months Imatinib Reference Reference Reference Reference Reference 4 Dasatinib 0.62 (0.26 to 1.01) 0.32 (-0.05 to 0.69) 0.21 (-0.43 to 0.85) 0.17 (-0.49 to 0.83) 0.59 (-0.05 to 1.25) 3 Nilotinib 300 0.92 (0.56 to 1.28) 0.81 (0.45 to 1.18) 1.02 (0.24 to 1.86) 0.19 (-0.51 to 0.89) -0.11 (-0.66 to 0.43) 1 Nilotinib 400 0.76 (0.41 to 1.12) 0.68 (0.31 to 1.05) 0.05 (-0.57 to 0.65) 0.81 (0.01 to 1.67) 0.30 (-0.20 to 0.81) 2 *Reported rank is valid for all outcomes, except for PFS and OS, where Nilotinib 400 ranks #1 and Nilotinib 300 ranks #2. Also, for rate of medication discontinuation due to adverse events, Dasatinib has the highest rate for discontinuation, followed by Nilotinib, both doses. Abbreviations: CrI, credible intervals; MMR, major molecular response, BCR-ABLIS ≤ 0.1%; MR4, deeper molecular responses, BCR-ABLIS ≤ 0.0032%; PFS, progression free survival; OS, overall survival. Disclosures No relevant conflicts of interest to declare.

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP‐CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP‐CML and enrolling 2,456 patients were included. Follow‐up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%IS) achievement with second‐generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed‐treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR4.5 ≤ 0.0032%IS) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new‐generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow‐up period. It is important to note out that MTC is not a substitute for well‐conducted RCTs investigating direct comparisons.