Multiple new agents are currently being developed in chronic myelogenous leukemia (CML). Most of these agents are now being investigated in patients who have developed resistance to imatinib. Their mechanisms of action are diverse and many may be synergistic with imatinib. These agents will be used soon in different combinations, most likely including imatinib, with the hope of obtaining a complete blockade of the intracellular pathways that are triggered by Bcr-Abl. If this is successful, complete eradication of disease may become a reality for the majority of patients with CML.
Jorge Cortes and Francis Giles
Jorge Cortes, John M. Goldman and Timothy Hughes
Despite the success with tyrosine kinase inhibitors (TKIs) in most patients with chronic myelogenous leukemia (CML), some patients still experience resistance or intolerance and need alternative therapies. Monitoring response to TKI therapy is a critical component of managing CML, and molecular response seems to be the most important milestone for predicting long-term outcomes. How best to assess response, including how to define treatment failure, and how monitoring should be conducted remain controversial. Strategies for overcoming imatinib resistance include increasing the imatinib dose or switching to a second-generation TKI. Another approach is to use higher doses of imatinib or second-generation TKIs up front to increase the rate of earlier responses, with the hope that this will translate into a reduced risk of resistance. Several investigational therapies are also being evaluated as a means of overcoming TKI resistance, including ponatinib (AP24534), omacetaxine, and bosutinib (SKI-606). Allogeneic hematopoietic stem cell transplantation has also shown efficacy in patients with imatinib-resistant disease. Alternatives to long-term TKI therapy that are currently being explored include discontinuation of treatment and eradication of minimal residual disease with investigational treatment regimens, such as those involving interferon, hydroxychloroquine, BCL6 inhibitors, and the smoothened antagonists LDF225 and BMS-833923.
Jorge Cortes, Clara Chen, Michael Mauro, Neela Kumar, Catherine Davis and Stuart L. Goldberg
Introduction: Dosing patterns of nilotinib (NIL) in chronic phase chronic myelogenous leukemia (CP-CML) patients (Pts) have not been well documented outside of clinical trials. SIMPLICITY (NCT01244750) is an ongoing observational study exploring tyrosine kinase inhibitor (TKI) use in routine clinical practice among CP-CML pts receiving TKIs in the US and Europe since 2010. This analysis reports NIL dosing patterns and explores predictors of dose reductions. A subset analysis focusing on the first-line (1L) approved dose of 300 mg twice daily (BID) will also be presented. Methods: Only SIMPLICITY pts receiving 1L NIL BID (n=349/408) were included. Baseline demographics and dosing patterns (starting dose, dose changes, time to dose reduction, and duration of therapy [DoT]) were analyzed descriptively. Statistical comparisons were made using t-tests, the Mann-Whitney U test for continuous variables, and chi-square for categorical variables. Logistic regression models were used to identify factors associated with dose reductions. Results: Of the 349 pts treated with 1L NIL, 281 (80.5%) started at the standard dose of 300 mg (BID) or the 400 mg (BID) dose for imatinib-resistance/intolerance, and 37 (10.6%) and 31 pts (8.9%) started on 150‒200 mg BID and 450‒800 mg BID. European pts were more likely to start on a dose >400 mg BID than US pts (P<.0001). Pts at academic centers were more likely to start on >400 mg BID than those treated at community practices (P<.0029). Among the pts starting NIL at 300 or 400 mg (BID) in 1L, 70.9% remained on these doses; 26.6% received a dose reduction (median time to dose reduction: 80.5 days); and 2.5% received a dose increase. Median DoT with NIL was 30.4 vs 43.9 months for pts with vs without a dose reduction (P=NS). The main reason for dose reduction was intolerance (n=51; 68.9%); in 51% of pts, a specific side effect was cited. Dose reductions were more likely in patients at academic centers (odds ratio=1.996; P=.021), but not in pts experiencing baseline fatigue (OR=1.799; P=0.072). Conclusions: Most pts treated with 1L NIL were started on 300 or 400 mg (BID); however, 1 in 4 pts required a dose reduction, most often due to intolerance. Physicians at academic centers were more likely to reduce the NIL dose than those in community practices. DoT with NIL for pts who received a dose reduction was shorter than that for those who did not. These findings will aid clinical decisions on dose optimization and maintaining response, whilst improving the patient quality of life.