One Size May Not Fit All for TKI Dosing in Chronic Phase CML—Deep Molecular Responses Despite Dose Reduction
Authors: McCloskey James K , Stanislaus Genique , Kuo Yen-Hong , Koprivnikar Jamie 
Published: October 2019

Abstract
Abstract
Background: The development of tyrosine kinase inhibitors (TKIs) has dramatically changed the landscape of chronic myelogenous leukemia (CML) treatment. Dosing of TKIs is based on the phase of disease at presentation, but is not altered based on body surface area (BSA), gender, or other patient characteristics. Although TKIs are generally well tolerated, lower grade hematologic and non-hematologic toxicities are not infrequent. Inability to maintain dosing during the first year of therapy (missing as few as 10% of doses per month) has been associated with lower rates of major molecular response (MMR), which might have survival implications and/or prevent treatment-free remission attempts. While the package insert of three TKIs (imatinib, dasatinib, nilotinib) commonly used in first line therapy provides specific dose-reduction instructions for hematologic toxicity, only nilotinib has recommendations for non-hematologic toxicities. Long-term outcome data on the effects of dose-reduction of TKI therapy based on toxicity is lacking. Furthermore, there is little data on risk factors for TKI intolerance. Thus, we sought to identify characteristics of patients requiring dose reductions as a part of first-line TKI treatment for chronic phase CML who successfully achieved an MMR 4 or greater as well to determine the long-term outcome of these patients in a retrospective fashion.
Methods: Using electronic medical records, we identified patients seen at the John Theurer Cancer Center for treatment of newly diagnosed chronic phase CML between November 1, 2012 and July 1, 2016 who had successfully achieved an MMR 4 or greater. These records were screened for individuals requiring chronic dose reductions as part of first-line treatment for chronic phase CML. We identified 35 consecutive patients that were able to tolerate full dose TKI therapy per package insert. This control group was used to determine risk factors for TKI intolerance compared to patients that required dose reduction.
Results: A total of 20 patients were identified who achieved an MMR 4 or greater and required long-term dose reduction of first-line TKI therapy with a median follow up of 48.5 months (range 18.7-172.6). The median time on full dose therapy prior to dose reduction was 7.7 months (range 0-40.2). The median time spent on reduced dose therapy was 43.5 months (range 12.1-159.0). The time to MMR was 8.3 months (1.8-40.2). The majority of patients remained in MMR 4 despite maintenance on dose reduction. Median progression free survival (PFS), as defined by loss of MMR, of dose-reduced patients had not yet been reached. One, two, and three year PFS rates were 100%, 95.0%, and 88.7% respectively. When compared to the control group of patients tolerating front line therapy at full-dose, patients requiring dose reduction were more likely to be female: 80% vs 46% (P=0.028) and have a lower BSA: 1.78 versus 2.03 mg/m2 (P=0.0014). Other variables including age, TKI, Sokol score, and performance status were similar in both groups.
Discussion: Among patients who achieved MMR4 or greater on first-line therapy, we noted that female sex and lower BSA were risk factors for TKI dose reduction. Based on the available control group, it cannot be determined if either of these are independent variables. This retrospective analysis demonstrates many patients are able to successfully achieve and maintain a deep molecular response with reduced doses of TKI therapy and perhaps provides justification for dose reduction to increase compliance and maximize treatment tolerability. The majority of patients remained in MMR4 despite dose reductions.

Disclosures
McCloskey: Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; COTA: Equity Ownership. Stanislaus:Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmacetucals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Koprivnikar:Otsuka Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Consultancy, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; COTA: Equity Ownership.