Resistance, Outcome and the Development of Mutations with Dasatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CML-CP).
Authors: Shah Neil , Bahceci Erkut , Lambert Alexandre , Ploughman Lynn , Radich Jerald 
Published: October 2019

Abstract
Abstract 1122
Poster Board I-144
Dasatinib is an FDA approved tyrosine kinase inhibitor (TKI) targeted at BCR-ABL for the treatment of CML after imatinib resistance or intolerance. A phase III dose-optimization study of dasatinib in CML-CP, where patients received either 100 mg or 140 mg of dasatinib on a once- or twice-daily schedule, indicated that 100 mg once daily dasatinib provided durable disease control with an estimated progression-free survival (PFS) of 73% at 36 months. We conducted a retrospective analysis to expand on these results to determine if earlier cytogenetic response (CyR) predicts superior outcomes within this dosing arm and also to quantify progression to advanced-phase CML and characterize the quality of BCR-ABL mutations associated with loss of response to dasatinib. Our landmark analysis demonstrated that 90% of patients receiving dasatinib 100 mg once daily who achieved complete cytogenetic response (CCyR) at 12 months were progression-free at 36 months, a considerable improvement over those without CCyR at 12 months (Table 1). Of the 164 patients receiving dasatinib 100 mg once daily, 59 had attained CCyR at 6 months of therapy. The rate of PFS after 36 months within this cohort was 93%, whereas those with partial CyR or those without major cytogenetic response (MCyR) at 6 months had 36-month PFS rates of 76% and 54%, respectively. A total of 36 subjects experienced progression events while receiving dasatinib 100 mg once daily: 8 due to death, 5 due to development of advanced phases of CML, 3 due to increases ≥30% in Ph+ metaphases, 9 due to increasing white blood-cell count, 4 due to loss of complete hematologic response, 4 due to loss of MCyR, and 3 for unknown reason. The majority (86%) of patients who do progress while receiving dasatinib remain in CP at 36 months.
The development of mutations in BCR-ABL is a known mechanism of loss of response to dasatinib. In participants with loss of response to dasatinib who have available mutation data (n=61), the incidence of developing mutations during dasatinib therapy (at any dose) is 19% (5/27) in patients without baseline mutations, and 47% (16/34) in those with mutations at initiation of dasatinib. Of the patients who lost response to dasatinib and developed new mutations during therapy, 13 patients harbored T315I, 6 possessed F317L, 3 had V299L, and 1 acquired E255K. Three other patients developed mutations not associated with resistance to dasatinib (Table 2). New mutations that emerged in the 100 mg once daily arm and 70 mg twice daily arm were of similar frequency. In conclusion, patients who achieve early and complete CyRs to second-line dasatinib exhibit reduced rates of long-term progression versus those without CCyR at 6 months. Of the patients who do progress while receiving dasatinib, the majority remain in CP at 36 months. Of patients treated with 100 mg once daily, only 3% progressed to accelerated or blast phase with 36 months of follow-up. This transformation-free survival rate favors the use of dasatinib following imatinib failure in patients who have the option of pursuing allogeneic stem cell transplantation. Finally, the development of new mutations leading to resistance during dasatinib therapy is uncommon, and the lower total daily dose employed by the 100 mg once daily regimen does not appear to select for a greater variety of mutations than have been previously identified in patients treated with 70 mg twice daily. In patients who lose response to dasatinib and develop new mutations, a switch to an alternate TKI or stem-cell transplantation may be appropriate.
Table 1. Progression-free survival of subjects with or without cytogenetic responses receiving dasatinib 100 mg once daily Cytogenetic Response PFS (95% CI) 12 months CCyR (n=55) 90% (81–100) partial CyR (n=23) 77% (60–95) minimal/minor/none (n=33) 63% (43–83) 6 months CCyR (n=59) 93% (85–100) partial CyR (n=26) 76% (59–93) minimal/minor/none (n=53) 54% (36–73) Abbreviation: CI, confidence interval.
Table 2. Subjects developing new mutations during dasatinib by select dosing arms All subjects* (n=61) 100 mg once daily* (n=13) 70 mg twice daily* (n=14) M244V 1 0 0 E255K 1 0 1 V299L 3 2 1 F311L 1 0 1 T315I 13 3 3 F317L 6 3 1 M351T 1 0 0 * Subjects with loss of response to dasatinib and available baseline and progression/end-of-treatment mutation data.

Disclosures
Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Bahceci:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Ploughman:Bristol-Myers Squibb: Employment. Radich:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.