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Long-Term Outcome of CML Patients Treated with Second-Generation Tyrosine Kinase Inhibitors in the Second Line: A Single Center Experience

Kamal Chamoun, Hagop M. Kantarjian, Mary Abisola Akosile, Rita Assi, Farhad Ravandi, Gautam Borthakur, Guillermo Garcia-Manero, Tapan Kadia, Marina Konopleva, Zeev Estrov, Courtney D. DiNardo, Naval Daver, Naveen Pemmaraju, Alessandra Ferrajoli, Jan A. Burger, William Wierda, Elias J. Jabbour and Jorge E. Cortes

Abstract

Background: Since the introduction of tyrosine kinase inhibitors (TKI), most patients (pts) with chronic myeloid leukemia (CML) have a favorable outcome with their initial therapy. However, some pts experience resistance or intolerance. Second generation TKI dasatinib, nilotinib and bosutinib are effective (and approved) for pts with failure to one prior TKI. In the absence of specific mutations or patient comorbidities driving the selection of a specific TKI, selecting the next TKI remains at the physician discretion, especially in the lack of randomized data comparing 2nd generation TKI.

Methods: We analyzed the outcomes of 621 consecutive patients with CML treated at a single institution with 2nd generation TKI in the 2nd line following failure of frontline TKI. For this analysis we focused on the 572 pts that received dasatinib, nilotinib or bosutinib as 2nd line TKI (not including 49 pts treated with ponatinib, imatinib or investigational TKI).

Results: The median age at diagnosis was 47 years (range, 12-86) and 49% were male. 516 pts received TKI as frontline treatment and 105 had other therapies (interferon, chemotherapy) prior to TKI. Pts were switched to a 2nd generation TKI for resistance (n=337; 54%) or intolerance (n= 279; 45%). The median time from diagnosis to start of 2nd line TKI was 32 mo (0 to 206 mo). Dasatinib, nilotinib and bosutinib were used as 2nd line TKI in 338 (54%), 194 (31%), and 40 (6%) pts, respectively. Overall, out of 572 pts who received one of these three TKIs, 401 had cytogenetic evaluation of which 323 (81%) achieved major cytogenetic response (34 (8%) partial (PCyR) and 289 (72%) complete (CCyR)). Out of 428 who had a molecular evaluation, 75% achieved molecular response (94 (18%) MMR, 52 (6%) MR4, 217 (51%) MR4.5). The rates of major cytogenetic response (MCyR) were, with dasatinib 85% (76% CCyR), nilotinib 76% (70% CCyR), and bosutinib 67% (50% CCyR) (p=0.015). Rates of molecular response (MMR or better) were with dasatinib 72% (55% MR4.5), nilotinib 65% (46% MR4.5), and bosutinib 55% (39% MR4.5), (p=0.07). At a median follow-up from diagnosis of 96 mo (range, 4-283), 39 (7%) pts transformed either to accelerated (n=26, 5%) or to blast phase (n=13, 2%) while on 2nd line TKI. Median overall survival (OS) and transformation-free survival (TFS) were not reached and the median event-free survival (EFS) was 121 mo. Seven-year probabilities of OS, TFS and EFS were 66%, 91% and 55%, respectively. Higher OS, TFS, and EFS were found in patients who received frontline TKI (7-yr 70%, 92% and 59%, respectively) vs those who failed another treatment prior to any TKI (49%, 83%, and 38%, respectively) (p<0.001, p=0.005, p<0.001, respectively) and in patients who switched to second line TKI due to intolerance (79%, 95% and 74%) vs resistance (58%, 87%, and 42%) (p<0.001, p=0.002, p<0.001, respectively). No difference in OS, TFS and EFS was found when comparing dasatinib, nilotinib and bosutinib in all pts (p=0.651, p=0.673, p=0.057). There were trends for better OS and EFS with dasatinib than nilotinib in patients who received their first TKI after failing another treatment (p= 0.034, p=0.009). Dasatinib had also better EFS than Nilotinib in patients who switched to 2nd line for resistance (p=0.007). 49 (9%) pts discontinued their 2nd TKI, including 18 (3%) due to intolerance, 9 (2%) due to transplant, 6 (1%) due to resistance, and 5 (1%) due to sustained MR4.5. Of these 5 pts with elective treatment discontinuation, all have remained treatment-free a median of 20 mo after treatment discontinuation. 248 (43%) switched to third line TKI due to resistance (n=110, 44%) or intolerance (n=128, 52%). 51 (9%) pts acquired mutations following first-line TKI with T315I and G250E being the most common (n=10, 19%, and n=7, 13%, respectively), and 70 (12%) after their 2nd TKI with T315I and F317L being the most common (n=16, 22%, and n=9, 12%, respectively).

Conclusion: This analysis shows that dasatinib, nilotinib and bosutinib remain largely effective in inducing cytogenetic and molecular response when used as a 2nd line TKI with similar OS, TFS and EFS in the overall pts population. A multivariate analysis to identify predictors of long-term outcome, including specific TKI as a variable, is ongoing.

Disclosures Kantarjian: Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding. DiNardo: Daiichi-Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Daver: Bristol-Myers Squibb Company: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Kiromic: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Pemmaraju: Incyte Corporation: Consultancy, Honoraria; cellectis: Research Funding; novartis: Consultancy, Honoraria, Research Funding; abbvie: Research Funding; roche diagnostics: Consultancy, Honoraria; affymetrix: Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding. Burger: Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy. Cortes: Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Teva: Research Funding.

  • * Asterisk with author names denotes non-ASH members.