Outcome of Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients Treated with Various Frontline Second-Generation Tyrosine Kinase Inhibitors: A Single-Center Experience

Background: The efficacy of second-generation tyrosine kinase inhibitors (2G-TKI) as frontline therapy for newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP) has been established. 2G-TKI treated patients achieved faster and deeper molecular responses compared with imatinib (IM) treated patients. Because CML patients currently have multiple treatment options, their impact on long-term outcomes needs to be determined and each agent should be chosen with a consideration of distinct toxicity profile and patient's comorbidities. The aim of this study is to provide a comprehensive analysis of the outcome of CML patients treated with different 2G-TKIs and to explore contributing factors on the outcome, as additional information to guide clinical decisions on selecting a frontline therapy.

Methods: 237 new CP CML patients who were treated with frontline 2G TKIs were analyzed. Molecular responses were monitored using qRT-PCR assay with 3 month intervals, and then 6 month intervals after achieving major molecular response (MMR). Main study objectives were to compare event-free survival (EFS), failure-free survival (FFS), and progression-free survival (PFS) to different 2G-TKIs as frontline therapy. FFS and EFS was measured from the date of treatment start until death, progression to AP or BP, or ELN failure on treatment (FFS), and until death, progression to AP or BP, ELN failure on treatment, or treatment discontinuation for any cause (except treatment-free remission) (EFS), respectively, whichever came first. PFS included progression to AP or BP as well as death resulting from any reason and collected on patients who were treated with other TKIs after frontline 2G-TKI discontinuation.

Results: From Oct 2007 to Jul 2015, a total of 237 patients were treated with nilotinib (NIL; n = 69), dasatinib (DAS; n = 113), and radotinib (RAD; n = 55). The median age was 43 years (range, 18-81). The percentages of patients with low, intermediate and high Sokal risk scores were 35%, 38% and 27%, respectively. With a median follow-up of 25.1 (NIL; range, 0.2-94.6), 13.8 (DAS; range, 2.0-86.8), and 36.8 (RAD; range, 9.9-48.2) months, 180 (75.9%) patients continue on the therapy and 57 (24.1%) patients were permanently discontinued the first 2G TKI due to intolerance (9 NIL, 11 DAS, 16 RAD), ELN failure (3 NIL, 7 DAS, 3 RAD), progression (2 NIL, 1 DAS), and others (2 NIL, 3 DAS). The probability of 2-year (y) EFS, FFS, and PFS were 72.6%, 89.4%, and 94.2%, respectively. There was no significant difference between treatment groups (NIL vs DAS vs RAD): 2-y EFS (78.9% vs 69.3% vs 66.1%, P = 0.363), 2-y FFS (89.4% vs 85.6% vs 92.7%, P = 0.487), and 2-y PFS (95.4% vs 88.8% vs 98.2%, P = 0.420). Among 209 patients with an available qRT-PCR data at 3 months, patients achieving BCR-ABL1 ≤ 10% (n = 182, 87.1%) had a better outcomes in terms of 2-y EFS (80.2% vs 44.2%, P<0.001), 2-y FFS (96.4% vs 52.3, P<0.001), and 2-y PFS (95.3% vs 88.7%, P = 0.051) compared with those of the patients with BCR-ABL1 >10%. In the 195 patients with an available 6-month data, achievement of 6-month early molecular response (BCR-ABL1 ≤1% at 6 months) was associated with a higher 2-y EFS (82.0% vs 61.8%, P = 0.002) and 2-y FFS (96.9% vs 69.0, P<0.001). In addition, Sokal risk was a potential predictive factor for lower EFS, FFS, and PFS, and increasing age was associated with lower EFS and FFS. The significant differences of safety profiles were determined and will be presented.

Conclusions: Our data showed the outcome of CML patients treated with different 2G-TKI as frontline therapy, which showed no difference of EFS, FFS, and PFS. However, the kind of intolerance resulting in treatment discontinuation was significantly different, suggesting that distinct toxicity profile should be a consideration when selecting a therapy. The 3-month and 6-month EMRs also provided prognostic information in patients treated with frontline 2G-TKI. Additively, the predictive impact of age and Sokal risk was observed. However, further investigations in a larger patient population with longer follow-up are needed.