The Impact of Early Molecular Response at 3 Months on Long-Term Survival Was Enhanced in the CP CML Patients Treated with Second-Generation Tyrosine Kinase Inhibitors

Background: Recent studies have demonstrated that early molecular milestones were able to identify high-risk chronic myeloid leukemia patients treated with frontline imatinib (IM) and second-generation tyrosine kinase inhibitors (2G-TKIs). 2G-TKI treated patients achieved faster and deeper molecular responses compared with IM treated patients. Because CML patients currently have multiple treatment options, the impact of early molecular milestones on long-term outcomes needs to be determined in each agent treated patients. The aim of this study is to evaluate the impact of 3-month early molecular response (EMR) on long-term outcomes of CML patients treated with IM and different 2G-TKIs, as additional information to guide clinical decisions on switching to a different TKI.

Methods: 646 new CP CML patients who were treated with frontline IM (n = 362) or 2G TKIs (n = 284) 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 evaluate the long-term outcomes, including failure-free survival (FFS), progression-free survival (PFS), and overall survival, according to 3-month EMR. FFS was measured from the date of treatment start until death, progression to AP or BP, or ELN failure on treatment, whichever came first. PFS and OS collected survivals on patients who were treated with other TKIs after frontline therapy discontinuation.

Results: A total of 646 patients were treated with IM (n = 362), dasatinib (DAS; n = 117), nilotinib (NIL; n = 85), and radotinib (RAD; n = 82). The median age was 43 years (range, 11-87). The percentages of patients with low, intermediate, and high Sokal risk scores were 37%, 39% and 22%, respectively, with 2% unknown risk. With a median follow-up of 75.4 (IM; range, 4.4-195.9) and 34.1 (2G-TKIs; range, 5.2-138.4) months, 383 (59.3%; 168 IM and 215 2G-TKIs) patients continue on the frontline therapy and 263 (40.7%) patients were permanently discontinued or changed to other TKIs due to intolerance (72 IM, 26 DAS, 2 NIL, 21 RAD), ELN failure (36 IM, 3 DAS, 2 RAD), progression (3 IM, 1 DAS, 2 NIL, 1 RAD), death (1 IM, 1 DAS, 1 NIL), and others (10 warning, 9 pregnancy, 59 treatment-free remission study, and 13 follow-up loss). In 362 patients treated with IM, patients achieving BCR-ABL1 ≤ 10% at 3 months (n = 270, 74.6%) had a better outcomes in terms of 8-y FFS (91.7% vs 64.4%, P<0.001), 8-y PFS (95.5% vs 84.2, P<0.001), and 8-y OS (97.0% vs 83.2%, P <0.001) compared with those of the patients with BCR-ABL1 >10%. In 284 patients treated with 2G-TKIs, achievement of 3-month EMR (n = 252, 88.7%) was associated with a higher 6-y FFS (95.5% vs 82.1%, P = 0.001), 6-y PFS (97.2% vs 36.0, P<0.001), and 6-y OS (100% vs 66.2%, P <0.001). The prognostic impact of 3-month EMR was observed in both IM and 2G-TKIs treated groups. However, in IM treated group, 3-month EMR failure showed relative risk (RR) of 4.96 (P <0.001) for PFS and 4.54 (P = 0.001) for OS, respectively, whereas in 2G-TKIs treated group, 3-month EMR failure showed RR of 10.71 (P <0.001) for PFS and 26.42 (P = 0.005) for OS, respectively.

Conclusions: Our data showed the 3-month EMR provided long-term prognostic information in patients treated with frontline IM and 2G-TKI. However, the prognostic impact of 3-month EMR failure was enhanced in the patients treated with 2-G TKIs. However, further investigations in a larger patient population with longer follow-up are needed.