Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

Introduction: Patients with chronic phase chronic myeloid leukemia (CML) who fail to respond to first- and second-line tyrosine kinase inhibitor (TKI) therapy may be treated with third-line TKIs or undergo allogeneic hematopoietic stem cell transplant (alloHSCT). However, data demonstrating the efficacy of third-line TKI therapy is limited other than those coming from industry-sponsored studies for individual drugs.

Objective: evaluate the efficacy of various third-line TKIs and identify factors predicting outcomes and response in patients with chronic phase CML

Methods: A retrospective study was conducted on 185 patients with chronic phase CML with failure to first- or second-line TKIs. Demographic factors and clinical parameters were noted along with TKI therapies. Treatment response and outcomes, including cytogenetic response, molecular response, overall survival (OS), event-free survival (EFS) and transformation-free survival (TFS) were measured. Events were defined by death on third-line TKI therapy, loss of MCyR, loss of CHR, increased WBC, or progression to AP/BC; whichever occurred first.

Results: The median age of patients was 55.0 years (range: 19-92 years), and the majority were female (n=97; 52%). Patients received the following TKIs: bosutinib (n=13, 7%); dasatinib (n=64, 35%); imatinib (n=19, 10%); nilotinib (n=67, 36%); and ponatinib (n=22, 12%). Patients received third-line TKI for a median of 18.07 months (5.40 - 93.60), and 78 (42.16%) remain on their third-line TKI. The 25% percentile of OS for all treatments combined was 3.2 years (95% CI, 2.1-6.3) At the final data cut-off, 75% of patients on third-line TKIs were alive (47 deaths). At 5 years, median EFS was 55.1 months, median TFS was not reached.

Third-generation ponatinib was associated with significantly better OS compared with imatinib (HR, 0.248; 95% CI, 0.067-0.917; p=0.037). Compared with imatinib, patients treated with bosutinib also had better survival, and this association approached significance (HR, 0.147; 95% CI, 0.017-1.240; p=0.078). There was no difference by TKI in either TFS (p=0.134), or OS (p=0.315).

At baseline, 39 patients (32.77%) had CCyR and 76 (63.86%) did not, while at best response 71 patients (59.66%) had CCyR, 48 (40.33%) did not have CCyR, and the rest were excluded due to missing data. 8% also achieved major molecular response (MMR, based on international scale) as best response.

On univariate Cox regression analysis, the following factors were significantly associated with improved OS: age, best cytogenetics (CCyR vs not CCyR), best molecular response (MMR vs. not MMR), reason for TKI switch (resistance vs. intolerance to 2^nd line TKI), baseline cytogenetics, baseline molecular response status, and stem cell transplantation. Baseline mutation status was not associated with OS (HR, 1.137; 95% CI, 0.438-2.948; p=0.792). Multivariate analysis identified the following as significant predictors of improved OS: age, gender, best molecular response, reason for TKI switch, stem cell transplant, and third-line treatment with ponatinib or bosutinib versus imatinib (Table 1).

Conclusion: In the largest cohort of chronic phase CML patients on third-line TKI therapy to date, we identified predictors of clinical outcomes in the context of this setting. In addition to confirming previous findings that third-line TKI therapy may prolong OS and EFS, we found that ponatinib is associated with significantly better OS than any other TKI used as third-line therapy.

View largeDownload slide

View largeDownload slide

Close modal