The Time to Cytogenetic Response Determines Survival in CML Patients (Pts) Receiving Second-Line Tyrosine Kinase Inhibitors, and Allows Early Identification of Pts Destined To Fail Therapy.
Authors: Tam Constantine S. , Kantarjian Hagop , Borthakur Gautam , Wierda William , Ravandi Farhad , O’Brien Susan , Shan Jenny , Cortes Jorge 
Published: April 2020

Abstract
Background: Novel Tyrosine Kinase Inhibitors (TKIs) are used in the treatment of CML pts who fail imatinib. However, more than half of chronic phase (CP) pts will not achieve complete cytogenetic response (CCyR), and the criteria for when to consider alternate therapy among such pts are not well defined.
Methods: We analyzed the pattern of cytogenetic response in 113 pts with CML in CP receiving nilotinib (n=43, 38%) or dasatinib (n=70, 62%) after imatinib failure in order to determine which milestones are important for long-term survival, and to develop a predictive model for the early identification of poor-risk pts. Pts (n=26, 23%) with clonal evolution with no other criteria for accelerated phase were included in the analysis. The previous best response to imatinib was CCyR in 24%, major cytogenetic response (MCyR, 1–35% Ph+) in 20%, minor cytogenetic response (mCyR, 36–95% Ph+) in 15%, complete hematological response (CHR) in 39%, and no response (NR) in 3%.
Results: Median follow-up was 27 months. The cumulative probability of CCyR was 35%, 42% and 48% after 3, 6 and 12 months of 2nd TKI therapy. The achievement of MCyR or better by 12 months (12MMCyR) was an important milestone in determining future survival: 1-year survival from the 12 month landmark was 97% for the pts who achieved 12MMCyR, compared with 84% for those who did not (p=0.01). In contrast, no protection was conferred by lesser responses, with comparable survival for pts in mCyR, CHR and NR (86%, 83% and 88% respectively, p=0.78). The one year risk of progression to accelerated or blast phase, loss of hematologic response or death was 3% for pts in 12MMCyR, and 17% for those in mCyR or CHR (p=0.003). Early cytogenetic response was predictive of eventual 12MMCyR, with pts not achieving any degree of cytogenetic response by 3 to 6 months being unlikely to reach MCyR or better by 12 months (Table). Significant (p&lt;0.05) univariate associations of 12MMyCR included age, time from diagnosis, more than one previous therapy, previous cytogenetic response to imatinib, low hemoglobin, high white cell count, blood blast percentage and platelet count; of these, only previous cytogenetic response to imatinib (p&lt;0.001) and hemoglobin (p=0.003) remained independent in a multivariate analysis. If the three month response was added to the multivariate model, it emerged as the only significant factor suggesting that early response is the most important determinant of 12MMCyR.
Conclusion: Achieving 12MMCyR was associated with superior survival and decreased risk of disease progression in pts receiving second-line TKI therapy. Since pts not achieving any degree of cytogenetic response by 3 to 6 months are unlikely (&lt;10%) to reach 12MMCyR, this milestone may be a reasonable indication for considering alternative therapy.
Assessment Response 12MMCyR(%) P-Value Three Months Minor CyR 10/15 (67%) &lt;0.001 Three Months No CyR 3/42 (7%) Six Months Minor CyR 8/16 (50%) &lt;0.001 Six Months No CyR 1/38 (3)