Prognostic Value of Clonal Evolution at the Time of Diagnosis in Patients with Chronic Myeloid Leukemia Treated with Frontline Tyrosine Kinase Inhibitors
Authors: Alhuraiji Ahmad , Kantarjian Hagop M. , Jabbour Elias J. , Boddu Prajwal Chaitanya , Ravandi Farhad , Borthakur Gautam , DiNardo Courtney D , Daver Naval , Kadia Tapan M. , Pemmaraju Naveen , Pierce Sherry , Garcia-Manero Guillermo , Cortes Jorge E. 
Published: October 2019

Abstract
Introduction:
Additional cytogenetic clonal evolution (CE) is a known risk factor for a poor prognosis in chronic myeloid leukemia (CML). However, its prognostic significance in the setting of new tyrosine kinase inhibitor (TKI) remains unclear. We sought to analyze the baseline characteristics and clinical outcome in chronic phase (CP) CML pts with or without CE treated on frontline TKI clinical trials in a single institution.
Methods:
Patients (pts) with Ph-positive CML in CP with or without CE at the time of diagnosis receiving initial therapy with imatinib 400 mg/d, imatinib 800 mg/d, dasatinib 100 mg/d, nilotinib 800 mg/d or ponatinib 30 or 45 mg/d in consecutive or parallel clinical trials at a single institution were analyzed. Overall survival (OS), transformation free survival (TFS), event free survival (EFS), failure free survival (FFS) were analyzed from the start of therapy by Kaplan-Meier method. Clonal evolution (CE) was defined by the presence of any cytogenetic abnormality other than a single Ph, variant Ph chromosome or loss of Y chromosome. Also we analyzed CML pts with CE with regard 'major route' abnormalities vs other. The major route abnormalities includes trisomy 8 (+8), trisomy 19 (+19), isochromosome 17q10 (i17q) and additional Ph chromosome.
Results:
A total of 603 pts were analyzed including 579 pts in CP without CE and 24 pts with CE. Pts in CP without CE received initial therapy with imatinib-400 (n=70), imatinib-800 (n=200), dasatinib (n=138), nilotinib (n=122), or ponatinib (n=49), and pts with CE received imatinib-400 (n=2), imatinib-800 (n=7), dasatinib (n=10), nilotinib (n=4), and ponatinib (n=1). Pts with CP were usually older, female and have a higher WBC (P < 0.001). There was a statistically significant higher Complete cytogenetic response (CCyR) at 6 mo in pts without CE (P = 0.012), however the cumulative and 3-month rates of complete hematologic response (CHR), and the cumulative rates of CCyR and MMR were not different (Table). Similarly, the rates of MR4.0 and MR4.5 were similar for the two groups. At 5 years, the presence of additional cytogenetic findings at diagnosis does not seem to affect the rate of transformation, failure-free, event-free and overall survival. Acknowledging the small sample size for subset analysis, response rates and survival outcomes were comparable in CP with CE irrespective of whether chromosomal abnormalities were 'major route' or other (n=12 in each arm).
Conclusion:
Additional cytogenetic CE at the time of diagnosis among patients with CML in CP is associated with a similar favorable outcome as those without CE when treated with TKI. The type of additional CE (major route vs other) does not seem to impact outcome. Patients with CML-CP with CE at the time of diagnosis can thus be treated with TKI as all other pts with CP with no need for consideration for SCT unless there is clear evidence of failure.

Disclosures
Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. DiNardo:Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.