Analysis Of Responses (complete cytogenetic response and major molecular response) Achieved With Different Tyrosine Kinase Inhibitor (TKI) Modalities and Their Impact On Long Term Outcomes In Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) – Analysis From a Single Institution
Authors: Jain Preetesh , Kantarjian Hagop M. , Alattar Mona Lisa , Quintas-Cardama Alfonso , Jabbour Elias , Cardenas-Turanzas Marylou , Romo Carlos Guillermo , Dellasala Sara E , Pierce Sherry , Verstovsek Srdan , Ravandi Farhad , O'Brien Susan , Cortes Jorge E. 
Published: October 2019

Abstract

Introduction
Since 2000, different TKI modalities have been used as initial therapy for CML-CP. We analyzed the responses and long-term clinical impact among pts treated with 4 TKI modalities as frontline CML-CP therapy in a single institution.

Methods
Outcomes of 476 consecutive pts (median age 49 yrs, range 15-86) receiving initial therapy with TKI from 2000 to 2013 were analysed. Patients received imatinib 400 mg/d (IM400; n=71), imatinib 800 mg/d (IM800; n=202), dasatinib (n=98) or nilotinib (n=105) in consecutive or parallel trials. Median follow-up was 85 months (mo) (3-154). Pts were followed uniformly with cytogenetics and PCR every 3 mo for the first 12 mo, then every 6 mo.

Results
Median follow-up was 144 mo for IM400, 112 mo for IM800, 52 mo for dasatinib and 48 mo for nilotinib. Overall CCyR rates were 85%, 92%, 96% and 96%, respectively. Corresponding rates of MMR were 83%, 88%, 91%, and 93%, respectively. The median time to achieve MMR was 11 mo for patients treated with IM400 and 6 mo with IM800, 5.8 mo with dasatinib, and 5.8 mo with nilotinib. Rates of MR4.5 were 61%, 76%, 75% and 68%. Rates of the CMR (5-log) were 48%, 54%, 55% and 46%. Because of the difference in follow-up between cohorts, we analyzed response at specific time points. Higher proportions of pts receiving IM800 and 2nd generation TKI achieved CCyR, MMR and MR4.5 at all time-points analyzed (3-60 months). Disease transformation occurred in 34 pts (7%), events occurred in 72 (15%) and 53 pts (11%) died. Overall, 195 (41%) pts have discontinued therapy, including 54% of pts treated with IM400, 46% with IM800, 28% with dasatinib and 27% with nilotinib. For pts taking IM400, 25% had lost CCyR by 60 mo, compared to 13% with IM800, 12% with dasatinib, and 5% with nilotinib. Estimated 60 mo outcomes for the total population were event-free survival (EFS) 85%, failure-free survival (FFS) 68%, transformation-free survival (TFS) 93%, and overall survival (OS) 93%. The 60 mo EFS was 69% with IM400, 87% with IM800, 91% with dasatinib, and 86% with nilotinib (P≤0.001). Pts who achieved a CCyR at 6 months (i.e., optimal response by ELN) had a better EFS rate at 60 mo (92%) compared to those not achieving this response (60%) (P≤0.001). Similarly, achievement of MMR at 12 mo (optimal response) resulted in 60 mo EFS probability of 92% vs. 74% for those without MMR (P≤0.001). Table -1depicts the time to event outcomes based on responses achieved by each TKI modality. The differences were similar regardless of the TKI modality used.

Conclusions
Excellent results are obtained with all TKI modalities with a suggestion for better long-term outcomes with IM800, dasatinib or nilotinib as compared to IM400. Higher proportions of pts who received imatinib discontinued treatment as compared to 2ndgeneration TKI. Achievement of CCyR and MMR at different time points has similar correlations with long-term outcome, regardless of the TKI used. Most patients with CML-CP can have an excellent outcome with TKI frontline therapy.

Disclosures:
Kantarjian: ARIAD: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.