Clinical Significance of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) Achieved with Different Treatment Modalities Used As Frontline Therapy In Chronic Myeloid Leukemia (CML) Chronic Phase (CP)
Authors: Alattar Mona Lisa , Kantarjian Hagop M. , Jabbour Elias , Quintas-Cardama Alfonso , Burton Elizabeth M , Borthakur Gautam , Verstovsek Srdan , Wierda William G. , Konopleva Marina , Burger Jan A. , O'Brien Susan , Cortes Jorge E. 
Published: October 2019

Abstract
Abstract 745FN2

Background:
Recent studies have shown that treatment of CML-CP with second generation tyrosine kinase inhibitors (2G-TKI) dasatinib and nilotinib result in a higher rate of CCyR and MMR and these responses are achieved earlier. Whether the same level of response at a given time-point achieved with different treatment modalities has the same implications for long-term outcome is unclear. Aim: To determine whether the early achievement of CCyR or MMR with different treatment modalities has similar long-term prognostic implications among patients with CML CP. Methods: The outcome of 485 patients treated in consecutive or parallel clinical trials of TKI's as initial therapy for CML-CP were analyzed. Patients were treated with imatinib 400mg (IM400) (n=73), imatinib 800mg (IM800) (n=208), nilotinib (n=105), and dasatinib (n=99). Patients were followed uniformly with cytogenetics and PCR every 3 months for the first 12 months, then every 6 months. We reviewed the rates of CCyR and MMR at early time points, and analyzed the probability of long-term event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS) according to the achievement of early responses. We then compared whether such outcome was similar for patients who achieved such response with different treatment modalities. For EFS an event was defined to include any of the following: loss of CCyR, in addition to standard IRIS definition of loss of complete hematologic remission (CHR), loss of major cytogenetic remission (MCyR), progression to accelerated phase (AC) or blast crisis (BC), or death due to any cause on treatment. Results: CCyR at any time was achieved by 94% of patients treated with nilotinib, 96% of those on dasatinib, 87% with IM400 and 91% with IM800. Rates of MMR (as defined by BCR-ABL/ABL ≤0.1% IS) of patients receiving nilotinib was 88%, dasatinib 86%, IM800 87% and IM400 73%. At six months, the rates of CCyR were 91%, 94%, 85%, 53% respectively. Corresponding rates at 12 months were 95%, 96%, 90% and 66%. The rate of MMR at 12 months was 86%, 74%, 81%, and 55%, respectively, and at 18 months 88%, 80%, 83%, and 67%. For patients taking nilotinib 9% had lost CCyR at 36mo, with dasatinib 6%, IM800 5%, and IM 400 13%. The median time to achieve MMR was 6 months for patients treated with nilotinib and dasatanib, compared to 6 months with IM800 and 9 months with IM400. For the total population, those achieving a CCyR at 6 months had a better EFS rate at 24 months (97%) compared to those not achieving this response (79%). Similarly, CCyR at 12 months correlated with a similar benefit in EFS (98% vs 72%). Achievement of CCyR and MMR at 18 months resulted in a 24 month probability of EFS of 98% compared to 87% for those with CCyR but no MMR and 71% for those with no CCyR. We then compared the results by treatment arm. Results are shown in Table 1. At two-year landmark, early achievement of CCyR by 6-mo was associated with higher EFS (but not OS) with all treatment modalities. Achieving MMR by 18 mo was a positive predictor of 24-mo EFS with IM and Dasatinib, but pts with Nilotinib so far had an excellent outcome regardless of 18-mo response. Conclusions: Time to achieving CCyR and MMR with frontline TKI's in CML-CP, reflects similar prognostic implications regardless of the modality of frontline therapy used to achieve it. However, earlier achievement of CCyR with nilotinib or dasatinib results in a higher percentage of patients obtaining the long-term benefit associated with early responses.

Disclosures:
No relevant conflicts of interest to declare.