Does the Achievement of MR4.5 Improve the Outcome of Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Front Line Tyrosine Kinase Inhibitors (TKI)?
Authors: Falchi Lorenzo , Kantarjian Hagop M. , Wang Xuemei , Jabbour Elias , Ravandi Farhad , Garcia-Manero Guillermo , Estrov Zeev , Kadia Tapan , Pemmaraju Naveen , Ferrajoli Alessandra , Daver Naval , Dellasala Sara Emogene , Pierce Sherry , Verstovsek Srdan , Cortes Jorge E. 
Published: November 2019

Abstract
Background: Aside from the possibility of treatment discontinuation, the prognostic significance of deep molecular responses regarding survival endpoints in pts with CP-CML treated with TKI remains controversial. Achievement of complete cytogenetic response (CCyR) correlates with improved overall survival (OS). Among pts with CCyR, achievement of major molecular response (MMR) correlates with improved event-free survival (EFS). We have previously shown that among pts in sustained CCyR, those who achieve deeper molecular responses at 18 or 24 months may have longer EFS and failure-free survival (FFS) but not transformation-free survival (TFS) or OS. In this analysis, we sought to determine whether the achievement of a MR4.5 might correlate with improved long-term outcome in CP-CML pts who achieve CCyR after frontline TKI therapy.
Methods: Pts with CP-CML treated with front line TKI, including imatinib 400 mg daily (IM400), imatinib 800 mg daily (IM800), nilotinib (NILO), or dasatinib (DASA), were included in the analysis. Landmark analyses were conducted at various time points to identify the association between achieving MR4.5 and various survival outcomes. Since the benefit of achieving CCyR is well established, only pts who were in CCyR were considered at each time point. The probabilities of OS, EFS, FFS and TFS were estimated using the Kaplan-Meier method and Cox proportional hazards regression models were fit to assess the association between OS, EFS, FFS, TFS and response. All outcomes were measured from the date treatment was started. OS was measured until death from any cause; TFS until death or transformation to accelerated (AP) or blast phase (BP) during study; EFS until loss of complete hematologic response or major cytogenetic response, transformation to AP or BP, or death from any cause; FFS until any event (as per EFS definition), failure (as defined by the ELN criteria), loss of CCyR, discontinuation or change of therapy for any reason.
Results: The study population consisted of 478 pts. 59% of them were males and 9% had high Sokal score at diagnosis. 71 pts received IM400, 204 IM800, 105 NILO, and 98 DASA. Median follow-up is 106 (4-177) months (163 for IM400, 133 for IM800, 61 for NILO and 71 for DASA). The overall cumulative rate of CCyR was 92% (85% for IM400, 90% for IM800, 99% for NILO, and 97% for DASA). The overall cumulative rate of MR4.5 was 73% (56%, 74%, 80% and 78%, respectively for the 4 treatment cohorts). Among pts with CCyR, corresponding rates of MR4.5 were 79% overall and 66%, 81%, 83% and 80%, respectively, for the 4 treatment cohorts. For the entire population, the 5-year OS was 92.7%, TFS 86.0%, EFS 80.7%, and FFS 69.1%. In pts who were in CCyR at 12, 18, 24, 30, 36 or 48 months after initiation of TKI therapy there was no significant difference in terms of EFS, FFS, TFS or OS between pts who achieved a MR4.5 and those who did not (Table).
Conclusion: Our analysis suggests that the achievement of MR4.5 does not provide a meaningful improvement in EFS, FFS, TFS, or OS for CP-CML pts who have achieved CCyR after being treated with frontline TKI. While obtaining a MR4.5 may enable the option of TKI discontinuation, our results suggest that failure to do so should not be considered failure or suboptimal response and thus should not prompt a change in TKI in pts who are in CCyR. Change of therapy to achieve MR4.5 with the goal of treatment discontinuation should be considered only within clinical trials.
Table 1. Cox proportional hazards models for EFS, FFS, TFS, and OS at various time points. Time point EFS FFS TFS OS HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value 12 months 0.82 0.42-1.61 0.57 0.94 0.58-1.53 0.81 0.99 0.46-2.12 0.98 1.06 0.47-2.39 0.89 18 months 0.96 0.51-1.82 0.9 0.75 0.45-1.25 0.27 1.34 0.69-2.81 0.36 1.41 0.68-2.94 0.35 24 months 0.85 0.44-1.65 0.63 0.8 0.49-1.33 0.39 0.9 0.41-2.01 0.8 0.99 0.43-2.25 0.97 30 months 0.75 0.35-1.62 0.47 0.64 0.36-1.15 0.14 0.82 0.34-1.96 0.65 0.98 0.40-2.39 0.97 36 months 0.98 0.46-2.09 0.96 0.55 0.30-1.02 0.06 1.11 0.47-2.65 0.81 1.24 0.52-2.95 0.63 48 months 0.86 0.35-2.10 0.73 0.7 0.35-1.40 0.31 0.84 0.29-2.43 0.75 0.86 0.30-2.48 0.78

Disclosures
Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding.