Impact Of Major Molecular Response On Overall Survival and Its Time Of Achievement On Complete Molecular Response Incidence In Chronic Myeloid Leukemia Patients Treated By Tyrosine Kinase Inhibitors In First Chronic Phase
Authors: Michallet Mauricette , Sobh Mohamad , Labussiere Helene , Gilis Lila , Barraco Fiorenza , Etienne Madeleine , Le Borgne Oriane , Tigaud Isabelle , Hayette Sandrine , Ducastelle Sophie , Thomas Xavier 
Published: October 2019

Abstract
Most patients with CML treated with Tyrosine Kinase Inhibitors (TKIs) achieve a major molecular response (MMR), that is, the absence of detectable Philadelphia chromosome. Even after this threshold is achieved, the disease burden continues to progressively decrease with continued treatment. Therefore, more sensitive polymerase chain reaction (PCR)–based molecular methods are required to detect and quantify levels of minimal residual disease leading to complete molecular response (CMR), especially at long time points after TKI initiation. Low levels of minimal residual disease, as measured by real-time quantitative PCR, have been shown to be an excellent surrogate marker for long-term prognosis. The objective of the present study is to describe the different clinical and therapeutic characteristics of chronic myeloid leukemia (CML) patients consecutively treated in first chronic phase (CP1) using tyrosine-kinase inhibitors (TKI) as first line treatment, followed at our centre between years 2001 and 2011, and at a second time to assess response to TKI with the incidence of major molecular response (MMR) and then its evolution to reach complete molecular response (CMR). Among 253 consecutive CML patients treated in CP1 at our centre, we analysed 183 (72%) who received TKI as first line treatment, 117 males and 66 females with a median age at diagnosis of 50 years (17-81)]. Among 135 patients evaluated for Sokal score, 41 (30%) were low, 63 (47%) were intermediate and 31 (23%) were high. According to hasford score (125 evaluated), 57 (46)% were low, 61 (49%) intermediate and 7 (5%) were high. First line treatment was imatinib for 161 (88%) patients, dasatinib for 14 (8%) patients and nilotinib for 8 (4%) patients. Overall, 167 (91%) patients obtained MMR [134 (80%) after first line treatment, 26 (16%) after second line treatment and 7 (4%) after third line treatment] within a median time of 13 months (range: 2-88); and 16 (9%) patients never reached MMR. Non-MMR patients, were as follow: 53% had high sokal score 33% intermediate and 14% low; 6% had high hasford score, 47% intermediate and 47% low; they received a median of 3 TKI-based treatment lines during a median follow-up of 37 months; 6 (37.5%) of them died after disease progression and 10 still under treatment. The median time to obtain MMR was correlated with sokal score: 9 months (range: 2-84) in patients with low score; 13 months (range: 3-78) in patients with intermediate score and 17 months (range: 3-63) in patients with high score, p=0.03, same according to hasford score with 11 months, 13 and 20 months respectively, p=0.05. Among MMR patients, 18 (11%) lost their MMR after a median time of 28 months (range: 3-65) while 57 (34%) achieved a CMR after a median time of 36 months (range: 0-73) from MMR. Interestingly, response enhancement from MMR to CMR was significantly impacted by the time to have a MMR, thus the 5 years incidence of CMR was 67% in patients who had MMR in ≤ 3 months, 56% in patients with MMR > 3 and ≤ 12 months, 28% in patients with MMR > 12 and ≤ 24 months, and 12% in patients with MMR > 24 months, p=0.01 (Figure 1). After a median follow-up of 62 months (range: 6-135), patients who were in MMR at 24 months had 5 years probability of overall survival of 99% compared to 64% for those who did not have it at that time nor later, p <0.001 (Figure 2).Figure 1CMR incidence according to time to obtain MMRFigure 1. CMR incidence according to time to obtain MMRFigure 2Overall survival for patients in MMR at 24 months vs. those never in MMRFigure 2. Overall survival for patients in MMR at 24 months vs. those never in MMR
We showed that MMR is a very significant factor predicting patient overall survival independently of treatment line number and delay of its achievement. In addition, we demonstrated that patients with low Sokal and Hasford scores have significant faster time to achieve MMR and that CMR incidence was significantly related to shorter time to obtain MMR.

Disclosures:
Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding.