Clinical Outcome of 27 Imatinib Mesylate Resistant Chronic Myelogenous Leukemia (CML) Patients Harbouring a T315I BCR-ABL Mutation.
Authors: Nicolini Franck E. , Bachy Emmanuel , Corm Sélim , Lê Quoc-Hung , Hayette Sandrine , Bories Dominique , Tulliez Michel , Sorel Nathalie , Guilhot Francois , Legros Laurence , Mahon François-Xavier , Maloisel Frédéric , Kiladjian Jean-Jacques , Roche-Lestienne Catherine , Preudhomme Claude , Michallet Mauricette 
Published: October 2019

Abstract
Most CML patients are sensitive to Imatinib Mesylate (IM), however, a small fraction develop resistance, mostly through the onset of BCR-ABL mutations. More than 30 mutations have been described, mostly in advanced phase, and confer different levels of clinical resistance. In this setting, clinical trials with 2nd generation tyrosine kinase inhibitors (TKI) provide encouraging results, however neither in vitro nor clinical activity has been demonstrated when the most frequent BCR-ABL mutation, T315I, has been identified. In this retrospective study from 5 French centers, we analysed the features and clinical outcomes of 27 CML patients treated with IM and presenting either clinical, cytological, cytogenetic resistance or molecular progression, and harboring a BCR-ABLT315I mutation detected by direct sequencing (same method in the 5 different laboratories, quality control exchanges). The 27 patients were in chronic phase (CP) at diagnosis, with 17 M and 10 F with a median age at diagnosis of 52 (25–70). Sokal scores were high for 8 pts, intermediate for 6 pts, low for 3 pts and unknown for 8, 2 were in blast crisis (BC) at CML diagnosis. Transcripts were M-BCR for 22 patients and m-BCR for 2 patients and unknown for 3 pts. At diagnosis 4 pts had additional chromosomal abnormalities as a variant Ph1 chromosome, a -7, a -Y, and an additional t(3;7;12) to the Ph1. Progression has been defined as a 2-fold rise in BCR-ABL transcripts levels, loss of any previous response to IM, and a transition towards a more advanced phase of the disease. At T315I discovery, 11 pts were in CP, 4 in accelerated phase, and a majority in BC [7 in myeloid and 5 in lymphoid]. The median interval between diagnosis and IM was 20 Mo. (0–145.2). The median initial dose of IM was 464 mg/day. Most of the patients were poor responders to IM of which 12 pts that obtained no more than a CHR, 2 pts a PCyR, 7 pts a CcyR, 2 pts a MMR, 1 pt no response, and 3 unknown. Twenty-one pts harboured a T315I alone, 1 a T315I with a Y253H, 2 with a M351T, 1 with a E255K+E255V, 1 with a L324Q, and 1 with a F311L, with no impact on survival. The median time for progression from day 1 IM was short [13 Mo. (0–49.6)] regardless of the phase of the disease at T315I identification, and the median interval IM start-T315I identification was 20 Mo. (0–57.6). Median overall survival from D1 of IM was 17.5 Mo. for advanced phases and 42.5 Mo. for CP (p=0.08). All patients progressed with no difference for time to progression between phases (p>0.05).
Figure Figure
Neither additional mutations (p=0.91), nor additional chromosomal abnormalities (p=0.11), nor Dasatinib treatment (p=0.15) modified overall survival. In conclusion, the onset of BCR-ABLT315I mutations occurs preferentially in high-risk CML, seems more frequent in advanced phases, and is always responsible for progression and poor survival, underlying the need for alternative treatments, in patients lacking a histocompatible donor.