Atypical BCR-ABL Transcripts Chronic Myelogenous Leukemias Show Particular Features, and Their Classical Worse Prognosis Seems Abrogated by Imatinib Mesylate. A Retrospective Analysis of 22 Patients, on the Behalf of the French Intergroup of CML (Fi(ϕ)-LMC Group).
Authors: Nicolini Franck E. , Grardel Nathalie , Hayette Sandrine , Cayuela Jean-Michel , Buzyn Agnès , Delabesse Eric , Bastard Christian , Blanchet Odile , Sorel Nathalie , Mozziconacci Marie-Josée , Turhan Ali , Eclache Virginie , Mahon François-Xavier , Dastugue Nicole , Legac Eric , Gaub Marie-Pierre , Corm Sélim , Preudhomme Claude 
Published: April 2020

Abstract
Chronic Myelogenous Leukemia (CML) originates in the chromosome (Ph1), a reciprocal translocation, corresponding to the BCR-ABL fusion oncogene. A small proportion (1–2%) of CML patients show breakpoints falling outside of the M-BCR gene on chromosome 22, leading to the synthesis of a variety of atypical BCR-ABL transcripts [either shortened: e1a2 (m-BCR), e6a2, e8a2, b2a3 (e13a3), b3a3 (e14a3), or elongated transcripts: e19a2 (m-BCR)] and to the synthesis of different BCR-ABL proteins. In this study, we retrospectively analysed the clinical characteristics and outcomes of cohorts of CML patients harbouring atypical transcripts in and treated with imatinib (IM). Twenty-two patients were analysed: 9 e1a2 [Group 1 (G1)], 4 e6a2 [Group 2 (G2)], 5 e19a2 [Group 3 (G3)], and 4 e8a2 [Group 4 (G4)] BCR-ABL transcripts. Two patients were in myeloid blastic phase at onset (1 in G1 and 1 in G2) and others in chronic phase. Age at diagnosis was significantly younger for e19a2 patients (39.5 years versus 64 for G1, 58.5 for G2, 72 for G3, p=0.005). Female patients were predominant for G1 (5F/3M), but not for other groups. All patients presented a classical Ph1 at karyotyping analysis at diagnosis, but 1 had a -7 (G1), 1 an additional t(11;16) with the Ph1 (G2), 1 a +8 (G3) and 1 a -Y (G3). The majority of patients presented typical CML features at diagnosis, however number of differences could be found: WBC counts were higher for e1a2 and e8a2 patients (74.2 109/l and 62.7 respectively vs 20.9 for G2, and 37.8 for G3, p&lt;0.03). A significant relative monocytosis was present for e1a2 patients (10% vs 4 (G2), 2.5 (G3), 5.5 (G4), p&lt;0.05), and a marked basophilia was present for e6a2 patients vs others (p&lt;0.0008). There was a trend for higher platelet counts in G3 vs others. Hasford and Sokal scores were somewhat comparable in all groups. Median follow-up since diagnosis was 24 months for G1, 10 for G2, 17 for G3 and 31 for G4. Only one patient received interferon for 7 months before IM (G1), all other patients did not receive any other treatment than hydroxyurea before IM. All patients were treated with IM alone initially at 400–600 mg/day. Median duration of IM was 18 months for G1, 9 for G2, 12 for G3, and 30 for G4. At time of analysis 1 pt in G2 and 1 patient in G3 died of progression (blastic phase), and the overall survival (OS) since IM start was better for e19a2 and e8a2 patients, but patients remain very few. However, these OS do not seem different from what has been observed for M-BCR transcripts (IRIS study). In conclusion, atypical BCR-ABL transcripts CMLs show particular diagnosis features, but their poor prognosis reputation seems abrogated by IM.