FAVORABLE OUTCOME IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA CO-EXPRESSING E13A2 AND E14A2 TRANSCRIPT TREATED FRONTLINE WITH NILOTINIB
Author(s): ,
Olga Mulas
Affiliations:
Department of Medical Sciences and Public Health,University of Cagliari,Cagliari,Italy
,
Giovanni Caocci
Affiliations:
Department of Medical Sciences and Public Health,University of Cagliari,Cagliari,Italy
,
Mario Annunziata
Affiliations:
Hematology Unit,Cardarelli Hospital,Naples,Italy
,
Bruno Martino
Affiliations:
Hematology Unit,Azienda Ospedaliera 'Bianchi-Melacrino-Morelli',Reggio Calabria,Italy
,
Luigiana Luciano
Affiliations:
Hematology Unit,'Federico II' University of Naples,Naples,Italy
,
Fausto Castagnetti
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital,University of Bologna,Bologna,Italy
,
Patrizia Pregno
Affiliations:
Hematology Unit,Azienda Ospedaliero-Universitaria Città della Salute e della Scienza,Torino,Italy
,
Sara Galimberti
Affiliations:
Department of Clinical and Experimental Medicine, Section of Hematology,University of Pisa,Pisa,Italy
,
Francesco Albano
Affiliations:
Hematology and Transplants Unit,University of Bari,Bari,Italy
,
Ester Maria Orlandi
Affiliations:
Hematology Unit,'S. Matteo' University Hospital,Pavia,Italy
,
Nicola Sgherza
Affiliations:
Hematology and Transplant Center,Casa Sollievo della Sofferenza Hospital,San Giovanni Rotondo,Italy
,
Alessandra Iurlo
Affiliations:
Hematology Unit,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milano,Italy
,
Massimiliano Bonifacio
Affiliations:
Department of Medicine, Section of Hematology,University of Verona,Verona,Italy
,
Gianni Binotto
Affiliations:
Hematology Unit,University of Padova,Padua,Italy
,
Antonella Gozzini
Affiliations:
Hematology Unit, AOU Careggi,University of Florence,Florence,Italy
,
Monica Bocchia
Affiliations:
Hematology Unit, Azienda Ospedaliera Universitaria Senese,University of Siena,Siena,Italy
,
Elisabetta Abruzzese
Affiliations:
Hematology Unit, Sant'Eugenio Hospital ,Tor Vergata University,Rome,Italy
,
Claudio Fozza
Affiliations:
Department of Clinical and Experimental Medicine,University of Sassari,Sassari,Italy
,
Maria Pina Simula
Affiliations:
Hematology and Transplant Center,Businco Hospital,Cagliari,Italy
,
Fiorenza De Gregorio
Affiliations:
Hematology Unit ,'Federico II' University of Naples,Naples,Italy
,
Gabriele Gugliotta
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital , University of Bologna,Bologna,Italy
,
Francesca Pirillo
Affiliations:
Hematology Unit,Azienda Ospedaliero-Universitaria Città della Salute e della Scienza,Torino,Italy
,
Claudia Baratè
Affiliations:
Department of Clinical and Experimental Medicine, Section of Hematology,University of Pisa,Pisa,Italy
,
Imma Attolico
Affiliations:
Hematology and Transplants Unit,University of Bari,Bari,Italy
,
Chiara Elena
Affiliations:
Hematology Unit,'S. Matteo' University Hospital,Pavia,Italy
,
Daniele Cattaneo
Affiliations:
Hematology Unit,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milano,Italy
,
Luigi Scaffidi
Affiliations:
Department of Medicine, Section of Hematology,University of Verona,Verona,Italy
,
Anna Sicuranza
Affiliations:
Hematology Unit, Azienda Ospedaliera Universitaria Senese,University of Siena,Siena,Italy
,
Malgorzata Monika Trawinska
Affiliations:
Hematology Unit,Sant'Eugenio Hospital, Tor Vergata University,Rome,Italy
,
Emilia Scalzulli
Affiliations:
Division of Hematology,Department of Cellular Biotechnologies and Hematology, Sapienza University,Rome,Italy
,
Robin Foà
Affiliations:
Division of Hematology, Department of Cellular Biotechnologies and Hematology,Sapienza University,Rome,Italy
,
Massimo Breccia
Affiliations:
Division of Hematology, Department of Cellular Biotechnologies and Hematology,Sapienza University,Rome,Italy
Giorgio La Nasa
Affiliations:
Department of Medical Sciences and Public Health,University of Cagliari,Cagliari,Italy
(Abstract release date: 05/14/20) EHA Library. Simula M. 06/12/20; 294672; EP754
Dr. Maria Pina Simula
Dr. Maria Pina Simula
Contributions
Abstract

Abstract: EP754

Type: e-Poster

Background

Chronic myeloid leukemia (CML) is characterized by a reciprocal translocation between the long arms of chromosome 9 and chromosome 22 leading to the formation of a fusion hybrid gene (BCR-ABL). The p210kda protein is most frequently encoded. Depending on alternative splicing, different transcripts have been described, such as e13a2, e14a2. Approximately 10-15% of patients carry both transcripts at diagnosis. So far, no data have been reported on the clinical outcome of CML patients co-expressing e13a2 and e14a2, and treated with second generation tyrosine kinase inhibitors (TKI).

Aims
The primary objective of this study was to evaluate the cumulative incidence of deep molecular response (MR4) in CML patients co-expressing at diagnosis e13a2 and e14a2 treated frontline with nilotinib, and to compare it with patients carrying a single transcript. Progression-free survival (PFS) represented a secondary endpoint.

Methods

We evaluated a consecutive series of CML patient in chronic phase treated frontline with nilotinib 300 mg bid between July 2007 and July 2017 in 19 Italian centers. Only patients co-expressing e13a2 and e14a2 were considered. MR4 or more were considered as deep molecular responses (DMR) and MR3 as a major molecular response. PFS was defined as the time elapsed between the start of nilotinib and one of the following events: death, resistance to treatment or change of TKI due to loss of molecular response.

Results
A total of 183 patients were recruited.  The median follow-up was 44 months (range 2-64). One hundred and two patients (56%) were male. The mean age at diagnosis was 50 years (18-81). Overall, 51 patients (28%) expressed the e13a14 transcript, 108 patients (59%) expressed e14a2 and 24 (13%) expressed both transcripts. Patients co-expressing both transcripts had a significantly higher incidence of DMR compared to patients carrying the e14a2 and e13a2 transcript alone: 100% vs 80.3±5% and 80.7±6.6%, respectively, p=0.037 (Fig. 1). In multivariate analysis, considering as independent variables gender, age, transcript type and Sokal risk, only co-expression was significantly associated with a DMR (p=0.008, HR=1.94 95% CI=1.18-3.19). The 60-month overall survival (OS) was 98.8±0.8% and the 60-month PFS was 97.8±1%. No significant differences in OS and PFS were found between patients harboring the different transcripts (e13a2 vs e14a2 vs both).

Conclusion
Our results underline the importance of a precise identification of the BCR-ABL transcript at the time of CML diagnosis. Co-expression of e13a2 and e14a2 might have an important impact in the achievement of a DMR in patients treated with nilotinib frontline and could become an additional criterion of TKI choice, particularly at a time when treatment-free remission is becoming an increasing treatment endpoint. Further studies are needed on this CML subgroup.

Session topic: 08. Chronic myeloid leukemia - Clinical

Abstract: EP754

Type: e-Poster

Background

Chronic myeloid leukemia (CML) is characterized by a reciprocal translocation between the long arms of chromosome 9 and chromosome 22 leading to the formation of a fusion hybrid gene (BCR-ABL). The p210kda protein is most frequently encoded. Depending on alternative splicing, different transcripts have been described, such as e13a2, e14a2. Approximately 10-15% of patients carry both transcripts at diagnosis. So far, no data have been reported on the clinical outcome of CML patients co-expressing e13a2 and e14a2, and treated with second generation tyrosine kinase inhibitors (TKI).

Aims
The primary objective of this study was to evaluate the cumulative incidence of deep molecular response (MR4) in CML patients co-expressing at diagnosis e13a2 and e14a2 treated frontline with nilotinib, and to compare it with patients carrying a single transcript. Progression-free survival (PFS) represented a secondary endpoint.

Methods

We evaluated a consecutive series of CML patient in chronic phase treated frontline with nilotinib 300 mg bid between July 2007 and July 2017 in 19 Italian centers. Only patients co-expressing e13a2 and e14a2 were considered. MR4 or more were considered as deep molecular responses (DMR) and MR3 as a major molecular response. PFS was defined as the time elapsed between the start of nilotinib and one of the following events: death, resistance to treatment or change of TKI due to loss of molecular response.

Results
A total of 183 patients were recruited.  The median follow-up was 44 months (range 2-64). One hundred and two patients (56%) were male. The mean age at diagnosis was 50 years (18-81). Overall, 51 patients (28%) expressed the e13a14 transcript, 108 patients (59%) expressed e14a2 and 24 (13%) expressed both transcripts. Patients co-expressing both transcripts had a significantly higher incidence of DMR compared to patients carrying the e14a2 and e13a2 transcript alone: 100% vs 80.3±5% and 80.7±6.6%, respectively, p=0.037 (Fig. 1). In multivariate analysis, considering as independent variables gender, age, transcript type and Sokal risk, only co-expression was significantly associated with a DMR (p=0.008, HR=1.94 95% CI=1.18-3.19). The 60-month overall survival (OS) was 98.8±0.8% and the 60-month PFS was 97.8±1%. No significant differences in OS and PFS were found between patients harboring the different transcripts (e13a2 vs e14a2 vs both).

Conclusion
Our results underline the importance of a precise identification of the BCR-ABL transcript at the time of CML diagnosis. Co-expression of e13a2 and e14a2 might have an important impact in the achievement of a DMR in patients treated with nilotinib frontline and could become an additional criterion of TKI choice, particularly at a time when treatment-free remission is becoming an increasing treatment endpoint. Further studies are needed on this CML subgroup.

Session topic: 08. Chronic myeloid leukemia - Clinical

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