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A novel BCR-ABL1 mutation in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia

Authors Vinhas R, Lourenço A, Santos S, Lemos M, Ribeiro P, Botelho Sousa A, Baptista PV, Fernandes AR

Received 12 June 2018

Accepted for publication 7 August 2018

Published 30 November 2018 Volume 2018:11 Pages 8589—8598

DOI https://doi.org/10.2147/OTT.S177019

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 4

Editor who approved publication: Dr William Cho


Raquel Vinhas,1 Alexandra Lourenço,2 Susana Santos,2 Marcos Lemos,2 Patrícia Ribeiro,2 Aida Botelho de Sousa,2 Pedro Viana Baptista,1 Alexandra Ramos Fernandes1

1UCIBIO, Life Sciences Department, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal; 2Hematology Service, Hospital dos Capuchos (CHLC), Lisbon, Portugal

Abstract: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) represents the most common genetic subtype of adult ALL (20%–30%) and accounts for approximately 50% of all cases in the elderly. It has been considered the subgroup of ALL with the worst outcome. The introduction of tyrosine kinase inhibitors (TKIs) allows complete hematologic remission virtually in all patients, with improved disease-free survival and overall survival. Nevertheless, the emergence of resistant mutations in BCR-ABL1 may require different TKI strategies to overcome the patient’s resistance and disease relapse. Here, we report a Ph+ B-ALL case with persistent minimal residual disease (MRD) after treatment with dasatinib. The patient expressed the P190BCR-ABL1 isoform and a novel BCR-ABL1 mutation, p.Y440C. The latter is in the C-terminal lobe of the kinase domain, which likely induces deviations in the protein structure and activity and destabilizes its inactive conformation. The treatment was substituted by bosutinib, which binds to the active conformation of the protein, prior to allogeneic bone marrow transplant to overcome the lack of a complete response to dasatinib. These findings strengthen the importance of BCR-ABL1 mutational screening in Ph+ patients, particularly for those who do not achieve complete molecular remission.

Keywords:
ALL, Philadelphia chromosome, e14a2, mutation, p.Y440C

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