The clonal evolution of two distinct T315I-positive BCR-ABL1 subclones in a Philadelphia-positive acute lymphoblastic leukemia failing multiple lines of therapy: a case report

De Benedittis, Caterina ; Papayannidis, Cristina ; Venturi, Claudia ; Abbenante, Maria Chiara ; Paolini, Stefania ; Parisi, Sarah ; Sartor, Chiara ; Cavo, Michele ; Martinelli, Giovanni ; Soverini, Simona (2017) The clonal evolution of two distinct T315I-positive BCR-ABL1 subclones in a Philadelphia-positive acute lymphoblastic leukemia failing multiple lines of therapy: a case report. BMC CANCER, 17 . ISSN 1471-2407
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Abstract

BACKGROUND: The treatment of Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients who harbor the T315I BCR-ABL1 mutation or who have two or more mutations in the same BCR-ABL1 molecule is particularly challenging since first and second-generation Tyrosine Kinase Inhibitors (TKIs) are ineffective. Ponatinib, blinatumomab, chemotherapy and transplant are the currently available options in these cases. CASE PRESENTATION: We here report the case of a young Ph+ ALL patient who relapsed on front-line dasatinib therapy because of two independent T315I-positive subclones, resulting from different nucleotide substitutions -one of whom never reported previously- and where additional mutant clones outgrew and persisted despite ponatinib, transplant, blinatumomab and conventional chemotherapy. Deep Sequencing (DS) was used to dissect the complexity of BCR-ABL1 kinase domain (KD) mutation status and follow the kinetics of different mutant clones across the sequential therapeutic approaches. CONCLUSIONS: This case presents several peculiar and remarkable aspects: i) distinct clones may acquire the same amino acid substitution via different nucleotide changes; ii) the T315I mutation may arise also from an 'act' to 'atc' codon change; iii) the strategy of temporarily replacing TKI therapy with chemo or immunotherapy, in order to remove the selective pressure and deselect aggressive mutant clones, cannot always be expected to be effective; iv) BCR-ABL1-mutated sub-clones may persist at very low levels (undetectable even by Deep Sequencing) for long time and then outcompete BCR-ABL1-unmutated ones becoming dominant even in the absence of any TKI selective pressure.

Abstract
Document type
Article
Creators
CreatorsAffiliationORCID
De Benedittis, CaterinaUniversità di Bologna
Papayannidis, CristinaUniversità di Bologna
Venturi, ClaudiaUniversità di Bologna
Abbenante, Maria ChiaraUniversità di Bologna
Paolini, StefaniaUniversità di Bologna
Parisi, SarahUniversità di Bologna
Sartor, ChiaraUniversità di Bologna
Cavo, MicheleUniversità di Bologna
Martinelli, GiovanniUniversità di Bologna
Soverini, SimonaUniversità di Bologna
Subjects
ISSN
1471-2407
DOI
Deposit date
14 Mar 2018 14:16
Last modified
14 Mar 2018 14:16
Project name
NGS-PTL - Next Generation Sequencing platform for targeted Personalized Therapy of Leukemia
Funding program
EC - FP7
URI

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