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 2017 Aug 5;17(1):523. Epub 2017 Aug 5.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Via Massarenti, 9-40138, Bologna, Italy.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-017-3511-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545087PMC
August 2017
8 Reads

Publication Analysis

Top Keywords

mutant clones
12
selective pressure
8
acute lymphoblastic
8
lymphoblastic leukemia
8
deep sequencing
8
clones
4
clones outgrew
4
additional mutant
4
reported previously-
4
deselect aggressive
4
previously- additional
4
pressure deselect
4
persisted despite
4
conventional chemotherapy
4
chemotherapy deep
4
sequencing dissect
4
blinatumomab conventional
4
transplant blinatumomab
4
aggressive mutant
4
despite ponatinib
4

References

(Supplied by CrossRef)

V Leoni et al.
Haematologica 2015

JM Ribera et al.
Leuk Lymphoma 2013

AK Fielding et al.
Curr Hematol Malig Rep 2013

S Soverini et al.
Clin Cancer Res 2006

S Soverini et al.
Cancer 2014

S Soverini et al.
Haematologica 2007

JE Cortes et al.
N Engl J Med 2012

MS Zabriskie et al.
Cancer Cell 2014

JM Ribera et al.
Onco Targets Ther 2015

J Wu et al.
J Hematol Oncol 2015

S Soverini et al.
Blood 2013

Similar Publications