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HALF OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS RELAPSING UNDER IBRUTINIB CARRY BTK AND PLCG2 MUTATIONS: A EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC) REAL-WORLD STUDY
Author(s): ,
Silvia Bonfiglio
Affiliations:
Centre for Translational Genomics and Bioinformatics and B-cell Neoplasia Unit, Experimental Oncology,IRCCS San Raffaele Scientific Institute,Milan,Italy
,
Lydia Scarfò
Affiliations:
Strategic Research Program on CLL and B-cell Neoplasia Unit,Università Vita-Salute and IRCCS San Raffaele Scientific Institute,Milan,Italy
,
Gianluca Gaidano
Affiliations:
Division of Hematology, Department of Translational Medicine,University of Eastern Piedmont,Novara,Italy
,
Livio Trentin
Affiliations:
Hematology and Clinical Immunology, Department of Medicine,University of Padua,Padua,Italy
,
Lisa Bonello
Affiliations:
Center for Experimental Research and Medical Studies,S. Giovanni Battista Hospital,Turin,Italy
,
Panayiotis Panayiotidis
Affiliations:
Department of Propaedeutic Internal Medicine,Laiko Hospital, University of Athens,Athens,Greece
,
Gianluigi Reda
Affiliations:
Oncohematology Department,Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milan,Italy
,
Francesco Forconi
Affiliations:
Hematology Department,University Hospital National Health Service Trust,Southampton,United Kingdom
,
Niki Stavroyianni
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Constantine Tam
Affiliations:
Haematology Department,St Vincent’s Hospital and Peter MacCallum Cancer Center, University of Melbourne,Melbourne,Australia
,
Marta Coscia
Affiliations:
Hematology Unit,Città della Salute e della Scienza, University of Turin,Turin,Italy
,
Ingo Ringshausen
Affiliations:
Department of Hematology,University of Cambridge,Cambridge,United Kingdom
,
Ozren Jaksic
Affiliations:
Dubrava University Hospital,Zagreb,Croatia
,
Zadie Davis
Affiliations:
Department of Haematology,Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Carolina Pavlovsky
Affiliations:
Fundaleu,Buenos Aires,Argentina
,
Antonella Capasso
Affiliations:
Internal Medicine,Università Vita-Salute San Raffaele,Milan,Italy
,
Pamela Ranghetti
Affiliations:
B-cell Neoplasia Unit, Experimental Oncology,IRCCS San Raffaele Scientific Institute,Milan,Italy
,
Diego Cortese
Affiliations:
Department of Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Aron Skaftason
Affiliations:
Department of Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Kostas Stamatopoulos
Affiliations:
Institute of Applied Biosciences,Centre for Research and Technology Hellas,Thessaloniki,Greece;Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Richard Rosenquist
Affiliations:
Department of Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
Paolo Ghia
Affiliations:
Strategic Research Program on CLL and B-cell Neoplasia Unit,Università Vita-Salute and IRCCS San Raffaele Scientific Institute,Milan,Italy
EHA Library. Scarfo L.
Jun 17, 2018; 218883
Dr. Lydia Scarfo
Dr. Lydia Scarfo
Contributions
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Abstract

Abstract: LB2601

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 11:15 - 11:30

Location: Room A1

Background

Acquired mutations within the Bruton’s tyrosine kinase (BTK) gene at C481, the binding site for ibrutinib, or, more rarely, the PLCG2 gene, have been reported in pre- and post-relapse samples of ibrutinib-treated CLL patients. Real-world evidence is lacking regarding the frequency of such mutations in relapsing patients but also those with sustained responses. 

Aims
To determine the prevalence of BTK and PLCG2 mutations in CLL patients (pts) relapsing or responding to ibrutinib in a real-world setting.

Methods
Libraries were prepared using an Agilent HaloPlexHS kit targeting BTK and PLCG2 and paired-end sequencing was performed on the NextSeq instrument (Illumina). Adaptor sequences and low-quality bases were removed, reads were aligned to the hg19 human reference genome using BWA and variants were detected by VarScan with a variant allelic frequency (VAF) cutoff of 1%.

Results

79 CLL pts treated with ibrutinib (28 relapsed and 51 still responding at last follow up >1 year from therapy initiation) at 14 institutions worldwide were included in the study. Of the 26 pts analyzed to-date all but 3 were previously treated (15 pts ≥3 lines). 13 (50%) progressed on ibrutinib (median 23 months; range 3-56); the remaining 13/26 (50%) had a sustained response at last follow up (median 33 months; range 16-58) (ibrutinib-responders). Best response to ibrutinib among 13 relapsed pts was PR while ibrutinib-responders achieved 11 PR and CR. Samples of ibrutinib-responders were obtained after at least 1 year of treatment (median time from ibrutinib initiation to sampling 17 months, range 12-37) while samples of relapsed cases were obtained at the time of relapse (median time 26 months, range 3-56). 7/13 (54%) relapsed patients carried a BTKC481S/R mutation (VAF: 4.4%>51.8%) at relapse. Of these 7 mutated pts, 1 carried 2 mutations at the BTKC481 hotspot with different VAFs (13.2% & 51.8%); 2 carried 2 mutations each within PLCG2 (VAF: 2.3%>28.5%); 1 pt carried a low frequency mutation in PLCG2 (p.M1141R: 1.5%). No patient had hotspot PLCG2 mutations in the absence of BTK mutations. Median time to progression was longer in pts without BTK/PLCG2 mutations (32.5 vs 13 months). After ibrutinib failure, 5 pts received the combination of idelalisib+rituximab, 6 pts venetoclax, and 2 obinutuzumab alone or in combination. Response to next line treatment in 6/7 pts with BTK mutations, was 1 CR, 2 PR and 3 treatment failures, not differing from 3 PR and 3 treatment failures in those without mutations. In 12/13 (92%) ibrutinib-responders, no mutations were detected in BTK or PLCG2. In one patient, still responding but with an increasing lymphocyte count, the sample at time point >1 year carried BTKC481S (VAF:19.5%) and two hotspot mutations in PLCG2 [p.L845F (28.5%) and p.D993H (2.3%)]. A patient sensitive to ibrutinib after 17.5 months of treatment carried BTKC481S mutations in minor subclones (VAF:1.1% & 2.3%) and a low frequency variant in PLCG2L848R at baseline with no increase during treatment.

Conclusion
Preliminary results for this multicenter, international study revealed that 50% of cases relapsing on ibrutinib had BTKC481 mutations that often associated with PLCG2 mutations. The absence of mutations in these genes was associated with a longer time to progression. These results indicate the outgrowth of several resistant clones and suggest multiple resistance mechanisms that need to be studied towards eventually designing innovative treatment to improve the outcome of CLL patients relapsing on ibrutinib. Results from the entire cohort of 79 patients will be presented at the Congress.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Resistance, ibrutinib, Chronic Lymphocytic Leukemia

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