Contributions
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 2 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
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 2 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