SEQUENCE VARIANTS IN PATIENTS WITH PRIMARY AND ACQUIRED RESISTANCE TO IBRUTINIB IN THE PHASE 3 MCL3001 (RAY) TRIAL
(Abstract release date: 05/19/16)
EHA Library. Lenz G. 06/11/16; 135195; S439
Prof. Dr. Georg Lenz
Contributions
Contributions
Abstract
Abstract: S439
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:00 - 12:15
Location: Auditorium 1
Background
The phase 3 MCL3001 (RAY) study compared the efficacy and safety of ibrutinib with that of temsirolimus in patients with relapsed or refractory mantle-cell lymphoma (MCL). Ibrutinib significantly prolonged progression-free survival (PFS) versus temsirolimus (14.6 vs 6.2 months; p < 0.0001) and increased overall response rate (ORR) (72 vs 40%; p < 0.0001). The current study explores underlying molecular mechanisms of resistance to ibrutinib in patients from the RAY study.
Aims
To identify specific mechanisms underlying ibrutinib resistance in MCL, and to correlate potential genetic signatures with patient response.
Methods
The clinical results of the RAY study are reported elsewhere (Dreyling 2015). Patients were grouped by best ORR + PFS: Durable Responder: complete response or partial response (PR) + PFS ≥ 4 months; Moderate Clinical Benefit: PR + PFS < 4 months or stable disease; and Primary Resistant Disease. For mutational analysis, the Durable Responder group was compared with the Poor/Non-responders group (Moderate Clinical Benefit + Primary Resistant Disease combined) using Fisher’s exact test for comparisons between the 2 groups. For primary resistance analysis, baseline variant differences between groups were compared. For acquired resistance analysis, initial samples and samples obtained at progression after response were compared. Deep sequencing was performed on DNA from tumor cells (Illumina HiSeq instrument) using a custom gene panel. Sequences were aligned to hg19 reference genome, variants were described using SAMtools, and germline filters were applied to identify possible somatic mutations. All patients provided written informed consent.
Results
Mutations associated with primary resistance to ibrutinib were identified in NF-kB signaling pathways, both canonical (eg, A20) and noncanonical (eg, BIRC2). Other mutations were found in epigenetic modifiers and in the EGFR family. To explore acquired resistance, 34 paired samples (11 ibrutinib; 23 temsirolimus) were analyzed. Two PLCg2 mutations were found in patients with durable PRs (18.5 and 8.5 months); a CARD11 mutation after PR was found in 1 patient (after 12 months). Mutations in epigenetic modifiers and alternate NF-kB or PI3K/mTOR pathways were found after a short treatment duration (< 4 months). No primary or acquired Bruton’s tyrosine kinase (BTK) C481S mutations were detected.
Conclusion
Mutations in the NF-kB pathway bypassing BTK appear to be a common mechanism of resistance in this population with MCL. The similarity between primary and acquired mutations, as well as the lack of BTK C481S mutations to date, may possibly be explained by the short follow-up and shorter response duration compared with chronic lymphocytic leukemia. Some mutations seen in the acquired setting (eg, CARD11, PLCg2) have been associated with ibrutinib resistance. Understanding both primary and acquired resistance patterns is key in order to improve outcomes and define the populations that benefit from ibrutinib treatment.
Session topic: Follicular and Mantle Cell Lymphoma - Clinical
Keyword(s): Mantle cell lymphoma, Non-Hodgkin's lymphoma
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:00 - 12:15
Location: Auditorium 1
Background
The phase 3 MCL3001 (RAY) study compared the efficacy and safety of ibrutinib with that of temsirolimus in patients with relapsed or refractory mantle-cell lymphoma (MCL). Ibrutinib significantly prolonged progression-free survival (PFS) versus temsirolimus (14.6 vs 6.2 months; p < 0.0001) and increased overall response rate (ORR) (72 vs 40%; p < 0.0001). The current study explores underlying molecular mechanisms of resistance to ibrutinib in patients from the RAY study.
Aims
To identify specific mechanisms underlying ibrutinib resistance in MCL, and to correlate potential genetic signatures with patient response.
Methods
The clinical results of the RAY study are reported elsewhere (Dreyling 2015). Patients were grouped by best ORR + PFS: Durable Responder: complete response or partial response (PR) + PFS ≥ 4 months; Moderate Clinical Benefit: PR + PFS < 4 months or stable disease; and Primary Resistant Disease. For mutational analysis, the Durable Responder group was compared with the Poor/Non-responders group (Moderate Clinical Benefit + Primary Resistant Disease combined) using Fisher’s exact test for comparisons between the 2 groups. For primary resistance analysis, baseline variant differences between groups were compared. For acquired resistance analysis, initial samples and samples obtained at progression after response were compared. Deep sequencing was performed on DNA from tumor cells (Illumina HiSeq instrument) using a custom gene panel. Sequences were aligned to hg19 reference genome, variants were described using SAMtools, and germline filters were applied to identify possible somatic mutations. All patients provided written informed consent.
Results
Mutations associated with primary resistance to ibrutinib were identified in NF-kB signaling pathways, both canonical (eg, A20) and noncanonical (eg, BIRC2). Other mutations were found in epigenetic modifiers and in the EGFR family. To explore acquired resistance, 34 paired samples (11 ibrutinib; 23 temsirolimus) were analyzed. Two PLCg2 mutations were found in patients with durable PRs (18.5 and 8.5 months); a CARD11 mutation after PR was found in 1 patient (after 12 months). Mutations in epigenetic modifiers and alternate NF-kB or PI3K/mTOR pathways were found after a short treatment duration (< 4 months). No primary or acquired Bruton’s tyrosine kinase (BTK) C481S mutations were detected.
Conclusion
Mutations in the NF-kB pathway bypassing BTK appear to be a common mechanism of resistance in this population with MCL. The similarity between primary and acquired mutations, as well as the lack of BTK C481S mutations to date, may possibly be explained by the short follow-up and shorter response duration compared with chronic lymphocytic leukemia. Some mutations seen in the acquired setting (eg, CARD11, PLCg2) have been associated with ibrutinib resistance. Understanding both primary and acquired resistance patterns is key in order to improve outcomes and define the populations that benefit from ibrutinib treatment.
Session topic: Follicular and Mantle Cell Lymphoma - Clinical
Keyword(s): Mantle cell lymphoma, Non-Hodgkin's lymphoma
Abstract: S439
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:00 - 12:15
Location: Auditorium 1
Background
The phase 3 MCL3001 (RAY) study compared the efficacy and safety of ibrutinib with that of temsirolimus in patients with relapsed or refractory mantle-cell lymphoma (MCL). Ibrutinib significantly prolonged progression-free survival (PFS) versus temsirolimus (14.6 vs 6.2 months; p < 0.0001) and increased overall response rate (ORR) (72 vs 40%; p < 0.0001). The current study explores underlying molecular mechanisms of resistance to ibrutinib in patients from the RAY study.
Aims
To identify specific mechanisms underlying ibrutinib resistance in MCL, and to correlate potential genetic signatures with patient response.
Methods
The clinical results of the RAY study are reported elsewhere (Dreyling 2015). Patients were grouped by best ORR + PFS: Durable Responder: complete response or partial response (PR) + PFS ≥ 4 months; Moderate Clinical Benefit: PR + PFS < 4 months or stable disease; and Primary Resistant Disease. For mutational analysis, the Durable Responder group was compared with the Poor/Non-responders group (Moderate Clinical Benefit + Primary Resistant Disease combined) using Fisher’s exact test for comparisons between the 2 groups. For primary resistance analysis, baseline variant differences between groups were compared. For acquired resistance analysis, initial samples and samples obtained at progression after response were compared. Deep sequencing was performed on DNA from tumor cells (Illumina HiSeq instrument) using a custom gene panel. Sequences were aligned to hg19 reference genome, variants were described using SAMtools, and germline filters were applied to identify possible somatic mutations. All patients provided written informed consent.
Results
Mutations associated with primary resistance to ibrutinib were identified in NF-kB signaling pathways, both canonical (eg, A20) and noncanonical (eg, BIRC2). Other mutations were found in epigenetic modifiers and in the EGFR family. To explore acquired resistance, 34 paired samples (11 ibrutinib; 23 temsirolimus) were analyzed. Two PLCg2 mutations were found in patients with durable PRs (18.5 and 8.5 months); a CARD11 mutation after PR was found in 1 patient (after 12 months). Mutations in epigenetic modifiers and alternate NF-kB or PI3K/mTOR pathways were found after a short treatment duration (< 4 months). No primary or acquired Bruton’s tyrosine kinase (BTK) C481S mutations were detected.
Conclusion
Mutations in the NF-kB pathway bypassing BTK appear to be a common mechanism of resistance in this population with MCL. The similarity between primary and acquired mutations, as well as the lack of BTK C481S mutations to date, may possibly be explained by the short follow-up and shorter response duration compared with chronic lymphocytic leukemia. Some mutations seen in the acquired setting (eg, CARD11, PLCg2) have been associated with ibrutinib resistance. Understanding both primary and acquired resistance patterns is key in order to improve outcomes and define the populations that benefit from ibrutinib treatment.
Session topic: Follicular and Mantle Cell Lymphoma - Clinical
Keyword(s): Mantle cell lymphoma, Non-Hodgkin's lymphoma
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:00 - 12:15
Location: Auditorium 1
Background
The phase 3 MCL3001 (RAY) study compared the efficacy and safety of ibrutinib with that of temsirolimus in patients with relapsed or refractory mantle-cell lymphoma (MCL). Ibrutinib significantly prolonged progression-free survival (PFS) versus temsirolimus (14.6 vs 6.2 months; p < 0.0001) and increased overall response rate (ORR) (72 vs 40%; p < 0.0001). The current study explores underlying molecular mechanisms of resistance to ibrutinib in patients from the RAY study.
Aims
To identify specific mechanisms underlying ibrutinib resistance in MCL, and to correlate potential genetic signatures with patient response.
Methods
The clinical results of the RAY study are reported elsewhere (Dreyling 2015). Patients were grouped by best ORR + PFS: Durable Responder: complete response or partial response (PR) + PFS ≥ 4 months; Moderate Clinical Benefit: PR + PFS < 4 months or stable disease; and Primary Resistant Disease. For mutational analysis, the Durable Responder group was compared with the Poor/Non-responders group (Moderate Clinical Benefit + Primary Resistant Disease combined) using Fisher’s exact test for comparisons between the 2 groups. For primary resistance analysis, baseline variant differences between groups were compared. For acquired resistance analysis, initial samples and samples obtained at progression after response were compared. Deep sequencing was performed on DNA from tumor cells (Illumina HiSeq instrument) using a custom gene panel. Sequences were aligned to hg19 reference genome, variants were described using SAMtools, and germline filters were applied to identify possible somatic mutations. All patients provided written informed consent.
Results
Mutations associated with primary resistance to ibrutinib were identified in NF-kB signaling pathways, both canonical (eg, A20) and noncanonical (eg, BIRC2). Other mutations were found in epigenetic modifiers and in the EGFR family. To explore acquired resistance, 34 paired samples (11 ibrutinib; 23 temsirolimus) were analyzed. Two PLCg2 mutations were found in patients with durable PRs (18.5 and 8.5 months); a CARD11 mutation after PR was found in 1 patient (after 12 months). Mutations in epigenetic modifiers and alternate NF-kB or PI3K/mTOR pathways were found after a short treatment duration (< 4 months). No primary or acquired Bruton’s tyrosine kinase (BTK) C481S mutations were detected.
Conclusion
Mutations in the NF-kB pathway bypassing BTK appear to be a common mechanism of resistance in this population with MCL. The similarity between primary and acquired mutations, as well as the lack of BTK C481S mutations to date, may possibly be explained by the short follow-up and shorter response duration compared with chronic lymphocytic leukemia. Some mutations seen in the acquired setting (eg, CARD11, PLCg2) have been associated with ibrutinib resistance. Understanding both primary and acquired resistance patterns is key in order to improve outcomes and define the populations that benefit from ibrutinib treatment.
Session topic: Follicular and Mantle Cell Lymphoma - Clinical
Keyword(s): Mantle cell lymphoma, Non-Hodgkin's lymphoma
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