Contributions
Abstract: S854
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 16:30 - 16:45
Location: Victoria Hall
Background
Ven is an oral BCL2 antagonist approved for the treatment of chronic lymphocytic leukemia. However, the role of venetoclax in WM is unknown. Immunophenotypic and genomic sequencing studies have shown that BCL2 is highly expressed and activated in WM cells (Chng Blood 2006; Hunter Blood 2016). In a study of pts with non-Hodgkin lymphoma, ven showed efficacy in 4 pts with WM (Davids J Clin Oncol 2017).
Aims
We initiated a phase II study to evaluate the safety and efficacy of ven monotherapy in previously treated pts with WM (NCT02677324).
Methods
Treatment was given in the outpatient setting and followed a ramp-up of 200 mg daily days 1-7, 400 mg daily days 8-14, then 800 mg daily thereafter, for maximum of 2 years. Pts were closely monitored for tumor lysis syndrome (TLS) during the first 24 hours of each dose escalation. Toxicity was graded per CTCAE v.4.03. Response was assessed based on IWWM6 criteria.
Results
30 pts with symptomatic WM were enrolled. Median follow-up time is 8 months (range 0.2-18 months). Median age was 66 years (range 39-80 years) and 17 pts (57%) were men. Indications to treat were constitutional symptoms (52%), anemia (44%), neuropathy (15%), extramedullary disease (11%) and thrombocytopenia (7%). Median number of previous lines of therapy was 2 (range 1-10), and 15 pts (50%) were previously exposed to BTK inhibitors (BTKi). The MYD88L265P mutation was detected in all pts, and CXCR4 mutations in 16 (53%). At baseline, median serum IgM was 3,543 mg/dl (range 642-7,970 mg/dl), median bone marrow involvement was 35% (range 4-95%) and median hemoglobin was 10.6 g/dl (range 6.4-13.5 mg/dl). All pts were successfully escalated to target dose of 800 mg. At 6 months, median serum IgM declined to 1,640 mg/dl (range 49-5,220 mg/dl), median bone marrow involvement declined to 5% (range 0-20%) and median hemoglobin increased to 12.6 g/dl (range 10-15.1 g/dl) (p<0.001 for all variables against baseline). At best response, very good partial response (VGPR) was attained in 5 pts (17%), partial response in 11 (37%), minor response in 8 (27%) and stable disease in 6 (20%), for overall response rate of 80% and major response rate of 53%. Major response rate was not statistically different based on relapsed or refractory disease, prior BTKi exposure or CXCR4 mutation status. However, VGPR rate at best response was lower in pts with previous BTKi exposure (7% vs. 27%), and those with CXCR4 mutations (6% vs. 29%). Median time to response (TTR) was 9 weeks and was slower in pts with prior BTKi exposure than in pts without (19 vs. 6 weeks; p=0.02). TTR was not impacted by relapsed vs. refractory disease or CXCR4 mutations. Only one instance of disease progression has been observed thus far, in a patient with MYD88, CXCR4 and TP53 mutations. Grade 4 neutropenia ocurred in 4 pts, who received G-CSG support; ven was dose reduced to 600 mg in 2 pts. Grade 3 adverse events included neutropenia (n=7), anemia (n=2), back pain (n=1), constipation (n=1), diarrhea (n=1), headache (n=1), upper respiratory infection (n=1). One instance of laboratory TLS occurred in a patient with significant extramedullary disease. No clinical TLS was seen. Most common grade 2 adverse events included anemia (n=5), nausea (n=4), neutropenia (n=3). Most common grade 1 adverse events included nausea (n=9), diarrhea (n=6), rash (n=5). No instances of IgM flare were observed, and there have been no deaths.
Conclusion
Our interim results show that venetoclax provides a safe and effective treatment option for pts with symptomatic, previously treated WM, including those previously exposed to BTKi.
Session topic: 20. Indolent Non-Hodgkin lymphoma – Clinical
Keyword(s): Clinical Trial, Targeted therapy, Waldenstrom's macroglobulinemia
Abstract: S854
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 16:30 - 16:45
Location: Victoria Hall
Background
Ven is an oral BCL2 antagonist approved for the treatment of chronic lymphocytic leukemia. However, the role of venetoclax in WM is unknown. Immunophenotypic and genomic sequencing studies have shown that BCL2 is highly expressed and activated in WM cells (Chng Blood 2006; Hunter Blood 2016). In a study of pts with non-Hodgkin lymphoma, ven showed efficacy in 4 pts with WM (Davids J Clin Oncol 2017).
Aims
We initiated a phase II study to evaluate the safety and efficacy of ven monotherapy in previously treated pts with WM (NCT02677324).
Methods
Treatment was given in the outpatient setting and followed a ramp-up of 200 mg daily days 1-7, 400 mg daily days 8-14, then 800 mg daily thereafter, for maximum of 2 years. Pts were closely monitored for tumor lysis syndrome (TLS) during the first 24 hours of each dose escalation. Toxicity was graded per CTCAE v.4.03. Response was assessed based on IWWM6 criteria.
Results
30 pts with symptomatic WM were enrolled. Median follow-up time is 8 months (range 0.2-18 months). Median age was 66 years (range 39-80 years) and 17 pts (57%) were men. Indications to treat were constitutional symptoms (52%), anemia (44%), neuropathy (15%), extramedullary disease (11%) and thrombocytopenia (7%). Median number of previous lines of therapy was 2 (range 1-10), and 15 pts (50%) were previously exposed to BTK inhibitors (BTKi). The MYD88L265P mutation was detected in all pts, and CXCR4 mutations in 16 (53%). At baseline, median serum IgM was 3,543 mg/dl (range 642-7,970 mg/dl), median bone marrow involvement was 35% (range 4-95%) and median hemoglobin was 10.6 g/dl (range 6.4-13.5 mg/dl). All pts were successfully escalated to target dose of 800 mg. At 6 months, median serum IgM declined to 1,640 mg/dl (range 49-5,220 mg/dl), median bone marrow involvement declined to 5% (range 0-20%) and median hemoglobin increased to 12.6 g/dl (range 10-15.1 g/dl) (p<0.001 for all variables against baseline). At best response, very good partial response (VGPR) was attained in 5 pts (17%), partial response in 11 (37%), minor response in 8 (27%) and stable disease in 6 (20%), for overall response rate of 80% and major response rate of 53%. Major response rate was not statistically different based on relapsed or refractory disease, prior BTKi exposure or CXCR4 mutation status. However, VGPR rate at best response was lower in pts with previous BTKi exposure (7% vs. 27%), and those with CXCR4 mutations (6% vs. 29%). Median time to response (TTR) was 9 weeks and was slower in pts with prior BTKi exposure than in pts without (19 vs. 6 weeks; p=0.02). TTR was not impacted by relapsed vs. refractory disease or CXCR4 mutations. Only one instance of disease progression has been observed thus far, in a patient with MYD88, CXCR4 and TP53 mutations. Grade 4 neutropenia ocurred in 4 pts, who received G-CSG support; ven was dose reduced to 600 mg in 2 pts. Grade 3 adverse events included neutropenia (n=7), anemia (n=2), back pain (n=1), constipation (n=1), diarrhea (n=1), headache (n=1), upper respiratory infection (n=1). One instance of laboratory TLS occurred in a patient with significant extramedullary disease. No clinical TLS was seen. Most common grade 2 adverse events included anemia (n=5), nausea (n=4), neutropenia (n=3). Most common grade 1 adverse events included nausea (n=9), diarrhea (n=6), rash (n=5). No instances of IgM flare were observed, and there have been no deaths.
Conclusion
Our interim results show that venetoclax provides a safe and effective treatment option for pts with symptomatic, previously treated WM, including those previously exposed to BTKi.
Session topic: 20. Indolent Non-Hodgkin lymphoma – Clinical
Keyword(s): Clinical Trial, Targeted therapy, Waldenstrom's macroglobulinemia