San Diego, California—Venetoclax is well-tolerated and produces high levels of response of patients with previously treated Waldenström macroglobulinemia (WM), according results from a recent phase 2 clinical trial.

These findings were presented by Jorge J. Castillo, MD, Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, at the 2018 ASH Annual Meeting.

“Gene expression and transcriptome studies have shown that BCL2 is highly expressed in WM cells, particularly in patients with activating MYD88 mutations,” explained Jorge J. Castillo, MD, and colleagues.

Venetoclax, a BCL2 inhibitor, showed efficacy in a phase 1 dose-finding study, which led Dr Castillo and colleagues to conduct a phase 2 study to evaluate the efficacy and safety of venetoclax monotherapy in previously treated patients with WM.

The trial enrolled a total of 30 patients with symptomatic WM (median age, 66 years), with a median of 2 previous therapies. Of these patients, 15 had previously received a Bruton’s tyrosine kinase (BTK) inhibitor. Indications for treatment included constitutional symptoms (52%), anemia (44%), peripheral neuropathy (15%), extramedullary disease (11%), and thrombocytopenia (7%). All patients in the study carried the MYD88L265P mutation; 16 also had a CXCR4 mutation.

Venetoclax was administered as outpatient therapy and followed with a ramp-up of 200 mg daily on days 1 through 7, 400 mg daily on days 8 through 14, and 800 mg daily for a maximum of 2 years. Patients were closely monitored for tumor lysis syndrome during the first 24 hours of each dose escalation.

At baseline, the median serum IgM was 3543 mg/dL, median bone marrow involvement was 35%, and media hemoglobin was 10.6 g/dL. All patients successfully escalated to the target dose of 800 mg.

At 6 months, the median serum IgM levels declined to 1750 mg/dL, median bone marrow involvement declined to 5%, and median hemoglobin increased to 12.4 g/dL. At best response, very good partial response was attained in 5 (17%) patients, partial response in 19 (63%), minor response in 2 (7%) and stable disease in 4 (13%), for an overall response rate of 87% and major response rate of 80%. 

Patients with refractory disease showed a lower major response rate (57%) compared with those who had relapsed disease (95%). Very good partial response rates were lower in patients who had previously received BTK inhibitors (7%) than in those who had not (27%), as well as in patients with a CXCR4 mutation (6%) versus those without the mutation (29%).

The median time to response was 9 weeks in patients who previously received BTK inhibitors versus 6 weeks in those without previous BTK inhibitor exposure. according to Dr Castillo and colleagues, the time to response was not affected by relapsed/refractory disease or CXCR4 mutation status.

A total of 2 patients had disease progression during therapy—1 at 8 months and 1 at 10 months; no clinical tumor lysis syndrome was reported.

Laboratory tumor lysis syndrome occurred in 1 patient with significant extramedullary disease and grade 4 neutropenia occurred in 4 patients. Grade 3 adverse events included neutropenia (n = 7), anemia (n = 2), back pain (n = 1), constipation (n = 1), diarrhea (n = 1), headache (n = 1), and upper respiratory infection (n = 1). Grade 2 adverse events included anemia (n = 5), nausea (n = 4), neutropenia (n = 3). Grade 1 advere events included nausea (n = 9), diarrhea (n = 6), and rash (n = 5).

Dose reductions had to be given to 2 patients because of adverse events. No instances of IgM flare were observed, and no deaths have been reported.

“The findings show that venetoclax is well tolerated, and produces high levels of response in patients with symptomatic, previously treated WM, including patients previously exposed to BTK-i [inhibitor]. Prior BTK-i exposure and presence of CXCR4 mutations impacted VGPR response attainment,” Dr Castillo and colleagues concluded.—Janelle Bradley

Castillo JJ, Gustine J, Meid K, et al. Multicenter Prospective Phase II Study of Venetoclax in Patients with Previously Treated Waldenstrom Macroglobulinemia. Presented at: the 60th ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 2888.