Venetoclax Safe and Highly Active for Previously Treated Waldenström Macroglobulinemia

Venetoclax (Venclexta) as a treatment for patients with previously treated Waldenström macroglobulinemia appeared to be safe and highly active, including for those previously treated with a Bruton tyrosine kinase (BTK) inhibitor, according to results from a phase 2 study (NCT02677324) published in the Journal of Clinical Oncology.¹

The overall response rate (ORR) among patients receiving venetoclax was 84% (95% CI, 66%-95%) and the major response rate was 81% (95% CI, 63%-93%). The ORR included a very good partial response rate (VGPR) of 19%, a partial response (PR) rate of 61%, and minor response rate of 3%. No complete responses were observed.

“Currently, the main treatment options for patients with this disease are chemotherapy or…proteasome inhibitors, in combination with monoclonal antibodies, or…BTK inhibitors,” lead author Jorge Castillo, MD, clinical director of the Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute, said in a press release.² “While these therapies are highly effective, they’re each associated with undesirable [adverse] effects [AEs]: chemotherapy, with nausea, hair loss, fatigue, secondary leukemia, and others; BTK inhibitors, with hypertension, heart arrhythmia, and bleeding. BTK inhibitors also need to be taken indefinitely.”

Previously treated patients with a Waldenström macroglobulinemia diagnosis, ECOG performance score of 2 or less, and adequate bone marrow function were eligible for the study.

For the first 6 patients, venetoclax was given daily at a dose of 200 mg orally for 1 week, followed by 400 mg for 1 week, and then 800 mg for 2 years. The remaining patients received the same dosing without the first week of 200 mg. An additional patient started with a 400 mg dose for one week and an 800 mg dose for 2 years.

The primary end point of the study was ORR, and secondary end points included major response rate, time to response, duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and safety.

A total of 33 patients enrolled on the study, 1 of whom was excluded from the analysis population. The median age at diagnosis was 58 years (range, 38-72) and 66 year (range, 39-80) at venetoclax treatment initiation. The majority of patients were male (56%), and the median number of prior therapies received by patients was 2 (range, 1-10).

ORR was lower among patients with refractory disease (60%) compared with relapsed disease (95%; P = .03). It was also lower among those who received 3 or more prior lines of therapy (63%) vs less than 3 lines of therapy (95%; P =.04). The median time to a minor response for patients was 1.9 months (95% CI, 1.1-2.1) and the median time to a major response was 5.1 months (95% CI, 4.7-8.2).

At a median follow-up of 33 months, 19 patients from the study had progressed. Investigators reported a median PFS of 30 months (95% CI, 27-38). The 12- and 24-month PFS rates in this population were 83% (95% CI, 64%-93%) and 80% (95% CI, 60%-90%), respectively.

Among the 19 patients who achieved a PR, the median DOR was 34 months (95% CI, 29-37). Moreover, the median DOR was 37 months (95% CI, 10–not evaluable) for the 6 patients who achieved a VGPR.

In terms of safety, 22% of patients undergoing treatment with venetoclax had dose reductions due to neutropenia (n = 2), pancytopenia (n = 1), fatigue (n = 1), diarrhea (n = 1), multiple grade 2 events (n = 1), and self-reduced dosing (n = 1). Grade 2 or higher AEs were observed in 94% of patients, with grade 4 AEs seen in 7 patients which included neutropenia (n = 6) and febrile neutropenia (n = 1).

“Venetoclax is safe and highly active in patients with previously treated Waldenström macroglobulinemia, including those previously treated with BTK inhibitors. CXCR4 mutation status did not affect treatment response. The optimal duration of venetoclax therapy in Waldenström macroglobulinemia is yet to be determined,” the investigators concluded.

References

1. Castillo JJ, Allan JN, Siddiqi T, et al. Venetoclax in previously treated Waldenström macroglobulinemia. J Clin Oncol. 2022;40(1):63-71. doi:10.1200/JCO.21.01194
2. Venetoclax shown to benefit patients with Waldenström Macroglobulinemia, including some who relapsed after previous therapy. News release. Dana-Farber Cancer Institute. November 18, 2021. Accessed January 17, 2022. https://tinyurl.com/bdhhv7th