High Response Rate With Venetoclax in Previously Treated Patients With Waldenström’s Macroglobulinemia

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In a phase II study reported in the Journal of Clinical Oncology, Castillo et al found that venetoclax produced a high major response rate in previously treated patients with Waldenström’s macroglobulinemia.

As stated by the investigators, “BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström’s macroglobulinemia. Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of Waldenström’s macroglobulinemia cells. The activity of venetoclax in Waldenström’s macroglobulinemia remains to be clarified.”

Study Details

The study enrolled 32 evaluable patients at four U.S. centers between June 2016 and February 2018. The first six patients received venetoclax at 200 mg once daily for 1 week, at 400 mg for 1 week, and then at 800 mg for 2 years. The remaining patients received 400 mg once daily for 1 week followed by 800 mg for 2 years.

All patients had a MYD88 L265P mutation, 17 had a CXCR4 mutation, and 16 had prior exposure to BTK inhibitors. Data cutoff was at the end of December 2020.


Median follow-up was 33 months (range = 24–38 months). Partial response was observed in 19 patients (61%), very good partial response was seen in 6 patients (19%), and minor response occurred in 1 patient (3%), yielding an overall response rate of 84% (95% confidence interval [CI] = 66%–95%) and a major response rate of 81% (95% CI = 63%–93%). No complete responses were observed. Median durations of response were 34 months (95% CI = 29–37 months) among patients with partial response and 37 months (95% CI = 10 months–not evaluable) in those with very good partial response; duration of response was 9 months in the patient with minor response.


  • Venetoclax produced a major response rate of 81%.
  • CXCR4 mutation status did not affect treatment response rate.

No difference in overall response was observed for CXCR4 wild-type vs mutant status (86% vs 82%, P = .60). The major response rate was lower in those with refractory vs relapsed disease (50% vs 95%, P = .007). Median times to major response were longer in patients with previous BTK inhibitor exposure (8.5 vs 4.4 months, P < .001), those with three or more prior lines of therapy (10.8 vs 4.8 months, P = .03), and those with refractory vs relapsed disease (8.2 vs 4.7 months, P = .007).

Median progression-free survival was 30 months (95% CI = 27–38 months), with 12- and 24-month rates of 83% and 80%. No difference in progression-free survival was observed for CXCR4 wild-type vs mutant status (P = .60). Median time to next treatment was not reached; the 30-month rate without subsequent therapy was 76%. All patients were alive at data cutoff, with a 30-month overall survival rate of 100%.

Adverse Events

The most common grade 2 to 4 adverse events were neutropenia (53%), anemia (25%), and lymphopenia (19%). Neutropenia was the only grade ≥ 3 treatment-related adverse event, occurring in 14 patients (45%); 1 patient had febrile neutropenia.

Treatment was discontinued due to pancytopenia in one patient. Adverse events led to 21 cases of treatment interruption in 14 patients, most commonly neutropenia (n = 6) and infections (n = 4). No paradoxical IgM flare, secondary myeloid neoplasms, aggressive transformation, peripheral neuropathy, cardiac arrhythmia, or clinical tumor lysis syndrome were observed.

The investigators concluded: “Venetoclax is safe and highly active in patients with previously treated Waldenström’s macroglobulinemia, including those who previously received BTK inhibitors. CXCR4 mutation status did not affect treatment response.”

Jorge J. Castillo, MD, of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by AbbVie. For full disclosures of the study authors, visit

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