High VGPR/CR rates with pirtobrutinib plus venetoclax in previously treated Waldenström macroglobulinemia: Results from a multicenter phase II study Free

Background: BTK inhibitors and BCL2 antagonists, as monotherapy, are highly active and well tolerated in Waldenström macroglobulinemia (WM). However, BTK inhibitor therapy has an indefinite duration with cumulative toxicity or subsequent resistance. Moreover, MYD88 and CXCR4 mutation status impact outcomes to BTK inhibitors. We therefore designed a prospective study evaluating the combination of the non-covalent BTK inhibitor pirtobrutinib and the BCL2 antagonist venetoclax as a fixed-duration regimen in previously treated WM.

Methods: This is an ongoing investigator-initiated, multicenter, prospective phase II study in symptomatic, previously treated WM (NCT05734495). Study therapy is administered in 4-week cycles. Therapy consists of pirtobrutinib at 200 mg/day during cycle 1. Venetoclax is added on cycle 2 at 100 mg/day for one week, then 200 mg/day for one week, then 400 mg/day for two weeks, followed by concurrent pirtobrutinib 200 mg/day and venetoclax 400 mg/day for cycles 3-24. The outcome of interest is the attainment of very good partial response/complete response (VGPR/CR). Responses are assessed using modified IWWM6 criteria. Assumptions include H0 15%, H1 35%, 2-sided alpha 0.03, and power 0.85 for a sample size of 42 patients. The null hypothesis will be rejected if 12 or more patients attain a VGPR/CR.

Results: Between May 2023 and July 2025, 38 patients were enrolled, including 36 MYD88-mutated (MYD88^MUT) and two MYD88-wild-type (MYD88^WT) patients. Twenty-nine patients have completed 6 months on study and are assessable for response. The median study follow-up is 11 months (95% CI 8-18) for all evaluable patients.

For the 27 MYD88^Mut patients, the median number of previous therapies was 1 (range 1-3); 14 (52%) were previously exposed to a covalent BTK inhibitor, of whom 10 had progressed while on therapy, and 15 (56%) had previous rituximab-containing regimens. CXCR4 mutations occurred in 12 (44%), and TP53 mutations in 5 (19%). CR was attained in 3 patients (11%), VGPR in 12 (44%), partial response (PR) in 11 (41%), and minor response (MR) in 1 (4%), for an overall response rate of 100%, and a VGPR/CR rate of 56%. CXCR4 mutations (25% v 87%; p=0.001), TP53 mutations (20% v 68%; p=0.048), and prior covalent BTK inhibitor exposure (43% v 77%; p=0.07) were associated with lower VGPR/CR rates. The median time to VGPR/CR was 5.8 months (95% CI 2.8-NR). CXCR4 mutations (NR v 2.8 months; p=0.003), TP53 mutations (8.8 v 2.8 months; p=0.10), and progression on covalent BTK inhibitor (NR v 2.8 months; p=0.09) were associated with longer median time to VGPR/CR. At best response, the median serum IgM level decreased from 2510 to 239 mg/dl (p<0.001), the median hemoglobin level increased from 9.4 to 12.1 g/dl (p<0.001), and the median bone marrow involvement decreased from 70% to 3% (p<0.001). Of the 11 patients with lymphadenopathy, 10 (91%) had resolution (one was not assessed), and of the three patients with splenomegaly, three (100%) had resolution. The 12-month progression-free survival rate was 94% (95% CI 67-99%), and the 12-month overall survival rate was 100%.

Two MYD88^WT patients treated with the combination attained MR and PR and progressed at 2 and 5 months, respectively. One of these patients died of COVID-19 after progressing on study therapy and having received a subsequent treatment; the death was considered unrelated to study therapy. These findings prompted a protocol amendment for the inclusion of only MYD88^MUT patients.

The most common grade ≥3 adverse events were neutropenia (37%), of which one event (4%) was grade 4, anemia (19%), thrombocytopenia (11%), respiratory infections (11%), diarrhea (7%), and headache, AST increase, myalgia, and fatigue (4% each). All neutropenia events were reversible, and there were no events of febrile neutropenia. There have been no arrhythmia or tumor lysis events thus far.Conclusion: Based on the statistical assumptions, the present prospective multicenter Phase II study evaluating pirtobrutinib and venetoclax in previously treated WM has met its primary endpoint with a VGPR/CR rate of 56% in the 27 MYD88^MUT patients who have completed 6 months on study. Limited activity was seen in MYD88^WT patients. No unexpected toxicities were observed, and study therapy was well tolerated. Fixed-duration pirtobrutinib and venetoclax represent a new option to treat patients with relapsed or refractory MYD88^MUT WM.