Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
Methods: This was an investigator-initiated, multicenter, prospective phase II study in symptomatic, previously treated WM patients (ClinicalTrials.gov ID NCT05734495). Study therapy was given in 4-week cycles. Intended therapy consists of pirtobrutinib at 200 mg/day on cycle 1. Venetoclax is added on cycle 2 at 100 mg/day for one week, 200 mg/day for one week, and 400 mg/day for two weeks, followed by pirtobrutinib 200 mg/day and venetoclax 400 mg/day given together for cycles 3-24. Patients undergo baseline laboratory studies, a bone marrow biopsy with MYD88, CXCR4, and TP53 genotyping, and CT scans of the chest, abdomen, and pelvis to evaluate extramedullary disease. The outcome of interest was attaining a very good partial response (VGPR) or better. Responses are assessed using modified IWWM6 criteria. Assumptions included 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 or better. For this interim analysis, if 3 VGPR or better events or fewer were observed in the first 16 patients, the study should be stopped early because of futility, with a probability of stopping early of 79%.
Results: Between May 2023 and June 2024, 16 (8 males; 8 females) patients have been enrolled. Baseline characteristics include median age 67 (range 57-76 years), median number of previous therapies 1 (range 1-3), previous covalent BTK inhibitor 9 (56%), previous rituximab-containing regimens 11 (69%), median serum IgM 2,401 (range 551-7,249 mg/dL), median hemoglobin 8.6 (range 6.6-11.5 g/dL), median bone marrow involvement 80% (20-90%), lymphadenopathy (>1.5 cm) 7 (44%), and splenomegaly (>15 cm) 2 (13%). MYD88 L265P was detected in 14 patients (88%), CXCR4 mutations in 6 (38%), and TP53 mutations in 1 (6%).
The median study follow-up is 6 months (range 3-12). VGPR was attained in 9 patients (56%), partial response in 5 (31%), and minor response in 2 (13%), for an overall response rate of 100%. No complete responses were observed. CXCR4 mutations (33% v 70%; p=0.35) and previous exposure to covalent BTK inhibitors (33% v 86%; p=0.05) might be associated with lower VGPR rates. The median time to VGPR was 1.9 months (95% CI 0.9-2.2). CXCR4 mutations (p=0.32) and previous exposure to covalent BTK inhibitors (p=0.50) did not seem to impact time to VGPR. At best response, median serum IgM decreased to 254 (range 35-3786 mg/dl; p<0.001), median hemoglobin increased to 12.1 (range 8.2-16.2 g/dl); p<0.001), and median bone marrow involvement decreased to 0% (range 0-40%; p<0.001) when compared to baseline. Of the seven patients with lymphadenopathy, 5 (71%) had improvement or resolution, and of the two patients with splenomegaly, 2 (100%) had improvement or resolution. Two patients had disease progression at two and five months; both had MYD88 WT disease. The 6-month progression-free survival rate is 84% (95% CI 49-96%), and the 6-month overall survival rate is 93% (95% CI 61-99). There have been no arrhythmia events thus far.
Conclusion: The combination of pirtobrutinib and venetoclax appears active in symptomatic, previously treated WM patients with a VGPR rate of 56%, exceeding the futility rate. CXCR4 mutations and previous exposure to covalent BTK inhibitors might impact VGPR rates. Accrual will continue to enroll 26 additional patients.
Disclosures: Castillo: Cellectar Biosciences: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy; Mustang Bio: Consultancy. Sarosiek: ADC Therapeutics: Research Funding; Cellectar Biosciences: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Branagan: Adapative: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Genzyme: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding. von Keudell: AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Merck: Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy. Treon: Eli Lilly: Research Funding; Parexel: Honoraria, Research Funding; AbbVie/Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene, Inc.: Honoraria, Research Funding.
OffLabel Disclosure: Pirtobrutinib is not FDA-approved or NCCN-endorsed to treat Waldenstrom macrolgobulinemia.