Background: Frontline therapy of chronic lymphocytic leukemia (CLL) typically consists of a Bruton tyrosine kinase inhibitor (BTKi) and/or BCL2 inhibitor (BCL2i) to which an anti-CD20 monoclonal antibody may be added; however, optimal consensus therapy remains undefined. CD19 is a B-cell surface antigen universally expressed in CLL, and there are no FDA-approved CD19-directed therapies for frontline treatment of CLL at this time. Tafasitamab is a humanized, FC-enhanced anti-CD19 monoclonal antibody which is approved in relapsed/refractory diffuse large B-cell lymphoma and follicular lymphoma; it has also demonstrated clinical efficacy in relapsed/refractory CLL (Staber PB et al, ASH 2019). We hypothesized that tafasitamab and the BTKi zanubrutinib (TaZa) would be safe and effective in untreated CLL; here we report updated results of TaZa.

Methods: This is an ongoing multi-center, phase II investigator-initiated trial with safety lead-in of TaZa in treatment-naïve CLL patients (NCT05718869). Eligibility: patients with CLL requiring treatment per iwCLL criteria with ECOG ≤2, creatinine clearance ≥30 ml/min, absolute neutrophil count ≥1000/mm3 and platelet count ≥75,000/mm3. The primary endpoint is safety/tolerability of TaZa (safety lead-in, 6-12 patients) and complete response (CR) in the overall phase II cohort assessed per iwCLL 2018 criteria. Tafasitamab is given intravenously at a dose of 12 mg/kg on days 1, 4, 8, 15, 22 in cycle 1, weekly in cycles 2-3, every other week in C4-6, and monthly during cycles 7-24. Zanubrutinib 160 mg (DL 1) or 80 mg (DL -1) is given orally twice daily. Each cycle is 28 days. All patients continue for at least 12 cycles in the absence of toxicities. Patients achieving undetectable minimal residual disease (uMRD) status by clonoSEQ in the peripheral blood and bone marrow after 12 or 24 cycles of combination therapy will stop both agents. Patients who remain with detectable MRD after 24 cycles may continue treatment with single-agent zanubrutinib for up to a total of 5 years. The study follows Simon's minimax two-stage design with a total sample size of 25 patients based on a projected CR rate ≥ 30% vs 10% (H0), type I error alpha 9.5% and a power 90%.

Results: 22 patients were enrolled; all were evaluable for safety. Median age was 64 years (range 41-80); 77% were male; Rai stage 0-1 (32%), 2 (32%) and 3-4 (36%). Baseline prognostic characteristics: unmutated IGVH in 12 pts (55%), TP53 alteration in 6 pts (27%) and complex karyotype (defined as 3 or more abnormalities) in 9 pts (41%). The most frequent treatment-related any grade AEs were infusion reactions (77%), neutropenia (59%) and bruising (45%). The most frequent treatment-related G3-4 AEs were neutropenia (32%), infusion reactions (18%) and hypertension (9%). One patient developed atrial fibrillation. Two patients died: one of pulmonary and brain aspergillus, and another from end-stage liver disease due to pre-existing cirrhosis. The median number of cycles received was 17 (range: 2-29). 20 patients were evaluable for response, and the best overall response rate was 85% (17/19) with a CR rate of 25% (5/20). No patients progressed on therapy, and at a median follow-up of 16.4 months among the survivors (range: 1.8-25.8), 18-month PFS/OS was 95%, with median PFS/OS not reached.

Conclusions: Our preliminary results suggest that the combination of tafasitamab and zanubrutinib leads to high overall response rate, including patients with unfavorable prognostic factors. Although generally well tolerated, there was one case of disseminated aspergillus infection leading to death which will be analyzed further. Updated response data with MRD analyses will be presented in the meeting.

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2025
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