Zanubrutinib Plus R-CHOP (ZR-CHOP) in Non-Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma Patients Who Were Positron Emission Tomography-Positive after Two Cycles of R-CHOP: A Single-Arm, Open-Label, Multicenter Prospective Study

Background: R-CHOP is a standard treatment for previously untreated diffuse large B-cell lymphoma (DLBCL), however, more than one-third of patients are not cured by R-CHOP. There is a clear need to improve the prognosis of patients, especially for those with factors associated with poor prognosis, such as non-germinal center B-cell-like (non-GCB) subtype and positive interim positron emission tomography (PET). Bruton's tyrosine kinase inhibitors (BTKi) have established therapeutic activity in B-cell malignancies, with modest activity in DLBCL. Zanubrutinib, a potent and selective BTKi, was evaluated in patients with relapsed or refractory (R/R) non-GCB DLBCL. Zanubrutinib showed minimized off-target activities against interleukin-2-inducible T cell kinase (ITK) and reduced interference of ITK-mediated, rituximab-induced, antibody-dependent cellular cytotoxicity. Therefore, ZR-CHOP is a potentially effective regimen. Aim: We designed a treatment escalation regimen with ZR-CHOP, followed by zanubrutinib maintenance, for non-GCB DLBCL patients who were PET positive after two cycles of R-CHOP (ChiCTR2100054552). Here, we report the preliminary results from this ongoing perspective trial. Methods: Patients with non-GCB DLBCL who were PET positive (Deauville scores 4 or 5) after two cycles of R-CHOP were enrolled. Patients with PET negative or PD were excluded. Patients received ZR-CHOP in a 21-day cycle for 6 cycles (induction), followed by zanubrutinib monotherapy as maintenance up to 6 months for patients who achieved PR or CR. Zanubrutinib was administered orally twice daily at 160 mg. The primary endpoint was 2-year event-free survival (EFS) from start of RCHOP treatment, defined as disease progression, relapse from CR, initiation of subsequent systemic antilymphoma therapy for either PET-positive or biopsy-proven residual disease upon completion of at least 6 cycles of R-CHOP therapy, or death, whichever occurred first. Secondary endpoints included overall remission rate (ORR), complete remission rate (CRR), response improvement rate (defined as the proportion of patients whose response was improved from PR to CR or from SD to CR or PR during ZR-CHOP induction), and safety. Results: As of June 26, 2024, a total of 28 patients were enrolled and treated. The median age of patients was 59.0 (range, 40-79), 53.6 % were male, and 32.1% had ECOG PS of ≥2. A total of 78.6% of patients were stage III-IV; 32.1% had double-expressor lymphoma; most had extra-nodal involvement (82.2%). Eight (28.6 %) patients had an international prognostic index score of ≥3. After a median follow-up of 11.0 months (range 5.3-26.8), 24 (85.7%) patients were efficacy evaluable, with a median of 6 (range, 1-6) induction cycles. The ORR after 2 cycles of ZR-CHOP was 91.7% (22/24). Among 14 patients who completed 6-cycle ZR-CHOP, 12 out of them attained response (8 CRs, 4 PRs), rendering an ORR of 85.7% and CRR of 57.1%. Three patients experienced PD before the completion of induction therapy. Response improvement rate during induction therapy was 50.0% (12/24; 95% CI, 29.1-70.9), with 75% (9/12) achieving response improvement after 2 cycles of ZR-CHOP. As of data cut-off, 13 patients received maintenance treatment, only 1 patient had disease progression during maintenance treatment. Of the 28 patients in the safety population, 26 patients (92.9%) experienced any-grade treatment emergent adverse events (TEAEs), with the majority being hematological toxicities: the most common (≥20%) events were white blood cell decreased (any grade, 71.4%; grade 3-4, 53.6%), neutrophil count decreased (60.7%; 50.0%), platelet count decreased (39.3%; 7.1%), and anemia (21.4%; 3.6%). The most common grade 3-4 non-hematological toxicities were febrile neutropenia occurred in 2 patients, infection in 4 patients (2 lung infection, 1 sepsis, 1 urinary tract infection). Remarkably, no cardiovascular events or hypertension at any grade occurred. Only 2 patients had grade 2 bleeding. One patient experienced grade 2 COVID-19 pneumonia during the pandemic. No grade 5 TEAE was reported. Conclusions: Our results showed that ZR-CHOP was a safe and effective scheme for non-GCB DLBCL patients who were PET positive after two-cycle R-CHOP. It indicates that adding zanubrutinib to escalate the treatment under the guidance of dynamic PET-CT can improve the remission of these patients without significantly increasing toxicity.