Time-Limited Therapy with Zanubrutinib Plus Rituximab in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia: Early Results of an Ongoing Phase II Trial

Introduction: The covalent Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib is approved for treatment of chronic lymphocytic leukemia (CLL). It induces durable remissions in most patients with CLL, and is generally administered as continuous monotherapy, until disease progression or toxicity prohibits further use. As an alternative to long-term BTKi monotherapy we designed a phase II study of time-limited therapy with zanubrutinib in combination with anti-CD20 antibody rituximab. Here, we report early results from the first 23 treatment-naïve patients with CLL enrolled in this ongoing trial (NCT04458610).

Methods: Patients with treatment-naïve CLL requiring therapy per iwCLL criteria receive zanubrutinib 160 mg orally twice daily and rituximab (375 mg/m² intravenously) on days 1, 8, 15, 22 of cycle 1, and then on day 1 of cycles 2 - 6 (each cycle is 28 days). Patients who achieve a complete remission (CR) by iwCLL 2018 criteria after 6 cycles of the combination therapy continue with zanubrutinib alone for another 6 cycles. Patients who achieve a partial remission (PR) or stable disease (SD) after 6 cycles continued with another 6 cycles of the combination therapy. Patients who achieve a CR after 12 cycles received 6 additional cycles of zanubrutinib alone, and then stopped treatment after a total of 18 cycles. Patients who achieve a PR or SD after 12 cycles continued zanubrutinib alone for another 12 cycles and stopped therapy after a total of 24 cycles. After treatment discontinuation, patients transitioned to observation and can resume therapy if they relapse and meet iwCLL criteria for starting salvage therapy. The primary objective of the trial is to determine the proportion of patients who have treatment-free remission 6 months after discontinuation of zanubrutinib. Secondary objectives are to determine the length of treatment-free remission, identify clinical factors associated with long lasting remissions, and to evaluate the efficacy of re-treatment with zanubrutinib plus rituximab in patients who relapse.

Results: The median age of patients was 68 years (range, 41 – 82 years), 39% had unmutated IgHV and 39% had advance stage disease (RAI stage III and IV). The baseline absolute lymphocyte count (ALC) and β2 microglobulin were 49.9 x 10⁹/L (range, 1.54 – 230.96 x 10⁹/L) and 3.9 mg/L (range, 2.3 – 6.8 mg/L), respectively. After a median follow-up of 19 months, all patients are alive, and the estimated two-year progression-free (PFS) and overall survival (OS) is 100%. Two patients came off study, one due to disease recurrence with isolated periorbital lymphadenopathy histologically confirmed as CLL 13 months after stopping therapy, and one due to requiring treatment for another cancer (Merkel cell carcinoma). The overall response rate is 100% in evaluable patients, with 24% CR and 76% PR as best response (n=22). The median levels of measurable residual disease (MRD) in the bone marrow quantified by flow cytometry declined from 82.90% at baseline (range, 25.80 – 93.20%) to 2.60% at end of therapy (range, 0.20 – 41.40%, p<0.0001).

Eleven patients have completed therapy (1 patient after 12 cycles, 1 after 18 cycles, 9 patients after 24 cycles) and transitioned to observation. With a median follow-up of 13 months after treatment discontinuation, 8 patients remain in remission, 3 patients experienced disease relapse, but only one required retreatment.

Conclusion: This early analysis indicates that time-limited therapy with zanubrutinib and rituximab is well tolerated and induces remissions. This therapy is also associated with a reduction in MRD levels in the bone marrow. After a median follow-up of 13 months after therapy discontinuation, 8/11 (73%) of patients remain off therapy and in remission. Longer follow-up in more patients is needed to determine the durability of responses after therapy discontinuation and to identify characteristics that predict longer responses after time-limited therapy with zanubrutinib and rituximab.