Time-Limited Zanubrutinib/Rituximab Yields Durable Remissions in Treatment-Naive CLL

Time-limited therapy with zanubrutinib (Brukinsa) plus rituximab (Rituxan) was safe and generated durable remissions in patients with treatment-naive chronic lymphocytic leukemia (CLL), according to findings from an early analysis from an ongoing phase 2 trial (NCT04458610) presented at the 2024 ASH Annual Meeting.1

At a median follow-up of 24 months, 21 of 23 enrolled patients remain on the study. One patient discontinued treatment early due to disease recurrence with isolated periorbital lymphadenopathy that was histologically confirmed as CLL after stopping treatment; and 1 patient was taken off the study due to requiring treatment for Merkel cell carcinoma. At a median follow-up of 13 months after discontinuation of zanubrutinib/rituximab, 10 patients remained off therapy and in remission. Three patients had experienced disease progression, and 1 patient required retreatment.

“This early analysis indicates that time-limited therapy with zanubrutinib and rituximab is well tolerated and induces durable remissions,” Jan A. Burger, MD, PhD, and coauthors wrote on the poster. “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.”

Burger is a professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Zanubrutinib Background and Phase 2 Trial Design

In 2023, the FDA approved zanubrutinib, a covalent BTK inhibitor, for the treatment of patients with CLL or small lymphocytic lymphoma, based on findings from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials.2 The agent is commonly administered as continuous monotherapy until disease progression or unacceptable toxicity.1 However, the phase 2 study evaluated zanubrutinib as a time-limited therapy with rituximab, an anti-CD20 antibody, as an alternative to long-term BTK inhibitor monotherapy.

The trial enrolled patients with treatment-naive CLL with an indication for treatment per the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and an ECOG performance status of 0 to 2.3

Eligible patients are treated with zanubrutinib at 160 mg orally twice daily and rituximab at 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2 to 6; each cycle lasted 28 days.1 Of note, patients who achieve a complete remission (CR) per iwCLL criteria following 6 cycles of zanubrutinib/rituximab can continue on to receive zanubrutinib monotherapy for another 6 cycles. Patients who achieve partial remission (PR) or stable disease (SD) after 6 cycles continue with another 6 cycles of zanubrutinib/rituximab. Subsequently, patients who achieve a CR following 12 cycles of zanubrutinib/rituximab can continue on to 6 cycles of zanubrutinib monotherapy and stop therapy after a total of 18 cycles. Those who have PR or SD following 12 cycles continue zanubrutinib monotherapy for another 12 cycles and stop treatment after receiving 24 total cycles. After treatment discontinuation, patients are transitioned to observation and can continue to receive treatment if they experience relapse and meet iwCLL criteria for beginning salvage therapy.

The primary end point is to determine the proportion of patients who achieve treatment-free remission 6 months after discontinuation of zanubrutinib; secondary end points include determining the length of treatment-free remission, identifying clinical factors associated with long-lasting remissions, and evaluating the efficacy of retreatment with zanubrutinib/rituximab in patients who experience relapse.

Patient Baseline Characteristics

Among all patients in the phase 2 study, the median age was 68 years (range, 41-82), and most were male (61%). Patients had low-risk (13%), intermediate-risk (48%), and high-risk (39%) disease per Rai classification; IGHV status included unmutated (39%), mutated (57%), and unknown (4%). The rates of cytogenetics—deletion 17p (del(17p)), del(11q), trisomy 12, normal, del(13q), and unknown— by fluorescence in situ hybridization (FISH) were 0%, 22%, 22%, 17%, 35%, and 4%, respectively. The median β2-microglobulin level was 3.9 mg/L (range, 2.3-6.8); β2-microglobulin levels of at least 4 mg/L were seen in 39% of patients. The median absolute lymphocyte count (ALC) was 49.88 K/μL (range, 1.54-230.95).

Additional Data

Thirteen patients completed therapy after 12 cycles (n = 1), 18 cycles (n = 1), and 24 cycles (n = 11). Sixteen months after treatment discontinuation, 5 patients with mutated IGHV and del(13q) had a bone marrow (BM) minimal residual disease (MRD) level of 2.78 at end of treatment (EOT), a peripheral blood (PB) MRD level of 3.56 at EOT, and a PB MRD level of 11.80 at 12 months post-treatment. At 18 months following treatment discontinuation, 6 patients with mutated IGHV and del(13q) had a BM MRD level of 19.10 at EOT, a PB MRD level of 9.20 at EOT, and a PB MRD level of 4.10 at 12 months post-treatment. Twenty months after treatment discontinuation, 7 patients with mutated IGHV and normal cytogenetics had a BM MRD level of 0.26 at EOT. At 25 months after treatment discontinuation, 2 patients with unmutated IGHV and del(13q) per FISH analysis had a BM MRD level of 14.70 at EOT, a PB MRD level of 16.70 at EOT, and a PB MRD level of 5.01 at 12 months post-treatment.

One patient with mutated IGHV and del(13q) had a the time to progression (TTP) of 11 months after treatment discontinuation; this patient experienced an asymptomatic increase in ALC levels to 8.39 K/μL and had a BM MRD level of 27.00 at EOT. Three patients with unmutated IGHV and trisomy 12 had a TTP of 13 months after treatment discontinuation; these patients experienced extranodal relapses with a BM MRD level of 1.59 at EOT, and their next treatment was acalabrutinib (Calquence). Four patients with mutated IGHV and del(11q) had a TTP of 15 months after treatment discontinuation; these patients experienced an asymptomatic increase in lymph node size and BM relapse from 0% to 4% cellularity and had a BM MRD level of 0.20 at EOT.

Of note, the 2-year Kaplan-Meir estimates of progression-free survival and overall survival rates were both 100%. At 6 cycles, 23 patients were evaluable for response assessment per 2018 iwCLL criteria; 21 patients were evaluable at 12 cycles; and 12 patients were evaluable after 24 cycles. The median level of BM infiltration by CLL cells declined from 82.90% at baseline to 2.10% at EOT, with 1 patient achieving undetectable MRD levels.

References

1. Burger JA, Kim E, Jayachandran G, et al. Time-limited therapy with zanubrutinib plus rituximab in patients with treatment-naive chronic lymphocytic leukemia: early results of an ongoing phase II trial. Blood. 2024;144(suppl 1):4631. doi:10.1182/blood-2024-198701
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 13, 2023. Accessed February 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. Zanubrutinib and rituximab for the treatment of previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. ClinicalTrials.gov. Updated February 4, 2025. Accessed February 21, 2025. https://clinicaltrials.gov/study/NCT04458610