Responses to Zanubrutinib Monotherapy Continue and Deepen in CLL, Updated Results Show

With longer follow-up, significant responses were still observed with the BTK inhibitor zanubrutinib as a single agent in patients with relapsed or refractory chronic lymphocytic leukemia in the phase 2 BGB-3111-205 trial.

With longer follow-up, significant responses were still observed with the BTK inhibitor zanubrutinib (Brukinsa) as a single agent in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) in the phase 2 BGB-3111-205 trial (NCT03206918).1

At 34 months of follow-up (range, 0.8-41.4), the BTK inhibitor elicited an objective response rate (ORR) of 87.9% per independent review committee (IRC) assessment in patients with relapsed/refractory CLL (n = 80/91), according to results presented during the European Hematology Association 2021 Virtual Congress.

Moreover, 6.6% of patients (n = 6) achieved a complete response (CR) as their best response to treatment, 69.2% (n = 63) experienced a partial response (PR), and 12.1% (n = 11) had a PR with lymphocytosis. Three patients achieved stable disease, 3 had progressive disease, and 2 were not determined to be evaluable. A total of 3 patients discontinued treatment before their first post-baseline assessment.

Notably, responses were found to deepen over time, and the ORR proved to be consistent across all subgroups evaluated. Specifically, patients who harbored del(17p) and/or TP53 mutation and del(11q) experienced ORRs of 91% (95% CI, 70.8%-98.9%) and 100% (95% CI, 83.2%-100%), respectively.

“Results with longer follow-up continue to show a deeper response in more patients, including those with prolonged lymphocytosis at a data cutoff with a median of 15 months of follow-up,” lead study author Wei Xu, MD, PhD, of The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, and colleagues, wrote in a poster. “Two-thirds of patients were still benefitting from continuous zanubrutinib treatment at the time of data cutoff.”

In November 2019, the FDA granted an accelerated approval to the BTK inhibitor for use in adult patients with mantle cell lymphoma (MCL) who had previously received at least 1 therapy.2 In June 2020, China’s National Medical Products Administration approved zanubrutinib for use in adult patients with CLL and SLL who had previously received at least 1 therapy, as well as for adult patients with MCL who have received at least 1 therapy.3

In the single-arm, multicenter, phase 2 trial, investigators set out to evaluate the safety and efficacy of zanubrutinib in Chinese patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL). Long-term data of the study were presented at the virtual congress.

To be eligible for enrollment, patients needed to be at least 18 years of age, have had relapsed or refractory disease following at least 1 previous line of standard chemotherapy regimen, measurable disease, an ECOG performance status of 0 to 2, as well as acceptable renal and liver function.4

If they had a history or evidence of central nervous systemic lymphoma, previously received a BTK inhibitor, had clinically significant cardiovascular disease or a myocardial infarction, cerebrovascular accident, or intracranial hemorrhage within the prior 6 months, they were excluded. Patients also could not have undergone allogeneic hematopoietic stem cell transplant.

Study participants were given zanubrutinib at a twice-daily dose of 160 mg in 28-day treatment cycles until either progressive disease or intolerable toxicity.

The primary end point of the trial was ORR per IRC assessment and International Workshop on CLL guidelines or the Lugano Classification for SLL; secondary end points comprised duration of response (DOR), progression-free survival (PFS), and safety.

A total of 91 patients were enrolled to the trial and included in the analysis. The median age of participants was 61 years (range, 35-87), 57.1% were male, and 69.2% had advanced-stage disease. Almost 54% (53.8%) of patients had an ECOG performance status of either 1 or 2, and 74.7% had beta-2 microglobulin that was greater than 3.5 mg/L.

Moreover, 74.7% of patients previously received an alkylating agent like bendamustine, 57.1% had received a purine analog, and 59.3% had received a CD20 antibody. The median number of prior lines of treatment was 1 (range, 1-9), and 79.1% of patients were refractory to their last therapy.

Regarding molecular risk, 24.2% harbored a TP53 mutation and/or 17p deletion, 56.0% had IGHV unmutated disease, 22.0% had a 11q deletion, 45.1% had a 13q deletion, and 23.1% had trisomy 12.

Earlier data showed that at a median follow-up of 15.1 months, the ORR had been 84.6% (n = 77) among 91 evaluable patients. At that time point, 3.3% achieved a CR with the BTK inhibitor, 59.3% experienced a PR, and 22.0% had a PR with lymphocytosis.2 The estimated 12-month event-free rate for DOR was 92.9%.

Additional data shared in the updated analysis showed that prolonged lymphocytosis during treatment with zanubrutinib did not indicate a suboptimal PFS.

After 34 months of follow-up the safety findings with the agent were noted to be consistent with what has previously been observed. Of the 91 evaluable patients, all experienced toxicities of any grade, and 83.5% experienced adverse effects (AEs) that were grade 3 or higher. A little more than half, or 51.6%, of patients reported serious AEs with the agent.

Moreover, 46.2% and 8.8% of patients experienced toxicities that resulted in dose interruptions or reductions, respectively. A total 15.4% experienced AEs that resulted in treatment discontinuation.

Six patients experienced a toxicity that resulted in death; 2 of these patients had pneumonia, 1 had cardiopulmonary failure, 1 had brain herniation, 1 had multiple organ dysfunction syndrome, and 1 had cardiac failure, pneumonia, and respiratory failure.

Treatment-emergent AEs that were reported in at least 20% of study participants included decreased neutrophil count (grade 1/2, 27.4%; grade ≥3, 49.5%), upper respiratory tract infection (grade 1/2, 43.9%; grade ≥3, 12.1%), decreased platelet count (34.1%; 8.8%), hematuria (grade 1/2, 42.9%), anemia (24.2%; 11.0%), pneumonia (13.2%; 24.2%), purpura (grade 1/2, 34.1%), hypokalemia (23.1%; 7.7%), hyperglycemia (grade 1/2, 28.6%), cough (24.2%; 1.1%), decreased white blood cell count (17.6%; 7.7%), increased carbon dioxide (grade 1/2, 25.3%), and diarrhea (grade 1/2, 22.0%).

Toxicities of special interest included anemia (all grade, 39.6%; grade ≥3, 11.0%), hemorrhage (72.5%; 1.1%), major hemorrhage (2.2%; 1.1%), hypertension (12.1%; 3.3%), infections (89.0%; 46.2%), neutropenia (78.0%; 50.5%), second primary malignancies (5.5%; 5.5%), and thrombocytopenia (52.7%; 16.5%).

“Data support the tolerability of long-term zanubrutinib treatment in relapsed/refractory CLL/SLL, with no new safety signals identified,” the study authors concluded.


1. Xu W, Yang S, Zhou K, et al. Zanubrutinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: 34-month follow-up results. Presented at: European Hematology Association 2021 Virtual Congress; June 9-19, 2021; virtual. Abstract EP639.

2. BeiGene announces the approval of Brukinsa (zanubrutinib) in China for patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed/refractory mantle cell lymphoma. News release. BeiGene. June 3, 2020. Accessed June 11, 2021.

3. FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage. News release. FDA. November 14, 2019. Accessed June 11, 2021.

4. Xu W, Yang S, Zhou K, et al. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm multicenter study. J Hematol Oncol. 2020;13(1):48. doi:10.1186/s13045-020-00884-4