Zanubrutinib Demonstrates Activity in Patients With CLL/SLL and Del(17p)

Zanubrutinib (Brukinsa), a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, was safe and effective in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) carrying chromosome 17p13.1 deletion [del(17p)], according to a recent report published in Haematologica.¹

Patients with CLL or SLL harboring del(17p) tend to have a poor prognosis and respond poorly to standard chemoimmunotherapy. This leads to reduced rates of overall survival (OS) and worse clinical outcomes. The majority of patients with del(17p) also lack wild-type TP53 due to a mutation of the other TP53 allele. This leads to genomic instability and reduced responsiveness to cytotoxic chemotherapy. For CLL, the rate of occurrence is approximately 5% to 8%, with incidences increasing at each relapse. Currently, several therapies hold FDA approval for the treatment of CLL/SLL, regardless of del(17p) status, including ibrutinib (Imbruvica) and acalabrutinib (Calquence).

The phase 3 SEQUOIA study (NCT03336333)² looks at the safety and efficacy of zanubrutinib in combination with bendamustine (Bendeka) plus rituximab (Rituxan) in previously untreated CLL or SLL. The randomized, parallel assignment, open-label study has an estimated enrollment of 710 participants and an estimated completion date of October 2022. The primary end point is progression-free survival (PFS). Secondary end points include overall response rate (ORR), duration of response (DoR), minimal residual disease, and adverse events (AEs). 

During the study, patients were split into 6 arms. In arm 1, patients received zanubrutinib at 80mg twice a day until unacceptable toxicity or progression. In arm 2, patients received bendamustine plus rituximab for up to 6, 28-day cycles. In arm 3, which was restricted to China only, patients received zanubrutinib twice a day at 80 mg until unacceptable toxicity of progression, in arm 4, which was also China only, patients received bendamustine plus rituximab for up to 6, 28-day cycles. In arm 5, patients received zanubrutinib until unacceptable toxicity or progression. In arm 6, patients with del17p or TP53 mutation received venetoclax (Venclexta) plus zanubrutinib. Venetoclax was continued until unacceptable toxicity, disease progression, or for a maximum of 24 cycles. Zanubrutinib was continued for a maximum of 27 cycles, unacceptable toxicity, or disease progression. 

Between February 3, 2018 and February 20, 2019, 109 patients with confirmed CLL/SLL and del(17p) were enrolled and received 1 or more doses of zanubrutinib. The median age of this cohort was 70 (range, 42-86). The vast majority were male (71.6%), presented with CLL (90.8), 12.8% had an ECOG score of 2, and the median time since diagnosis was 21.6 months (range, 7.7-54.8). Sixty-five percent were IGHV unmutated and 56% had cytopenia. The mean proportion of cells with del(17p) was 36%. Over half, 62.8%, had a non-complex karyotype status. 3 or more abnormalities were seen in 37.2% of patients and 5 or more abnormalities were seen in 26.7% of patients. 

At the median follow-up of 18.2 months, the ORR was 94.5%. Complete responses were seen in 2.8% of patients and partial responses (PR) were seen in 87.2% of patients. Stable disease was seen in 4.6% and progressive disease in 0.9% of patients. The median time to response for PR or higher was 2.89 months. The median duration of response was 92.8 months (range, 85.4-96.5). The estimated PFS at 12 months was 94.5% and 88.6% at 18 months.

In terms of safety, 97.1% of patients had at least one AE of any grade. Grade 1/2 AEs were seen in 48.6% of patients, grade 3 AEs were seen in 40.4% of patients, grade 4 AEs in 6.4% of patients, and grade 5 AEs in 1.8% of patients. Any grade neutropenia was seen in 11.9% of patients and 5.5% of patients saw their neutrophil count decrease. Common AEs of any grade included contusion (20.2%), upper respiratory tract infection (19.3%), diarrhea (16.5%), and nausea (14.7%).

In order to participate in the study, patients must be unsuitable for chemoimmunotherapy, have a confirmed diagnosis of CD20-positive CLL or SLL that requires treatment, have measurable disease, an ECOG score of 0, 1, or 2, a life expectancy of 6 months of greater, adequate bone marrow function, and adequate renal and hepatic function. Patients who received previous systemic treatment for CLL/SLL, have an ongoing need for corticosteroids, known prolymphocytic leukemia, significant cardiovascular disease, a prior malignancy within the past 3 years, a history of severe bleeding disorder, or known central nervous system (CNS) involvement are not eligible to participate.

“The clinically meaningful activity noted in this patient series appears to be associated with a favorable toxicity profile and is consistent with that reported in other studies of zanubrutinib to date. Despite enrolling a more elderly and comorbid population and allowing for therapeutic anticoagulation on study, the incidence of grade ≥3 AE or serious AE leading to major bleeding was 5.6% with no CNS events reported, and all patients able to continue study drug after dose interruption,” study authors wrote.

“Consistent with its greater selectivity for BTK and less inhibition of kinases such as EGFR, Src, and others, the incidence of grade 3 AE such as diarrhea, arthralgia, and myalgia were all ≤1%. Importantly, only three patients on this study reported treatment-emergent atrial fibrillation, six patients required ongoing dose reduction, and four patients discontinued zanubrutinib due to an AE. Two phase 3 randomized studies in patients with R/R CLL/SLL and Waldenström macroglobulinemia are ongoing to directly compare the efficacy and safety profiles of ibrutinib and zanubrutinib.”

_REFERENCE:

_{1.Tam C, Robak T, Ghia P, et al. Zanubrutinib monotherapy for patients with treatment-naïve chronic lymphocytic leukemia and 17p deletion. Haematologica. 2021;106(9):2354-2366. doi: 10.3324/haematol.2020.259432}