Zanubrutinib Plus Venetoclax Generates 100% ORR in Treatment-Naive Del17p/TP53+ CLL/SLL


Key Takeaways

  • Zanubrutinib and venetoclax combination achieved a 100% overall response rate in treatment-naive CLL/SLL patients with 17p deletions and/or TP53 mutations.
  • At a median follow-up of 31.6 months, the complete response rate was 46%, with a favorable safety profile.
Paolo Ghia, MD, PhD

Paolo Ghia, MD, PhD

Treatment with the combination of zanubrutinib (Brukinsa) and venetoclax (Venclexta) led to an overall response rate (ORR) of 100% in patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) harboring 17p deletions and/or TP53 mutations, according to data from arm D of the phase 3 SEQUOIA trial (NCT03336333).1

Findings presented at the 2024 EHA Congress showed that at a median follow-up of 31.6 months (range, 0.4-50.5), patients from arm D evaluable for response (n = 65) experienced a complete response (CR) rate of 46%, a CR with incomplete count recovery (CRi) rate of 2%, a partial response (PR) rate of 51%, and a PR with lymphocytosis rate of 2%.

“With preliminary results for zanubrutinib plus venetoclax [in arm D of SEQUOIA], we do see a favorable safety and tolerability profile with no new [safety signals]. Rates of atrial fibrillation and hypertension were low,” presenting study author Paolo Ghia, MD, PhD, of IRCCS Ospedale San Raffaele and Universita Vita-Salute San Raffaele in Milan, Italy, said during the presentation.

SEQUOIA was a phase 3 trial that included 4 arms. In arms A and B, patients with previously untreated CLL or SLL were randomly assigned 1:1 to received zanubrutinib alone (arm A) or bendamustine (Bendeka) plus rituximab (Rituxan; arm B). Notably, prior findings from the randomized portion of the study helped support the FDA approval of zanubrutinib for the treatment of patients with CLL or SLL in January 2023.2

The trial also included 2 nonrandomized groups. In arm C, patients with previously untreated CLL/SLL harboring 17p deletions received zanubrutinib monotherapy.1

To enroll in arm D, patients needed to have previously untreated CLL/SLL that met International Workshop on CLL criteria for treatment and have measurable disease per CT or MRI. Centrally confirmed 17p deletions per fluorescence in situ hybridization and/or TP53 mutations were also required for this group.

Within arm D, the population (n = 114) included 2 groups: patients with 17p deletions and/or TP53 mutations (n = 66) and patients without 17p deletions (n = 48). Enrollment in these groups began in November 2019 and January 2022, respectively. Data from the former group were presented at the 2024 EHA Congress. All patients in arm D were treated with zanubrutinib and venetoclax. Zanubrutinib was given at 160 mg twice per day as monotherapy for 3 lead-in cycles, then at the same dose in combination with venetoclax. Venetoclax was ramped up to 400 mg once per day for 12 to 24 cycles, and zanubrutinib was given for at least 27 cycles.

Trial protocol also included stopping rules for each agent based on undetectable minimal residual disease (MRD). Venetoclax needed to be given for at least 12 cycles before being stopped, and zanubrutinib needed to be administered for at least 27 cycles before treatment cessation. All the following conditions also needed to be met to stop treatment with either agent:

  • Confirmed CR/CRi via bone marrow biopsy
  • Undetectable MRD achieved at a 10-4 sensitivity in 2 consecutive peripheral blood tests conducted at least 12 weeks apart
  • Undetectable MRD achieved at a 10-4 sensitivity in 2 consecutive bone marrow aspirate blood tests conducted at least 12 weeks apart

The end points in arm D included investigator-assessed ORR, investigator-assessed progression-free survival (PFS), undetectable MRD rate at a 10-4 sensitivity, and safety.

Among the 66 patients with CLL harboring a 17p deletion and/or TP53 mutation, 3 left the study prior to the initiation of venetoclax due to death (n = 2) or patient withdrawal (n = 1). At the January 31, 2024, data cutoff, 3 of the 63 patients who started zanubrutinib plus venetoclax were off study due to death (n = 2) or loss to follow-up (n = 1). Five patients were in study follow-up for long-term survival (n = 2) and post-treatment efficacy (n = 3). Fifty-five patients remained on treatment, including 8 receiving zanubrutinib plus venetoclax and 47 receiving zanubrutinib monotherapy after discontinuing venetoclax.

Eleven patients (17%) discontinued zanubrutinib due to adverse effects (AEs; 8%), progressive disease (3%), completed treatment with early stopping per undetectable MRD status (5%), and patient withdrawal (2%). Fifty-five patients (83%) discontinued venetoclax due to AEs (3%), progressive disease (3%), investigator decision (2%), and completion of treatment (76%). In those who completed treatment with venetoclax, reasons for stopping included reaching 24 cycles (74%) and early stopping per MRD status (2%).

The median age of patients within arm D was 66 years (range, 26-87), and 55% of patients were at least 65 years of age. Most patients were male (52%) and White (88%). Regarding ECOG performance status, 48% of patients had a score of 1, and 3% of patients had a score of 2. Five percent of patients had SLL. Forty-four percent of patients had any target lesion with a longest diameter of at least 5 cm, and 8% of patients had any target lesion with a longest diameter of at least 10 cm.

All patients harbored 17p deletions and/or TP53 mutations. Patients had either a 17p deletion with a TP53 mutation (64%); a 17p deletion with TP53 wild-type disease (26%); or no 17p deletion with a TP53 mutation (11%). Notably, unmutated IGHV was observed in 85% of patients. Regarding complex karyotypes, 50% of patients had at least 3 abnormalities, and 36% of patients had at least 5 abnormalities. The median percentage of abnormal nuclei with 17p deletions was 60.5% (range, 1%-98%).

Additional data showed that the proportion of patients at high risk for tumor-lysis syndrome (TLS) dropped by 91% following the zanubrutinib lead-in period. At baseline, 34.8% of patients were at high risk for TLS, and before initiating venetoclax, that rate dropped to 3.0%.

As duration of treatment increased, rates of undetectable MRD in peripheral blood increased. The highest rate of undetectable MRD in peripheral blood at any point in evaluable patients with at least 1 sample (n = 66) was 59%. The highest rate of undetectable MRD in bone marrow for patients with at least 1 sample (n = 35) was 37%.

The median PFS was not reached, and the 12- and 24-month PFS rates were 95% and 94%, respectively.

Regarding safety, treatment-emergent AEs (TEAEs) reported in at least 10% of patients included COVID-19 (grade 1/2, 52%; grade ≥ 3, 3%), diarrhea (30%; 9%), nausea (30%; 0%), contusion (29%; 0%), fatigue (23%; 0%), neutropenia (5%; 17%), arthralgia (15%; 0%), epistaxis (11%; 0%), fall (11%; 0%), and petechiae (11%; 0%).

TEAEs of special interest included infections (grade 1/2, 56%; grade ≥ 3, 15%), hemorrhage (52%; 2%), neutropenia (5%; 17%), second primary malignancy (5%; 8%), hypertension (2%; 8%), anemia (6%; 2%), thrombocytopenia (6%; 2%), and atrial fibrillation/flutter (0%; 2%).

TEAEs led to zanubrutinib discontinuation, venetoclax discontinuation, and death in 8%, 3%, and 5% of patients, respectively.

“The study is ongoing, and hopefully in the next few years, we will be presenting results after stopping [treatment] due to undetectable MRD,” Ghia concluded.

Disclosures: Dr Ghia reported receiving honoraria from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Janssen, Galapagos, Lilly/Loxo, MSD, Roche, and Sanofi; and receiving research funding from AbbVie, AstraZeneca, Bristol Myers Squibb, and Janssen.


  • Ma S, Munir T, Lasica M, et al. Combination of zanubrutinib + venetoclax for treatment-naive CLL/SLL with del(17p) and/or TP53: preliminary results from SEQUOIA arm D. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S160.
  • FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed June 14, 2024.
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