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Although rare in treatment-naïve patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), chromosome 17p deletion (del(17p)) is associated with rapid disease progression and poor response to treatment.1 The treatment of choice for this high-risk disease group is the Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib; however, off-target toxicities are common. Zanubrutinib is a highly potent and selective second-generation BTKi. With greater selectivity than ibrutinib, it is anticipated that zanubrutinib may have an improved safety profile. In an article recently published in Haematologica, Constantine Tam, a member of our Scientific Advisory Board, and colleagues, presented 18-month follow-up data from Arm C of the phase III SEQUOIA study (NCT03336333) of zanubrutinib monotherapy in treatment-naïve CLL/SLL patients with del(17p).2
Table 1. Hematologic improvement in patients with cytopenias at baseline2
Baseline cytopenia (n) |
Sustained improvements by parameter (%) |
Anemia (8) |
Hemoglobin level (86.0) |
Neutropenia (43) |
Absolute neutrophil count, (75.0) |
Thrombocytopenia (28) |
Platelet count (85.7) |
Table 2. Most common AEs of any grade, and Grade ≥ 3 AEs2
AE, adverse event. |
|
Most common AE (≥ 10%), any grade |
% |
Arthralgia |
11.0 |
Back pain |
12.8 |
Constipation |
13.8 |
Contusion |
20.2 |
Cough |
11.9 |
Diarrhea |
16.5 |
Fatigue |
10.1 |
Nausea |
14.7 |
Upper respiratory tract infection |
19.3 |
Rash |
13.8 |
Grade ≥3 AE |
% |
Atrial fibrillation/flutter |
1.8 |
Infections |
13.8 |
Major bleeding |
4.6 |
Neutropenia/decreased neutrophil count |
12.9 |
Pneumonia |
3.7 |
The results of this arm of the phase III global SEQUOIA trial showed that zanubrutinib monotherapy is active and well tolerated in a previously untreated cohort of high-risk patients with del(17p) CLL/SLL. Despite recruiting an older patient population with chronic comorbidities, major bleeding (resulting from Grade ≥ 3 AEs or serious AEs) was low (5.6%), and no central nervous system event was reported. The high selectivity of zanubrutinib for BTK inhibition was demonstrated by a low incidence (< 1%) of Grade ≥ 3 AEs, such as diarrhea, joint stiffness, muscle pain or muscle injuries. Study limitations included a single-arm study design and a relatively short duration of follow-up.
In summary, zanubrutinib holds promise for treating patients with high-risk, del(17p) CLL/SLL. However, similarly to other BTKi therapies, single-agent zanubrutinib is unlikely to promote deep responses. Enrolment of patients with del(17p) CLL/SLL into Arm D of the SEQUOIA trial, evaluating zanubrutinib combined with the BCL-2 inhibitor venetoclax, is underway.
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