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C.S. Tam et al.
Table 3. Most common adverse events regardless of causality. Adverse events of any grade occurring in ≥ 5% of patients and all grade ≥3 adverse events occurring in ≥2% of patients are shown.a
Term
Patients with at least one AE
Hematologic AE
Neutropenia
Neutrophil count decreased
Nonhematologic AE
Contusion
Upper respiratory tract infection Diarrhea
Nausea
Constipation
Rash
Back pain
Cough
Arthralgia
Fatigue
Dyspepsia
Headache
Fall
Pain in extremity
Pneumonia
Abdominal pain
Dyspnea
Epistaxis
Hematuria
Nasopharyngitis
Pruritus
Pyrexia
Hypertension
Muscle spasms
Urinary tract infection
Vomiting
Hematoma
Musculoskeletal pain
Skin laceration
Any Grade
106 (97.2)
13 (11.9) 6 (5.5)
22 (20.2) 21 (19.3) 18 (16.5) 16 (14.7) 15 (13.8) 15 (13.8) 14 (12.8) 13 (11.9) 12 (11.0) 11 (10.1) 10 (9.2) 9 (8.3)
9 (8.3) 9 (8.3) 9 (8.3) 8 (7.3) 8 (7.3) 8 (7.3) 8 (7.3) 8 (7.3) 8 (7.3) 8 (7.3) 7 (6.4) 7 (6.4) 7 (6.4) 7 (6.4) 6 (5.5) 6 (5.5) 6 (5.5)
Grade 1/2
53 (48.6)
3 (2.8) 2 (1.8)
22 (20.1) 21 (19.3) 17 (15.6) 16 (14.7) 15 (13.8) 15 (13.8) 13 (11.9) 13 (11.9) 12 (11.0) 10 (9.2) 10 (9.2) 8 (7.3)
7 (6.4) 8 (7.3) 5 (4.6) 8 (7.3) 8 (7.3) 7 (6.4) 6 (5.5) 8 (7.3) 8 (7.3) 7 (6.4) 5 (4.6) 7 (6.4) 5 (4.6) 7 (6.4) 6 (5.5) 5 (4.6) 6 (5.5)
Grade 3 n (%)
44 (40.4)
7 (6.4) 1 (0.9)
0 (0)
0 (0) 1 (0.9) 0 (0) 0 (0) 0 (0) 1 (0.9) 0 (0) 0 (0) 1 (0.9) 0 (0) 1 (0.9) 2 (1.8) 1 (0.9) 3 (2.8) 0 (0) 0 (0) 1 (0.9) 2 (1.8) 0 (0) 0 (0) 1 (0.9) 2 (1.8) 0 (0) 2 (1.8) 0 (0) 0 (0) 1 (0.9) 0 (0)
Grade 4
7 (6.4)
3 (2.8) 3 (2.8)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Grade 5
2 (1.8)
0 (0) 0 (0)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0.9) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
AE: adverse event. aData are for treatment-emergent adverse events in the 109 patients in this arm of the study.
bleeding events affecting the CNS were reported.
A history of atrial fibrillation or flutter was reported in seven patients (6.4%); four patients (3.7%) entered the study with controlled and hemodynamically stable atrial fibrillation or flutter. An AE of atrial fibrillation or flutter was reported in three patients (2.8%). One grade 2 event was reported in a 71-year-old male patient with hyperten- sion and prior history of atrial fibrillation, while a grade 3 event was reported in a 78-year-old male patient who was septic from cholecystitis. Both of these events resolved and did not require discontinuation of study treatment. Finally, one grade 4 event was reported in a 77-year-old male patient with grade 3 hypertension at baseline, who discontinued treatment due to sepsis secondary to Pseudomonas; atrial fibrillation resolved following recov-
ery from sepsis.
Discussion
In this report, we have shown the activity and safety of zanubrutinib in a large non-randomized cohort of treat- ment-naïve CLL/SLL patients with centrally confirmed del(17p), enrolled as part of the global SEQUOIA trial. As expected, these results compare favorably with those
from previous studies of TN patients treated with chemoimmunotherapy, including the CLL8 trial of FCR.1,2,32 At the present time, prospective clinical trial data from BTK inhibitor-treated patients with TN del(17p) CLL/SLL are limited. Patients with del(17p) were not eligi- ble for enrollment in RESONATE-233 and the ECOG- E191234 trials evaluating ibrutinib in the TN setting. The Alliance A041702 study, comparing chemotherapy, ibruti- nib, or ibrutinib and rituximab in older patients with TN CLL/SLL, did allow patients with del(17p) to enroll; of these, 6% had del(17p), and only nine patients were assigned to receive ibrutinib alone.35 Two studies examin- ing combinations of novel targeted therapies with anti- CD20 antibodies also enrolled a small number of TN patients with del(17p), including the iLLUMINATE study, where 14 patients with del(17p) received combination ibrutinib and obinutuzumab.36 In a single-center, phase 2 study, single-agent ibrutinib was evaluated in 35 patients with TN CLL; notably, this population was selected based on cytogenetics or TP53 sequencing and allowed younger and/or fit patients, leading to enrollment of a population with a median age of 62.37,38 At a median follow-up time of 15 months, ORR was reported as 97%, including 12% CR, 70% PR, and 15% PR-L.
The ORR with zanubrutinib observed in the present
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