Page 70 - 2021_09-Haematologica-web

C.S. Tam et al.
Table 1. Key patient and disease characteristics.
TN del(17p) CLL/SLL
Table 2. Summary of investigator-assessed efficacy.
Follow-up, median (range), mo
Demographics
Age, median (range), years
Male sex, n (%)
ECOG PS of 2, n (%)
Months since diagnosis, median (Q1 - Q3)
Disease characteristics
SLL, n (%)
Binet stage C for patients with CLL, n (%) ALC (x 109/L), median
Hemoglobin (g/L), median
Platelet count (x 109/L), median β2-microglobulina > 3.5 g/dL, n (%)
IGHV mutational status,b n (%) Mutated
Unmutated
Bulky disease,c n (%)
AnyTLLDi≥5cm AnyTLLDi≥10cm
d Cytopeniapresent, n(%)
Proportion of cells with del(17p), n (%) 7.5% – 10%
10.5% – 20.0%
20.5% – 50.0%
50.5% – 100% Mean % (SD)
Karyotype status,e n (%) Non-Complex (0 to 2 abnormalities) Complex
3 or more abnormalities
5 or more abnormalities
(n=109)
18.2 (5.0-26.3)
70.0 (42-86) 78 (71.6) 14 (12.8) 21.6 (7.7-54.8)
10 (9.2) 40/99 (40.4) 65.1 120.0 154.0 78/99 (78.8)
36/103 (35.0) 67/103 (65.0)
42 (38.5) 11 (10.1)
61 (56.0)
16 (14.7) 44 (40.4) 13 (11.9) 36 (33.0) 36.0 (31.6)
54/86 (62.8)
32/86 (37.2)
23/86 (26.7)
Efficacy Variable
Best response, n (%)
ORR (CR, PR, or PR-L), n (%) [95% CI]a CR
CRi PR PR-L
SD PD
Time to response, mo
PR-L or higher, median (range) PR or higher, median (range)
DOR
Response ≥ 12 mo, % [95% CI]a Estimated PFS rate, %
12 months [95% CI]a
18 months [95% CI]a
TN del(17p) CLL/SLL (n = 109)
103 (94.5) [88-98] 3 (2.8)
1 (0.9)
95 (87.2)
4 (3.7)
5 (4.6)
1 (0.9)
2.79 (1.9-16.5) 2.89 (1.9-16.5)
92.8 [85.4-96.5]
94.5 [88.2-97.5]
88.6 [79.0-94.0]
AE: adverse event; ALC: absolute lymphocyte count; CLL: chronic lymphocytic leukemia; ECOG PS: Eastern Cooperative Oncology Group performance status; IGHV: immunoglobulin heavy chain variable; LDi: longest diameter; SD: standard deviation; SLL: small lymphocytic lymphoma; TL: target lesion; TN: treatment-naïve; mo: months. aTen patients had missing data. bSix patients had RNA quantity/quality not sufficient for polymerase chain reaction (PCR) amplification of heavy-chain variable (VH) region for sequencing. cPatients with any target lesion with longest diameter present- ed.dPatients having anemia (≤110 g/L),thrombocytopenia (≤ 100x109/L),or neutrope- nia (≤ 1.5 x 109/L). e23 patients had insufficient metaphases available for analysis.
[del(17p) high] versus patients with a percentage of >7% to <20% [del(17p) low] (Online Supplementary Table S4). Patients in the del(17p) high category were observed to have a higher rate of unmutated IGHV (75% vs. 56.4% of patients with a resulted test; P=0.0478) and complex kary- otype status (56.8% vs. 22.4% of patients with sufficient metaphases for analysis; P=0.0011); no other differences in baseline characteristics were observed. Best ORR and estimated 18-month PFS were 98% and 89%, respectively, in the del(17p) high category and 92% and 88%, respec- tively, in the del(17p) low category.
Safety
AE of any grade reported in ≥10% of patients included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), diarrhea (16.5%), nausea (14.7%), rash (13.8%), constipa- tion (13.8%), back pain (12.8%), cough (11.9%), arthralgia (11.0%), and fatigue (10.1%) (Table 3). Grade ≥3 events were reported in 53 patients (48.6%), with neutropenia/decreased neutrophil count (12.9%) and pneumonia (3.7%) being the most common. Serious AE
CI: Confidence Interval; CLL: chronic lymphocytic leukemia; CR: complete response; DOR: duration of response; ORR: overall response rate; PD: progressive disease; PFS: progression-free survival; PR: partial response; PR-L: PR with lymphocytosis; SD: stable disease; SLL: small lymphocytic lymphoma; TN: treatment-naïve. aTwo-sided Clopper- Pearson 95% CI.
(SAE) were reported in 36.7% of patients, with pneumo- nia (3.7%) being the most common. AE led to dose reduc- tion in 6 (5.5%) patients and included thrombocytopenia, diarrhea, gastritis, blood bilirubin increased, arthralgia, myalgia, and headache. All six patients remain on treat- ment.
Four patients discontinued treatment due to AE; a 77- year-old male patient had grade 4 pseudomonal sepsis associated with grade 4 neutropenia and atrial fibrillation who recovered, while another 72-year-old male patient had grade 3 melanoma requiring surgery and adjuvant therapy. One grade 5 event was reported in a 84-year-old female patient with health-care associated pneumonia diagnosed 8 days after the last dose of zanubrutinib which was held for an unrelated procedure. This case was com- plicated by the development of sepsis which was assessed as related to zanubrutinib. Finally, one grade 5 event was reported in a 72-year-old male patient who developed dis- ease progression at the week 36 response assessment including massive enlargement of intra-abdominal lymph nodes associated with hypercalcemia. Prior to discontinu- ation of study drug, the patient shortly thereafter had renal failure requiring dialysis and subsequently died due to pulmonary edema. No sudden or unknown deaths were reported.
AEI known to be associated with BTK inhibitors were characterized in greater detail, including grouping of simi- lar AE by category (Online Supplementary Table S1). AEI reported in ≥10% of treated patients included infections (64.2%; 13.8% grade ≥3), minor bleeding (26.6%), bruis- ing (24.8%; 0% grade ≥3), neutropenia (18.3%; 13.8% grade ≥3), diarrhea (15.6%; 0.9% grade ≥3), nausea (13.8%; 0% grade ≥3), arthralgia (11.0%; 0% grade ≥3), fatigue (10.1%; 0.9% grade ≥3) (Online Supplementary Table S5). The most common infections reported in ≥ 5% of patients included upper respiratory tract infection (19.3%), pneumonia (8.3%), nasopharyngitis (7.3%), and urinary tract infection (6.4%); most of these were grade 1 or 2 events. Prophylaxis against opportunistic infections was allowed per local standard of care but not required;
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