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Letters to the Editor
Table 1. Adverse events. Adverse events, N (%)
Adverse Events - All
Hematologic Adverse Events Neutrophil count decreased Platelet count decreased Anemia
Febrile neutropenia
Lymphocyte count increased
Non-hematologic Adverse Events Fatigue
Infusion related reaction Nausea
Diarrhea
Fever
Alanine aminotransferase increased Aspartate aminotransferase increased Other Infection
Creatinine increased
Pneumonia
Chills
Dizziness
Vomiting
Tremor
Tumor lysis syndrome
All Patients (N=23)
Table 2. Clinical characteristics of patients with chronic lymphocytic leukemia.
Any Grade
22 (95.7)
11 (47.8) 5 (21.7) 3 (13.0) 3 (13.0) 1 (4.3)
11 (47.8) 10 (43.5) 8 (34.8) 7 (30.4) 7 (30.4) 5 (21.7) 5 (21.7) 5 (21.7) 4 (17.4) 3 (13.0) 3 (13.0) 3 (13.0) 2 (8.7) 2 (8.7) 2 (8.7)
Grade ≥ 3 15 (65.2)
10 (43.5) 4 (23.5) 1 (4.3) 3 (13.0) 1 (4.3)
2 (8.7) 4 (17.4) 1 (4.3) 0
0
3 (13.0) 3 (13.0) 1 (4.3) 0
1 (4.3) 1 (4.3) 0
1 (4.3) 1 (4.3) 1 (4.3)
Characteristics
All patients N=21 (%)
Age
< 65 years 7 ≥ 65 years 14
Sex
Male 15 Female 6
(33.3) (66.7)
(71.4)
(28.6)
(38.1) (57.1) (4.8)
(31.3)
(68.7)
(80.0) (20.0)
(66.7) (14.2) (9.5) (23.8)
(28.6) (23.8) (4.8)
(42.9) (9.5) (19.0)
(61.9)
(26.8) (38.1) (33.3) (57.1) (66.7) (33.3) (4.8)
ECOG performance status
0 8 1 12 2 1
β2-microglobulin (n=16)
≤3.5 mg/L 5 >3.5 mg/L 11
IgG* (n=20)
<700 mg/dL 16 >700 mg/dL 4
FISH
Deletion 13q 14 Trisomy 12 3 Deletion 11q 2 Deletion 17p 5
Once the RP2D was determined, a phase II study enrolled patients with R/R CLL only. CR was the primary endpoint.7 Secondary endpoints included objective response rate (ORR), event-free survival (EFS), (defined as the interval between the first study treatment and objec- tive signs of disease recurrence, subsequent anti- leukemic therapy, or death), and safety. Patients with CLL enrolled at the RP2D level in the phase I were included in the phase II part of the study.
The planned sample size of 17 patients in the phase II part of the study provided 83% power to detect a differ- ence in CR of 0.30 (0.20 vs. 0.50) using a one-sided bino- mial test (P<0.05). The null hypothesis (H0)=2 was based on CLL11 study data (CR 21%).8 Patients who received at least one dose of the study therapy were evaluable for safety. Response rates and exact 95% Confidence Interval (CI) were estimated by Clopper-Pearson method and EFS by the Kaplan-Meier method. Data cut-off date for analysis was January 1, 2020. The study was approved by the Oregon Health and Science University Institutional Review Board and conducted in accordance with the principles of the Declaration of Helsinki.
A total of 24 patients (n=22 CLL and n=2 follicular lym- phoma [FL]) were enrolled between 08/2017 and 10/2018 (Online Supplementary Table S2). One patient had CLL in Richter’s transformation leading to ineligibility on study entry and was removed from subsequent analysis. Twelve patients were enrolled in the phase I part of the study. The phase II part of the study included 17 patients with CLL (of which six received entospletinib at DL2 on the phase I part of the study).
Among the 23 evaluable patients, the median follow-up was 17 months (range, 7-28 months). The median relative dose intensity of entospletinib was 96%. The median treatment duration was 16 months (range, 2-26). Four patients (17.4%) experienced permanent dose reductions due to toxicities. An additional nine patients had tempo- rary dose holds/reductions. Thirteen patients (56.5%) dis- continued study therapy due to: progressive disease (n=8),
Complex Karyotype (CK, ≥3 abnormalities) 6 CK + TP53 aberration 5 ≥5 abnormalities 1
Mutational Status
TP53 9 Notch1 2 SF3B1 4
High Risk CLL** 13
Prior Treatments
1 6 2 8 ≥3 7 Fludarabine 12 Bendamustine 14 Ibrutinib 7 Idelalisib 1
*Normal range: 700–1,600 mg/dL. **High-Risk CLL defined as complex karyotype (CK), TP53 aberration, NOTCH1 and SF3B1 mutations. CLL: chronic lymphocytic leukemia: ECOG: Eastern Cooperative Oncology Group; FISH: fluorescense in situ hybridization.
adverse event related to entospletinib (n=1; recurrent AST/ALT abnormalities); a new diagnosis of breast cancer unrelated to study treatment (n=1), withdrawal of con- sent (n=2), and achievement of CR with undetectable MRD in the bone marrow after 12 cycles of therapy (n=1).
Twelve patients enrolled in the phase I part of the study received a median of 18 cycles (range, 7-28) of study therapy. Of six patients (four CLL, two FL) who received entospletinib 200 mg (DL1), one patient experi- enced a DLT (grade 3 asymptomatic AST/ALT abnormal- ities) attributed to entospletinib. No DLT were observed among the six patients who received entospletinib 400 mg (DL2). Thus, entospletinib 400 mg twice-daily was determined to be the RP2D in combination with obinu- tuzumab.
Treatment-related AE were reported in 95.7% of patients (Table 1). Grade 3 or higher AE occurred in 65.2%. The most common hematologic AE observed across all patients were neutropenia (47.8%), thrombocy-
haematologica | 2021; 106(7)
2023