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Letters to the Editor
topenia and anemia, as in earlier studies of SYK inhibitors.6,9,10 Neutropenia (43.5%; including four patients [17.4%] who had transient grade 4 neutropenia attributed to obinutuzumab), thrombocytopenia and anemia were the most common grade ≥3 hematologic toxicities. The median onset of neutropenia was 7 days after the first obinutuzumab infusion, median duration was 28 days. In six of 11 patients, first onset occurred during cycle one of therapy. Growth factor support was not required.
The most frequently occurring non-hematological AE of all grades were fatigue, infusion-related reaction and nausea. The most frequent grade 3-4 non-hematological AE were: infusion-related reaction (17.4%; all attributed to obinutuzumab) and increased AST/ALT abnormalities (13.0%), the latter adverse event reported in 10-20% of patients receiving SYK inhibitors.6,10-12 Despite the fact that patients had received a median of two prior thera- pies, including fludarabine and bendamustine, few patients (13%) developed febrile neutropenia or pneumo- nia. There were no grade 5 AE.
Of 23 patients, only one patient discontinued therapy due to AE (recurrent AST/ALT abnormalities which resolved upon cessation of entospletinib). This discontin- uation rate (4.3%) compares favorably with those seen in early-phase trials and real-world analyses of BTK inhibitors over a similar follow-up period.1,13-15
Efficacy of entospletinib+obinutuzumab was analyzed in the 21 patients with CLL, of which 17 received entospletinib at RP2D (400 mg twice daily). Among an additional four patients who were initially treated with 200 mg entospletinib, two escalated to RP2D after 12 and 13 treatment cycles.
Patients with CLL had a median age of 66 years (range, 48-76; Table 2). Ten patients (47.6%) had either complex karyotype (CK; n=6) or a TP53 aberration (n=9). Including CK, TP53 aberration, NOTCH1 and SF3B1 mutations, 13 patients (61.9%) had unfavorable cytoge- netic and molecular characteristics, defined as “high-risk CLL”. The median number of prior therapies was two (range, 1-6). Seven patients had received prior ibrutinib and one patient received the phosphoinotiside-3 kinase (PI3K) inhibitor idelalisib. Of those, four patients discon- tinued ibrutinib due to intolerance, one per their discre- tion, and three patients discontinued ibrutinib and idelal- isib for progressive disease. Baseline median absolute neutrophil count was 2,700/mL, hemoglobin 10.9 g/dL, platelet count 150,500/mL, immunoglobulin (Ig) G level 494 mg/dL (range, 176-1475 mg/dL).
Treatment with entospletinib for 7 days during run-in resulted in redistribution lymphocytosis (Figure 1A). Among the 21 efficacy-evaluable participants with CLL, the ORR was 66.7% (95% CI: 43.0–85.4). Three patients (14.3%, 95% CI: 3.1–36.3) achieved a CR, and 11 patients (52.4%) had a partial response (PR). The remaining seven patients had stable disease as their best response. Two of three patients with confirmed CR had undetectable MRD in the bone marrow. The median time to CR was 10.7 months (range, 7.0-17.9 months) and time to PR was 5.8 months (range, 2.8-6.5 months; Online Supplementary Table S3). Nineteen patients with evaluable lymphadenopathy demonstrated a reduction in lymph node sizes (Figure 1B). The low CR rate is con- sistent with that seen with BCR-signaling inhibitors.13,15
Median EFS was 24 months, treatment duration – 17 months (95% CI: 16–28; Figure 1C and D). Nine patients with CLL (eight out of nine discontinued due to progres- sive disease) started subsequent therapy (six with BTK
inhibitors, two with venetoclax and one with PI3K inhibitor). All but one patient remains alive.
Thirteen patients with high-risk disease genetics had an ORR of 53.8% (five PR and two CR). Five patients remain on treatment, with a median EFS of 24 months. Among the eight patients who had previously received kinase inhibitors, ORR was 62.5% (all PR) and median EFS was 17 months.
Among the 17 patients with CLL who received entospletinib at RP2D in phase II of the study ORR was 82.4% (64.7% PR, 17.6% CR). The median EFS has not been reached, and the estimated 2-year EFS is 64%. This compares favorably with entospletinib monotherapy in patients with R/R CLL (ORR 61%, median PFS 13.8 months).6
Thus, the combination of entospletinib and obinu- tuzumab has an acceptable safety profile and shows a strong efficacy signal warranting continued exploration in CLL.
Adam S. Kittai,1° Scott Best,1 Bria Thurlow,1 Vi Lam,1 Taylor Hashiguchi,1 Shaun Goodyear,1 Daniel O. Persky,2 Craig Okada,1 Byung Park,1 Stephen E. Spurgeon1
and Alexey V. Danilov1,3
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR; 2University of Arizona Cancer Center, Tucson, AZ and 3City of Hope Comprehensive Cancer Center, Duarte, CA, USA
°Current address: Ohio State University, Columbus, OH, USA
Correspondence:
ALEXEY V. DANILOV - adanilov@coh.org
doi:10.3324/haematol.2020.270298 Received: August 20, 2020. Accepted: January 18, 2021. Pre-published: January 28, 2021.
Disclosures: AVD received research funding from Aptose Biosciences, AstraZeneca, Gilead Sciences, Takeda Oncology, Genentech, Bayer Oncology, Verastem Oncology and Bristol-Myers Squibb, and consulted for Astra Zeneca, Abbvie, Beigene, Bayer Oncology, Bristol-Meyers-Squibb, Genentech, Karyopharm, Pharmacyclics, TG Therapeutics, Nurix and Rigel Pharmaceuticals; SES received research fundingfrom Janssen, Bristol-Myers Squibb, Acerta, Velos-Bio, Gilead Sciences, Genentech and Astra Zeneca as well as consultancy fees from Janssen.
Contributions: AVD designed the study, provided oversight at all stages of the study, performed research and analyzed data; ASK, SB, BT, FX, VL, TH, DO, CO, BP and SES performed research and analyzed data; ASK, BT, SG and AVD wrote the manuscript; all authors participated in drafting, revising, and approving the final manuscript.
Acknowledgements: we extend our thanks to the patients and their families. We would also like to thank Sarah Dreumont, Basak Gokcora, Renee MacKinnon, Kirsten Orand, Bethany Wollam, Nan Subbiah, Stephen Monette, Lacy Moore, Debbie Ryan and the rest of the lymphoma team at Oregon Health and Science University for their contribution to this study.
Funding: this Investigator-sponsored study was funded by Gilead Sciences Inc and Roche/Genentech; AVD was supported in part by the Leukemia & Lymphoma Society Scholar in Clinical Research Award #2319-19.
References
1. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874-879.
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