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Letters to the Editor
Entospletinib and obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia and B-cell malignancies
Therapeutic resistance and intolerance of Bruton tyro- sine kinase (BTK) inhibitors is an emerging unmet med- ical need in chronic lymphocytic leukemia (CLL).1,2 Entospletinib is a small molecule inhibitor of spleen tyro- sine kinase (SYK), which is integral to the activation of BTK and the B-cell receptor (BCR) signaling cascade.3 SYK is overexpressed in CLL and its inhibition induces apoptosis of CLL cells in pre-clinical models.4,5 We have shown that BAFF-mediated SYK activation triggered BCR signaling and rendered protection of CLL cells from spon- taneous apoptosis in vitro.5 Single agent entospletinib was efficacious in treatment of patients with relapsed/refrac- tory (R/R) CLL who had progressed following chemoim- munotherapy.6 Here we report the results of a single arm, open label, investigator-initiated phase I/II clinical trial which evaluated safety and efficacy of entospletinib in combination with obinutuzumab, a glycoengineered monoclonal anti-CD20 antibody, in patients with R/R CLL and non-Hodgkin lymphoma (NHL) (clinicaltrails gov. Identifier: NCT03010358).
Patients enrolled in the phase I dose-escalation portion of the trial included adult patients with CLL7 or NHL (phase I part of the study only) after ≥1 prior therapy. Participants had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, aspartate transaminase (AST) and alanine transaminase (ALT) <2.5x, bilirubin <2x upper limit of normal and creatinine clearance (CrCl)
≥50 mL/min.
Complex karyotype (CK) was determined as presence
of ≥3 cytogenetic abnormalities on a CpG-stimulated karyotype. Gene mutations were identified using a 76- gene next-generation sequencing panel (GeneTrails®). Bone marrow examinations were required to confirm complete response (CR), with minimal residual disease (MRD) assessment using 8-color flow cytometry (MRD- undetectable at <10-4).
Patients were enrolled at two dose levels to receive entospletinib 200 mg (dose level 1 [DL1]) or 400 mg (dose level 2 [DL2]) twice-daily orally according to a stan- dard 3+3 design (Online Supplementary Table S1). The pri- mary endpoint for the phase I portion of the study was to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) of the combina- tion. All patients received single agent entospletinib as part of a 7-day run-in. Thereafter, patients received entospletinib on days 1-28 of each 28-day cycle continu- ously, and obinutuzumab intravenously in standard doses for 6 cycles.
Adverse events were graded according to Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 and international workshop CLL (iwCLL) criteria.7 Dose limiting toxicity (DLT) was defined as grade≥3 non- hematological toxicity (except grade 3 nausea, vomiting, diarrhea or asymptomatic grade 3-4 laboratory abnormal- ities reversible within 72 hours; grade 3 infusion reac- tions, grade 3 tumor lysis syndrome); grade 4 neutrope- nia lasting >7 days or febrile neutropenia; grade 4 throm- bocytopenia/anemia or grade 3 thrombocytopenia with bleeding.
AB
CD
Figure 1. Efficacy of entospletinib and obinutuzumab in patients with chronic lymphocytic leukemia. (A) Redistribution lymphocytosis. Peripheral blood absolute lymphocyte count (ALC) prior to (day -7) and after 7 days of treatment with entospletinib single agent, prior to introduction of obinutuzumab (cycle 1 day 1 [C1D1]). **P<0.01. (B) Nodal response (maximum percent change in the sum of the product [SPD] of the longest perpendicular dimensions) in patients with chronic lymphocytic leukemia evaluable lymphadenopathy. (C) Event-free survival. (D) Duration of treatment.
2022
haematologica | 2021; 106(7)