Frontline Triplet Generates High Response Rates in Treatment-Naïve CLL

The triplet combination of obinutuzumab (Gazyva) plus ibrutinib (Imbruvica) with venetoclax (Venclexta; GIVe) demonstrated encouraging response rates in patients with treatment-naïve chronic lymphocytic leukemia (CLL) in a prospective phase 2 clinical trial (NCT02758665) presented during the Virtual 25th Congress of the European Hematology Association (EHA).

Patients with high-risk CLL who have 17p deletion and/or TP53 mutation are generally associated with inferior outcomes, although novel agents like venetoclax and ibrutinib have demonstrated marked improvements in this population. Frontline venetoclax in combination with obinutuzumab has also appeared safe and effective, inducing high response rates and undetectable minimal residual disease (MRD), but patients with 17p deletion or TP53 mutations retain adverse prognostic impact. This served as the rationale for combining these 3 agents in this treatment landscape.

Complete responses (CRs) or CRs with incomplete hematologic recovery (CRis) were observed in 24 patients (58.5%; 95% CI, 42.1%-75.7%; P <.001), while partial responses (PRs) occurred in 14 patients (34.2%). Among 3 patients who were not assessable, 2 patients died at cycle 15 when ovarian cancer was diagnosed and at cycle 9 due to cardiac failure, and 1 patient withdrew consent at cycle 10. However, all 3 of these patients had reached a PR as their best response.

Minimal residual disease (MRD) was undetectable in the peripheral blood in 33 patients (80.5%), while 4 patients were still MRD-positive and 4 were not assessable.

Per protocol, treatment was discontinued at cycle 15 due to undetectable MRD and CR/CRi in 22 patients, while 13 patients also discontinued treatment due to other reasons.

Grade AEs 1 occurred in 45.0%, 2 in 30.0%, 3 in 20.5%, 4 in 4.3%, and 5 in 0.2% of patients. Overall, 63.4% of AEs were related to the study treatment. Dose interruptions were needed in 14.0% of patients, dose reductions in 5.2%, and permanently discontinued in 0.6%.

GIVe demonstrated an overall acceptable safety profile. Thirty-nine of the 41 patients experienced an adverse event (AE), and the AEs were resolved in 87.5%, persisting in 10.8%, resolved with sequelae in 1.3%, and fatal in 0.2%.

The most common any grade AEs included gastrointestinal disorders (82.9%), infections and infestations (70.7%), blood and lymphatic system disorders (58.5%), neutropenia (48.8%), and thrombocytopenia (19.5%). Grade 3 to 5 AEs included neutropenia (43.9%), infections and infestations (19.5%), thrombocytopenia (14.6%) IRR (7.3%), atrial fibrillation (2.4%), arthralgia (2.4%), and headache (2.4%). Some high-grade infections were of concern, the study authors noted.

Notably, there was also 1 case of cerebral aspergillosis, PML without PCR testing, urosepsis, staphylococcal sepsis, and febrile infection each were observed on the study. Laboratory TLS was also reported in 9.8% of patients in any grade and 9.8% in grades 3-5, while infusion-related reactions were reported in 29.3% and 7.3% of patients, respectively.

Patients were treated with GIVe for 6 months. Obinutuzumab was given in the standard schedule dose of 1000 mg on days 1, 8, and 15 of the first cycle and day 1 of cycles 2 through 6. Ibrutinib was given continuously at 420 mg per day from day 1 cycle 1. Venetoclax was given to patients on day 22 of cycle 1 with a standard ramp-up dose to 40 mg per day over 5 weeks until the end of cycle 12.

The primary end point of the study was CR rate at final restaging, while secondary end points included progressive disease-free rate, ORR, MRD levels, PFS, EFS, OS, and duration of response in patients who achieved a response, among other efficacy and safety parameters.

Overall, 41 patients enrolled to the study between September 2016 and October 2018, which included 24 men and 17 women. The median age was 62 years (range, 35-85), and the majority of patients had Binet stage B/C disease (78.0%), where 41.4% had stage B, 36.6% had stage C, and 22.0% had stage A. The median CIRS score was 3 (range, 0-8).

Twenty-six patients had a 17p deletion, and 39 patients had TP53-mutant disease. Overall, 58.5% of patients had both a 17p deletion and TP53 mutation, while 36.6% had only a TP53 mutation and 4.9% had only 17p deletion. IGHV was observed in 14.6% of patients and was indeterminable in 7.3% of patients.

_Reference

_{Huber H, Edenhofer S, von Tresckow J, et al. Preliminary safety and efficacy results from a phase-ii trial of obinutuzumab, ibrutinib and venetoclax (CLL2-GIVe) in untreated CLL with TP53 mutation and/or 17p deletion. Presented at: Virtual 25th EHA Congress; June 12, 2020.}