Real-World Efficacy of Venetoclax-Based Regimens in Patients with Chronic Lymphocytic Leukemia in Israel: A Multicenter Prospective Study
Authors: Herishanu Yair , Goldschmidt Neta , Itchaki Gilad , Levi Itai , Aviv Ariel , Fineman Riva , Dally Najib , Tadmor Tamar , Ruchlemer Rosa , Abadi Uri , Shvidel Lev , Braester Andrei , Cohen Raanan , Frankel Neta , Ofek Keren , Berelovich Jenia , Grunspan Moshe , Benjamini Ohad 
Published: November 2021

Abstract
Background: The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) has demonstrated superior outcomes and manageable safety as compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL). Moreover, venetoclax-based regimens induced high rates of undetectable minimal residual disease (uMRD). Prospective data on the effectiveness of venetoclax-based regimens specifically with regard to achieving uMRD in a real-world setting are still lacking. Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/small lymphocytic lymphoma (SLL).
Method: A prospective observational nationwide multicenter study. Treatment-naïve (TN) and relapsed/refractory (R/R) CLL/SLL patients were enrolled in 13 medical centers in Israel. The primary endpoint was clinical response, per physician assessment 12-months after the initiation of venetoclax treatment. Key secondary endpoints included progression free survival (PFS), overall survival (OS) and uMRD as assessed at a central laboratory by 8-color flow-cytometry.
Results: Between February 10, 2019, and Jun 17, 2021 (data cut), 199 CLL/SLL patients were enrolled from 13 medical centers in Israel to receive venetoclax based therapy. The study included 83 TN and 116 R/R evaluable CLL/SLL patients with a median age of 69 years (range, 34-85) and 70.5 years (range, 25-91), respectively (Table 1). R/R patients had received a median of one prior therapy with a range up to 8, of these patients 60 (51.7%) were previously treated with a B-cell receptor inhibitor (BCRi) including ibrutinib in 52 (44.8%) and idelalisib in combination with rituximab in 6 (5.2%). TN patients had been treated with venetoclax in combination with obinutuzumab (92.8%) or rituximab (4.8%) and R/R patients received either venetoclax with rituximab (60.3%) or obinutuzumab (9.5%), venetoclax monotherapy (25.8%) or triple therapy with venetoclax, rituximab and ibrutinib in 5 (4.3%).
Dose escalation of venetoclax to the recommended dose of 400 mg daily was achieved in 80.7% (n=67) of TN and 81% (n=94) of R/R patients. The median duration of ramp-up was 38 and 42 days in TN and R\R patients, respectively. Prior to therapy, tumor lysis syndrome (TLS) risk was considered high in 12% and 29.3% of TN and R/R patients, respectively (Table 1). Laboratory TLS occurred in one TN patient and 4 R/R patients, whereas 3 of the R/R patients experienced clinical TLS.
Nineteen TN and 75 R/R patients had a follow-up of at least 12 months or discontinued study prematurely. The 12-month overall response rate (ORR) for TN and R/R patients was 89.5% [complete response (CR) 13 (68.4%), partial response (PR) 4 (21.1%)] and 73.3% [CR 37 (49.3%), PR 18 (24%)], respectively. In the R/R cohort, the 12-month ORR among assessed patients was 67.6% (25/37) in BCRi-exposed versus 85.7% (30/35) in BCRi-naïve patients. At 12 months, peripheral blood uMRD (&lt;0.01%) was achieved in 12 out of 14 (85.7%) TN and 26 out of 38 (68.4%) R/R evaluated patients. At a median follow-up of 5.1 months (range, 0.5-15.6) for TN and 10.1 months (range, 0-25.7) for R/R patients, the median PFS and OS, for both cohorts have not been reached. The estimated 12-month PFS was 90.9% for TN and 81.1% for R/R patients. For R/R patients with prior exposure to BCRi, the estimated 12-month PFS was 69.6% versus 94.8% in BCRi-naïve patients (figure 1).
Grade ≥3 adverse events (AEs) were reported in 34.9% of TN patients and 43.9% R/R patients. The most frequent grade ≥3 AEs documented were neutropenia (TN: 19.2% and R/R 17.2%), infections (TN: 4.8% and R/R: 21.5%) and febrile neutropenia (TN: 2.4% and in R/R: 2.6%). COVID-19 occurred in 7 patients including one death. At the time of data cut, 10 deaths occurred, one TN and 9 R/R patients. Causes for death included infections (5 patients), disease progression (2 patients), acute myeloid leukemia/ myelodysplastic syndrome (2 patients) and a soft-tissue sarcoma (1 patient).
Conclusions: This first interim analysis of our ongoing prospective real-world study of venetoclax-based treatment for TN and R/R CLL/SLL, demonstrates high efficacy together with a high proportion of undetectable MRD levels and a favorable toxicity profile. These efficacy results are comparable to those reported in previous Phase III clinical trials for CLL, with no new safety signals.
Figure 1 Figure 1.

Disclosures
Herishanu: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Itchaki: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levi: AbbVie: Consultancy, Research Funding. Aviv: AbbVie: Honoraria, Research Funding. Fineman: AbbVie: Research Funding. Dally: AbbVie: Honoraria, Research Funding. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Abadi: AbbVie: Honoraria, Research Funding. Shvidel: AbbVie: Honoraria, Research Funding. Braester: AbbVie: Honoraria, Research Funding. Cohen: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Benjamini: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.