Ibrutinib combined with Venecla is an effective oral non-chemotherapeutic regimen for initial treatment of CLL patients

The application of oral targeted drugs has completely changed the treatment model of chronic lymphocytic leukemia (CLL)
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A variety of Bruton's tyrosine kinase inhibitors (BTKi), including ibrutinib, and the BCL-2 inhibitor, Venecla, are currently approved for the treatment of CLL
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Previous studies have shown that continuous treatment with BTKi alone can achieve partial remission (PR) for most CLL, but the proportion of patients with complete remission (CR) is lower, and the proportion of patients with undetectable minimal residual disease (U-MRD) is even lower
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Based on the characteristics of preclinical synergy and non-overlapping toxic effects of ibrutinib and veneclair, the researchers conducted a non-randomized, II evaluation of the efficacy of ibrutinib and veneclair in newly-treated CLL patients.
Phase clinical research
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Research methods The newly diagnosed CLL patients included in this study are all indicated for treatment and meet at least one of the following characteristics: del(17p), TP53, del(11q), IGHV without mutation or age ≥65 years
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All patients were treated with Ibrutinib as a single agent in the first 3 treatment cycles, and then combined with Venecla, each cycle was 28 days, and the combined treatment plan was to be administered for 24 cycles
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Research results 1 Patient baseline characteristics The study included a total of 80 patients from August 17, 2016 to June 5, 2018 (see Table 1 for baseline characteristics), of which the majority were male patients, accounting for 71%, and the median age of the patients was 65 years old (range: 26-83 years old); a total of 14 patients (18%) carried del(17p), 11 (14%) patients carried TP53 mutation, and 18 (23%) patients carried del(17p) and/ Or TP53 mutation
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Five patients discontinued the study due to reasons other than disease progression during the monotherapy period of ibrutinib, and the remaining 75 patients received the combination therapy of ibrutinib and venacral
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The median follow-up time for all 80 patients was 38.
5 months (range: 5.
6-51.
1 months)
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Table 1: Baseline characteristics of patients 2 Bone marrow MRD status of patients In general, in the continuous evaluation during the combination therapy, more and more patients have achieved bone marrow U-MRD (see Figure 1 for details)
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The results of the analysis of the intent-to-treat population of the combination therapy showed that 56% of the patients achieved bone marrow U-MRD in the evaluation of 12 cycles of treatment; 66% of the patients achieved bone marrow U-MRD in the evaluation of 24 cycles of treatment; In the trial design, 51 patients discontinued Ibrutinib and Venecla, and 2 patients continued to use Ibrutinib monotherapy according to the judgment of the treating doctor
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75% of patients reached bone marrow U-MRD at any time during the study period
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In addition, among 18 subjects with del(17p) and/or TP53 mutations, 13 patients completed 24 cycles of combination therapy; among them, the bone marrow U-MRD of patients was in 12 and 24 treatment cycles.
The rates are 69% and 77% respectively
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Figure 1: Bone marrow MRD status of patients with intention-to-treat at different time points 3 CR/CRi status of patients Overall, 62 patients (78%) achieved the best remission during the study period (CR and CR with incomplete cell count recovery [CRi] )
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In 24 cycles of combined therapy, 55 patients (69%) achieved CR/CRi, and 10 (13%) patients achieved PR
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Similar remissions were observed in all high-risk subgroups, regardless of the patient's IGHV mutation status, del(17p) or TP53 mutation
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4 Survival status of patients The estimated 3-year progression-free survival (PFS) rate of patients in this study was 93% (95% CI: 88%-99%), and the estimated 3-year overall survival (OS) rate was 96% ( 95% CI: 92%-100%) (Figures 2A and 2B)
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Subgroup analysis, the PFS of patients with IGHV mutation and non-mutated CLL is shown in Figure 2C; the PFS of patients with CLL with and without del(17p) and/or TP53 mutation is shown in Figure 2D, which is accompanied by del(17p) and/or The estimated 3-year PFS rate of CLL patients with TP53 mutation is 86%
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No disease progression was observed, and 2 patients had Richter transformation
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Figure 2: A and B are the PFS and OS status of all patients, respectively; C is the PFS status of IGHV mutant and non-mutated patients; D is the PFS status of patients with or without del(17p) and/or TP53 mutations.
5 Adverse events A total of 41 patients (51%) had grade 3-4 neutropenia, and 2 patients (2%) had grade 3 thrombocytopenia
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Common (≥5%) non-hematological adverse events (AE) are detailed in Table 2
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4 patients developed neutropenic fever; other infectious complications that led to hospitalization included pneumonia, cellulitis, and non-neutropenic fever, anaplasmic infection, septic arthritis, and disseminated cryptococcal infection , Aspergillus/Cryptococcal infections and appendicitis/cholecystitis
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Table 2: Conclusions of common non-hematological AE studies.
This study shows that the combination of Ibrutinib and Venecla can benefit newly treated CLL patients
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The results of follow-up for more than 3 years showed that the above-mentioned combination therapy in newly treated CLL patients seemed to produce long-lasting remission, and it also had significant clinical activity in the high-risk subgroup including patients with del(17p)/TP53 mutations
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References: Nitin Jain, Michael Keating, Philip Thompson, et al.
Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia: A Nonrandomized Phase 2 Trial.
JAMA Oncol.
2021 Aug 1;7(8):1213-1219.
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