First-line ibrutinib-venetoclax allows for treatment-free remissions in patients with chronic lymphocytic leukaemia obtaining minimal residual disease negativity

Fixed duration treatment with 12 cycles of ibrutinib and venetoclax induces high rates of minimal residual disease (MRD) in previously untreated chronic lymphocytic leukaemia (CLL). Interestingly, patients with a durable undetectable MRD status with ibrutinib plus venetoclax who subsequently only received a placebo demonstrated a 1-year disease free survival rate of 95%. As such, these findings demonstrate that fixed duration ibrutinib-venetoclax opens the door for a treatment free remission for previously untreated CLL patients.

Background

Ibrutinib is the only targeted therapy that was shown to induce a significant overall survival (OS) benefit in randomised phase III studies with previously untreated chronic lymphocytic leukaemia (CLL) patients. Ibrutinib and venetoclax previously demonstrated synergistic and complementary antitumour activity with deep responses in patients with CLL. In the phase II CAPTIVATE study a total of 164 previously untreated CLL patients were treated with 3 cycles of ibrutinib (420mg once daily) followed by 12 cycles of ibrutinib (420mg once daily) plus venetoclax (ramp up to 400mg once daily). Patients with undetectable minimal residual disease (uMRD) were subsequently randomized between placebo or ibrutinib. Of note, in this study, confirmed uMRD was defined as < 10^-4 by 8-color flow cytometry serially over at least 3 cycles, both in peripheral blood and in bone marrow. In contrast, patients without uMRD were randomly assigned to ibrutinib with or without venetoclax. At ASH 2020, the primary analysis results of one-year disease-free survival (DFS) rates from the uMRD cohort were presented. As such, this analysis evaluates whether the fixed duration ibrutinib-venetoclax regimen is able to provide a durable treatment-free remission to patients obtaining an uMRD status after 12 cycles of therapy. In order to be eligible for the study, patients had to be younger than 75 years of age with previously untreated CLL requiring therapy.

Results

The median age of study participants was 58 years, 60% had an unmutated IGHV status, 19% had a complex karyotype and 20% of patients harboured a del(17p) or a TP53 mutation. When comparing baseline characteristics by randomised treatment arm, there seemed to be a higher rate of unmutated IGHV patients in the confirmed uMRD arm, compared to patients without uMRD (70% vs. 46%).

Interestingly, in the pre-randomisation phase of the MRD cohort, three cycles of ibrutinib lead-in substantially reduced the tumour lysis syndrome (TLS) risk and hospitalisation. In fact, after the ibrutinib lead-in, 90% of patients with baseline high TLS risk shifted to a medium or low TLS risk category. Among the 77 patients for whom hospitalisation would have been indicated with venetoclax initiation, hospitalisation was no longer indicated in 51 patients (66%) after ibrutinib lead-in. Overall, 82% of patients initiated the venetoclax post-ibrutinib lead-in without hospitalisation. In total, after twelve cycles of combined ibrutinib plus venetoclax, 75% of patients achieved undetectable MRD status as best response in blood and 72% in the bone marrow. Additionally, in patients with uMRD in peripheral blood with matched bone marrow samples at cycle 16, 93% had uMRD in both blood and bone marrow.

After the initial 12 cycles of ibrutinib-venetoclax 86 patients entered the uMRD cohort. After a median follow-up time of 16.6 months post-randomisation, the one-year DFS rate in the confirmed uMRD group was not significantly different between patients receiving placebo or ibrutinib (95.3% vs. 100%, respectively, p=0.1475). The 30-month PFS rates were more than 95% across all randomised arms. For the patients who did not achieve confirmed uMRD at the end of twelve cycles of combined ibrutinib-venetoclax, increases in uMRD were greater with continued ibrutinib-venetoclax than with ibrutinib alone.

Overall, very few patients required dose reductions or dose discontinuations. Adverse events (AEs) were primarily of grade 1 or 2 and mostly occurred during the first six cycles of ibrutinib-venetoclax and thereafter decreased over time, irrespective of subsequent randomised treatment. During the overall study period across all-treated patients (with median treatment duration 29 months), most common grade 3-4 AEs were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhoea (5%).

Conclusions

The one-year DFS rate of 95% in patients with uMRD randomised to placebo after twelve cycles of combined ibrutinib-venetoclax supports a fixed-duration treatment approach. The 30-months PFS rates of more than 95% across all treatment arms compare favourable to other first-line fixed-duration regimens including fludarabine-cyclophosphamide-rituximab and venetoclax-obinutuzumab. Adverse events generally decreased after the first six months of ibrutinib-venetoclax treatment and no new safety signals emerged over time. Overall, ibrutinib-venetoclax thus is an all-oral, once-daily, chemotherapy-free, fixed-duration regimen that provides highly concordant, deep MRD remissions in bone marrow and peripheral blood in first line CLL.

Reference

Wierda WG, Tam CS, Allan JN, et al. Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 1-Year Disease-Free Survival (DFS) Results From the MRD Cohort of the Phase 2 CAPTIVATE Study. Presented at ASH 2020; Abstract 123.