Ibrutinib plus venetoclax confers high rates of undetectable minimal residual disease in the first-line treatment of chronic lymphocytic leukaemia

The CAPTIVATE study is a multicenter phase II study that evaluates the combination of ibrutinib plus venetoclax to assess  the depth of minimal residual disease (MRD) response in both bone marrow and peripheral blood in the first-line treatment of chronic lymphocytic leukaemia/small lymphocytic lymphoma. With this all-oral, chemotherapy-free regimen, deep MRD remissions in bone marrow and peripheral blood were obtained, including in high-risk patients. In addition, the need for hospitalisation for high-risk tumour lysis syndrome was reduced and the ibrutinib plus venetoclax combination showed a favourable safety profile with high completion rates.

Background

Ibrutinib is the only once-daily Bruton’s Tyrosine Kinase inhibitor that demonstrated a significant overall survival benefit in two randomised phase III studies in first-line CLL (RESONATE-2; ECOG1912). When combined, ibrutinib plus venetoclax (oral inhibitor of BCL2) may have synergistic antitumour activity via mobilization and clearance of chronic lymphocytic leukaemia (CLL) cells from protective niches and disease compartments beyond peripheral blood (PB) and bone marrow (BM). An all-oral, once-daily, fixed duration option with ibrutinib and venetoclax may offer improved patient convenience and ease of administration with reduced risk of tumour lysis syndrome (TLS) and reduced need for hospitalisation for venetoclax initiation. CAPTIVATE is a multicenter phase II study evaluating ibrutinib plus venetoclax to achieve a deep response, including undetectable minimal residual disease (uMRD), in first-line treatment of CLL or small lymphocytic lymphoma (SLL).

Patients (n=164) aged less than 70 years with previously untreated CLL/SLL requiring therapy received three cycles of ibrutinib lead-in followed by twelve cycles of ibrutinib (orally 420 mg/day) plus venetoclax (with a ramp-up to 400 mg/day orally). At EHA 2020, results were presented for the pre-randomisation phase of the CAPTIVATE MRD cohort with twelve cycles of ibrutinib plus venetoclax prior to MRD-guided randomisation. Median age of the study participants was 58 years with a fair number of patients that have poor risk features such as del(17p) in 16%, del(17p) or TP53 mutation in 20%, del(11q) in 16%, complex karyotype in 19% and unmutated IGHV in 59% of the patients.

Results

Overall, 148 patients (90%) completed the ibrutinib lead-in and all 12 cycles of ibrutinib plus venetoclax. Median treatment duration was 14.7 months with ibrutinib and 12.0 months with venetoclax. Among patients with high TLS risk at baseline, 90% were downgraded to medium/low risk after 3 cycles of ibrutinib lead-in and hospitalisation was no longer indicated in 66% of at-risk patients. Moreover, 82% of patients initiated venetoclax ramp-up without hospitalisation. Undetectable minimal residual disease (uMRD, 10^-4) was achieved as best MRD response in 75% of patients in the PB and 72% in BM and were highly concordant (90%). In addition, the proportion of patients with uMRD in peripheral blood increased over the twelve cycles of combination therapy. After a median follow-up of 14.8 months in all-treated patients, the ORR was 97%, with 51% of the patients who achieved a complete response. Moreover, at 15 months, 98% of the patients were progression-free with no deaths. High rates of uMRD in BM were observed independent of baseline disease risk characteristics, including high-risk patients with del(17p) (75%), del(17p) or TP53 mutation (70%), del(11q) (83%), complex karyotype (83%), and unmutated IGHV (81%).

There were no fatal adverse events (AEs) and AEs leading to discontinuation of all study treatments were infrequent (5%). The most common AEs with ibrutinib plus venetoclax were primarily grade 1/2 events with no new safety signals. The most common grade 3/4 AEs were neutropenia (35%), hypertension (7%), thrombocytopenia (5%), and diarrhoea (5%). Only low grades of grade 3 atrial fibrillation, major haemorrhage, infections and febrile neutropenia were observed. No patients developed clinical TLS and laboratory TLS was reported as an AE in three patients, of which only one met Howard criteria.

Conclusions

The all-oral, once daily, chemotherapy-free regimen of ibrutinib plus venetoclax provides highly concordant, deep MRD remissions in bone marrow and peripheral blood in the first-line treatment of CLL. Results from CAPTIVATE thereby validate the preclinical synergism of this combination. Furthermore, the ibrutinib lead-in substantially reduced venetoclax-related TLS risk and need for intensive monitoring or hospitalization. Finally, the safety profile of ibrutinib plus venetoclax was favourable with a low rate of discontinuation due to AEs and 90% completing all planned treatment with 3 cycles of ibrutinib and 12 cycles of the ibrutinib plus venetoclax combination.

Reference

Siddiqi T, Tam CS, Allan JN, et al. First-line ibrutinib (IBR) + venetoclax (VEN) for patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): efficacy and safety results from CAPTIVATE MRD cohort. Presented at EHA 2020; Abstract S158.