Ibrutinib Plus Venetoclax Shows Favorable Efficacy and Safety Outcomes in R/R CLL

The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a favorable benefit-risk profile in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) treated in the VISION/HOVON 141, according to data published in Blood.

VISION/HOVON 141 (NCT03226301) is ongoing and aims to determine the feasibility MRD-guided treatment cessation and reinitiation in patients with R/R CLL.

Despite the long-term efficacy of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, undetectable minimal residual disease (uMRD) is rarely seen. Minimal residual disease (MRD) is an important predictor of survival and long-term outcomes for R/R CLL patients treated with chemo-immunotherapy. More novel therapies and treatment options are needed for this patient population in order to reduce MRD. Venetoclax is a Bcl-2 inhibitor that in combination with a CD-20 targeting antibody has been found to increase the rate of uMRD. Early data also suggests that there is a correlation between MRD status and progression-free survival (PFS).

The study enrolled 230 eligible patients. The primary outcome of the study is the rate of PFS at 27 months after treatment initiation. Secondary outcomes include the number of patients with MRD negativity at 27 months after starting treatment, the rate of PFS at 7 years, the number of patients reinitiating treatment at 7 years, the number of patients with treatment failure after reinitiating treatment up to 7 years, the number of patients initiating new CLL treatment, the number of MRD negative patients at 12 and 15 months, the number of patients alive up to 7 years, the number of patients with complete remission (CR), patrial remission (PR), and stable disease (SD), the number of adverse events (AEs), and the number of patients with improved quality of life. 

Patients in the study received the combination of ibrutinib until disese progression and venetoclax for 15 cycles in the first experimental arm. In the arm ibutinib was dose at 420 mg and venetoclax was dosed at a minimum of 20 mg and maximum og 400 mg. Those who achieved at leasy a partial response then were randomized 1:2 to received either ibrutinib maintenance of observations.

Regarding patients with MRD positive tumors, they were randomized into the remaining 2 arms. During arm A, patients received ibrutinib as maintenance until progression or unacceptable toxicity. For patients randomized into arm B, therapy was reinitiated after progression or an MRD greater than or equal to 10-3 PB at least 1 month later of and MRD greater than or equal to 10-2 PB. Treatment would continue for 12 cycles.

In order to participate, patients must have been 18 years old or older, have adequate bone marrow function, creatinine clearance (CrCL) of greater than or equal to 30ml/min, adequate liver function, negative serological testing for hepatitis B, and WHO/ECOG performance status of 0-3, and a negative pregnancy test at study entry for people with childbearing potential. Patients with any prior therapy with ibrutinib and/or venetoclax, transformation of CLL, a history of confirmed progressive multifocal leukoencephalopathy, malignancies other than CLL requiring systemic therapies, not being treated with curative intention, or showing signs of progression after curative treatment, known bleeding disorders, or uncontrolled active infection are not eligible to participate.

Of the 230 patients, the first 24 with uMRD have been randomized into arm A or B. The interim analysis published in Blood includes data on the first 51 eligible patients reaching the time point for the first 15 cycles of treatment. The median age of the evaluable patients was 67 years. Seventy-one percent were male, 65% had a WHO performance status of 0, 84% were Binet stage B/C, 71% had received prior standard CIT, 18% had TP53 aberrations, and 57% ha IGHV unmutated status. Of the 51 patients included in the report, 49 completed the first 2 cycles, and 43 completed all 15 cycles of treatment. Of the patients who did not continue, 2 refused to continue, 2 discontinued due to toxicity of intolerance, 2 discontinued for a second malignancy, and 2 patients discontinued due to death. One patient died of tick-borne encephalitis and 1 patient died of Richter’s transformation.

Grade 2 AEs were the highest grade of AEs in 16% of patients. Grade 3 and grade 4 AEs were experienced by 50% and 26% of patients respectively. Twenty percent of patients reported grade 2 or higher atrial fibrillation, 14% reported bleeding. CR was reached for 29 patients and 13 patients reached PR. Over half, 55%, of patients reached uMRD in peripheral blood at cycle 15 and 33% also obtained bone marrow aspirate uMRD. The concordance uMRD status between peripheral blood and bone marrow was 71%. The remaining 29% of patients had low MRD in the bone marrow while uMRD in the peripheral blood.

_REFERENCE:

_{Niemann C, Dubois J, Kersting S, et al. Venetoclax and ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) - 15-month safety, response and MRD evaluation: Third interim analysis from the phase II Vision HO141 Trial. Blood 2019; 134 (Supplement_1): 4292. doi: https://doi.org/10.1182/blood-2019-124377}