Combining ibrutinib and venetoclax seems to work for treatment-naïve CLL

In treatment-naïve patients with chronic lymphocytic leukemia (CLL), combined oral treatment with ibrutinib and venetoclax brought about durable remission over three years, with responses even in patients with high-risk disease, such as those with del(17p)/TP53-mutations.

“Treatment of [CLL] has undergone a substantial evolution with the development of oral targeted therapies. The Bruton tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib, and venetoclax, a Bcl-2 inhibitor, are approved for treatment of CLL,” wrote Nitin Jain, MD, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, and fellow researchers in JAMA Oncology.

“Bruton tyrosine kinase inhibitors typically are administered as monotherapy continuously daily, with most responses being partial remission; complete remission (CR) is uncommon, and undetectable measurable residual disease (U-MRD) remissions are rare. Venetoclax is typically combined with the CD20 monoclonal antibody obinutuzumab and is given for 1 year in the treatment-naive setting,” they added.

The advantages of both classes of agents are also to be considered. Regimens based on venetoclax reduce risks for long-term, treatment-related adverse events, are more cost effective, and bring about higher rates of blood and bone marrow U-MRD remission compared with BTK inhibitors. On the other hand, noted researchers, “Bruton tyrosine kinase inhibitors have the advantage of the availability of long-term follow-up data, lower risk of tumor lysis syndrome and neutropenia, and durable responses in patients with del(17p)/TP53-mutated CLL.”

For this study, they enrolled 75 patients (median age: 65 years; 71% men) with previously untreated CLL, with at least one of the following: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 or older. Primary outcomes were complete remission (CR), complete remission with incomplete count recovery (Ci), and bone marrow-undetectable measurable residual disease (U-MRD).

Patients received treatment with ibrutinib monotherapy (420 mg/d) for three cycles, after which they received ibrutinib combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for 24 cycles.

After a median follow-up of 38.5 months, intent-to-treat analysis showed that 56% of patients reached bone marrow U-MRD remission after 12 cycles, while 66% did so at 24 cycles. Best response was bone marrow U-MRD remission, which was seen in 75% of patients.

After 12 cycles of treatment, 69% of patients achieved CR/CRi, and 18% were in partial remission. After 24 cycles, 69 achieved CR/Cri and 13% were in partial remission. In all, 78% of patients had CR/Cri as a best response.

At three years, estimated progression-free survival (PFS) was 93% (95% CI: 88%-99%), and overall survival was 96% (95% CI: 92%-100%). CLL progression did not occur in any patients, while two developed diffuse, large B-cell lymphoma Richter transformation.

Patients in all high-risk subgroups demonstrated response to treatment, and this was independent of their immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. In the 18 patients with del(17p)/TP53-mutated CLL, 3-year PFS was 86%.

Grade 3/4 neutropenia occurred in 51% of patients, and grade 3 thrombocytopenia in 2%. The most common, nonhematologic adverse events included easy bruising (76%), arthralgia (58%), and diarrhea (53%). Infectious complications that led to hospitalization included pneumonia in five patients and cellulitis in three.

Jain and fellow researchers noted that the optimal duration of treatment with combination therapies that include venetoclax is, as yet, an undefined but important question. The 24 scycles of combined ibrutinib/venetoclax therapy elicited good responses, and therefore, the study protocol was amended to include an extra year of combined therapy for patients with bone marrow MRD-positive results after 24 cycles.

“Whether this additional year of therapy will lead to U-MRD remission remains to be determined,” wrote Jain et al.

“The findings of this nonrandomized trial suggest that combined ibrutinib and venetoclax therapy may be an effective oral nonchemotherapy regimen for patients with CLL. In first-line treatment of older patients and those with high-risk CLL, during a follow-up of more than 3 years, remissions appeared to be durable, with activity seen across high-risk disease subgroups,” they concluded.

Study limitations include its single-center, nonrandomized, phase II design, and the relatively short median follow-up.

  1. Combined ibrutinib and venetoclax therapy may be an effective oral nonchemotherapy regimen for patients with chronic lymphocytic leukemia (CLL).

  2. In the first-line treatment of older patients and those with high-risk CLL, remissions appeared to be durable, with activity seen across high-risk disease subgroups after a follow-up of over 3 years.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

AbbVie provided funding and supplied the study drug venetoclax. The study was supported by The University of Texas M.D. Anderson Cancer Center (MDACC) Chronic Lymphocytic Leukemia Moon Shot program, a grant from the Andrew Sabin Family Foundation, and grants from the CLL Global Research Foundation, and MDACC.

Jain reported receiving grants and personal fees from AbbVie during the conduct of the study; and grants and personal fees from Pharmacyclics, Genentech, AstraZeneca, BMS, ADC Therapeutics, Servier, Cellectis, Precision Biosciences, and Adaptive Biotechnologies; personal fees from Janssen, BeiGene, and TG Therapeutics; and grants from Pfizer, Incyte, Fate Therapeutics, Aprea Therapeutics, Mingsight Pharmaceuticals, and Kite/Gilead outside the submitted work.

Cat ID: 466

Topic ID: 78,466,730,466,192,925