NCCN guidelines find that continuous BTKi and fixed-duration venetoclax plus obinutuzumab offer longer PFS and OS vs chemoimmunotherapy as first-line treatment in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.
There is a lack of published first-line, head-to-head studies comparing venetoclax and BTKi in patients with CLL.
Venetoclax-based combination regimens offer a defined treatment course and potentially reduce the development of medication resistance.
The treatment for chronic lymphocytic leukemia (CLL) has changed dramatically in recent years. To date, it’s been difficult to choose among multiple effective options, with oncologists needing to consider disease and patient factors, as well as the need to sequence available therapies in the case of relapse, according to authors of a 2023 article in the Journal of Hematology & Oncology.
Of high priority is the consideration of fixed-duration venetoclax vs a Bruton’s tyrosine kinase inhibitor (BTKi) as first-line (1L) treatment for CLL.
Diminished role of chemoimmunotherapy (CIT)
BTKi and the anti-apoptotic protein B-cell lymphoma 2 (BCL2i) are highly effective targeted 1L treatments indicated for CLL, with significant activity in all genomic risk subgroups. The most highly developed BCL2i in development is venetoclax.
Overall continuous BTKi and fixed-duration venetoclax plus obinutuzumab (VenO) exhibit superior improved progression-free survival (PFS) and overall survival (OS) when compared with CIT—regardless of patient fitness.
“While CIT is unsuitable for the majority of patients, it may be considered for carefully selected individuals without genomic adverse-risk disease,” wrote the Journal of Hematology & Oncology review authors.
According to the authors, the use of time-limited CIT in younger CLL patients with mutated immunoglobulin heavy-chain gene variable region (IGHV, without TP53 mutation), after careful counseling, is preferred.
Guidelines from the NCCN
Because CLL and small lymphocytic lymphoma (SLL) represent different manifestations of the same disease, the National Comprehensive Cancer Network (NCCN) conflates the two conditions when providing treatment recommendations.
NCCN guidelines highlight that CLL/SLL is usually diagnosed in older adults (median age: 72 years), and an age cutoff of 65 years is typically used in most CIT clinical trials (eg, German CLL Study Group).
Comorbidities are usually present in older patients, with two or more comorbidities independently associated with clinical outcomes—regardless of patient age or disease stage. Patient age, performance status, comorbidities, and the presence or absence of del(17p) or TP53 mutation help guide treatment planning in patients with indications for treatment.
Based on the results of phase 3 trials involving different small-molecule inhibitors, the NCCN makes the following recommendation:
“In addition to the aforementioned disease- and patient-specific factors, agents’ toxicity profile and duration of treatment (continuous vs fixed duration) should also be considered for the selection of first-line therapy. [BTKis] are given continuously until disease progression, whereas venetoclax-based combination regimens offer a defined treatment course. Fixed duration treatment with venetoclax-based combination regimens also results in higher rates of undetectable minimal residual disease (uMRD), which is an independent predictor of improved survival.”
Venetoclax vs BTKi
There is a paucity of published head-to-head studies comparing venetoclax vs BTKi as 1L treatment options. The results of the CLL17 study are hotly anticipated, which will compare PFS in ibrutinib continuous monotherapy vs fixed-duration VenO vs fixed-duration IbVen.
Although perceived efficacy is a principal factor in treatment planning, patient-specific factors may be equally or more important, according to the Journal of Hematology & Oncology authors.
“It is important to consider general fitness and specific comorbidities, adverse event profiles described, and perceived tolerability, acknowledging discontinuation rates due to adverse events in pivotal studies. Further factors to consider include the logistics of treatment administration, frequency of safety monitoring by venipuncture and/or clinic attendances, and potential burden placed on the patient and their carers,” the authors noted.
“More broadly, it is also important to appreciate the ability to bidirectionally sequence novel therapies (ie, Ven → BTK or BTK → Ven), appreciating the longitudinal context of the patient’s age and fitness,” they added.
The authors go on to generally suggest time-limited VenO as 1L, with the potential to re-treat.
Authors of a case study published in Hematology, ASH Education Program also noted that results of the CLL17 study are necessary to directly compare BTKi with fixed-duration VenO in treatment-naïve CLL. To date, these two treatments appear to have comparable efficacy, with an estimated 4-year PFS of 76% for continuous ibrutinib vs 74% for fixed-duration VenO in older adults with treatment-naïve CLL.
Current data also indicate that there could be differences in efficacy among CLL subgroups. For example, the 5-year PFS in the unmutated IGHV subgroup was 67% in those receiving ibrutinib vs 56% in those receiving VenO.
In patients with TP53 aberration, data favor continuous treatment with ibrutinib, with a PFS of 70% at 5 years vs that of 41% at 5 years in VenO patients.
“In the setting of these very limited data, most investigators favor a BTKi for patients with TP53 aberration in the absence of a clinical trial. For U-IGHV, although fixed-duration therapy may result in a shorter initial PFS, patients may be eligible for [VenO] retreatment that would extend the total benefit of the regimen,” the authors wrote.
“The opportunity to have long durations off therapy has intrinsic value and may reduce the development of resistance. More data are certainly needed to inform treatment selection in patients with higher-risk markers. These would include prospective trials specific to TP53 aberrant CLL and extended follow-up data that encompass 2 or more lines of therapy (and/or retreatment),” they added.
Which BTKi is best?
Although study investigators used ibrutinib, it should be noted that acalabrutinib and zanubrutinib appear to have greater efficacy, are less toxic, and are preferred at treatment initiation.
Fixed-duration therapy is considerably less expensive. Among BTKis, zanubrutinib is currently the least expensive, but the Inflation Reduction Act established the ability for CMS to negotiate for price in certain scenarios—ibrutinib is one of the first 10 agents that will be part of this program.
Acalabrutinib and zanubrutinib are more selective and have less off-target inhibition vs ibrutinib and aim for a lower toxicity burden. These next-generation BTKis demonstrate stable and near-complete BTK occupancy at recommended dosing and aim for a lower toxicity burden.
“Overall, while there are data supporting efficacy all three covalent BTKi in the treatment-naïve setting, [zanubrutinib] and [acalabrutinib] are the preferred BTKi due to at least similar efficacy and reduction in important toxicities compared with [ibrutinib] in [relapsed/refractory CLL]. There are specific situations in which these preferences may be stronger such as those with pre-existing cardiac comorbidities and/or those receiving concomitant anticoagulant or antiplatelet therapy,” according to the Journal of Hematology & Oncology authors.
What this means for you
Until the results of the CLL17 trial are published comparing BTKi and fixed-duration venetoclax in treatment-naïve CLL, the choice of either agent as 1L relies on patient factors and clinical opinion. Based on current efficacy data, the drugs are comparable. Importantly, patients with TP53 aberration may respond better to BTKi, whereas venetoclax may be a better choice in those with U-IGHV due to the potential for consideration of retreatment with this regimen at relapse.