Is the optimal first-line treatment of chronic lymphocytic leukemia (CLL) monotherapy with a Bruton’s tyrosine kinase (BTK) inhibitor or some combination regimen? This clinical question was explored by two speakers at the 2024 Pan Pacific Lymphoma Conference, sponsored by the University of Nebraska.1 Danielle M. Brander, MD, is Associate Professor of Medicine, Hematologic Malignancies and Cellular Therapy, Duke University Medical Center. Matthew S. Davids, MD, MMSc, is Clinical Research Director of the Division of Lymphoma at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School.
Danielle M. Brander, MD
Matthew S. Davids, MD, MMSc
“Long-term follow-up—10-plus years—confirms the efficacy of BTK inhibitors as monotherapy in the front-line treatment of CLL. They can be well tolerated..., and toxicities can often be managed successfully,” Dr. Brander said. However, Dr. Davids cited these limitations of continuous BTK inhibitor therapy as opposed to fixed-duration treatment: complete responses and undetectable measurable residual disease (MRD) are rare, -resistance mutations arise, drug-drug interactions pose risks, toxicity can be cumulative and ongoing, adherence can be poor, and the treatment is more expensive.
Single-Agent Efficacy
Acknowledging that higher rates of complete response and undetectable MRD can be achieved with combinations, Dr. Brander countered with these comments: “It is a fallacy that BTK inhibitors by themselves cannot achieve deep responses. And there is insufficient evidence that achieving deeper responses with combinations vs monotherapy leads to improved progression-free or overall survival outcomes.”
This stance is supported by findings from key ibrutinib trials:
In the 10-year follow-up of the phase III RESONATE trial, median progression-free survival reached 8.9 years with ibrutinib (hazard ratio [HR] = 0.16; P < .0001); at study closure, 27% of patients remained on first-line ibrutinib, and the complete response rate was 36%.2
In a phase II study of ibrutinib, 54% of patients with TP53 mutations were alive at 9.8 years; 20% remained on ibrutinib, and 15% had undetectable MRD at 5 years.3 In a treatment-naive subset, 70% were alive, and 39% were progression-free at 9 years.
In other key trials, ibrutinib was found to be more effective than bendamustine plus rituximab or fludarabine, cyclophosphamide, and rituximab (FCR), and the addition of rituximab to ibrutinib did not appear to improve outcomes over ibrutinib alone.4,5
In the E1912 trial, disease progression was uncommon in patients able to remain on ibrutinib long term.5
Second-Generation BTK Inhibitors
“The second-generation covalent BTK inhibitors—acalabrutinib and zanubrutinib—have similar or superior efficacy and less toxicity,” said Dr. Brander. In the ELEVATE-TN trial, at 6 years’ follow-up, acalabrutinib plus the monoclonal antibody obinutuzumab was more effective than acalabrutinib alone with respect to progression-free survival, though not in patients with high-risk disease including del(17) and TP53 mutation.6 In the front-line SEQUOIA trial, single-agent zanubrutinib significantly extended progression-free survival (HR = 0.42; P < .0001) over bendamustine plus rituximab, with particular benefit in patients with the more aggressive immunoglobulin heavy chain variable unmutated disease.7
Focus on Toxicity
“We aren’t just talking about efficacy but also about long-term safety,” Dr. Brander commented. In the final analysis of the RESONATE-2 trial, about one-third of patients discontinued ibrutinib because of toxicity, although 80% of patients had resolution of adverse events with dose modifications.2 With second-generation BTK inhibitors, treatment discontinuation from toxicity is less common.
Commenting on the combination of ibrutinib and venetoclax,8 Dr. Brander noted a more “impressive” 75% rate of undetectable MRD and a 93% progression-free survival rate at 3 years. However, she cautioned, “this comes with some risk,” even for a “relatively healthy” group of patients…. Outcomes were inferior for patients with comorbidities. Similarly, in the phase III GLOW trial, several patients died because of adverse events.9 Furthermore, it remains unclear whether the combination is better than single-agent ibrutinib.
“Any toxicities, especially if prolonged, are meaningful and can impact quality of life…,” Dr. Brander noted. “There might be [with combinations] fancier complete responses or MRDs, but there’s also a lot more toxicity. In the end, that balance can tip things.”
The Case Against Continuous Use of BTK Inhibitors
On the other hand, Dr. Davids argued, “intermittent time-limited combination therapy may ultimately win over continuous BTK inhibitor monotherapy, as the progression-free survival will likely be similar, but the cost and toxicity will be less. There will, however, remain a place for continuous BTK inhibitor monotherapy for certain patients, such as older individuals seeking simplicity, particularly once generic BTK inhibitors become available.”
Dr. Davids pointed to the toxicity observed with single-agent ibrutinib in RESONATE-2, where at 8 years just 42% of patients remained on treatment. “Years into ibrutinib therapy, patients can develop hypertension or atrial fibrillation, which can be difficult to manage. And, in the real-world setting, treatment discontinuation from adverse events is even higher.”
Drug interactions are also a risk. Patients on a continuous BTK inhibitor for 10 years will likely also be prescribed other drugs that enhance toxicity risks, he added.
Dr. Davids acknowledged second-generation BTK inhibitors cause less toxicity. However, he explained, toxicities can be cumulative over the years, including ongoing risks of atrial fibrillation, hypertension, bleeding events, diarrhea, and arthralgias. In the ALPINE trial, for example, dose reductions or interruptions were needed for 74% of the ibrutinib cohort as well as 62% of the zanubrutinib arm.10 Additionally, prolonged use of these drugs can lead to resistance. “I would argue that the covalent BTK inhibitors are more similar than they are different,” he commented.
The Case for Time-Limited Therapy
A key goal with fixed-duration therapy is achievement of undetectable MRD, which is associated with prolonged progression-free survival and, in some studies, longer overall survival. Patients who enter deep remission often have lengthy treatment-free intervals without the ongoing toxicities and cost, noted Dr. Davids.
For example, in the CLL14 trial,11 which evaluated venetoclax plus obinutuzumab in an older population with comorbidities, most patients achieved undetectable MRD after 1 year of treatment, and this persisted over time—even off therapy—and led to median progression-free survival of 76 months. Benefit was seen even in high-risk patients, and median time to next treatment was not reached. Although adverse events did occur with this front-line combination, “they were modest for most patients,” he observed.
Dr. Davids continued: “The important point is that when patients come off treatment, these toxicity rates drop dramatically, which is very different from what we saw in RESONATE-2, where there were ongoing risks 4 years after starting ibrutinib therapy. With venetoclax plus obinutuzumab, once you finish 1 year, you have very little toxicity from treatment.”
The doublet of venetoclax plus obinutuzumab may be just as effective in younger patients. So far, there is no evidence the time-limited therapies induce resistance mutations, he said.
“If you compare the CLL14 data with studies of continuous BTK inhibitor–based treatment,” he noted, “the progression-free survival curves look very similar. So, you’re seeing similar efficacy with 1 year of treatment compared with 5, 6, 7 years.”
Fixed-duration therapy also allows for retreatment, accumulating data suggest. “We can use the same drugs again, because for many patients, they are going to work a second time,” Dr. Davids explained.
More Answers to Come
Answers are being sought for a number of treatment questions. One is whether triplets might be even better; activity has been shown for the more specific BTK inhibitors given with venetoclax and obinutuzumab. The AMPLIFY study is evaluating acalabrutinib plus venetoclax with and without obinutuzumab in treatment-naive patients with CLL who do not have del(17p) or TP53 mutations. The CLL17 trial is comparing continuous BTK inhibitor therapy with time-limited venetoclax-based doublets. The global MAJIC study aims to define the optimal MRD-guided, time-limited venetoclax doublet for front-line CLL treatment.
In closing, Dr. Davids noted, ibrutinib plus venetoclax is not an approved regimen in the United States, but he hopes that acalabrutinib plus venetoclax will be approved soon based on the results of the AMPLIFY study. “This would be an appealing option, because it is all-oral, time-limited, and therefore should be well tolerated for most patients,” he said.
DISCLOSURE: Dr. Brander has received clinical research support from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Catapult, DTRM, Genentech, Merck & Co., neWave, Nurix Pharmacyclics, and TG Therapeutics and has served as an advisor or consultant to AbbVie, Genentech, and Pharmacyclics. Dr. Davids has reported personal financial relationships with AbbVie, Adaptive Biosciences, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Genmab, Janssen, Merck, Nuvalent, Secura Bio, Takeda, TG Therapeutics, and Up-to-Date.
REFERENCES
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