Data for fixed-duration regimens in CLL suggest benefits over chemoimmunotherapy but still require improvements for high-risk patients.
With numerous fixed-duration regimens utilizing targeted therapies approved by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), these options have helped maintain efficacy outcomes and reduce toxicity burden compared with continuous treatment approaches. While treatment-free intervals and efficacy outcomes are encouraging leaps forward for patients receiving fixed-duration therapy, progress remains to be made for patients with higher-risk disease, according to a review of currently approved fixed-duration regimens.1
Examples of fixed-duration regimens approved by the FDA or other regulatory agencies for CLL/SLL include:
Data for each of the regimens from their respective studies demonstrated improvements in progression-free survival (PFS) and rates of undetectable minimal residual disease (MRD) over chemoimmunotherapy, enabling treatment-free intervals and supporting subsequent regulatory approvals.1
“At the end of the day, these regimens are very similar, whether it's an efficacy standard or a safety standard,” John N. Allan, MD, said in an interview with OncLive®. “Patients who are [at] high risk, like those with 17p deletions and complex karyotypes, still represent a very unique problem for us…While these drugs hit home runs and can [lead to] remission for decades with each line of therapy, there are still only really 2 classes of drugs [in BTK inhibitors and BCL2 inhibitors] that we have that continue to extend the lines of therapy...Identifying new molecules, the best combinations, and the best way to deepen remissions [for patients with high-risk disease] is a high priority and still an unmet need [in CLL].”
Allan is an associate attending physician at New York-Presbyterian Hospital and an associate professor of clinical medicine at Weill Cornell Medical College in New York, New York.
Improvements in efficacy seen with fixed-duration regimens are reduced in patients who are considered high-risk. For example, in CLL14, subgroup analyses revealed that patients without 17p deletions or TP53 mutations who received venetoclax plus obinutuzumab achieved a median PFS of 76.6 months compared with 51.9 months in those with such high-risk features. Although venetoclax plus obinutuzumab improved PFS in both groups, Allan highlighted that patients without high-risk features still experienced improved outcomes in the experimental arm.
Moreover, in GLOW, patients who received ibrutinib plus venetoclax with mutated IGHV region achieved a 42-month PFS rate of 90% vs 69.8% in patients with unmutated IGHV.
“As we are now starting to really look decades into the future for these patients, we do start to see that [those with high-risk features] are the ones at most risk of developing resistance to these various classes of drugs,” Allan explained. “As you look long-term, 10 years or longer, patients [who are high risk] are still the ones at risk of, maybe [progressing on] several classes of these drugs and needing more things into the future.”
In his narrative review, Allan also accounted for increased cardiovascular treatment-emergent adverse effects (TEAEs) that are often associated with fixed-duration regimens containing BTK inhibitors, such as ibrutinib. Allan highlighted how in GLOW, 4 patients experienced sudden or cardiac death, in addition to rates of any-grade atrial fibrillation being 14.2% in the ibrutinib plus venetoclax arm and 1.9% in the chlorambucil plus obinutuzumab arm.
The gaps left for specific subsets of patients by current fixed-duration regimens underscore the importance of the continued development of novel treatments and approaches for the CLL field, according to Allan. Specifically, Allan looked to newer generations of BCL2 inhibitors like sonrotoclax (Beqalzi), the covalent BTK inhibitors acalabrutinib and zanubrutinib (Brukinsa), and the noncovalent BTK inhibitor pirtobrutinib (Jayprica), as well as MRD-guided approaches to optimizing fixed-duration regimens.
Allan shed light on ongoing studies in the treatment-naïve setting that are utilizing points of emphasis from Allan’s review, including the phase 3 CELESTIAL-TNCLL trial (NCT06073821) evaluating fixed-duration zanubrutinib plus sonrotoclax vs venetoclax plus obinutuzumab. Additionally, the phase 3 MAJIC study (NCT05057494) is evaluating acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab with an MRD-guided approach.
“The next big group of studies is going to be bringing MRD results into management of patients. Whether you extend treatment, add on treatment, or shorten treatment, all of these study designs are being done and performed right now,” Allan added. “Second-generation drug combinations with acalabrutinib or zanubrutinib plus venetoclax do have cardiovascular safety improvements…We are still favoring these combinations [with second-generation BTK inhibitors].”
In addition to prioritizing novel approaches and treatments, Allan also noted the importance of head-to-head comparisons to help better understand the nuances between each fixed duration-regimen.
“The other thing that is important is that we need to understand a little bit better is if there are certain patients, whether they are high risk or low risk, who might do better with a specific approach,” Allan said. “Maybe we need to maximize treatment and even maintain treatment. It's unclear what to do for some of these patients who are high risk. The next layer of studies are going to be looking towards optimization of patients, as well as bringing in the MRD guidance in terms of duration of therapy. While fixed-duration [therapy] is great, simple to deploy, and patients like it, there are certain patients who might actually have an improved outcome if we can deepen their response before we stop their therapy.”
