Although BTK inhibitor–based regimens occupy key roles in the chronic lymphocytic leukemia (CLL) treatment paradigm, ongoing clinical trials may help clarify unanswered questions to improve frontline treatment approaches, according to Nicole Lamanna, MD.
Lamanna specifically highlighted the phase 3 CLL17 (NCT04608318) and FLAIR (EudraCR2013-001944-76) trials, which evaluated Bruton tyrosine (BTK) inhibitor–based regimens as frontline therapy for CLL. CLL17 compared the efficacy of continuous ibrutinib (Imbruvica) monotherapy vs time-limited venetoclax (Venclexta) plus obinutuzumab (Gazyva) and time-limited ibrutinib plus venetoclax.1 Findings showed fixed-duration venetoclax plus obinutuzumab (HR, 0.87; 98.3% CI, 0.54-1.41) and venetoclax plus ibrutinib (HR, 0.84; 98% CI, 0.53-1.32) were noninferior to ibrutinib monotherapy in terms of investigator-assessed progression-free survival (PFS).
FLAIR evaluated the efficacy of ibrutinib with or without venetoclax vs chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab; FCR), with personalized BTK inhibitor treatment durations based on minimal residual disease (MRD) status.2 Data showed ibrutinib plus venetoclax improved PFS vs FCR at a median follow-up of 43.7 months (HR, 0.13; 95% CI, 0.07-00.24; P < .001).
“[These data] show that all these regimens are good [for patients with CLL]. We’ll have to see with more time whether efficacy in certain subgroups starts separating, but [these data] show that, right now, these are all good regimens,” Lamanna said in an interview with OncLive®.
In the interview, Lamanna discussed the importance of both trials, breaking down the designs and data for each, and how they could contribute to the broader CLL space.
Lamanna is an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Irving Medical Center in New York, New York.
OncLive: How was CLL 17 designed? What implications do its data have for BTK inhibitors in CLL?
Lamanna: A trial that really leveled the playing field [for the CLL space was] the German study, CLL17, that compared ibrutinib continuous therapy vs venetoclax plus obinutuzumab vs ibrutinib plus venetoclax. It was a prospective study that did not include any chemoimmunotherapy, and they included patients with 17p deletions and TP53 mutations due to this. [There were] all these modern therapies prospectively being evaluated, and although the data are still early, with approximately 3 years of follow-up, PFS in all these arms was [similar].
Conversations regarding treatment preferences of patients that weigh different factors, such as comorbidities, will be longer [as] they have multiple options of great therapy. I think the only question that I have for CLL17 regarding the ibrutinib plus venetoclax and ibrutinib plus venetoclax regimens has to do with patients [who] had TP53 mutations. PFS [for patients with TP53 mutations] did seem to be a little bit better with chronic, continuous therapy with ibrutinib vs the time-limited approaches. We’ll have to see if that [difference] is clinically meaningful when we look longer term with regard to PFS and overall survival [OS]. Right now, the 3-year [rate] is similar at about 95% for all the arms. These data at least show that all these modern-day regimens are excellent options for our patients.
What unanswered questions about MRD need to be addressed in CLL? How does FLAIR answer these questions?
One of the questions that is talked about is: How do we use MRD in the frontline setting of CLL? This question is something that we need a lot more data on [to answer it]. Many of the studies have been looking at MRD either per flow cytometry, next-generation sequencing, or clonoSEQ to try to evaluate MRD levels in patients after time-limited approaches. One of the studies that’s been going on for many years that recently had long-term follow-up [data] presented was the FLAIR study.
[FLAIR] was a European study evaluating patients who [received] either continuous ibrutinib, ibrutinib plus venetoclax, or chemoimmunotherapy. What was interesting [about the study] is that for the ibrutinib plus venetoclax arm, when patients became MRD negative, they would double the [treatment] time period. Patients would stay on [treatment for double] the time period when they first became MRD negative. For example, if patients became MRD negative at 12 months, they would stay on the combination for 24 months, and so on and so forth. Twelve months was the first time [patients were evaluated for MRD in the FLAIR study]; therefore, the minimum time that patients would be on therapy [in the ibrutinib-containing arms] would be 24 months. The maximum time was up to 6 years.
CLL17 and FLAIR: Nuances of BTK Inhibitor–Based Therapy in Frontline CLL
- Optimal frontline BTK inhibitor–based regimens and the role of MRD remain unanswered questions in CLL.
- CLL17 evaluated multiple BTK inhibitor-based regimens, which showed noninferiority in terms of PFS with venetoclax plus obinutuzumab and venetoclax plus ibrutinib vs ibrutinib monotherapy.
- FLAIR evaluated ibrutinib with or without venetoclax vs FCR, with treatment duration for the ibrutinib arms guided by MRD status after 12 months.
For this study, patients were receiving an oral-oral combination for a prolonged…period [compared with] many of the studies that we’ve had running. [Treatment durations for our studies] have been approximately either 12 months or 15 months. The PFS of ibrutinib and venetoclax was much higher than [that of] ibrutinib, but these patients were on the therapy for several years, begging the question: Is this really a time-limited approach?
[We can ask this question] because we’re having people now on treatments for years, similar to a chronic, continuous BTK inhibitor [regimen]. [Ultimately, these data] show that if patients are receiving 2 oral agents, the longer they receive each agent, the better their PFS will be.
Five-year OS curves are starting to separate a little bit. But the question again is, what is the right amount of time for a time-limited approach? Should it be 12 months? Should it be longer? [These questions] address an area with MRD guidance that [the CLL field] needs a lot more work on.
What are the next steps for frontline CLL following CLL17 and FLAIR?
[We may find] that not every patient needs to achieve MRD negativity. Maybe our favorable patients [with] IGHV-mutated disease really don’t [need to achieve MRD negativity], and they can come off therapy early [because] they are going to do well. Maybe our higher-risk patients with 17p deletions or TP53 mutations would do better on a longer duration [of treatment], maybe 24 months. MRD is still not quite defined yet in CLL, but hopefully, with some of these future trials or longer follow-up with some of the ongoing trials like [CLL17 and FLAIR], we’ll be able to sort of distinguish [which patients] might be better for longer-term therapy.
How to finesse [these data] to make individualized [treatment] approaches in CLL depends upon the regimen or patients’ cytogenetics and mutational status. As [the CLL field] separates different individual groups of CLL, then maybe we can enhance regimens so patients achieve a prolonged PFS time to next treatment, and ultimately, the goal would be improvement in OS.
References
- Al-Sawaf O, Stumpf J, Zhang C, et al; CLL17 Trial Investigators. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. 2026;394(11):1084-1096. doi:10.1056/NEJMoa2515458
- Munir T, Cairns DA, Bloor A, et al; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063
