Exploring the role of triplet therapy in relapsed chronic lymphocytic leukemia (CLL) and an emerging role for ctDNA in CLL: key takeaways from the CLL2-BAAG trial

In the recently published final efficacy analysis of the CLL2-BAAG trial, Furstenau and colleagues describe efficacy outcomes for the triplet combination of acalabrutinib, venetoclax and obinutuzumab (AVO) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL) (1). Forty-five CLL patients, including 40% with prior Bruton’s tyrosine kinase inhibitor (BTKi) or venetoclax exposure, were treated with the AVO triplet with a minimal residual disease (MRD)-guided duration of treatment exposure. The combination demonstrated excellent efficacy with an estimated 3-year progression-free survival (PFS) of 85% and 3-year overall survival (OS) of 93.8% (1). In addition, the authors report provocative data regarding circulating tumor DNA (ctDNA) alongside traditional flow cytometry MRD results for CLL patients treated with the AVO triplet, demonstrating that in some cases ctDNA was positive prior to peripheral blood MRD testing by flow cytometry in patients with later clinical CLL progression (1). The CLL2-BAAG trial results add critical data to help answer two key emerging questions in the CLL field: (I) is there a role for covalent BTKi (cBTKi), venetoclax and antiCD20 monoclonal antibody triplet therapy in relapsed CLL; and (II) will there be a role for ctDNA in CLL? This commentary reviews key data the CLL2-BAAG trial in the context of the current CLL treatment landscape and the importance of these key questions.

cBTKi and venetoclax +/– antiCD20 monoclonal antibody combination therapies in CLL

In the initial treatment of CLL, the standard approach is continuous therapy with a cBTKi +/− obinutuzumab (with obinutuzumab as an option when paired with acalabrutinib) (2,3) versus fixed-duration venetoclax + obinutuzumab (4). In the relapsed setting, treatment approaches are dependent on the patients’ prior therapies and reasons for discontinuation of prior therapies (i.e., toxicity, completion of planned therapy, or progression of disease), but often include cBTKi or venetoclax-based therapies if patients have not been previously exposed to, or are not resistant to, these agents (5-7). It is currently not standard to combine cBTKi and venetoclax in the relapsed setting outside of a clinical trial.

Doublet and triplet combination approaches that incorporate both a cBTKi and venetoclax have been studied in clinical trials for patients with CLL with promising results (8-17); however, the role of cBTKi and venetoclax combinations in clinical practice has yet to be clearly defined. For example, ibrutinib + venetoclax as a time-limited combination showed excellent results in the GLOW (42-month PFS 74.6%) (8) and CAPTIVATE (fixed-duration cohort 5-year PFS 67%) (9) trials in the initial treatment of CLL. However, whether ibrutinib + venetoclax is superior to a continuous cBTKi monotherapy and/or fixed-duration venetoclax + obinutuzumab is not known, and toxicity concerns with the ibrutinib + venetoclax combination have limited its adoption. Data from a randomized trial of ibrutinib + obinutuzumab (IO) versus ibrutinib + venetoclax + obinutuzumab (IVO) in CLL patients ≥70 years demonstrated that PFS for IVO was not superior to IO [14-month PFS 87.5% IO vs. 85% IVO, with the pre-defined futility boundary crossed, hazard ratio (HR) 1.20 favoring IO, 95% confidence interval (CI): 0.73–1.97] (10). In the GLOW trial, there were 7 deaths during ibrutinib + venetoclax treatment, including 2 cardiac and 2 sudden/unknown deaths (8). Given the results of these clinical trials, the role for doublet and triplet therapy incorporating both a cBTKi and venetoclax has yet to be defined.

Many clinical trials have explored triplet combinations in the initial treatment of CLL, including combinations of IVO (10,11,18) and combinations incorporating second generation BTKis to address toxicity concerns with ibrutinib (12-17). The AMPLIFY trial demonstrated that the combination of acalabrutinib and venetoclax had superior PFS and OS to a chemoimmunotherapy control arm (investigator’s choice of fludarabine cyclophosphamide and rituximab or bendamustine and rituximab), and the triplet combination of AVO had improved PFS, but not OS, compared to a chemoimmunotherapy control arm (17). The doublet and triplet combinations of acalabrutinib and venetoclax (AV) and AVO are now listed by the National Comprehensive Cancer Center Network Guidelines as initial treatment options for CLL (19); AV and AVO are not currently Food and Drug Administration (FDA) approved at the time of this article. While these frontline approaches are promising, data are limited for triplet approaches in the relapsed setting. A phase II study of IVO included 25 relapsed patients with a median of 1 prior therapy, but the details of the prior regimens were not reported (11). Generating clinical trial data for triplet cBTKi, venetoclax and antiCD20 monoclonal antibody therapy in the relapsed setting is an important step in identifying a time-limited regimen that can further maximize depth of remission, PFS and the treatment-free interval. The CLL2-BAAG trial results fill a gap in the literature by providing data on the AVO triplet in the relapsed setting for a population that is relevant in the modern targeted therapy era (20), including in 40% of patients with prior BTKi and venetoclax therapy (1).

CLL2-BAAG study results: efficacy data for AVO triplet therapy in relapsed CLL

In the CLL2-BAAG trial, after an optional debulking with bendamustine, patients with relapsed CLL were treated with obinutuzumab (started cycle 1, days 1, 8, 15) followed by acalabrutinib introduced at cycle 2 and venetoclax introduced at cycle 3 (1). There was an induction period of 8 cycles (6 cycles of AVO triplet with monthly obinutuzumab) followed by final restaging followed by maintenance which consisted of AVO every 12 weeks. Criteria to discontinue treatment during maintenance was a complete (clinical) response (CR, clinical, not requiring bone marrow biopsy or imaging) and undetectable MRD (uMRD) in the peripheral blood, measured by flow cytometry at a sensitivity of <1 cell in 10⁻⁴, for two consecutive measurements. A maximum of eight cycles (1 cycle =84 days) of maintenance treatment were administered (1).

Forty-five patients were treated with the AVO combination and included in the final data analysis. High-risk cytogenetic and molecular features were present in the overall population: TP53 aberrancy was present in 31.8% of patients and unmutated IGHV was present in 75.6% of patients. Prior therapies included 18 patients with prior BTKi and/or venetoclax, including some patients who received these therapies in combination (3 combination, 8 BTKi, 7 venetoclax). Of patients with prior BTKi exposure, 9 received time-limited combinations and 2 had received continuous intent BTKi that was discontinued previously due to intolerance (prior exposure BTKi ranged from 9.1–34 months) (1). The inclusion of patients with prior targeted agent exposure makes this regimen applicable to patients treated in 2025.

At the time of data reporting, all 45 patients completed treatment (optional bendamustine debulking in 18 patients). Reasons for discontinuation of treatment included: (I) uMRD and clinical CR: 25 (58.1%); (II) completed the maximum 8 maintenance cycles due to detectable MRD and/or no CR: 9; (III) toxicity: 8; (IV) other: 2; and (V) progressive disease: 1. Patients received a median of 2 maintenance cycles (1).

Efficacy outcomes with MRD-guided fixed duration AVO were excellent with the median PFS not reached (median observation time 36.3 months), a 3-year estimated PFS of 85.0% and a 3-year estimated OS of 93.8% (3 deaths, all due to COVID-19 infection). uMRD at final restaging (following the 6-month triplet induction) was 75.6% and best overall uMRD rate during the study was 93.3%. The uMRD rate among patients with prior BTKi and/or venetoclax exposure was 92.9%. Following completion of treatment, 85.9% of patients had not received subsequent therapy at 3 years and median time to next treatment has not been reached, supporting the durability of responses for this MRD guided, fixed-duration triplet approach in the relapsed setting (1).

If doublet or triplet fixed-duration therapies are adopted in the initial treatment of CLL in the future, a key question will be what subsequent therapy should be at the time of relapse. The CLL2-BAAG trial is unique in that 40% of patients had prior BTKi or venetoclax-exposure (1), suggesting a role for this therapy in the modern era, including potentially as a re-treatment regimen following prior fixed-duration therapy, including regimens incorporating BTKi and/or venetoclax. It should be noted that no patients with prior BTK or PLCG2 resistance mutations were included in the CLL2-BAAG analysis, and the data do not apply to patients harboring resistance mutations or having a history of progression during prior BTKi treatment. In addition, the generalizability of this data is limited by the fact that patients in the CLL2-BAAG study received a heterogenous group of prior therapies even within the prior BTKi and prior venetoclax subgroups, including 4 different prior venetoclax-based regimens and 7 different regimens incorporating BTKi.

Overall, the CLL2-BAAG efficacy data serve as proof-of-concept that fixed-duration triplet therapy may have a role in relapsed CLL in the modern era, including as a re-treatment regimen after prior targeted agent exposure including with prior BTKi + venetoclax combination therapy. The data are also applicable for patients who have no prior targeted therapy exposure but had prior chemoimmunotherapy as their initial CLL treatment.

The emerging role of ctDNA in CLL: should ctDNA analysis accompany MRD assessments in clinical trials?

The CLL2-BAAG trial results include important data correlating ctDNA with traditional flow cytometry MRD data in CLL and suggest that ctDNA may be complementary to traditional peripheral blood MRD assessments.

MRD at the end of treatment in patients with CLL has been shown to be prognostic and correlates with improved PFS for patients treated with chemoimmunotherapy (21) as well as fixed-duration venetoclax-based regimens (18,22). Traditional methods being utilized include flow cytometry and more sensitive next generation sequencing assays, with measurements being assessed in the peripheral blood and bone marrow (23). However, CLL is a multi-compartmental disease, with peripheral blood, bone marrow, and nodal compartments and is heterogenous in its clinical modes of progression. For example, some patients may exhibit lymphocytosis at relapse while others have a nodal progression without lymphocytosis in the peripheral blood. Recent work has suggested that ctDNA has the potential to be complementary to traditional peripheral blood flow cytometry and may improve the ability to detect nodal compartment relapse (24,25). For example, ctDNA may detect nodal disease progression that is not detectable using peripheral blood MRD testing (24). Conducting correlative studies to understand whether earlier detection of nodal relapses by ctDNA correlates with clinical outcomes for patients with CLL is critical in understanding whether ctDNA may have a future role to monitor disease status following treatment or guide therapeutic duration alongside MRD.

An earlier publication detailed results from 381 paired samples of ctDNA [measured by patient-specific variable-diversity-joining (VDJ) rearrangements as well as somatic mutations] and flow cytometry collected as part of the prospective CLL2-BAAG study (25). Eighty-one percent (308 of 381) samples were concordant between flow cytometry MRD and ctDNA testing, with 29% of samples with detectable disease by ctDNA and uMRD at 10⁻⁴ and 9.4% as detectable by flow cytometry, but negative by ctDNA analysis (25). In this updated analysis of the CLL2-BAAG trial, Furstenau and colleagues present updated results of 585 prospectively collected, paired samples of flow cytometry MRD analysis and ctDNA analysis (1). There was 82% concordance between uMRD by flow and ctDNA (1).

Importantly, updated data from the CLL2-BAAG study reports outcomes for MRD recurrences following completion of fixed-duration therapy. Eighteen patients had recurrent MRD, with five patients having clinical progression, including one patient with Richter Transformation (1). For the patient with Richter Transformation, ctDNA was positive at clinical progression and flow cytometry remained undetectable. For the four CLL progressions, three were nodal progressions without lymphocytosis. Two of these had ctDNA detectable prior to flow cytometry MRD becoming detectable and prior to clinical progression. In two patients, flow cytometry and ctDNA became detectable at the same timepoint. For patients without clinical progression but MRD recurrence, 3 patients had detectable flow MRD prior to ctDNA becoming positive, 1 patient had concurrent ctDNA and flow and 9 patients had ctDNA detectable prior to flow MRD (1). While a small number of patients were studied, this study provides critical information that ctDNA may enhance detection of relapse and should be further studied alongside traditional MRD.

While this small data set suggests a role for ctDNA in improving detection of relapse, particularly for nodal compartment relapses, whether ctDNA detection correlates with future clinical outcomes is not certain (1), and ctDNA remains in early stages of investigation. Despite the limitations of the ctDNA data set, including small patient numbers and a lack of an established relationship for ctDNA to future clinical outcomes, these data do suggest that ctDNA analysis is ripe for further investigation in CLL. Based on the CLL2-BAAG data, future clinical trials should attempt to incorporate ctDNA as an exploratory endpoint to accompany traditional MRD analysis in clinical trials. This will help establish whether ctDNA status at end of therapy correlates with outcomes, including PFS. A next step will be to see whether early detection of relapse improves clinical outcomes. While more research is needed, it is possible that there is an opportunity to explore a more integrated, comprehensive approach to remission assessment, particularly when depth of remission is guiding therapeutic duration. In particular, future work should examine whether integrating both traditional MRD testing in the peripheral blood as well as ctDNA together may further maximize the depth of remission across various disease compartments. These data suggest that there may be a need for an updated definition of “undetectable” MRD in CLL that addresses not only the peripheral blood compartment, but also better accounts for residual nodal disease.

In summary, the CLL2-BAAG trial is proof-of-concept that triplet AVO therapy achieves durable remissions in relapsed CLL, including following fixed duration therapy of BTKi and/or venetoclax-based regimens. In addition, ctDNA appears to have an emerging role in CLL with the potential for early detection of nodal relapses. Further research to establish the prognostic value of ctDNA in CLL is required, and clinical trials should incorporate ctDNA analyses as an exploratory endpoint. As more data are generated regarding ctDNA in CLL, the definition of what it means to be “undetectable” may need to be revisited to account for the heterogeneous, multi-compartmental nature of CLL.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-192/prf

Funding: This study was funded in part through the NIH/NCI Cancer Center Support Grant (No. P30 CA008748).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-192/coif). M.C.T. reports research support from AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, GenMab, Nurix Therapeutics, Genentech; honoraria from PeerView Medical Institute, Dava Oncology, eScientiq, Mashup Media LLC, Prescisca, Philips Group Oncology Communications, Intellisphere LLC/MJH Life Sciences, Clinical Care Options; travel support from Nurix Therapeutics, Genmab, Dava Oncology; and has also served as a consultant or advisory board member for AbbVie, AstraZeneca, BeiGene, Jannsen, Loxo Oncology at Lilly. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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