Six-year results of the CLL14 study—redefining long-term outcomes in chronic lymphocytic leukemia management

The management of chronic lymphocytic leukemia (CLL) has undergone a paradigm shift with the advent of fixed-duration, targeted combination therapies (1,2). The phase 3 CLL14 trial, evaluating venetoclax (Ven) combined with obinutuzumab (Obi) (Ven-Obi) against chemoimmunotherapy with chlorambucil and Obi (Clb-Obi), marks a milestone in achieving long-lasting remissions and reducing treatment burden (2). The 6-year follow-up data reinforce the efficacy and durability of fixed-duration Ven-Obi therapy, providing critical insights into its impact on progression-free survival (PFS), time-to-next-treatment (TTNT), and prognostic implications in previously untreated CLL (3).

The results confirm that Ven-Obi offers a sustained PFS advantage, with a 6-year PFS rate of 53.1% compared to 21.7% for Clb-Obi. This extended benefit is particularly significant in high-risk subsets, including patients with del(17p) or TP53 mutations, who achieved a median PFS of 51.9 months with Ven-Obi vs. 20.8 months with Clb-Obi. Similarly, patients with unmutated immunoglobulin heavy chain variable region (IGHV) status demonstrated markedly superior PFS with Ven-Obi (median PFS, 64.8 vs. 26.9 months), emphasizing the regimen’s ability to overcome traditionally poor prognostic factors.

The study highlights measurable residual disease (MRD) as a potent predictor of long-term outcomes. After 5 years from starting Ven-Obi, almost 8% of patients in the Ven-Obi arm maintained uMRD4, correlating with prolonged PFS and overall survival (OS). Notably, patients with uMRD4 and unmutated IGHV achieved a 6-year PFS rate of 48.5%, underlining the prognostic significance of MRD-guided stratification in CLL management.

Ven-Obi also extended TTNT, with a 6-year TTNT rate of 65.2% compared to 37.1% for Clb-Obi. This delay in requiring subsequent therapy underscores the durability of the regimen. Importantly, the fixed-duration approach aligns with patient preferences for treatment-free intervals, contributing to an improved quality of life. In addition, some patients will never need retreatment allowing a decrease in the health cost.

Baseline biomarkers emerged as independent predictors of outcomes in the Ven-Obi arm. The presence of del(17p), unmutated IGHV status, and lymph node bigger than 5 cm independently predicted inferior PFS. Instead, in multivariable analysis age ≥75 years and complex karyotype emerged as independent negative prognostic factors for OS. These findings pave the way for personalized treatment strategies, focusing on tailoring therapies to individual risk profiles.

The 6-year CLL14 data validate Ven-Obi as a highly effective, fixed-duration option for managing CLL, especially in patients with coexisting conditions. By achieving deep remissions with sustained benefits, this regimen sets a new standard for first-line therapy. Further integration of MRD status and biomarker analysis could enhance risk-adapted approaches, ensuring optimal outcomes for diverse patient populations.

However, whether Ven-Obi treatment duration can be tailored based on an individual patient depth of response to optimize outcomes has not been well studied. During the 2024 American Society of Hematology (ASH) congress Roeker et al. try to adapt the duration of Ven-Obi according to the ability to achieved a deep response in a phase 2 clinical trial (4). Eighty-one out of 99 enrolled patients who have reached cycle (C) 9, 41 patients were uMRD6 (i.e., <10⁻⁶ as assessed by clonoSEQ) at both C7 and C9 and discontinued therapy. Twenty-nine patients were uMRD5 at C12 stopped therapy and enter follow-up. Three patients with dMRD5 at C12 continued till C24, 1 achieved uMRD5 and 2 maintained dMRD5. Three patients discontinued (1 intolerance, 1 withdrawal of consent, 1 death unrelated to therapy) Ven-Obi before C9 MRD testing and 16 are still receiving Ven-Obi before C9. After a median follow-up of 24 months, the 2-year PFS and OS is 92% and 95% for the entire cohort, respectively.

However, whether Ven-Obi is superimposable or a better treatment option for all patients with CLL or just for some specific subsets then the oral therapies with time limited ibrutinib-Ven or continuous BTK inhibitor, or whether it should be associated with a better safety profile in particular for infections is unknown (5,6). The CLL17 trial will prospectively compared Ven-Obi vs. ibrutinib-Ven vs. continuous ibrutinib (2,5). With the limit of indirect trial comparisons, severe infusion reaction and some cases of tumor lysis syndrome have been reported during the first doses of Obi, while cardiovascular adverse events during ibrutinib are a concern for some elderly and comorbid patients (2). Recently, during the 2024 ASH congress, it has been demonstrated that ibrutinib-Ven was equally effective in patients whose lymph node were smaller or bigger than 5 cm (7).

The MAJIC trial is an international phase III randomized study comparing acalabrutinib + Ven vs. Ven-Obi in elderly and/or comorbid patients (8). In both treatment arms, disease response and MRD will be used to guide therapy duration, with all patients ultimately discontinuing treatment after a maximum of 2 years.

In conclusion, the CLL14 trial’s long-term findings solidify the role of Ven-Obi in redefining the treatment landscape of CLL. Its ability to deliver durable remissions, coupled with a favorable safety profile, underscores the potential for fixed-duration therapies to transform chronic cancer care into a manageable condition, with extended periods of treatment-free living.

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-24-267/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-267/coif). A.V. has participated on the advisory boards for Abbvie, Johnson&Johnson, AstraZeneca, BeiGene, and Takeda. The author has no other conflicts of interest to declare.

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References

1. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med 2019;380:2225-36. [Crossref] [PubMed]
2. Visentin A, Frazzetto S, Trentin L, et al. Innovative Combinations, Cellular Therapies and Bispecific Antibodies for Chronic Lymphocytic Leukemia: A Narrative Review. Cancers (Basel) 2024;16:1290. [Crossref] [PubMed]
3. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood 2024;144:1924-35. [Crossref] [PubMed]
4. Roeker L, Mato AR, Zelenetz AD, et al. Minimal Residual Disease (MRD)-Adapted Duration of Front-Line Venetoclax and Obinutuzumab Treatment for Fit Patients with Chronic Lymphocytic Leukemia (CLL). Blood 2024;144:1010.
5. Mauro FR, Frustaci AM, Visentin A, et al. Severe infections in patients with chronic lymphocytic leukemia included in trials investigating BTK and BCL2 inhibitors. Crit Rev Oncol Hematol 2024;201:104408. [Crossref] [PubMed]
6. Niemann CU, Munir T, Moreno C, et al. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2023;24:1423-33. [Crossref] [PubMed]
7. Wierda WG, Jacobs R, Barr PM, et al. Consistently High 5.5-Year Progression-Free Survival (PFS) Rates in Patients with and without Bulky Baseline Lymphadenopathy ≥5 Cm Are Associated with High Undetectable Minimal Residual Disease (uMRD4) Rates after First-Line Treatment with Fixed-Duration Ibrutinib + Venetoclax for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) in the Phase 2 CAPTIVATE Study. Blood 2024;144:1869.
8. Ryan CE, Davids MS, Hermann R, et al. MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Future Oncol 2022;18:3689-99. [Crossref] [PubMed]