Introduction Current treatment for chronic lymphocytic leukemia (CLL) follows two seminal paradigms: continuous Bruton tyrosine kinase inhibitor (BTKi) therapy until progression and fixed-duration regimens combining BCL2 inhibitors with a CD20 antibody or BTKi, typically given over one year. These two different approaches were established through comparisons to chemo(immuno)therapy and are yet to be compared directly. Here we present data of a prospective trial comparing continuous ibrutinib (I) monotherapy to fixed-duration venetoclax plus obinutuzumab (VO) and venetoclax plus ibrutinib (VI) for CLL.

Methods CLL17 (NCT04608318) is an investigator-initiated, international, randomized phase 3 trial for patients (pts) with previously untreated CLL. Pts were randomized to receive ibrutinib (I), fixed-duration venetoclax plus obinutuzumab (VO) or fixed-duration venetoclax plus ibrutinib (VI). Randomization was stratified by IGHV status, del(17p)/TP53mut and patient fitness, defined by cumulative illness rating scale (CIRS) score >6 and/or creatinine clearance <70 mL/min.

Ibrutinib was given continuously until intolerance or progression; VO consisted of 6 cycles (28 days each) of venetoclax plus obinutuzumab, followed by 6 additional cycles of venetoclax monotherapy; VI was initiated with a 3-cycle ibrutinib lead-in, followed by 12 cycles of VI.

The study was designed to test non-inferiority of VO vs I and VI vs I. The primary endpoint was investigator-assessed progression-free survival (PFS). A ≤8% reduction in 3-year (yr) PFS was deemed not clinically meaningful (non-inferiority HR margin 1.608). Per protocol, an interim analysis was planned once 65% of required PFS events (138 of 213) were reached. Secondary endpoints included overall response rate (ORR), undetectable minimal residual disease (uMRD), overall survival (OS) and safety.

Results In total, 909 pts were randomized to VO (N=303), VI (N=305), and I (N=301). Data cut-off was on April 11th, 2025, median observation time was 34.2 months (range 0-49). Median age was 66 yrs (34-90), 67.8% were male, median CIRS score was 3 (0-18); 33.7% had a creatinine clearance <70 mL/min. Overall, 7.6% had del(17p) and/or TP53 mutation, 56.5% unmutated IGHV and 19.2% complex karyotype (≥3 aberrations); 53.8% and 6.5% had high or very high CLL-IPI, respectively.

Three-yr PFS was 81.1% in the VO arm compared to 81.0% in the I arm (HR 0.87, type-I-error adjusted CI [98.3%] 0.54-1.41) and 79.4% in the VI arm (compared to I arm: HR 0.84, type-I-error adjusted CI [98.0%] 0.53-1.32), respectively, with the upper limit of each adjusted CI below the pre-defined non-inferiority margin, providing early evidence of non-inferiority.

At final staging (C18D1), the ORR was 84.2% in the VO arm, 88.5% in the VI arm, and 86.0% in the I arm, with a CR rate of 51.5%, 46.2%, and 8.3%, respectively; the uMRD (<10-4) rate in ITT population in peripheral blood was 73.3% (62.0% in bone marrow) in the VO arm, 47.2% (40.0% in bone marrow) in the VI arm and 0% (0% in bone marrow) in the I arm.

At 3 yrs, the OS rate was 91.5% in the VO arm, compared to 95.7% in the I arm (HR 1.67, 95% CI 0.86-3.28) and 96.0% in the VI arm (compared to I: HR 0.96, 95%CI 0.45-2.05), respectively.

For pts with unmutated IGHV, 3-yr PFS in the VO arm was 75.8% (87.6% for mutated IGHV) compared to 79.7% (83.5%) in the I arm (HR 0.98, 95% CI 0.61-1.59), and 78.9% (80.0%) in the VI arm (compared to I: HR 0.81, 95% CI 0.49-1.32). For pts with del(17p)/TP53mut, 3-yr PFS in the VO arm was 62.0% (82.7% for pts without del(17p)/TP53mut) compared to 79.4% (81.0%) in the I arm (HR 1.20, 95% CI 0.40-3.59), and 69.0% (80.1%) in the VI arm (compared to I: HR 0.70, 95% CI 0.22-2.16).

The most frequent AEs were infections and infestations (VO: 76.3%, VI: 80.2%, I: 79.9%), gastrointestinal disorders (VO: 59.7%, VI: 74.3%, I: 63.4%), and blood and lymphatic system disorders (VO: 59.0%, VI: 42.9%, I: 28.5%). Covid-19 infection was reported in 38.3%, 42.2% and 39.3% of pts; cardiac disorders occurred in 13.9%, 23.8% and 34.6% of pts; second cancers were reported in 11.5%, 11.2% and 18.5% of pts, respectively.

Conclusion This is the first phase 3 trial comparing the main paradigms of continuous vs fixed-duration targeted therapy of CLL. Early findings indicate that fixed-duration treatment with VO or VI are non-inferior to continuous treatment with I and may therefore represent the preferred treatment option for pts with previously untreated CLL.

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2025
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