Background: Over the last decade, the standard of care (SOC) for previously untreated chronic lymphocytic leukemia (CLL) has transitioned from traditional chemoimmunotherapy to targeted therapies such as Bruton tyrosine kinase inhibitors (BTKi) and BCL-2 inhibitors (BCL2i). The Alliance A041202 and CLL14 trials demonstrated substantial progression-free survival (PFS) benefits of BTKi monotherapy and fixed-duration venetoclax plus obinutuzumab (Ven/Obi), respectively, establishing them as standard first-line treatments. The rapid evolution of CLL treatment raises concerns, though, that many ongoing clinical trials utilize outdated or suboptimal control arms. Such misalignment may overstate the benefits of investigational therapies and limit the external validity of these studies. To evaluate this issue, we conducted a systematic review of first-line phase III trials in untreated CLL initiated after the publication of A041202 and CLL14, assessing whether their control arms aligned with contemporary SOC as defined by expert consensus.

Methods: We searched ClinicalTrials.gov for all phase III trials in CLL with start dates on or after July 1, 2019 through June 2025. Eligible trials enrolled only previously untreated CLL patients. We excluded trials that included relapsed/refractory CLL, early-stage or asymptomatic disease, multiple malignancies, or prophylactic interventions. Extracted data included the control arm, investigational arm, sponsor type, and trial location. Control arms were classified as either consistent or inconsistent with modern SOC, defined per NCCN and ESMO guidelines as regimens containing either a BCL2i (Ven/Obi) or an approved BTKi.

Results: The initial search strategy identified a total of 33 trials. Of these, 14 met the inclusion criteria. All trials are ongoing, with start dates between January 2020 and April 2024. Sponsor types included industry-sponsored (85.7%) and cooperative group (14.3%). Eight trials enrolled at least partially in the US, three exclusively in East Asia and/or China, and three in other locations outside the US. Four trials had enrollment under 250, 4 trials between 250 and 400, 5 trials between 600 and 900, and 1 trial at 1200.

Six trials (42.8%) employed substandard control arms, all utilizing a combination of chemoimmunotherapy: fludarabine/cytarabine/rituximab or bendamustine/rituximab (n=4) or chlorambucil and rituximab (n=2). Rates of substandard control arms varied by study location: exclusively China/East Asia (100%), partially in the US (37.5%), and other locations outside the US (0%). Rates of substandard control arm also differed by sponsor type: industry-sponsored (50%) and cooperative group (0%). The eight trials that employed SOC control arms included Ven/Obi (n=5) and BTKi (n=3). Notably, 2 of the BTKi trials utilized ibrutinib rather than next-generation BTKis, such as acalabrutinib or zanubrutinib. Of the eight trials with SOC control arms, seven are enrolling primarily in the US and EU.

All three trials enrolling in the US with substandard control arms are industry-sponsored. Two of the trials are investigating next-generation BTKis that are not currently approved in the first-line setting for CLL. One trial is investigating Ven/Obi in fit patients who would not have met the inclusion criteria for CLL14.

Conclusions: Of all modern phase III trials for treatment-naive CLL, nearly half did not utilize control arms that align with the current SOC in the US or EU, risking inflated estimates of the efficacy of their experimental therapies and compromising the external validity of their results. However, although the small sample size limited statistical analysis, we found that the majority of these trials were conducted either exclusively or primarily outside the US and EU, suggesting regional differences in regulatory policies, drug access, and healthcare infrastructure contribute to the disparities in control arms. As research and clinical trial implementation become increasingly globalized, these findings highlight the need to ensure the external validity of trials conducted in diverse regulatory landscapes.

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2025
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