A genomic analysis of patients with chronic lymphocytic leukemia treated with fixed duration therapy in a first-line setting in alberta, Canada
Bibliographic record
Abstract
Abstract Introduction: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Canada. Current Canadian guidelines recommend genetic prognostic testing at diagnosis to guide individualized treatment selection (Owen et al., 2023). For younger, fit patients with favourable-risk genetic markers such as the absence of del(17p)/TP53 mutations and mutated IGHV, first-line (1L) chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) remains a reasonable option. With the emergence of targeted fixed-duration (FD) therapies, such as venetoclax plus obinutuzumab (V+O) and ibrutinib plus venetoclax (I+V), which have demonstrated superior efficacy and reduced toxicity, CIT use has declined in the 1L setting (Al-Sawaf et al., 2024; Schnaiter et al., 2024; George et al., 2025). Moreover, given the limited efficacy of CIT in patients harboring high-risk genetic features (del(17p)/TP53 mutations and/or unmutated IGHV), Canadian guidelines favour targeted therapies in these patients, including continuous BTK inhibition (Owen et al., 2023). The therapeutic paradigm is increasingly shifting towards targeted FD therapies in all patients as these offer ‘drug holidays’, less cumulative toxicity, lower healthcare costs, and potential for re-treatment. Limited Canadian real-world evidence exists examining the frequency of genetic testing prior 1L FD therapy, and how this aligns with guideline-directed treatment selection for CLL patients. Methods: We conducted a retrospective observational study using administrative health data from Alberta, Canada. We identified 589 adult patients diagnosed with CLL between January 1, 2010, and December 31, 2022, who initiated a 1L FD therapy between January 1, 2010, and December 31, 2023 (George et al., 2025). Of these, 200 patients were randomly selected for detailed analysis as genetic testing information is only available in medical charts. Manual chart extraction was used to capture genomic testing rates (IGHV mutational status and del(17p)), clinical characteristics, and treatment patterns. As both V+O was publicly funded in Alberta and updated guidelines of differential therapy based on genomic testing was recommended in 2022, a secondary analysis was then conducted among a subset of these 200 patients, who initiated 1L FD therapy between January 1, 2022, and December 31, 2023, to describe genetic testing patterns and 1L therapy selection following the introduction of targeted FD options. Results: In this chart-reviewed cohort of 200 patients, the average age at diagnosis was 65 years and 69.8% were male. 22% and 22.5% presented with Rai stage 3 or 4, respectively, at 1L therapy initiation. 24% had an ECOG performance status of 0, and 15.5% of patients had a performance status of 1. Over the entire study cohort, 169 of 200 patients (85%) received a 1L CIT regimen, while 31 patients (15%) received a 1L targeted FD regimen of V+O; notably, 29 (94%) patients initiated V+O therapies between 2022 and 2023. Among patients receiving CIT, 61 (30.5%) received FCR, 76 (38%) received bendamustine plus rituximab (BR), 26 (13%) received chlorambucil plus obinutuzumab (Clb+O), and 6 (3%) received chlorambucil plus rituximab (Clb+R). Across the study cohort, genomic testing rates were 48.0% for IGHV and 60.0% for del(17p). Patients treated with targeted therapies had higher genomic testing rates (93.5%-100%) compared to those treated with CIT (38.5%-53.8%). In the secondary analysis, 52 patients initiated 1L therapy between 2022 and 2023, with 23 (43%) receiving CIT and 29 (57%) receiving a targeted FD regimen (V+O). Among CIT-treated patients, 5 (21.7%) had unmutated IGHV, contrary to Canadian guideline recommendations and despite availability of targeted FD regimens. Further, 5 (21.7%) and 7 (30.4%) of CIT-treated patients had no recorded testing for IGHV and del(17p) respectively, indicating potential underutilization of recommended genomic testing and risk of suboptimal therapy. Conclusions: Our study characterizes the genomic and clinical profiles of CLL patients receiving 1L FD therapy from a real-world setting in Alberta, Canada. Despite the availability of targeted regimens and established Canadian guidelines, gaps may persist in the utilization of genetic testing to inform appropriate therapy selection. Increased adherence to genetic testing recommendations and longer-term follow up is essential to ensure guideline-concordant, personalized care and improved outcomes
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".