A decade of progress: A comparative analysis of real-world survival in chronic lymphocytic leukemia across therapeutic eras Free

Management of chronic lymphocytic leukemia (CLL) has advanced significantly over the past two decades with the introduction of novel targeted therapies. The ECOG E1912 randomized study demonstrated superior overall survival of ibrutinib-based therapy compared to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR). Nevertheless, comprehensive real-world data comparing clinical outcomes across distinct therapeutic eras remain scarce. This study investigates the association between treatment era and clinical outcomes, including survival, relapse, and remission.

A retrospective cohort study was conducted using de-identified patient data from the TriNetX global health research network. We identified all patients (135,579) aged 18 years or older with a diagnosis of Chronic Lymphocytic Leukemia (CLL) from 2005 through 2023. Two primary analyses were performed.

First, to assess temporal trends, the entire patient population was stratified by era of diagnosis: Pre-2015 (2005–2014), 2015–2020, and Post-2020. For these cohorts, 5-year all-cause mortality was compared between the pre-2015 and 2015-2020 groups, and 2-year all-cause mortality was compared between the pre-2015 and post-2020 groups.

Second, to directly compare treatment effectiveness, patients who received systemic therapy were stratified into two cohorts based on the class of agent received, irrespective of the treatment date:

• Chemoimmunotherapy (CIT): Regimens including FCR, BR, Fludarabine with Rituximab, Chlorambucil ± Obinutuzumab, and Alemtuzumab-based treatments.

• Novel Targeted Therapy: Regimens including covalent BTK inhibitors (Ibrutinib, Acalabrutinib, Zanubrutinib), BCL-2 inhibitor Venetoclax (± Rituximab or Obinutuzumab), and PI3K inhibitors (Idelalisib, Duvelisib).

For these treatment-regimen cohorts, 10-year outcomes for all-cause mortality, relapse, and remission were compared. Cohorts in both analyses were 1:1 propensity score-matched (PSM) based on baseline demographics, and comorbidities. Outcomes were assessed using Kaplan-Meier survival analysis, with Hazard Ratios (HR) for survival and Odds Ratios (OR) for relapse and remission.

The analysis of all diagnosed patients revealed a progressive and significant improvement in survival relative to the pre-2015 era. In the comparison with the 2015–2020 era, initial cohorts of 31,910 (pre-2015) and 42,528 (2015-2020) patients were balanced via PSM to 25,556 patients each (mean age 66.4 ± 10.6 years; 59.7% male). Patients diagnosed pre-2015 had a significantly higher risk of 5-year all-cause mortality compared to the 2015–2020 cohort (HR 1.291; 95% CI: 1.221–1.365; p < 0.0001). This survival benefit was sustained when comparing the pre-2015 era (initial n=31,910) to the post-2020 era (initial n=27,648), where cohorts were matched to 18,013 patients each (mean age 66.3 ± 10.4 years; 59.6% male). The pre-2015 cohort again demonstrated a significantly higher hazard of death at 2 years relative to the post-2020 cohort (HR 1.222; 95% CI: 1.137–1.315).

The 10-year comparative effectiveness analysis of treated patients also showed significant differences. The CIT cohort (initial n=2,755) and the Novel Targeted Therapy cohort (initial n=10,584) were balanced via PSM to 2,619 patients each (mean age 65.2 ± 10.2 years; 63.5% male). Patients treated with CIT experienced a higher risk of all-cause mortality (HR 1.249; 95% CI: 1.108–1.407) and had significantly higher odds of relapse (OR 1.677; 95% CI: 1.409–1.996) compared to patients treated with novel targeted therapies. Conversely, the CIT cohort had significantly higher odds of achieving remission (OR 3.024; 95% CI: 2.631–3.476).

In this large real-world analysis, patients diagnosed with CLL after 2015 had significantly improved 2-year and 5-year overall survival compared to the pre-2015 era, coinciding with the introduction of novel targeted agents. A direct 10-year comparative effectiveness analysis confirmed that novel targeted therapies are associated with lower all-cause mortality and relapse rates than chemoimmunotherapy (CIT). Our findings strongly support the use of novel targeted agents over chemoimmunotherapy as the standard of care in the management of CLL.