Survival Rates in CLL: Targeted Agents vs Fludarabine Combo Therapy Study

Researchers conducted an analysis of 4 phase 3 trials, covering 2751 patients, to address the potential for targeted agents in younger and physically fit patients who have chronic lymphocytic leukemia (CLL).

Targeted agents for treating chronic lymphocytic leukemia (CLL) may have an advantage over chemotherapy-based immunotherapy for first-line therapy, according to an analysis published in a recent issue of Cancers.1

Researchers conducted an analysis aimed at addressing the potential of targeted agents (TAs) and their impact on overall survival in younger and physically fit patients with CLL who were deemed suitable for the standard fludarabine, cyclophosphamide, and rituximab (FCR) regimen. This analysis of phase 3 trials supports TAs being used as the preferred first-line treatment for patients with CLL due to the favorable impact on overall survival.

CLL is the most prevalent form of leukemia in Western society. Traditionally, standard therapy has been the FCR combination regimen. This chemo-immunotherapy (CIT) regimen is an effective treatment that can achieve remission in CLL and extend survival. Recent years have seen the treatment of CLL evolve with the introduction and use of TAs, which offer an alternative to traditional chemotherapy.

Health care data analysis | Image Credit: Nuttapong punna -

With this analysis, the investigators wanted to evaluate targeted agent potential and their impact on overall survival in chronic lymphocytic leukemia | Image Credit: Nuttapong punna -

The study is based on an aggregated analysis of 4 phase 3 trials (N = 2751 patients), using 2 FLAIR sub-studies: ECOG1912 and CLL13. The overall survival (OS) of treatment with TAs or a CIT regimen was compared with age- and sex-matched individuals in the general population (AGMGP) in 2 centers located in America and Italy. OS rates over the entire course of the disease were measured using restricted mean survival time (RMST) to minimize biases associated with trials with a short follow-up time.

Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI, 57.4-58.8) compared with those treated with CIT (56.9 months; 95% CI, 56.7-58.2). There was a similar trend in OS when comparing TAs with the US AGMGP cohort (5-year RMST difference, 0.3 months; 95% CI, −0.1 to 0.9) and the Italian AGMGP cohort (5-year RMST difference, −0.4 months; 95% CI, −0.8 to 0.2). In contrast, patients treated with the CIT regimen showed differences in the rate of OS when comparing the US AGMGP cohort (−0.9 months; 95% CI, −1.7 to −0.2) to the Italian AGMGP cohort (−1.6 months; 95% CI, −2.4 to −0.9).

Some study limitations noted include the individual patient data in the analysis lacking some variables, such as race, ethnicity, and individual CLL risk characteristics. There were also differences in comorbidity burdens across trials, between individual client trial participants, and between individuals within the AGMGP cohorts, which could have influenced the study outcomes.2

TAs often exhibit a more favorable safety profile with a reduced incidence of severe adverse events commonly associated with CIT, translating into better tolerability and quality of life for CLL patients.3 The present study suggests they offer not only potential survival advantages but also an enhanced safety profile over CIT.

The authors pointed out, "Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis generating."

A more extended follow-up period and assessment are needed to better understand the relative survival of younger physically fit patients who have CLL and are treated with TAs compared with the general population.


  1. Molica S, Shanafelt TD, Allsup D, Giannarelli D. Impact of targeted agents on survival of chronic lymphocytic leukemia patients fit for fludarabine, cyclophosphamide, and rituximab (fcr) relative to age- and sex-matched population. Cancers (Basel). 2024;16(6):1085. doi:10.3390/cancers16061085
  2. Molica S, Shanafelt TD, Allsup D, Giannarelli D. Impact of targeted agents on survival of chronic lymphocytic leukemia patients age >65 relative to age- and sex-matched population. Am J Hematol. 2024;99(3):480-483. doi:10.1002/ajh.27182
  3. Molica S. Redefining efficacy and safety endpoints for chronic lymphocytic leukemia in the era of targeted therapy. Expert Rev Hematol. 2023;16(11):803-806. doi:10.1080/17474086.2023.2271170
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