CLL Progression Within 12 Months Linked to 5-Fold Increase in Mortality Risk

Progression-free survival in chronic lymphocytic leukemia (CLL) is often used as a benchmark for success, but the timing of that progression carries vastly different survival implications.

Findings presented at the 67th American Society of Hematology annual meeting identify the 12-month post-treatment mark as the "gold standard" for differentiating early from late progressive disease (PD).¹ Patients falling into the early PD category faced a 5-fold increase in mortality risk, regardless of whether they were treated with traditional chemoimmunotherapy or modern targeted agents.

Challenging Inconsistent Treatment Guidelines

Current CLL treatment guidelines advise switching to a different therapeutic class following early PD, whereas patients who experience later PD may be considered for retreatment with the same regimen. However, the timeframe used to distinguish early from late PD is inconsistent across guidelines, ranging from 12 to 36 months after the end of treatment (EOT).² “This analysis challenges the current definition of early vs. late PD commonly used in CLL treatment guidelines in the context of targeted fixed-duration therapy,” the authors explain.

The analysis included patient data from 7 landmark trials, CLL4, CLL5, CLL8, CLL10, CLL11, CLL13, and CLL14, enrolling 3,829 patients who received at least 1 dose of study treatment. These trials spanned more than two decades of CLL research and included both chemoimmunotherapy (CIT) and modern targeted therapy (TT) approaches. CIT (bendamustine + rituximab [R]; fludarabine +/- cyclophosphamide +/- R; or chlorambucil + R or + obinutuzumab [O]) was administered to 2921 patients (76.3%), and TT (venetoclax + O, venetoclax + R, or venetoclax + O + ibrutinib) was used in 908 patients (23.7%). CIT was limited to 6 cycles, whereas TT duration ranged from 12 to 36 cycles.

After a median follow-up period of 65 months from the EOT, 2131 patients (55.7%) experienced PD, and 1143 patients (29.9%) died. PD was more frequent after CIT than TT, occurring in 62.9% versus 32.4% of patients, respectively, with 67.3% of PD occurring more than 12 months after EOT.

The 12-Month Threshold and Survival Risk

To determine the most clinically meaningful threshold for early PD, investigators modeled overall survival (OS) from EOT across multiple candidate cutoffs. A 12-month threshold consistently demonstrated the greatest discrimination between early and late PD in terms of mortality risk. This cutoff yielded the largest standardized difference in hazard between early and late PD (z = 8.72). In addition, this finding was replicated in subgroup analyses of patients treated with CIT (z = 7.42) and TT (z = 3.84).

In total, 696 patients (18.2%) of the study population developed disease progression within 12 months of completing therapy. This early PD was associated with a markedly increased risk of death compared with patients who did not experience progression (HR, 5.43; 95% CI, 4.66-6.33; P < .001). Progression more than 12 months after treatment (late PD) was also associated with inferior overall survival (OS), although the magnitude of risk was substantially lower (HR, 2.52; 95% CI, 2.09-3.04; P < .001).

When stratified by treatment type, early PD after CIT was associated with an HR of 4.57 (3.89-5.37, P < .001), while late PD was associated with an HR of 2.35 (1.94-2.86, P < .001) compared with no progression. In contrast, late PD after TT was not statistically associated with worse OS (HR, 1.73; 95% CI, 0.81-3.71; P = .157). Additional analyses evaluating time to progression from study entry rather than EOT supported these findings. They found early PD occurring before 18 months for CIT and before 24 months for TT conferred the highest mortality risk.

Genomic Drivers and High-Risk Profiles

Researchers identified several factors associated with early PD. In patients treated with CIT, unmutated IGHV, TP53 aberrations, del(11q), absence of B symptoms, a cumulative illness rating scale score > 6, and creatinine clearance < 70 mL/min were associated with early PD. In patients who received TT, unmutated IGHV and TP53 aberrations were linked to early progression. However, neither IGHV mutational status (HR, 1.52; 95% CI, 0.91-2.5; P = .108) nor TP53 abnormalities (HR, 1.65; 95% CI, 0.71-3.87; P = .245) independently predicted OS after adjusting for progression timing.

Given the markedly inferior survival associated with early PD, the authors propose that “This group may represent a distinct high-risk population warranting further clinical investigation and tailored treatment strategies.”

References

1. Simon F, Ligtvoet R, Fürstenau M, et al. Redefining early vs late progressive disease in chronic lymphocytic leukemia: a pooled analysis of fixed-duration therapies. Blood. 2024;144(suppl S1):47. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, FL.

2. Hallek M. Chronic lymphocytic leukemia: 2025 update on the epidemiology, pathogenesis, diagnosis, and therapy. Am J Hematol. 2025;100(3):450-480. doi:10.1002/ajh.27546