Overall Survival In Early Stage Chronic Lymphocytic Leukemia Patients With Treatment Indication Due To Disease Progression: Follow-Up Data Of The CLL1 Trial Of The German CLL Study Group (GCLLSG)
Authors: Bergmann Manuela A. , Busch Raymonde , Eichhorst Barbara , Buehler Andreas , Fischer Norbert , Eckart Michael J , Vehling-Kaiser Ursula , Jäger Ulrich , Hopfinger Georg , Wendtner Clemens , Fischer Kirsten , Emmerich Bertold , Döhner Hartmut , Hallek Michael , Stilgenbauer Stephan 
Published: October 2019

Abstract

Introduction
Chronic lymphocytic leukemia (CLL) is typically diagnosed at an early stage and a watch & wait (W&W) strategy is applied. Only when the disease progresses to a more active, symptomatic form, treatment is indicated. The prospective CLL1 trial was designed to evaluate the benefit of early risk-adapted therapy with fludarabine (F) monotherapy, and to document the natural course of the disease from diagnosis. Here we present follow-up data to assess overall survival from the time point of treatment indication.

Methods
At enrolment, risk stratification was performed based on bone marrow (BM) infiltration pattern, lymphocyte doubling time (LDT), serum beta2-microglobulin (ß2-MG), and serum thymidine kinase (TK). Pts were “high-risk” (HR) if they had diffuse BM infiltration pattern and/or LDT<12 months (mo) combined with TK >7.0 U/L and/or ß2-MG >3.5 mg/L at enrolment. HR pts were randomized in a 1:1 ratio to early F (HR-F), or to W&W until classical treatment indication (HR-W&W), which was also applied to all low-risk (LR) pts.

Results
Between 1997 and 2004, 710 pts with Binet A stage CLL were enrolled and underwent risk stratification (RS) per protocol. Median time from diagnosis to enrolment was 3.2 mo (range 0-33.7) and median follow-up time was 8.5 years (yrs) (range 0-13.9). 521 pts (73%) were stratified to LR and 189 pts (27%) to HR, of whom 93 pts (49%) were randomized to HR-F and 96 pts (51%) to HR-W&W. Median age was 60 (range 32-75) yrs, 61% were male, 34% had unmutated IGHV status; high-risk cytogenetic features (17p- and 11q-) had 3% and 8% of pts, respectively. Early intervention with F among HR pts significantly prolonged progression-free survival (PFS) (30 vs. 13 mo; p<.001) and treatment-free survival (TFS) (74 vs. 41 mo; p=0.036) but did not significantly impact overall survival (OS) (127 mo vs. not reached; p=0.75). 303 patients had received treatment due to disease progression. 23% of patients received combination chemotherapy, 22% chemoimmunotherapy, 18% monotherapy with chlorambucil, and 15% monotherapy with purine analogues. Median OS for all pts was 91 mo (95% CI, 86 to 101 mo) from start of first treatment due to active disease. Patients with high risk (HR) for disease progression according to risk stratification had a significant shorter OS from start of first treatment than patients with low risk (LR) (71 mo vs. not reached; p=0.001). Early treatment with F did not show a significant impact on survival, when patients progressed after risk-adapted F, but showed a trend to a more favorable outcome for the watch and wait arm receiving their first therapy only when they had progressed to active disease (HR-F: median OS 51 mo versus HR-W&W not reached; p=0.055). Multivariate analyses on 237 pts identified 17p-, 11q-, unmutated IGHV, ß2-MG >3.5 mg/L, and age >60 yrs as independent prognostic factors for OS for patients with progressive, active disease and treatment indication.

Conclusions
Monotherapy with fludarabine is not superior to the W&W approach for the management of early stage CLL pts, since early F did not improve OS or outcome following subsequent therapies.

Disclosures:
No relevant conflicts of interest to declare.