Prospective Evaluation of Prognostic Parameters in Early Stage Chronic Lymphocytic Leukemia (CLL): Results of the CLL1-Protocol of the German CLL Study Group (GCLLSG).

Background: Early stage CLL is a heterogeneous disease with a prognosis ranging from an overall survival of a few months to two decades. Prognostic markers helping to predict the individual course of CLL are highly warranted. The CLL1 trial was initiated to investigate all major prognostic parameters used at the time of its initiation for prediction of the course of CLL.

Patients: From 1997 to 2004 877 Binet A pts (median age 60 yrs) were enrolled. The median follow up was 45 months (mo). Risk stratification was possible for 788 pts. Pts with high risk (HR) were defined by elevated thymidine kinase (TK) or beta-2-microglobulin (beta-2-MG)) and either short lymphocyte doubling time (LDT, <12 months)) or diffuse bone marrow infiltration (BMI). 99 pts were not eligible due to trial violation. HR pts were randomized to W&W vs. immediate therapy with fludarabine. Treated pts (n=104) were excluded from this analysis. Analyses on PFS and OS on 585 pts are presented. Progression was defined by slightly modified NCI-WG criteria.

Results: 114 pts (19.5%) were stratified to HR, 471 pts (80.5%) to low risk (LR). At enrolment there was no significant difference with regard to age, performance state, comorbidity. Significantly more male pts were assigned to HR (p=0.03). Beside parameters for stratification the cohorts differed in leukocyte/lymphocyte count (p<0.001), cervical and inguinal lymphadenopathy (LN) (p=0.001 resp. 0.005) and splenomegaly (p=0.02). B symptoms, hemoglobin, platelets, hepatomegaly and axillary LN were similar distributed in both groups. The median PFS for all was 57.3 mo. The median PFS for HR was significantly shorter than for LR (88 vs.18 mo; p<0,001). Although the median OS was not reached for both, HR had significantly shorter OS time (p<0,001). Pts had a significantly shorter PFS (25 vs. 88 mo; p<0.001) if they had TK>7 U/L, beta-2-MG>3.5 mg/L (13 vs. 75 mo; p<0.001) or LDT <12 mo (20 vs. 75 mo; p<0.001). For these parameters OS was also significantly shorter for HR, although the median OS was not reached. Pts with diffuse BMI had shorter PFS (49 vs. 75 mo; p=0.003), but OS was not different (p=0.2). Furthermore lymphocyte counts >30 G/L (PFS 17 vs. 88 mo; p<0.001) or non-smouldering CLL (PFS 46 mo vs. n.r.; p<0.001) predicted shorter PFS/OS. Male pts had shorter PFS (49 mo vs. n.r.; p=0.001), but not OS (p=0.08). OS was significantly shorter for older pts than 55 (p=0.014) or 65 yrs (p<0.001), while PFS was not different. A multivariate Cox analysis revealed that TK, LDT, beta-2-MG, absolute lymphocyte count, sex and age were independent variables for PFS, while LDT, beta-2-MG, lymphocytes and age were also independent for OS.

Conclusion: This prospective trial defined clinical and biological factors (TK, LDT, beta-2-MG, absolute lymphocyte count, age, sex) which help to predict progression in early CLL. Our model for risk stratification reliably separated between HR and LR. Due to the weak impact of BMI we do not further recommend the use of BM biopsy for assessment of prognosis in CLL.