Towards a Comprehensive Prognostic Score in CLL Based On a Combination of Genetic Parameters.
Authors: Haferlach Claudia , Dicker Frank , Weiss Tamara , Schnittger Susanne , Beck Christian , Grote-Metke Albert , Oruzio Daniel V , Kern Wolfgang , Haferlach Torsten 
Published: October 2019

Abstract
Abstract 1234
Poster Board I-256
CLL is a heterogeneous disease with a variable clinical course. In this study the prognostic power of chromosome banding analysis (CBA), interphase FISH and IgVH status was evaluated. In total 399 untreated cases were analyzed. First, we could confirm the prognostic significance of established parameters such as age (≥65 yrs), white blood cell count (≥20.000/μl), IgVH status, TP53 deletion and 11q deletion in our cohort. In addition, a negative prognostic impact of translocations involving the IgH locus, especially t(14;18)(q32;q21) and of the complexity of the karyotype measured by the number of clonal chromosome aberrations in CBA was observed. Furthermore it became obvious that some parameters discriminated better for overall survival and other for time to treatment. While the impact of the IgVH status on overall survival was low within the first 5 years after diagnosis (mutated 88.5% surviving vs unmutated 82.0% surviving, log rank test p=0.022), an unmutated IgVH status was strongly correlated with a shorter median time to treatment (18.3 months unmutated vs 110.7 months mutated, log rank test p<0.0001). On the other hand the impact of TP53 deletion was more pronounced on overall survival as compared to time to treatment. Age was associated with a shorter overall survival but was not significantly associated with time to treatment. Based on these results we propose a score for overall survival (OS) based on: age ≥65 yrs, WBC ≥20.000/μl, unmutated IgVH status, TP53 deletion, t(IgH), and the number of chromosome aberrations observed in CBA. Three respective risk groups showed considerable differences in OS (94.5% vs 64.3% vs 41.1% surviving at 5 yrs, p<0.0001). In contrast, time to treatment (TTT) was predicted best by unmutated IgVH status, ATM deletion, t(IgH) and number of chromosome aberrations. Four subgroups could be separated with median TTT of 110.7 months, 39.8 months, 19.5 months, and 3.8 months, respectively (p<0.0001). In conclusion, our data show that in combination with established prognostic markers such as an unmutated IgVH status, TP53/17p deletions or 11q deletions also the newly defined complexity of the karyotype measured by the number of chromosome aberrations has an important impact both on overall survival and also on time to treatment in CLL. These newly combined parameters translate into a more distinct separation of prognostic subgroups within the first years after diagnosis as compared to other prognostic systems using FISH data only or based on FISH data in combination with IgVH status. Prospective studies should evaluate the power for early stage CLL patients.

Disclosures
Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Dicker:MLL Munich Leukemia Laboratory: Employment. Weiss:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.