Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients.

Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab can induce longterm remissions in patients with chronic lymphocytic leukemia. Treatment efficacy with Bruton's tyrosine kinase inhibitors was found similar to fludarabine, cyclophosphamide and rituximab in untreated chronic lymphocytic leukemia patients with a mutated immunoglobulin heavy chain variable gene. To identify patients who specifically benefit from fludarabine, cyclophosphamide and rituximab, we developed integrative models including established prognostic parameters and gene expression profiling. Gene expression profiling was conducted on n=337 CLL8 trial samples, "core" probe sets were summarized on gene levels and RMA normalized. Prognostic models were built using penalized Cox proportional hazards models with the smoothly clipped absolute deviation penalty. We identified a prognostic signature of less than a dozen genes, which substituted for established prognostic factors, including TP53 and immunoglobulin heavy chain variable gene mutation status. Independent prognostic impact was confirmed for treatment, β2-microglobulin and del(17p) regarding overall survival and for treatment, del(11q), del(17p) and SF3B1 mutation for progression-free survival. The combination of independent prognostic and gene expression profiling variables performed equal to models including only established non-gene expression profiling variables. Gene expression profiling variables showed higher prognostic accuracy for patients with long progression-free survival compared to categorical variables like the immunoglobulin heavy chain variable gene mutation status and reliably predicted overall survival in CLL8 and an independent cohort. Gene expression profiling based prognostic models can help to identify patients who specifically benefit from fludarabine, cyclophosphamide and rituximab treatment. The CLL8 trial is registered under EUDRACT- 2004-004938-14 and Identifier NCT00281918.

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Authors: Johannes Bloehdorn, Julia Krzykalla, Karlheinz Holzmann, Andreas Gerhardinger, Billy Michael Chelliah Jebaraj, Jasmin Bahlo, Kathryn Humphrey, Eugen Tausch, Sandra Robrecht, Daniel Mertens, Christof Schneider, Kirsten Fischer, Michael Hallek, Hartmut Döhner, Axel Benner, Stephan Stilgenbauer