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Chronic Lymphocytic Leukemia
Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients
Johannes Bloehdorn,1 Julia Krzykalla,2 Karlheinz Holzmann,3 Andreas Gerhardinger,3 Billy Michael Chelliah Jebaraj,1 Jasmin Bahlo,4 Kathryn Humphrey,5 Eugen Tausch,1 Sandra Robrecht,4 Daniel Mertens,1,6 Christof Schneider,1 Kirsten Fischer,4 Michael Hallek,4 Hartmut Döhner,1 Axel Benner2# and Stephan Stilgenbauer1#
1Department of Internal Medicine III, University of Ulm, Ulm, Germany; 2Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany; 3Genomics Core Facility, University of Ulm, Ulm, Germany; 4Department I for Internal Medicine and Center for Integrated Oncology, University of Cologne, Cologne, Germany, 5Clinical Development Oncology, Roche Products Ltd, Welwyn Garden City, UK and 6German Cancer Research Center (DKFZ), Heidelberg, Germany
#AB and SS contributed equally as co-senior authors.
ABSTRACT
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) can induce long-term remissions in patients with chronic lymphocytic leukemia. Treatment efficacy with Bruton's tyrosine kinase inhibitors was found similar to FCR in untreated chronic lymphocytic leukemia patients with a mutated immunoglobulin heavy chain variable (IGHV) gene. In order to identify patients who specifically benefit from FCR, we developed integrative models including established prognostic parameters and gene expression profiling (GEP). GEP was con- ducted 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 IGHV 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 GEP variables performed equal to models including only established non-GEP variables. GEP variables showed higher prognostic accuracy for patients with long progression-free survival compared to cat- egorical variables like the IGHV gene mutation status and reliably predict- ed overall survival in CLL8 and an independent cohort. GEP-based prog- nostic models can help to identify patients who specifically benefit from FCR treatment. The CLL8 trial is registered under EUDRACT-2004- 004938-14 and clinicaltrials gov. Identifier: NCT00281918.
Introduction
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) was defined as the standard first-line therapy for patients with chronic lymphocytic leukemia (CLL) who are eligible for intensive treatment.1,2
There is prognostic impact of recurrent genetic alterations and NOTCH1 mutations were identified as a predictive marker for reduced benefit of FCR over FC.3,4,5,6,7 While substantial treatment benefit has been established for FCR in distinct patient popula- tions,1 high efficacy of novel targeted compounds such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib was recently reported in previously untreated patients,8,9 and for cohorts with genetic high-risk subgroups or refractory populations.10,11,12,13,14 However, progression-free survival (PFS) in previously untreated patients ≤70 years old with a mutated immunoglobulin heavy chain variable (IGHV) gene was similar
Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):615-624
Correspondence:
STEPHAN STILGENBAUER
stephan.stilgenbauer@uniklinik-ulm.de
Received: March 1, 2020. Accepted: March 11, 2021. Pre-published: March 18, 2021.
https://doi.org/10.3324/haematol.2020.251561 ©2022 Ferrata Storti Foundation
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