Universität zu Köln

Bloehdorn, Johannes ORCID: 0000-0003-1433-9702, Krzykalla, Julia, Holzmann, Karlheinz, Gerhardinger, Andreas, Jebaraj, Billy Michael Chelliah, Bahlo, Jasmin, Humphrey, Kathryn, Tausch, Eugen, Robrecht, Sandra, Mertens, Daniel ORCID: 0000-0003-0227-7188, Schneider, Christof, Fischer, Kirsten, Hallek, Michael ORCID: 0000-0002-7425-4455, Doehner, Hartmut, Benner, Axel and Stilgenbauer, Stephan (2022). Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients. Haematologica, 107 (3). S. 615 - 625. PAVIA: FERRATA STORTI FOUNDATION. ISSN 0390-6078

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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 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 IGHV gene mutation status. Independent prognostic impact was confirmed for treatment, beta 2-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 categorical variables like the IGHV gene mutation status and reliably predicted overall survival in CLL8 and an independent cohort. GEP-based prognostic models can help to identify patients who specifically benefit from FCR treatment.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bloehdorn, Johannes UNSPECIFIED orcid.org/0000-0003-1433-9702 UNSPECIFIED Krzykalla, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzmann, Karlheinz UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerhardinger, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Jebaraj, Billy Michael Chelliah UNSPECIFIED UNSPECIFIED UNSPECIFIED Bahlo, Jasmin UNSPECIFIED UNSPECIFIED UNSPECIFIED Humphrey, Kathryn UNSPECIFIED UNSPECIFIED UNSPECIFIED Tausch, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Robrecht, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Mertens, Daniel UNSPECIFIED orcid.org/0000-0003-0227-7188 UNSPECIFIED Schneider, Christof UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED orcid.org/0000-0002-7425-4455 UNSPECIFIED Doehner, Hartmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Benner, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbauer, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-681031
DOI:	10.3324/haematol.2020.251561
Journal or Publication Title:	Haematologica
Volume:	107
Number:	3
Page Range:	S. 615 - 625
Date:	2022
Publisher:	FERRATA STORTI FOUNDATION
Place of Publication:	PAVIA
ISSN:	0390-6078
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENE MUTATION STATUS; DNA METHYLATION; EXPRESSION; CHEMOIMMUNOTHERAPY; VENETOCLAX; PHENOTYPE; RITUXIMAB; TIME Multiple languages Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68103