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

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...

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Autores principales: Bloehdorn, Johannes, Krzykalla, Julia, Holzmann, Karlheinz, Gerhardinger, Andreas, Jebaraj, Billy Michael Chelliah, Bahlo, Jasmin, Humphrey, Kathryn, Tausch, Eugen, Robrecht, Sandra, Mertens, Daniel, Schneider, Christof, Fischer, Kirsten, Hallek, Michael, Döhner, Hartmut, Benner, Axel, Stilgenbauer, Stephan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883563/
https://www.ncbi.nlm.nih.gov/pubmed/33730841
http://dx.doi.org/10.3324/haematol.2020.251561
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author Bloehdorn, Johannes
Krzykalla, Julia
Holzmann, Karlheinz
Gerhardinger, Andreas
Jebaraj, Billy Michael Chelliah
Bahlo, Jasmin
Humphrey, Kathryn
Tausch, Eugen
Robrecht, Sandra
Mertens, Daniel
Schneider, Christof
Fischer, Kirsten
Hallek, Michael
Döhner, Hartmut
Benner, Axel
Stilgenbauer, Stephan
author_facet Bloehdorn, Johannes
Krzykalla, Julia
Holzmann, Karlheinz
Gerhardinger, Andreas
Jebaraj, Billy Michael Chelliah
Bahlo, Jasmin
Humphrey, Kathryn
Tausch, Eugen
Robrecht, Sandra
Mertens, Daniel
Schneider, Christof
Fischer, Kirsten
Hallek, Michael
Döhner, Hartmut
Benner, Axel
Stilgenbauer, Stephan
author_sort Bloehdorn, Johannes
collection PubMed
description 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, 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 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. The CLL8 trial is registered under EUDRACT-2004-004938-14 and clinicaltrials gov. Identifier: NCT00281918.
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spelling pubmed-88835632022-03-18 Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients Bloehdorn, Johannes Krzykalla, Julia Holzmann, Karlheinz Gerhardinger, Andreas Jebaraj, Billy Michael Chelliah Bahlo, Jasmin Humphrey, Kathryn Tausch, Eugen Robrecht, Sandra Mertens, Daniel Schneider, Christof Fischer, Kirsten Hallek, Michael Döhner, Hartmut Benner, Axel Stilgenbauer, Stephan Haematologica Article 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, 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 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. The CLL8 trial is registered under EUDRACT-2004-004938-14 and clinicaltrials gov. Identifier: NCT00281918. Fondazione Ferrata Storti 2021-03-18 /pmc/articles/PMC8883563/ /pubmed/33730841 http://dx.doi.org/10.3324/haematol.2020.251561 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Bloehdorn, Johannes
Krzykalla, Julia
Holzmann, Karlheinz
Gerhardinger, Andreas
Jebaraj, Billy Michael Chelliah
Bahlo, Jasmin
Humphrey, Kathryn
Tausch, Eugen
Robrecht, Sandra
Mertens, Daniel
Schneider, Christof
Fischer, Kirsten
Hallek, Michael
Döhner, Hartmut
Benner, Axel
Stilgenbauer, Stephan
Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients
title Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients
title_full Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients
title_fullStr Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients
title_full_unstemmed Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients
title_short Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients
title_sort integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883563/
https://www.ncbi.nlm.nih.gov/pubmed/33730841
http://dx.doi.org/10.3324/haematol.2020.251561
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