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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Published in | Haematologica (Roma) Vol. 107; no. 3; pp. 615 - 624 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Italy
Fondazione Ferrata Storti
01.03.2022
Ferrata Storti Foundation |
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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, 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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AbstractList | 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. 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. |
Author | Bahlo, Jasmin Fischer, Kirsten Stilgenbauer, Stephan Hallek, Michael Döhner, Hartmut Holzmann, Karlheinz Tausch, Eugen Mertens, Daniel Benner, Axel Bloehdorn, Johannes Humphrey, Kathryn Schneider, Christof Krzykalla, Julia Jebaraj, Billy Michael Chelliah Robrecht, Sandra Gerhardinger, Andreas |
AuthorAffiliation | 2 Division of Biostatistics, German Cancer Research Center , Heidelberg, Germany 1 Department of Internal Medicine III, University of Ulm , Ulm, Germany 6 German Cancer Research Center (DKFZ) , Heidelberg, Germany 4 Department I for Internal Medicine and Center for Integrated Oncology, University of Cologne , Cologne, Germany 5 Clinical Development Oncology, Roche Products Ltd , Welwyn Garden City, UK 3 Genomics Core Facility, University of Ulm , Ulm, Germany |
AuthorAffiliation_xml | – name: 6 German Cancer Research Center (DKFZ) , Heidelberg, Germany – name: 5 Clinical Development Oncology, Roche Products Ltd , Welwyn Garden City, UK – name: 1 Department of Internal Medicine III, University of Ulm , Ulm, Germany – name: 3 Genomics Core Facility, University of Ulm , Ulm, Germany – name: 2 Division of Biostatistics, German Cancer Research Center , Heidelberg, Germany – name: 4 Department I for Internal Medicine and Center for Integrated Oncology, University of Cologne , Cologne, Germany |
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Cites_doi | 10.18637/jss.v045.i03 10.1073/pnas.1413374111 10.1038/ng.2443 10.1084/jem.194.11.1625 10.1182/blood.V94.6.1848.418k05_1848_1854 10.1182/blood-2018-120779 10.1038/leu.2011.125 10.1200/JCO.2005.12.051 10.1182/blood-2011-09-379966 10.1182/blood-2015-06-651125 10.1186/s13059-015-0694-1 10.1016/S1470-2045(16)30019-5 10.1084/jem.194.11.1639 10.1056/NEJM200012283432602 10.1056/NEJMoa040857 10.1182/blood-2014-01-546150 10.1056/NEJMoa1315226 10.1016/j.leukres.2015.05.005 10.1182/bloodadvances.2019000237 10.1182/blood-2010-09-304881 10.1056/NEJMoa1215637 10.1200/JCO.2016.68.2856 10.1016/S1470-2045(16)30029-8 10.1182/blood.V94.6.1840 10.1016/S1470-2045(18)30788-5 10.1002/bimj.201300222 10.1056/NEJMoa1513257 10.1198/016214501753382273 10.18637/jss.v050.i11 10.1038/ng.3488 10.1056/NEJMoa1812836 |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors declare that there are no conflicts of interest to disclose that interfered with the experiments and presentation of data. Disclosures Contributions JB, AB and SS conceptualized study; JB performed expression profiling; JB, JK and AB analyzed data. Data were gathered by all authors. JB wrote the paper with input from JK, AB and SS and all authors reviewed the manuscript. |
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SubjectTerms | Antineoplastic Combined Chemotherapy Protocols - therapeutic use Cyclophosphamide - therapeutic use Humans Leukemia, Lymphocytic, Chronic, B-Cell - diagnosis Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemia, Lymphocytic, Chronic, B-Cell - genetics Mutation Prognosis Rituximab - therapeutic use |
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Title | Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients |
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