Survival predictor for diffuse large B cell lymphoma
Inventors
Rimsza, Lisa • Lister, Andrew T. • Chan, Wing C. • Weisenburger, Dennis • Delabie, Jan • Smeland, Erlend B. • Holte, Harald • Kvaloy, Stein • Braziel, Rita M. • Fisher, Richard I. • Jares, Pedro • Lopez-Guillermo, Armando • Guerri, Elias Campo • Jaffe, Elaine S. • Lenz, Georg • Wilson, Wyndham H. • Wright, George • Dave, Sandeep S. • Staudt, Louis M. • Gascoyne, Randy D. • Connors, Joseph M. • Muller-Hermelink, Hans-Konrad • Rosenwald, Andreas • Ott, German
Assignees
British Columbia Cancer Agency BCCA • Julius Maximilians Universitaet Wuerzburg • Universitat de Barcelona UB • Hospital Clinic de Barcelona • Queen Mary University of London • Oslo Universitetssykehus hf • Oregon Health and Science University • University of Rochester • University of Arizona • University of Nebraska System • US Department of Health and Human Services
Publication Number
US-9970059-B2
Publication Date
2018-05-15
Expiration Date
2029-06-05
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Abstract
The invention provides methods and materials related to a gene expression-based survival predictor for DLBCL patients.
Core Innovation
The invention provides methods and materials related to a gene expression-based survival predictor for diffuse large B cell lymphoma (DLBCL) patients, including patients treated with the current standard of care such as chemotherapy and administration of Rituximab (R-CHOP). The survival predictor uses gene expression profiles derived from biopsy samples to calculate signature values for germinal center B cell (GCB) gene expression, stromal-1 gene expression, and stromal-2 gene expression, which are then combined in a survival predictor score to estimate a subject's survival outcome.
The problem being solved is that DLBCL is a molecularly heterogeneous disease with different subtypes having varying prognosis after treatment. Current standard treatments, including R-CHOP, cure about 60% of patients but the molecular basis of response or resistance is unknown. Existing gene expression profiling identifies DLBCL subtypes with different prognoses under chemotherapy alone; however, these distinctions are less predictive in patients receiving combined Rituximab therapy. Thus, there is a need for new methods of distinguishing among DLBCL subtypes that are prognostically significant for patients treated with R-CHOP.
Claims Coverage
The patent includes one independent claim, which covers methods of treating a subject suffering from DLBCL by predicting survival outcome using gene expression profiles and treating accordingly.
Method of predicting survival outcome using specific gene expression signatures and a multivariate survival predictor score
A method comprising obtaining one or more DLBCL biopsy samples, isolating gene expression product, obtaining a gene expression profile with expression levels for genes in GCB, stromal-1, and stromal-2 gene expression signatures, determining signature values, calculating a survival predictor score using the equation survival predictor score=8.11−[0.419*(GCB signature value)]−[1.015*(stromal-1 signature value)]+[0.675*(stromal-2 signature value)], where lower scores indicate more favorable outcomes.
Use of survival predictor score to generate survival estimate curves
The method includes tracking survival outcomes post-treatment, generating survival estimate curves correlating survival probability with time and predictor score, and calculating probabilities of survival outcomes beyond a defined time using a defined equation with scale factors.
Method of selecting subjects for antiangiogenic therapy based on stromal signature values
A method that includes obtaining gene expression profiles from biopsy samples, calculating stromal-1 and stromal-2 signature values, subtracting these to obtain a stromal score, comparing it to a standard, and indicating antiangiogenic therapy if the stromal score is higher than the standard.
The claims collectively cover methods of predicting survival outcomes of DLBCL patients by analyzing gene expression profiles for GCB, stromal-1, and stromal-2 signatures and calculating survival predictor scores, methods for generating survival estimates from those scores, and methods of selecting patients for antiangiogenic therapy based on stromal scores derived from the same gene expression data.
Stated Advantages
Provides prognostic information useful to both patient and physician to better predict survival outcomes following treatment.
Enables identification of patients with inferior outcomes under standard R-CHOP therapy who may benefit from alternative therapeutic regimens.
Facilitates improved clinical trial design and analysis by enabling quantitative comparison of patient cohorts based on molecular characteristics.
Supplies data that allows patients to make informed decisions about personal life planning based on predicted survival likelihoods.
Documented Applications
Predicting survival outcomes in patients with diffuse large B cell lymphoma by analyzing gene expression profiles of biopsy samples.
Selecting DLBCL patients for treatment with antiangiogenic therapy based on gene expression signature analysis indicating angiogenic activity.
Use in clinical trial design and analysis to stratify patients based on molecular subtype and predicted response to R-CHOP and similar therapies.
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