Survival predictor for diffuse large b cell lymphoma

a survival predictor technology, applied in the field of survival predictors of diffuse large b cell lymphoma, can solve the problems of inferior survival with chop therapy, bcl-2 or low expression of bcl-6, and unknown molecular basis of response or resistance to this therapy

Inactive Publication Date: 2011-08-11
UNITED STATES OF AMERICA +10
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]The invention also provides a targeted array comprising at least one probe or at least one set of probes for each gene in a germinal center B cell gene (GCB) expression signature, a stromal-1 gene expression signature, and a stromal-2 gene expression signature. The array can include probes for fewer than 20,000 genes or fewer than 10,000 genes.

Problems solved by technology

Nonetheless, the molecular basis of response or resistance to this therapy is unknown.
High expression of BCL-2 or low expression of BCL-6 was associated with inferior survival with CHOP therapy.

Method used

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  • Survival predictor for diffuse large b cell lymphoma
  • Survival predictor for diffuse large b cell lymphoma
  • Survival predictor for diffuse large b cell lymphoma

Examples

Experimental program
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Effect test

example 1

[0097]This example demonstrates that significant differences were found between the survival outcomes for R-CHOP treated ABC DLBCL and GCB DLBCL patients and that survival outcome correlated with three prognostic gene expression signatures.

[0098]Pre-treatment tumor biopsy specimens and clinical data were obtained from 414 patients with de novo DLBCL treated at 10 institutions in North America and Europe and studied according to a protocol approved by the National Cancer Institute's Institutional Review Board. Patients included in a “LLMP CHOP cohort” of 181 patients were treated with anthracycline-based combinations, most often cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or similar regimens, as previously described (Rosenwald et al., N. Engl. J. Med., 346: 1937-47 (2002)). The remaining 233 patients constituted an R-CHOP cohort that received similar chemotherapy plus Rituximab. The median follow-up in the R-CHOP cohort was 2.1 years (2.8 years for survivors). A...

example 2

[0108]This example demonstrates the development of GCB, stromal-1, and stromal-2 survival signatures and a related multivariate model of survival for R-CHOP-treated DLBCL.

[0109]Unless otherwise indicated, patient cohorts and methods of gene expression analysis are as described in Example 1.

[0110]In the LLMPP CHOP cohort data, 936 genes were identified as associated with poor prognosis p0.6 and containing myc was identified as the proliferation survival signature. 1396 genes were identified as associated with favorable outcome. The largest cluster with average correlation of >0.6 and containing BCL6 was identified as the germinal center B cell (GCB) survival signature. A cluster with average correlation of >0.6 and containing FM was identified as the stromal-1 survival signature, whereas another cluster with average correlation of >0.6 containing HLADRA was identified as the MHC class II survival signature. The expression levels of genes within each signature were then averaged to cr...

example 3

[0117]This example demonstrates the use of a survival predictor score to predict the probability of progression free and overall survival outcomes at a period of time t following R-CHOP treatment in accordance with the invention.

[0118]RNA is isolated from a patient's DLBCL biopsy and hybridized to a U133+ array from Affymetrix (Santa Clara, Calif.). The array is scanned, and MAS 5.0 algorithm is applied to obtain signal values normalized to a target intensity of 500. Signal values are log 2 transformed to intensity values. For genes of interest with multiple probe sets, the intensity value of the multiple probe sets are averaged to obtain a single intensity value for each gene. The single intensity values of genes in the GCB signature are averaged to obtain a GCB signature average of 9.2. The single intensity values of genes in the stromal-1 signature are averaged to obtain a stromal-1 signature average of 8.5. The single intensity values of genes in the stromal-2 signature are aver...

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Abstract

The invention provides methods and materials related to a gene expression-based survival predictor for diffuse large B cell lymphoma (DLBCL) patients.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Patent Application No. 61 / 059,678, filed on Jun. 6, 2008, the disclosure of which is incorporated by reference.INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY[0002]Incorporated by reference in its entirety herein is a computer-readable nucleotide sequence listing submitted concurrently herewith and identified as follows: One 1,231,630 Byte ASCII (Text) file named “704777_ST25.TXT,” created on Jun. 5, 2009.BACKGROUND OF THE INVENTION[0003]The current standard of care for the treatment of diffuse large B cell lymphoma (DLBCL) includes anthracycline-based chemotherapy regimens such as CHOP in combination with the administration of the anti-CD20 monoclonal antibody Rituximab. This combination regimen (R-CHOP) can cure about 60% of patients and has improved the overall survival of DLBCL patients by 10-15% (Coiffier et al., N. Engl. J. Med., 346: 235-42 (2002)). Nonetheless,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C40B30/00A61P35/00G06F19/00
CPCG01N33/57407G01N2800/56G01N2800/52A61P35/00C12Q1/6886C12Q2600/106C12Q2600/112
Inventor RIMSZA, LISALISTER, ANDREW T.WEISENBURGER, DENNISDELABIE, JANSMELAND, ERLEND B.HOLTE, HARALDKVALOY, STEINBRAZIEL, RITA M.FISHER, RICHARD I.JARES, PEDROLOPEZ-GUILLERMO, ARMANDOGUERRI, ELIAS CAMPOJAFFE, ELAINE S.LENZ, GEORGWILSON, WYNDHAM H.WRIGHT, GEORGEDAVE, SANDEEP S.STAUDT, LOUIS M.GASCOYNE, RANDY D.CONNORS, JOSEPH M.MULLER-HERMELINK, HANS-KONRADROSENWALD, ANDREASOTT, GERMAN
Owner UNITED STATES OF AMERICA
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