Methods for treating diffuse large b-cell lymphoma and the use of biomarkers as a predictor to responsiveness to drugs

Abstract

In one aspect, provided herein are methods for predicting the responsiveness of DLBCL patients to treatment with lenolidomide or Compound A; or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof utilizing biomarkers or classfiers that correlate with responsiveness to one of these drugs. In another aspect, provided herein are methods for treating a DLBCL patient determined to be responsive to treatment with lenolidomide or Compound A; or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof utilizing biomarkers or classifiers (or output thereof) that correlate with responsiveness to one of these drugs.

1 . A method for predicting the responsiveness of a diffuse large B-cell lymphoma (DLBCL) patient to treatment with a drug comprising:
 (I)   (a) obtaining a first biological sample from a first patient having a DLBCL;   (b) determining the level of expression of one, two, three, four, five or more of the genes identified in Table 1, 2 or 3;   (c) comparing the level of expression of the one, two, three, four, five or more of the genes identified in Table 1, 2 or 3 in the first biological sample with the level of expression of the same genes in a second biological sample(s) from a second patient(s), wherein the second DLBCL patient(s) is not responsive to the drug, and   wherein the differential expression of the one, two, three, four, five or more of the genes in the first biological sample relative to the level of expression of the one, two, three, four, five or more of the genes in the second biological sample(s) indicates that the DLBCL in the first patient will be responsive to treatment with the drug, wherein the drug is 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (lenalidomide); 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A); or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof, or   (II)   (a) obtaining a first biological sample from a first patient having a DLBCL;   (b) determining the level of expression of one, two, three, four, five or more of the genes identified in Table 1, 2 or 3;   (c) comparing the level of expression of the one, two, three, four, five or more of the genes identified in Table 1, 2 or 3 in the first biological sample with the level of expression of the same genes in a second biological sample(s) from a second patient(s), wherein the second DLBCL patient(s) is responsive to the drug, and   wherein the similar expression of the one, two, three, four, five or more of the genes in the first biological sample relative to the level of expression of the one, two, three, four, five or more of the genes in the second biological sample(s) indicates that the DLBCL in the first patient will be responsive to treatment with the drug, wherein the drug is 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (lenalidomide); 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A); or a stereoisomer thereof or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof or a polymorph thereof.   
     
     
         2 . (canceled) 
     
     
         3 . A method for predicting the responsiveness of a DLBCL patient to treatment with a drug comprising:
 (a) obtaining a first biological sample from a first DLBCL patient;   (b) determining the expression of the genes or a certain subset of genes set forth in Table 1, 2 or 3, or any combination thereof in the first biological sample; and   (c) comparing the gene expression profile of the genes or subset of genes in the first biological sample to (i) the gene expression profile of the genes or subset of genes in biological samples from DLBCL patients which are responsive to the drug and (ii) the gene expression of the genes or subset of genes in biological samples from DLBCL patients which are not responsive to the drug,   wherein a gene expression profile for the genes or subset of genes in the first biological sample similar to the gene expression profile for the genes or subset of genes in biological samples from DLBCL patients which are responsive to the drug indicates that the first DLBCL patient will be responsive to treatment with the drug, and a gene expression profile for the genes or subset of genes in first biological sample similar to the gene expression profile for the genes or subset of genes in biological samples from DLBCL patients which are not responsive to the drug indicates that the first DLBCL patient will not be responsive to treatment with the drug, wherein the drug is 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (lenalidomide); 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A); or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof.   
     
     
         4 . A method for treating a DLBCL patient with a drug comprising:
 (I)   (a) obtaining a first biological sample from a first DLBCL patient;   (b) determining the level of expression of one, two, three, four, five or more of the genes identified in Table 1, 2 or 3;   (c) comparing the level of expression of the one, two, three, four, five or more of the genes identified in Table 1, 2 or 3 in the first biological sample with the level of expression of the same genes in a second biological sample(s) from a second DLBCL patient(s), wherein the second DLBCL patient is not responsive to the drug; and   (d) administering the drug to the first patient if the one, two, three, four, five or more of the genes in the first biological sample are differentially expressed relative to the level of expression of the one, two, three, four, five or more of the genes in the second biological sample(s), wherein the drug is 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (lenalidomide); 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A); or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof,   (II)   (a) obtaining a first biological sample from a first DLBCL patient;   (b) determining the level of expression of one, two, three, four, five or more of the genes identified in Table 1, 2 or 3;   (c) comparing the level of expression of the one, two, three, four, five or more of the genes identified in Table 1, 2 or 3 in the first biological sample with the level of expression of the same genes in a second biological sample(s) from a second DLBCL patient(s), wherein the second DLBCL patient is responsive to the drug; and   (d) administering the drug to the first patient if the one, two, three, four, five or more of the genes in the first biological sample are similarly expressed relative to the level of expression of the one, two, three, four, five or more of the genes in the second biological sample(s), wherein the drug is 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (lenalidomide); 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A); or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof, or   (III)   (a) obtaining a first biological sample from a first DLBCL patient;   (b) determining the expression of a certain subset of genes set forth in Table 1, 2 or 3, or any combination thereof in the first biological sample,   (c) comparing the gene expression profile of the subset of genes in the first biological sample to (i) the gene expression profile of the subset of genes in biological samples from DLBCL patients which are responsive to the drug and (ii) the gene expression of the subset of genes in biological samples from DLBCL patients which are not responsive to the drug; and   (d) administering the drug to the first patient if: (i) the gene expression profile for the subset of genes in the first biological sample is similar to the gene expression profile for the subset of genes in biological samples from DLBCL patients which are responsive to the drug and (ii) the gene expression profile for the subset of genes in first biological sample is not similar to the gene expression profile for the subset of genes in biological samples from DLBCL patients which are not responsive to the drug, wherein the drug is 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (lenalidomide); 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A); or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof.   
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the biological samples are tumor biopsy samples. 
     
     
         8 . The method of  claim 1 , wherein the determining step comprises detecting the presence and/or amount of a complex in the biological sample, wherein the presence and/or amount of the complex indicates the expression level of the genes in each subset of genes. 
     
     
         9 . The method of  claim 8 , wherein the complex is a hybridization complex. 
     
     
         10 . The method of  claim 9 , wherein the hybridization complex is attached to a solid support. 
     
     
         11 . The method of  claim 10 , wherein said complex is detectably labeled. 
     
     
         12 . The method of  claim 1 , wherein the determining step comprises detecting the presence and/or amount of a reaction product in the biological sample, wherein the presence and/or amount of the reaction product indicates the expression level of the genes. 
     
     
         13 . The method of  claim 12 , wherein said reaction product is detectably labeled. 
     
     
         14 . The method of  claim 1 , wherein the DLBCL is refractory in the first DLBCL patient. 
     
     
         15 . The method of  claim 1 , wherein the DLBCL is relapsed in the first DLBCL patient. 
     
     
         16 . The method of  claim 1 , wherein the DLBCL is a germinal center B-cell-like subtype in the first DLBCL patient. 
     
     
         17 . The method of  claim 1 , wherein the DLBCL is activated B-cell like in the first DLBCL patient. 
     
     
         18 . The method of  claim 1 , wherein the DLBCL is Type III in the first DLBCL patient.