Use of inhibitors of brutons tyrosine kinase (btk)

Abstract

Disclosed herein are methods for treating a cancer comprising: a. administering a Btk inhibitor to a subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping; b. determining the expression profile of one or more biomarkers from one or more subpopulation of lymphocytes; and c. administering a second agent based on the determined expression profile.

What is claimed is: 
     
         1 . A method for treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in an individual comprising:
 orally administering to the individual a therapeutically effective amount of an irreversible inhibitor of Bruton’s tyrosine kinase (Btk) on a continuous daily regimen until progression of the CLL or SLL or unacceptable toxicity; wherein:
 lymphocytosis is not considered progression of the CLL or SLL, 
 the irreversible inhibitor of Btk is a small organic molecule having the structure:
                     
 
 Z′ is a substituted fused heterocyclic ring system comprising from 2-4 nitrogen heteroatoms; 
 the fused heterocyclic ring system consists of a 5-membered ring comprising at least one nitrogen heteroatom fused to a 6-membered ring comprising at least one nitrogen heteroatom; 
 the fused heterocyclic ring system is substituted with L s R s ; 
 L s  is selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —NHC(O)—, — C(O)NH—, S(═O) 2 NH—, —NHS(═O) 2 , —OC(O)NH—, — NHC(O)O—, —(substituted or unsubstituted C 1 -C 6  alkyl), or —(substituted or unsubstituted C 2 -C 6  alkenyl); and 
 R s  is independently selected from H, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, heteroaryl, or heteroalkyl. 
   
     
     
         2 . The method of  claim 1 , wherein Z′ is substituted with L S R S , wherein:
 L s  is selected from —NH—, —NHC(O)—, —C(O)NH—, —OC(O)NH—, —NHC(O)O—; and 
 R s  is H. 
 
     
     
         3 . The method of  claim 2 , wherein Z′ is substituted with L s R s , wherein:
 L s  is —C(O)NH—; and 
 R s  is H. 
 
     
     
         4 . The method of  claim 2 , wherein Z′ is substituted with L s R s , wherein:
 L s  is —NH—; and 
 R s  is H. 
 
     
     
         5 . The method of  claim 3 , wherein said administration of the therapeutically effective amount is an amount that results in >90% of the Btk active sites in the peripheral blood mononuclear cells of the individual being occupied by the irreversible inhibitor of Btk twenty-four hours following said administration. 
     
     
         6 . The method of  claim 3 , wherein the therapeutically effective amount is determined by measuring pharmacodynamic parameters of the irreversible inhibitor of Btk. 
     
     
         7 . The method of  claim 4 , wherein said administration of the therapeutically effective amount is an amount that results in >90% of the Btk active sites in the peripheral blood mononuclear cells of the individual being occupied by the irreversible inhibitor of Btk twenty-four hours following said administration. 
     
     
         8 . The method of  claim 4 , wherein the therapeutically effective amount is determined by measuring pharmacodynamic parameters of the irreversible inhibitor of Btk. 
     
     
         9 . The method of  claim 4 , wherein the irreversible inhibitor of Btk is
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