USE OF INHIBITORS OF BRUTONS TYROSINE KINASE (BTK)
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.
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
.