Methods for evaluating and treating waldenstrom's macroglobulinemia

Abstract

Methods for evaluating and treating Waldenstrom's macroglobulinemia are provided.

1 . A method for evaluating a subject having Waldenstrom's macroglobulinemia comprising:
 obtaining diseased B cells from the subject, and performing an assay on the diseased B cells to determine whether the diseased B cells contain a mutation in the carboxyl-terminal cytoplasmic tail of the gene encoding CXCR4, wherein the presence or absence of the mutation in the diseased B cell indicates the subject's likely responsiveness to treatment with various therapies.   
     
     
         2 . The method of  claim 1 , wherein the presence of the mutation in the diseased B cell indicates that the subject is unlikely to be responsive to BTK inhibitor treatment. 
     
     
         3 . The method of  claim 2 , further comprising:
 identifying the subject having the mutation in the diseased B cell (i) as unlikely to be responsive to treatment with a BTK inhibitor and/or (ii) as a candidate for treatment with a BTK inhibitor in combination with a CXCR4 inhibitor, an AKT inhibitor and/or an ERK inhibitor.   
     
     
         4 . The method of  claim 1 , wherein the presence or absence of the mutation is determined by isolating nucleic acids obtained from the B cells, amplifying the nucleic acids and determining the presence or absence of the mutation in the amplified nucleic acids. 
     
     
         5 . The method of  claim 4 , wherein the presence or absence of the mutation is determined by allele-specific polymerase chain reaction (AS-PCR). 
     
     
         6 . The method of  claim 1 , wherein the diseased B cells are isolated from other blood cells of the subject prior to determining the presence or absence of the mutation. 
     
     
         7 . The method of  claim 1 , wherein the mutation is a frame shift or nonsense mutation in the gene encoding the carboxyl-terminal cytoplasmic tail of CXCR4. 
     
     
         8 . The method of  claim 1 , further comprising, obtaining non-B cells from the subject, and performing an assay on the non-B cells to determine whether the non-B cells contain a mutation in the carboxyl-terminal cytoplasmic tail of the gene encoding CXCR4. 
     
     
         9 - 15 . (canceled) 
     
     
         16 . A method for evaluating a subject comprising,
 obtaining B cells from the subject, performing an assay on the diseased B cells to determine whether the diseased B cells contain a mutation in the carboxyl-terminal cytoplasmic tail of the gene encoding CXCR4, obtaining non-B cells from the subject, and performing an assay on the non-B cells to determine whether the non-B cells contain a mutation in the carboxyl-terminal cytoplasmic tail of the gene encoding CXCR4.   
     
     
         17 . The method of  claim 1 , further comprising first performing a test on the subject to determine if the subject has or is suspected of having Waldenström's macroglobulinemia. 
     
     
         18 - 28 . (canceled) 
     
     
         29 . A method to distinguish Waldenström's macroglobulinemia from other B cell neoplasms, the method comprising:
 performing an assay on a biological sample obtained from a subject in need thereof to determine whether the subject has a mutation at position 38182641 in chromosome 3p22.2; performing an assay on diseased B cells obtained from the subject to determine whether the diseased B cells contain a mutation in the carboxyl-terminal cytoplasmic tail of the gene encoding CXCR4, wherein the subject has Waldenström's macroglobulinemia if the subject has a mutation at position 38182641 in chromosome 3p22.2 and a mutation in the carboxyl-terminal cytoplasmic tail of the gene encoding CXCR4. 
 
     
     
         30 . The method of  claim 29 , wherein the biological sample is a sample of bone marrow, lymph node, spleen or blood. 
     
     
         31 . The method of  claim 29 , wherein:
 (i) the mutation at position 38182641 results in a single nucleotide change from T to C in the myeloid differentiation primary response 88 (MYD88) gene;   (ii) the mutation at position 38182641 results in an amino acid change from leucine to proline at position 265 in the myeloid differentiation primary response 88 protein;   (iii) the assay to determine whether the subject has a mutation at position 38182641 in chromosome 3p22.2 comprises allele specific polymerase chain reaction performed using an allele specific primer, wherein the allele specific primer hybridizes at or near its 3′ end to the mutation at position 38182641 in chromosome 3p22.2;   (iv) the mutation is a frame shift or nonsense mutation in the gene encoding the carboxyl-terminal cytoplasmic tail of CXCR4; or   (v) the assay to determine whether the diseased B cells contain a mutation in the carboxyl-terminal cytoplasmic tail of the gene encoding CXCR4 comprises allele specific polymerase chain reaction.   
     
     
         32 - 35 . (canceled)