Methods of treating myeloproliferative disorders

Abstract

The present disclosure provides methods of mitigating thiamine deficiency.

1 . A method of treating a myeloproliferative disorder, comprising
 (i) administering to a patient in need thereof Compound I, or a pharmaceutically acceptable salt or hydrate thereof; and   (ii) monitoring the patient's thiamine levels;   wherein the patient's thiamine levels are adjusted if the level of thiamine is below a reference standard.   
     
     
         2 . The method of  claim 1 , wherein the patient's thiamine levels are assessed by analyzing one or more biomarkers for thiamine deficiency. 
     
     
         3 . The method of  claim 2 , wherein the biomarker for thiamine deficiency is a serum thiamine level. 
     
     
         4 . The method of  claim 2  or  claim 3 , wherein the level of the biomarker following administration of Compound I is lower than the reference standard 
     
     
         5 . The method of any of  claims 1 - 4 , wherein the patient's thiamine levels are adjusted by administering to the patient thiamine or a thiamine equivalent. 
     
     
         6 . A method of treating myelofibrosis comprising administering to a patient in need thereof a combination therapy comprising Compound I, or a pharmaceutically acceptable salt or hydrate thereof, and thiamine or a thiamine equivalent. 
     
     
         7 . A method of mitigating thiamine deficiency comprising administering Compound I, or a pharmaceutically acceptable salt or hydrate thereof, to a patient at risk for developing thiamine deficiency, wherein the patient is simultaneously exposed to thiamine or a thiamine equivalent. 
     
     
         8 . The method of any of  claims 1 - 7 , wherein the thiamine equivalent is thiamine pyrophosphate. 
     
     
         9 . A method for treating a patient comprising:
 (i) administering to the patient Compound I, or a pharmaceutically acceptable salt or hydrate thereof,   (ii) analyzing the thiamine level in the patient, and   (iii) administering to the patient thiamine or a thiamine equivalent if the patient's thiamine level is less than or equal to about 30 nM/L.   
     
     
         10 . The method of  claim 9 , wherein thiamine is administered to the patient at an amount of about 100 mg per day. 
     
     
         11 . The method of  claim 10 , wherein thiamine is administered orally. 
     
     
         12 . The method of  claim 9 , wherein thiamine is administered to the patient at an amount of about 250 mg to about 500 mg. 
     
     
         13 . The method of  claim 12 , wherein thiamine is administered to the patient at an amount of about 250 mg. 
     
     
         14 . The method of  claim 12 , wherein thiamine is administered to the patient at an amount of about 500 mg. 
     
     
         15 . The method of any of  claims 12 - 14 , wherein thiamine is administered intravenously. 
     
     
         16 . The method of  claim 9 , wherein thiamine is administered according to the following schedule:
 about 500 mg TID for 2 or 3 days;   about 250 mg to about 500 mg daily (QD) for 3-5 days; and   about 100 mg QD for 90 days.   
     
     
         17 . The method of  claim 9 , wherein the patient is administered a thiamine equivalent sufficient to deliver about 100 mg of thiamine mg per day. 
     
     
         18 . The method of  claim 17 , wherein the thiamine equivalent is administered orally. 
     
     
         19 . The method of  claim 9 , wherein the patient is administered a thiamine equivalent sufficient to deliver about 250 mg to about 500 mg of thiamine. 
     
     
         20 . The method of  claim 19 , wherein the thiamine equivalent is sufficient to deliver about 250 mg of thiamine. 
     
     
         21 . The method of  claim 19 , wherein the thiamine equivalent is sufficient to deliver about 500 mg of thiamine. 
     
     
         22 . The method of any of  claims 19 - 21 , wherein the thiamine equivalent is administered intravenously. 
     
     
         23 . The method of  claim 17 , wherein the thiamine equivalent is sufficient to deliver an amount of thiamine according to the following schedule:
 about 500 mg TID for 2 or 3 days;   about 250 mg to about 500 mg daily (QD) for 3-5 days; and   about 100 mg QD for 90 days.   
     
     
         24 . The method of any of  claims 1 - 23 , further comprising increasing the patient's magnesium level. 
     
     
         25 . The method of any of  claims 1 - 24  wherein the patient has a myeloproliferative disorder. 
     
     
         26 . The method of  claim 25 , wherein the myeloproliferative disorder is myelofibrosis. 
     
     
         27 . The method of  claim 26 , wherein the myelofibrosis is primary myelofibrosis. 
     
     
         28 . The method of  claim 27 , wherein the primary myelofibrosis is selected from intermediate risk primary myelofibrosis and high risk primary myelofibrosis. 
     
     
         29 . The method of  claim 26 , wherein the myelofibrosis is secondary myelofibrosis. 
     
     
         30 . The method of  claim 26 , wherein the myelofibrosis is post essential thrombocythemia myelofibrosis. 
     
     
         31 . The method of  claim 26 , wherein the myelofibrosis is post polycythemia vera myelofibrosis. 
     
     
         32 . The method of  claim 25 , wherein the myeloproliferative disorder is acute myeloid leukemia (AML). 
     
     
         33 . The method of  claim 25 , wherein the myeloproliferative disorder is polycythemia vera. 
     
     
         34 . The method of  claim 25 , wherein the myeloproliferative disorder is essential thrombocythemia. 
     
     
         35 . A method for treating a patient comprising:
 (i) administering Compound I, or a pharmaceutically acceptable salt or hydrate thereof, and   (ii) conducting a cognitive assessment.   
     
     
         36 . The method of  claim 35 , wherein the assessment occurs during the 2 nd  28-day cycle of Compound I administration. 
     
     
         37 . The method of  claim 35 , wherein the assessment occurs during the 3 rd  28-day cycle of Compound I administration. 
     
     
         38 . The method of  claim 35 , wherein the assessment occurs during at least every 3 rd  28-day cycle of Compound I administration. 
     
     
         39 . The method of  claim 35 , wherein the assessment comprises a mini-mental state examination. 
     
     
         40 . The method of  claim 35 , further comprising analyzing the thiamine level in the patient.