Crenolanib for treating FLT3 mutated proliferative disorders associated mutations

1 . A method for treating a human patient with Crenolanib, wherein the human patient is suffering from a FLT3 mutated leukemia, the method comprising:

a) obtaining or having obtained a leukemia biological sample from the human patient;

b) performing or having performed a genotyping assay on the biological sample to determine that the human patient has both a mutated FLT3 or a constitutively active FLT3 mutant and one or more driver mutations in a TET2 epigenetic regulator gene that result in a loss-of-function mutation of a TET2 protein;

c) determining that the human patient has a poor prognosis for the FLT3 mutated leukemia based on detecting the presence of both the mutated FLT3 and the one or more driver mutations in TET2 in the sample; and

d) administering to the patient determined to have the poor prognosis a therapeutically effective amount of Crenolanib or a pharmaceutically acceptable salt thereof, to treat the leukemia.

2 . The method of claim 1 , wherein the FLT3 mutation is selected from at least one of FLT3-ITD or FLT3-TKD.

3 . The method of claim 1 , wherein the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof are from about 50 to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day.

4 . The method of claim 1 , wherein the Crenolanib or the pharmaceutically acceptable salt thereof is Crenolanib besylate, Crenolanib phosphate, Crenolanib lactate, Crenolanib hydrochloride, Crenolanib citrate, Crenolanib acetate, Crenolanib toluenesulphonate, and Crenolanib succinate.

5 . A method for treating a human patient suffering from acute myelogenous leukemia (AML) comprising:

a) obtaining a biological sample from the human patient;

b) determining from the sample that the human patient has AML with a deregulated FLT3 receptor or a constitutively active FLT3 receptor;

c) determining from the sample that the human patient has one or more driver mutations in epigenetic regulator protein TET2 that result in a loss-of-function mutation of TET2;

d) determining that the human patient has a poor prognosis for AML based on determining the presence of both the mutated FLT3 and the one or more driver mutations in TET2 in the sample; and

e) administering to the patient determined to have the poor prognosis a therapeutically effective amount of Crenolanib or a pharmaceutically acceptable salt thereof, thereby treating the AML.

6 . A method for specifically inhibiting a deregulated or constitutively active FLT3 receptor tyrosine kinase, comprising:

a) obtaining a sample from a human patient having acute myelogenous leukemia (AML);

b) determining that the AML has a FLT3 receptor tyrosine kinase that is deregulated or constitutively active and one or more driver mutations in TET2 that result in a loss-of-function mutation of TET2 by performing or having performed genetic testing on the sample from the patient;

c) determining that the human patient has a poor prognosis based on determining that the AML has both the deregulated or constitutively active FLT3 receptor tyrosine kinase and the one or more driver mutations in TET2; and

d) administering a therapeutically effective amount of Crenolanib or a salt thereof, sufficient to eliminate the AML, to the human patient determined to have both the deregulated or constitutively active FLT3 receptor tyrosine kinase and the one or more driver mutations in TET2.

7 . The method of claim 1 , wherein the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof is administered at least one of continuously, intermittently, systemically, or locally.

8 . The method of claim 1 , wherein the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof is administered orally, intravenously, or intraperitoneally.

9 . The method of claim 1 , wherein the therapeutically effective amount of Crenolanib is administered up to three times or more a day for as long as the human patient is in need of treatment for the leukemia.

10 . The method of claim 1 , wherein the therapeutically effective amount of Crenolanib is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed human leukemia patient, to maintain remission of an existing human leukemia patient, or in a relapsed/refractory human leukemia patient.

11 . The method of claim 1 , wherein the therapeutically effective amount of Crenolanib is provided as a single agent or in combination with another pharmaceutical agent in a patient with a newly diagnosed leukemia, to maintain remission, or in a relapse/refractory human leukemia patient.

12 . The method of claim 1 , wherein the therapeutically effective amount of Crenolanib is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed human pediatric leukemia patient, to maintain remission, or in a relapsed/refractory human pediatric leukemia patient.

13 . The method of claim 1 , wherein the therapeutically effective amount of Crenolanib is provided to a human patient relapsed/refractory to another tyrosine kinase inhibitor or chemotherapy.

14 . The method of claim 5 , wherein the FLT3 mutation is selected from at least one of FLT3-ITD or FLT3-TKD.

15 . The method of claim 5 , wherein:

the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof are from about 50 to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day;

the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof is administered at least one of continuously, intermittently, systemically, or locally;

the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof is administered orally, intravenously, or intraperitoneally;

the therapeutically effective amount of Crenolanib is administered up to three times or more a day for as long as the human patient is in need of treatment for the leukemia;

the therapeutically effective amount of Crenolanib is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed human leukemia patient, to maintain remission of an existing human leukemia patient, or in a relapsed/refractory human leukemia patient;

the therapeutically effective amount of Crenolanib is provided as a single agent or in combination with another pharmaceutical agent in a patient with a newly diagnosed leukemia, to maintain remission, or in a relapse/refractory human leukemia patient;

the therapeutically effective amount of Crenolanib is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed human pediatric leukemia patient, to maintain remission, or in a relapsed/refractory human pediatric leukemia patient; or

the therapeutically effective amount of Crenolanib is provided to a human patient relapsed/refractory to another tyrosine kinase inhibitor or chemotherapy.

16 . The method of claim 5 , wherein the Crenolanib or the pharmaceutically acceptable salt thereof is Crenolanib besylate, Crenolanib phosphate, Crenolanib lactate, Crenolanib hydrochloride, Crenolanib citrate, Crenolanib acetate, Crenolanib toluenesulphonate, and Crenolanib succinate.

17 . The method of claim 6 , wherein the FLT3 mutation is selected from at least one of FLT3-ITD or FLT3-TKD.

18 . The method of claim 6 , wherein:

the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof are from about 50 to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day;

the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof is administered at least one of continuously, intermittently, systemically, or locally;

the therapeutically effective amount of Crenolanib or the pharmaceutically acceptable salt thereof is administered orally, intravenously, or intraperitoneally;

the therapeutically effective amount of Crenolanib is administered up to three times or more a day for as long as the human patient is in need of treatment for the leukemia;

the therapeutically effective amount of Crenolanib is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed human leukemia patient, to maintain remission of an existing human leukemia patient, or in a relapsed/refractory human leukemia patient;

the therapeutically effective amount of Crenolanib is provided as a single agent or in combination with another pharmaceutical agent in a patient with a newly diagnosed leukemia, to maintain remission, or in a relapse/refractory human leukemia patient;

the therapeutically effective amount of Crenolanib is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed human pediatric leukemia patient, to maintain remission, or in a relapsed/refractory human pediatric leukemia patient; or

the therapeutically effective amount of Crenolanib is provided to a human patient relapsed/refractory to another tyrosine kinase inhibitor or chemotherapy.

19 . The method of claim 6 , wherein the Crenolanib or the pharmaceutically acceptable salt thereof is Crenolanib besylate, Crenolanib phosphate, Crenolanib lactate, Crenolanib hydrochloride, Crenolanib citrate, Crenolanib acetate, Crenolanib toluenesulphonate, and Crenolanib succinate.