Methods for Treating Immune Thrombocytopenia By Administering (R)-2-[3-[4-Amino-3-(2-Fluoro-4-Phenoxy-Phenyl)Pyrazolo[3,4-D]Pyrimidin-1-YL]Piperidine-1-Carbonyl]-4-Methyl-4-[4-(Oxetan-3-YL)Piperazin-1-YL]Pent-2-Enentrile

1 . A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with a thrombopoietin receptor agonist (TPO-RA) or rituximab comprising administering to the human patient who has not received prior treatment with a TPO-RA or rituximab a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period, wherein the human patient in need thereof has at least one characteristic chosen from:

a. a platelet count of count <33,000/μL on two occasions no less than 7 days apart in the 15 days prior to beginning study treatment; and

b. a history of response (two or more platelet counts ≥50,000/μL with an increase of ≥20,000/μL) to at least one prior line of therapy.

2 . A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with a thrombopoietin receptor agonist (TPO-RA) comprising administering to the human patient who has not received prior treatment with a TPO-RA a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period, wherein the human patient in need thereof has at least one characteristic chosen from:

a. a platelet count of <33,000/μL on two occasions no less than 7 days apart in the 15 days prior to beginning study treatment; and

b. a history of response (two or more platelet counts ≥50,000/μL with an increase of ≥20,000/μL) to at least one prior line of therapy.

3 . A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with rituximab comprising administering to the human patient who has not received prior treatment with rituximab a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period, wherein the human patient in need thereof has at least one characteristic chosen from:

a. a platelet count of <33,000/μL on two occasions no less than 7 days apart in the 15 days prior to beginning study treatment; and

b. a history of response (two or more platelet counts ≥50,000/μL with an increase of ≥20,000/μL) to at least one prior line of therapy.

4 . The method of claim 1 or 2 , wherein the TPO-RAs are chosen from: recombinant thrombopoietin (rTPO), romiplostim, eltrombopag, and avatrombopag.

5 . The method of any one of claims 1-2 or 4 , wherein the patient has not received prior treatment with rituximab.

6 . The method of any one of claims 1-5 , wherein the at least one prior line of therapy, wherein at least one prior therapy is chosen from a splenectomy, intravenous immunoglobin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs.

7 . The method of any one of claims 1-6 , wherein the patient achieves at least one platelet count of at least 20,000/μL above a baseline platelet count, wherein the baseline platelet count is the mean of two platelet counts taken on two occasions no less than 7 days apart in the 15 days prior to beginning treatment and a third count taken on the first day of the study.

8 . The method of any one of claims 1-7 , wherein the patient achieves at least two platelet counts of at least 20,000/μL above the baseline platelet count.

9 . The method of claim 8 , wherein the patient achieves at least two consecutive platelet counts of at least 20,000/μL above the baseline platelet count.

10 . The method of any one of claims 8 or 9 , wherein at least two consecutive platelet counts of at least 20,000/μL above the baseline platelet count are separated by at least five days, for example at least seven days.

11 . The method of any one of claims 1-10 , wherein the patient achieves a platelet count of at least 50,000/μL.

12 . The method of any one of claims 1-11 , wherein the patient achieves at least two platelet counts of at least 50,000/μL.

13 . The method of claim 12 , wherein the patient achieves at least two consecutive platelet counts of at least 50,000/μL.

14 . The method of claims 12 or 13 , wherein the at least two consecutive platelet counts of at least 50,000/μL are separated by at least five days, for example at least seven days.

15 . The method of any one of claims 1-14 , wherein the human patient achieves at least one platelet count of at least 50,000/μL within eight days of initiating treatment.

16 . The method of any one of claims 11-15 wherein the human patient does not receive rescue medication during the four weeks prior to the most recent platelet count of at least 50,000/μL.

17 . The method of any one of claims 1-16 , wherein the human patient has had ITP for six or less years.

18 . The method of any one of claims 1-17 , wherein the human patient has a history of taking at least one prior ITP therapy prior to the start of the treatment period.

19 . The method of any one of claims 1-18 , wherein the human patient has a history of taking at least two prior ITP therapies prior to the start of the treatment period.

20 . The method of any one of claims 1-19 , wherein the human patient has a history of taking at least three prior ITP therapies prior to the start of the treatment period.

21 . The method of any one of claims 1-20 , wherein the human patient has a history of taking at least four prior ITP therapies prior to the start of the treatment period.

22 . The method of any one of claims 1-21 , wherein the human patient has a history of taking at least five prior ITP therapies prior to the start of the treatment period.

23 . The method of any one of claims 1-22 , wherein the human patient has platelet counts between 2,000/μL and 33,000/μL on two occasions no less than 7 days apart and within 15 days prior to the start of the treatment period.

24 . The method of any one of claims 1-23 , wherein the human patient had a splenectomy prior to the start of the treatment period.

25 . The method of any one of claims 2 or 4-24 , wherein the human patient has a history of taking rituximab prior to the start of the treatment period.

26 . The method of any one of claims 3-25 , wherein the human patient has a history of taking at least one TPO-RA prior to the start of the treatment period.

27 . The method of claim 26 , wherein the at least one TPO-RA is selected from rTPO, romiplostim, eltrombopag, and avatrombopag.

28 . The method of any one of claims 1-27 , wherein the patient has a history of response to at least one prior line of therapy, wherein at least one prior therapy is chosen from a splenectomy, intravenous immunoglobin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs.

29 . The method of any one of claims 1-28 , wherein the human patient has a history of taking intravenous immunoglobin (IVIG) prior to the start of the treatment period.

30 . The method of any one of claims 1-28 , wherein the human patient has a history of taking corticosteroids prior to the start of the treatment period.

31 . The method of any one of claims 1-28 , wherein the human patient has a history of taking anti-D immunoglobulin therapy prior to the start of the treatment period.

32 . The method of any one of claims 1-28 , wherein the human patient has a history of taking at least one immunosuppressive drug prior to the start of the treatment period.

33 . The method of claim 32 , wherein the at least one immunosuppressive drug is selected from fostamatinib, mycophenolate mofetil (MMF), and cyclosporine.

34 . The method of any one of claims 28-33 , wherein the response to the prior ITP therapy comprised a platelet count of ≥50,000/μL.

35 . The method of any one of claims 1-34 , wherein the human patient has primary ITP.

36 . The method of any one of claims 1-34 , wherein the human patient has secondary ITP.

37 . The method of any one of claims 1-34 , wherein the human patient does not have chronic ITP.

38 . The method of any one of claims 1-34 , wherein the human patient has persistent ITP.

39 . The method of any one of claims 1-34 , wherein the human patient has chronic ITP.

40 . The method of any one of claims 1-34 , wherein the human patient has relapsing ITP.

41 . The method of any one of claims 1-34 , wherein the human patient has refractory ITP.

42 . The method of any one of claims 1-41 , wherein the treatment period is at least 8 days.

43 . The method of any one of claims 1-42 , wherein the treatment period is at least 28 days.

44 . The method of any one of claims 1-43 , wherein the treatment period is at least 84 days.

45 . The method of any of claims 1-44 , wherein the treatment period is at least 169 days.

46 . The method of any one of claims 1-45 , comprising administering to the human patient 400 mg of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day.

47 . The method of any one of claims 1-46 , wherein the at least one compound consists of at least one compound chosen from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.

48 . The method of any one of claims 1-46 , wherein the at least one compound consists of at least one compound chosen from the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.

49 . The method of any one of claims 1-46 , wherein the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or a pharmaceutically acceptable salt of the foregoing.

50 . The method of any one of claims 1-45 , comprising administering to the human patient 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile twice a day.

51 . The method of any one of claims 1-45 or 50 , wherein the at least one compound is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

52 . The method of any one of claims 1-45 or 50 , wherein the at least one compound is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

53 . The method of any one of claims 1-45 or 50 , wherein the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

54 . The method of any one of claims 1-53 , wherein the at least one compound is orally administered to the human patient.

55 . The method of any one of claims 1-54 , wherein the at least one compound is administered to the human patient in the form of at least one tablet.

56 . The method of any one of claims 1-55 , wherein the at least one compound is administered with water.

57 . The method of any one of claims 1-56 , wherein the at least one compound is administered with food.

58 . The method of any one of claims 1-57 , wherein the at least one compound is administered without food.

59 . The method of any one of claims 1-58 , wherein the human patient has had ITP for four or less years.