COMPOSITIONS AND METHODS FOR TREATING MYELOFIBROSIS
Provided herein are compositions and methods for treating myelofibrosis in a subject. The methods comprise administering to the subject an effective amount of compound which is which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutical salt thereof or a hydrate thereof.
1 - 16 . (canceled)
17 . A method of treating myelofibrosis in a subject, comprising orally administering a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight for the compound is the free base moiety weight of the compound, and wherein the compound is in a capsule containing an admixture of (i) the compound, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate.
18 . The method of claim 17 , wherein the weight ratio of the compound to microcrystalline cellulose in the admixture is between about 1:1.5 to 1:15, and the weight ratio of the compound to sodium stearyl fumarate in the admixture is between about 5:1 to about 50:1, and wherein the weight for the compound in the weight ratio is the free base moiety weight of the compound.
19 . A method of ameliorating bone marrow cellularity or bone marrow fibrosis associated with myelofibrosis in a subject, comprising administering to the subject an effective amount of a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof.
20 . A method of improving pruritus associated with myelofibrosis in a subject, comprising administering to the subject an effective amount of a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof.
21 . A method of treating myelofibrosis in a subject, comprising administering to the subject an effective amount of a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzene sulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject is negative for the valine 617 to phenylalanine mutation of human Janus Kinase 2 (JAK2) or negative for the mutation corresponding to the valine 617 to phenylalanine mutation of human JAK2.
22 - 23 . (canceled)
24 . The method of claim 17 , wherein the subject is a human.
25 . The method of claim 24 , wherein the compound is administered at a dose of 240 mg per day to 680 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
26 . The method of claim 24 , wherein the compound is administered at a dose of 300 mg per day to 500 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
27 . The method of claim 24 , wherein the compound is administered over a period of at least 1 cycle, at least 6 cycles, at least 10 cycles, or at least 15 cycles of a 28-day treatment cycle.
28 . The method of claim 17 , wherein the compound is in a capsule and administered orally.
29 . The method of claim 28 , wherein the capsule contains an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate.
30 . The method of claim 29 , wherein the weight ratio of the compound to microcrystalline cellulose in the admixture is between about 1:1.5 to 1:15, and the weight ratio of the compound to sodium stearyl fumarate in the admixture is between about 5:1 to about 50:1, and wherein the weight for the compound is the free base moiety weight of the compound.
31 . The method of claim 17 , wherein the compound is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
32 . A method of monitoring treatment of myelofibrosis to a subject, comprising administering to the subject an effective amount of a compound which is N-tert-butyl-3-[(5-methyl-2-{[ 4 -(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, and discontinuing the treatment upon indication of elevated levels of one or more enzymes or molecules selected from the group consisting of amylase, lipase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine in the serum of the subject without prior dose reduction.
33 . (canceled)
34 . A method of monitoring treatment of myelofibrosis to a subject, comprising administering to the subject an effective amount of a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, and discontinuing the treatment upon indication of one or more hematologic conditions selected from the group consisting of anemia, thrombocytopenia, and neutropenia without prior dose reduction.
35 - 38 . (canceled)
39 . An article of manufacture comprising (a) a capsule suitable for oral administration comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule, and (b) a package insert or a label indicating that the capsule is useful for treating myelofibrosis in a subject.
40 . An article of manufacture comprising (a) of a unit dosage form for treatment of myelofibrosis in a subject comprising an admixture of (i) 10 mg to 500 mg of a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base moiety weight of the compound, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, and (b) a package insert or a label indicating that the capsule is useful for treating myelofibrosis in a subject.
41 . An article of manufacture comprising (a) a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutical salt thereof or a hydrate thereof, and (b) a package insert or a label indicating that the compound can be used for (1) ameliorating bone marrow cellularity and/or bone marrow fibrosis associated with myelofibrosis, (2) improving pruritus associated with myelofibrosis, (3) treating myelofibrosis in a subject, and that the treatment can be discontinued without prior dose reduction upon indication of elevated levels of one or more of amylase, lipase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine in the serum of the subject, or (4) treating myelofibrosis in a subject, and that the treatment can be discontinued without prior dose reduction upon indication of a hematologic conditions selected from the group consisting of anemia, thrombocytopenia, and neutropenia.
42 - 46 . (canceled)