Treatment of conditions associated with myeloproliferative neoplasms

Abstract

Therapeutic methods and pharmaceutical compositions for treating conditions associated with myeloproliferative neoplasms in human subjects are described. In certain embodiments, the disclosure includes therapeutic methods using BTK inhibitors to treat conditions associated with myeloproliferative neoplasms.

Description

[Technical field]

[0001]

[0001] Disclosed herein are methods of treating conditions associated with myeloproliferative neoplasms using Bruton's tyrosine kinase (BTK) inhibitors. [Background technology]

[0002]

[0002] Myeloproliferative neoplasms (MPNs) are blood cancers that occur when the body produces too many white blood cells, red blood cells, and / or platelets. MPNs include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), and can lead to significant morbidity and mortality in affected patients.

[0003]

[0003] For example, MF is a chronic leukemia that is a cancer that affects the blood-forming tissues in the body. MF is a rare type of bone marrow cancer that disrupts the normal production of blood cells. MF causes extensive scarring in the bone marrow, leading to severe anemia that can cause weakness and fatigue, and MF can also cause a decrease in platelet count that increases the risk of bleeding. MF often causes enlarged spleens and lymph nodes due to the accumulation of CD34+ malignant bone marrow cells in the spleen.

[0004]

[0004] The clinical spectrum of MF includes primary myelofibrosis and MF occurring during essential thrombocythemia or polycythemia vera. Myelofibrosis is a chronic hematological malignancy characterized by splenomegaly, leukoerythroblastosis, cytopenia, teardrop poikilocytosis, bone marrow fibrosis, extramedullary hematopoiesis, increased bone marrow microvascular density, and constitutive mobilization of hematopoietic stem cells (HSCs) and progenitor cells (HPCs) expressing CD34. Ruxolitinib, fedratinib, and allogeneic stem cell transplantation are the main means of treating patients with MF.

[0005]

[0005] In general, the symptom burden of MPN is severe and has a significant impact on the quality of life of patients. Complications of MPN include constitutional symptoms related to the abnormal overproduction of proinflammatory cytokines (e.g., fatigue, night sweats, weight loss, pruritus, fever, bone pain, and joint pain), and symptoms associated with splenomegaly. Methods to reduce or alleviate these symptoms in patients with MPN are needed to improve the quality of life of patients.

[0006]

[0006] Bruton's tyrosine kinase is a non-receptor tyrosine kinase belonging to the Tec family, and has important functions in several types of benign and malignant cells of the hematopoietic system. Furthermore, recent clinical studies with the irreversible oral BTK inhibitors acalabrutinib and ibrutinib have demonstrated excellent clinical activity and tolerability against a variety of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL). Furthermore, it is now clear that the mechanism of action of BTK inhibitors is multifactorial, and a key component of their function is the disruption of tumor cells and the microenvironment that protects them. Inhibition of BTK has been shown to regulate malignant myeloid cell migration in CLL, MCL, and acute myeloid leukemia by downregulating the expression of a number of vascular adhesion molecules and inhibiting CXCR4-CXCL12-induced cell trafficking, homing, and integrin adhesion (Zaitseva (2014) Oncotarget 5, pp. 9930-9938). CXCL12 plays a central role in CLL pathogenesis and progression by regulating CLL cell interactions with the stromal microenvironment, leading to cell survival and proliferation. BTK has a role in signal transduction activated by the CXCR4-CXCL12 signaling axis and is involved in rapid integrin activation. BTK inhibition blocks CXCL12-induced induction of lymphocyte function-associated antigen-1 (LFA-1) and VLA-4 integrins. In addition, BTK inhibition blocks activation of the small GTP-binding protein RhoA, which controls integrin affinity. Of great importance, BTK tyr phosphorylation and activation by CXCL12 is dependent on upstream activation of JAK2 (Janus kinase 2). Thus, BTK and JAK protein tyrosine kinases display hierarchical activity in both chemokine and integrin activation and dependent cell adhesion (Montresor (2018) Oncotarget, 9, 35123-35140). Finally, BTK is highly expressed in both mature and primitive myeloid cells, including HSCs and HPCs. Summary of the Invention

[0007]

[0007] The present disclosure relates to a method of reducing or alleviating a symptom selected from the group consisting of night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof in a human subject having a myeloproliferative neoplasm (MPN), comprising administering to the human subject an amount of a Bruton's tyrosine kinase (BTK) inhibitor effective to reduce or alleviate the symptom. In some embodiments, the MPN is primary myelofibrosis. In some embodiments, the MPN is post-polycythemia vera myelofibrosis. In some embodiments, the MPN is post-essential thrombocythemia myelofibrosis. In some embodiments, the MPN is chronic myelogenous leukemia. In some embodiments, the MPN is chronic neutrophilic leukemia. In some embodiments, the MPN is chronic eosinophilic leukemia. In some embodiments, the MPN is acute myelogenous leukemia with precursor MPN (also known as blast phase MPN (MPN-BP)). In some embodiments, the MPN is chronic myelomonocytic leukemia. In some embodiments, the human subject is afflicted with splenomegaly, hepatomegaly, or hepatosplenomegaly.

[0008] In some embodiments, the BTK inhibitor is selected from Table 1 herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one, or a pharma- ceutically acceptable salt thereof.

[0009] In some embodiments, the BTK inhibitor is administered in combination with a JAK2 inhibitor. In some embodiments, the JAK2 inhibitor is ruxolitinib, fedratinib, pacritinib, momelotinib, jactinib, or irginatinib. In some embodiments, the BTK inhibitor is administered in combination with an MDM2 inhibitor.

[0010]

[0010] In some embodiments, the human subject has a JAK2V617F mutation. In some embodiments, the human subject is homozygous for the JAK2V617F mutation. In some embodiments, the MPN is a JAK2-V617F myeloproliferative neoplasm.

[0011]

[0011] In some embodiments, the symptoms persist for at least 1 day prior to administration of the BTK inhibitor, e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days prior to administration of the BTK inhibitor.

[0012] In some embodiments, the method further comprises assessing the severity of the symptoms prior to administration of the BTK inhibitor. In some embodiments, the method further comprises assessing the severity of the symptoms after administration of the BTK inhibitor. In some embodiments, the severity of the symptoms is determined by self-assessment. In some embodiments, the severity of the symptoms is determined by self-report.

[0013] In some embodiments, the night sweats comprise repeated occurrences of sweating during sleep in the human subject. In some embodiments, the night sweats comprise repeated occurrences of excessive sweating during sleep in the human subject. In some embodiments, the fatigue comprises unexplained and recurrent tiredness in the human subject. In some embodiments, the fatigue comprises unexplained, persistent, and recurrent tiredness in the human subject. In some embodiments, the pruritus comprises itching of the skin of the human subject. In some embodiments, the pruritus comprises severe itching of the skin of the human subject. In some embodiments, the abdominal pain occurs between the thoracic and pelvic regions and is acute. In some embodiments, the abdominal pain occurs between the thoracic and pelvic regions and is chronic. In some embodiments, the subcostal pain occurs on the left side of the human subject and is acute. In some embodiments, the subcostal pain occurs on the left side of the human subject and is chronic. In some embodiments, the bloating is associated with satiety in the human subject. In some embodiments, the bone pain is characterized by tenderness, pain, or other discomfort in one or more bones of the human subject. In some embodiments, the bone pain is characterized by extreme tenderness, pain, or other discomfort in one or more bones of the human subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014]

[0014] While preferred embodiments of the present disclosure have been shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the present disclosure. Various alternatives to the described embodiments of the present disclosure may be employed in practicing the present disclosure.

[0015]

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0016]

[0016] As used herein, the terms "administered in combination with" and "co-administration" include administration of two or more active pharmaceutical ingredients to a subject such that both agents and / or metabolic products of both agents are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in one composition in which two or more agents are present.

[0017] The term "effective amount" or "effective amount" or "therapeutically effective amount" or "sufficient amount" refers to an amount of an active pharmaceutical ingredient or active pharmaceutical ingredient combination described herein that is sufficient to achieve the intended application, including but not limited to disease treatment that reduces or alleviates symptoms. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease state being treated (e.g., weight, age, and sex of the subject), the severity of the disease state, the mode of administration, and other factors that can be easily determined by a person skilled in the art. The term also applies to a dose that will induce a specific response in target cells (e.g., malignant CD34+ myeloid cells). The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which the compound is administered, and the physical delivery system to which the compound is delivered.

[0018]

[0018] "Myelofibrosis" refers to spontaneous scarring (fibrosis) of bone marrow that disrupts normal production of blood cells and leads to severe anemia and enlargement of the spleen, lymph nodes, and liver. Myelofibrosis can be associated with a variety of diseases, primarily myeloproliferative (preleukemic) disorders. Myelofibrosis is also known as myeloid metaplasia of unknown etiology. As used herein, myelofibrosis includes, but is not limited to, primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. As used herein, myelofibrosis is characterized by the accumulation of malignant CD34+ myeloid cells in the bone marrow, spleen, and lymph nodes.

[0019]

[0019] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and agents for active pharmaceutical ingredients is known in the art. Except insofar as any conventional media or agent is incompatible with the active pharmaceutical ingredient, use of any conventional media or agent in the therapeutic compositions of the present disclosure is contemplated. Supplementary active ingredients may also be incorporated into the compositions described.

[0020]

[0020] "Solvate" refers to a compound that is physically associated with one or more molecules of a pharma ceutically acceptable solvent.

[0021] The term "pharmaceutically acceptable salts" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In selected embodiments, the pharma-ceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts. The term "cocrystal" refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike salts, cocrystals typically do not involve proton transfer between the cocrystal and the drug, but instead involve intermolecular interactions such as hydrogen bonding, aromatic ring stacking, or dispersion forces between the cocrystal former and the drug in the crystal structure.

[0022] The terms "QD", "qd", or "qd" mean daily, once a day, or once a day. The terms "BID", "bid", or "bid" mean twice per day, twice a day, or twice a day. The terms "TID", "tid", or "tid" mean three times per day, three times a day, or three times a day. The terms "QID", "qid", or "qid" mean four times per day, four times a day, or four times a day.

[0023]

[0023] As used herein, the term "splenomegaly" refers to enlargement of the spleen, assessed by size or weight, typically by volume as determined by medical imaging. In some embodiments, the enlargement results from sequestration of malignant CD34+ bone marrow cells and the resulting development of extramedullary hematopoiesis.

[0024]

[0024] A "therapeutic effect," as that term is used herein, encompasses the therapeutic benefits and / or prophylactic benefits described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0025]

[0025] When ranges are used herein to describe physical or chemical properties, such as, for example, molecular weight or chemical formula, all combinations and subcombinations of the ranges and specific embodiments within the ranges are intended to be included. The use of the term "about" when referring to a number or range means that the number or range referred to is an approximation within experimental variation (or within statistical experimental error), and thus the number or range may vary, for example, by 1% to 15% of the stated number or range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes, for example, embodiments "consisting of" or "consisting essentially of" the described characteristic, such as any composition of matter, method, or process.

[0026] The BTK inhibitor compounds of the present disclosure also include any crystalline and amorphous forms of the compounds in Table 1, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof. "Crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is referenced.

[0027] Methods for reducing or alleviating symptoms of myeloproliferative neoplasms (MPNs)

[0027] The present disclosure relates to the discovery that BTK inhibitors can be used to reduce or alleviate various symptoms of MPN, including, for example, night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof. Thus, in certain embodiments, the present disclosure relates to a method for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or combinations thereof, by administering an effective amount of a BTK inhibitor to a human subject in need of treatment, optionally in combination with one or more other supportive therapies or active agents for treating MPN. The present disclosure also relates to a method for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or combinations thereof, by administering an effective amount of a BTK inhibitor to a human subject having MPN, optionally in combination with one or more other supportive therapies or active agents for treating MPN. The disclosure herein demonstrates that desirable therapeutic agents can be selected based on BTK inhibition. Thus, without wishing to be bound by a particular mechanism of action, it is expected that BTK inhibition will alter one or more downstream signaling components (e.g., CXCR-4, CXCL12, VLA-4, VCAM-1) to recruit CD34+ cell migration to peripheral blood, where the CD34+ cells will be useful in reducing or alleviating symptoms associated with MPNs, particularly, but not limited to, night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof.

[0028]

[0028] Thus, the present disclosure relates to a method of reducing or alleviating symptoms associated with MPN in a human subject suffering from MPN, comprising administering a BTK inhibitor to the human. In some embodiments, the MPN is myelofibrosis (MF). In some embodiments, the MF is primary myelofibrosis, also known as chronic idiopathic myelofibrosis (cIMF). In one embodiment, the primary myelofibrosis is selected from the group consisting of prefibrotic / early PMF and overt fibrotic stage PMF. In some embodiments, the MF is secondary myelofibrosis. In some embodiments, the MF is myelofibrosis secondary to polycythemia vera or essential thrombocythemia. In some embodiments, the MF is myelofibrosis secondary to chronic myelogenous leukemia (CML). In some embodiments, the MF is idiopathic myelofibrosis. In some embodiments, the MPN is chronic myelogenous leukemia. In some embodiments, the MPN is acute myeloid leukemia with precursor MPN (also known as blast phase MPN (MPN-BP)). In some embodiments, the MPN is chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, or chronic myelomonocytic leukemia (CMML). In some embodiments, the MPN is idiopathic systemic mastocystosis (SM), chronic eosinophilic leukemia-not otherwise specified (CEL-NOS), myeloproliferative neoplasm unclassified (MPN-U), myelodysplastic syndrome (MDS), systemic mast cell disease (SMCD), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplastic / myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0029] In one embodiment, the human is assessed as hydroxyurea (HU) intolerant (unacceptable side effects). In one embodiment, the human subject is assessed as hydroxyurea resistant (inadequate response).

[0030] In some embodiments, the human subject additionally suffers from splenomegaly, hepatomegaly, or hepatosplenomegaly. In one embodiment, the human subject has splenomegaly, hepatomegaly, or hepatosplenomegaly and is phlebotomy dependent. In one embodiment, the human subject is phlebotomy dependent without splenomegaly, hepatomegaly, or hepatosplenomegaly.

[0031] In one embodiment, the human subject has elevated levels of proinflammatory cytokines, and administration of a BTK inhibitor reduces the elevated proinflammatory cytokines. In one embodiment, the proinflammatory cytokines are selected from interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), interleukin-18 (IL-18), tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), or combinations thereof. In one embodiment, administration of a BTK inhibitor to a human subject downregulates nuclear factor kappa B (NF-κB). In one embodiment, administration of a BTK inhibitor to a human subject upregulates an anti-inflammatory cytokine. In one embodiment, the anti-inflammatory cytokine is selected from interleukin-4 (IL-4), interleukin-10 (IL-10), or a combination thereof. In one embodiment, the human subject has splenomegaly, hepatomegaly, or hepatosplenomegaly, and administration of a BTK inhibitor to the human subject alleviates the splenomegaly, hepatomegaly, or hepatosplenomegaly.

[0032]

[0032] In one embodiment, the BTK inhibitor is any of the compounds in Table 1 or a pharma- ceutically acceptable salt thereof.

[0033] In one embodiment, the human subject is JAK2 inhibitor naive (i.e., has not been treated with a JAK2 inhibitor). In one embodiment, the human subject is JAK2 inhibitor intolerant. In one embodiment, the human subject is JAK2 inhibitor ineligible due to low platelet count. In one embodiment, the human subject has relapsed after JAK2 inhibitor treatment. In one embodiment, the human subject is refractory to JAK2 inhibitor treatment. In one embodiment, the human subject has failed ruxolitinib or fedratinib therapy. Failure of ruxolitinib or fedratinib therapy includes, but is not limited to, (i) no reduction in severity or progression of any myeloproliferative neoplasm in a human subject receiving ruxolitinib or fedratinib, or (ii) recurrence of any myelofibrosis in a human subject following ruxolitinib or fedratinib therapy. In one embodiment, failure of ruxolitinib or fedratinib therapy is a failure to reduce the severity or progression of any myelofibrosis in a human subject receiving ruxolitinib or fedratinib. In one embodiment, failure of ruxolitinib or fedratinib therapy is a recurrence of any myelofibrosis in a human subject following ruxolitinib or fedratinib therapy.

[0034] In one embodiment, the BTK inhibitor is administered in combination with a JAK2 inhibitor. In one embodiment, the JAK2 inhibitor is ruxolitinib, fedratinib, pacritinib, momelotinib, jactinib, irginatinib, or a combination thereof.

[0035]

[0035] In one embodiment, the BTK inhibitor is administered in combination with an MDM2 inhibitor.

[0036]

[0036] In one embodiment, the MPN is a JAK2-V617F myeloproliferative neoplasm.

[0037] In one embodiment, a human subject has an accumulation of malignant CD34+ myeloid cells in their spleen. In one embodiment, malignant CD34+ myeloid cells have decreased expression of CXCR4 compared to normal myeloid cells. In one embodiment, administration of a BTK inhibitor stimulates migration of malignant CD34+ myeloid cells from the spleen to the peripheral blood of a human subject. In one embodiment, administration of a BTK inhibitor inactivates VLA-4 in malignant CD34+ myeloid cells. In one embodiment, administration of a BTK inhibitor reduces the activity of CXCR4 and CXCL12, thereby reducing the chemoattractant effect of these molecules on malignant CD34+ myeloid cells. In one embodiment, reduced CXCR4 and CXCL12 activity contributes to sequestration of malignant myeloid CD34+ cells in the spleen.

[0038]

[0038] In one embodiment, the method includes reducing or alleviating symptoms associated with myelofibrosis, such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof, but does not include treating myelofibrosis itself (e.g., only the symptoms of myelofibrosis are reduced or alleviated in a human, and not myelofibrosis).

[0039] In one embodiment, the BTK inhibitor is 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 560 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID, and 480 mg BID. In one embodiment, the BTK inhibitor is administered to a human according to the section entitled Dosages and Dosing Regimens herein.

[0040]

[0040] In one embodiment, a human suffering from symptoms such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof has myelofibrosis characterized by the presence of CALR mutations (calreticulin, located on chromosome 19p13.2) in human subjects, as described in Massie, New Engl. J. Med. (2013) 25, pp. 2379-2390, the entire contents of which are incorporated herein by reference.

[0041]

[0041] In one embodiment, a human suffering from symptoms such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof has myelofibrosis characterized by the presence of the MPL mutation (myeloproliferative leukemia viral oncogene; located on chromosome 1p34) in human subjects, as described in Pikman, Plos Med (2006) 3, e270, the entirety of which is incorporated herein by reference.

[0042] In one embodiment, a human suffering from symptoms such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof has myelofibrosis characterized by JAK2V617F mutation in a human subject. JAK2V617F is a functional mutation that promotes cytokine-independent proliferation of myeloid cells, as described by Nakatake (Oncogene (2012) 31, pp. 1323-1333), the entire contents of which are incorporated herein by reference.

[0043]

[0043] In one embodiment, a human suffering from symptoms such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof has myelofibrosis characterized by one or more mutations selected from the group consisting of JAK2V617F, MPL, CALR, and combinations thereof.

[0044] In one embodiment, a human suffering from symptoms such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof has myelofibrosis characterized by absence of JAK2V617F mutation, absence of MPL mutation, absence of CALR mutation, absence of a combination of two of JAK2V617F mutation, MPL mutation, and CALR mutation, or absence of all three of JAK2V617F mutation, MPL mutation, and CALR mutation. In one embodiment, a human suffering from symptoms such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof has myelofibrosis characterized by absence of JAK2V617F mutation.

[0045]

Table 1

[0046]

[0045] In some embodiments, the BTK inhibitor is TG-1701 or Loxo-305.

[0047]

[0046] In one embodiment, the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharma- ceutically acceptable salt thereof.

[0048] In one embodiment, the disclosure relates to the use of a composition comprising a BTK inhibitor or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for reducing or alleviating a symptom selected from the group consisting of night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof in a human subject with MPN. In one embodiment, the BTK inhibitor is selected from Table 1.

[0049] Symptoms of myeloproliferative neoplasms

[0048] In some embodiments, the disclosure relates to a method for reducing or alleviating a symptom associated with MPNs, such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof. In some embodiments, the disclosure relates to a method for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof in a human subject with MPNs, comprising administering to the human subject an amount of a BTK inhibitor effective to reduce or alleviate the symptom. In some embodiments, the symptom is associated with overproduction and release of proinflammatory cytokines by malignant cells. In some embodiments, the symptom is associated with splenomegaly. In some embodiments, the symptom is associated with overproduction and release of proinflammatory cytokines by malignant cells and splenomegaly. In some embodiments, malignant cells in the human subject overproduce and release proinflammatory cytokines.

[0050]

[0049] In some embodiments, the symptoms persist for at least 1 day prior to administration of the BTK inhibitor, such as at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days prior to administration of the BTK inhibitor.

[0051] In some embodiments, the method further comprises assessing the severity of the symptoms prior to administration of the BTK inhibitor. In some embodiments, the method further comprises assessing the severity of the symptoms after administration of the BTK inhibitor. In some embodiments, the severity of the symptoms is determined by self-assessment. In some embodiments, the severity of the symptoms is determined by self-report.

[0052]

[0051] In some embodiments, the severity of symptoms is assessed by assigning a numerical value (which may also be referred to as a score) to the severity of the symptoms, for example, by assigning a value on a scale of zero to 10, where a value of zero indicates the absence of the symptom and a value of 10 indicates the severity of the symptom is the worst imaginable for a human subject. In some embodiments, a total symptom score is determined by summing the scores for each individual symptom. In some embodiments, the scores for 2, 3, 4, 5, 6, 7, 8, 9, or 10 symptoms are summed to obtain a total symptom score. In some embodiments, a symptom score or total symptom score is obtained by reporting a score (e.g., on a scale of zero to 10) in response to 1, 2, 3, 4, 5, 6, or 7 of the following questions:

[0053] [Table 2]

[0054] In some embodiments, a human subject is considered to be symptomatic and has a total symptom score as assessed by the seven questions in Table 2 of at least 10, such as at least 12, at least 14, at least 15, at least 16, at least 18, at least 20, at least 22, at least 24, at least 25, at least 26, at least 28, at least 30, at least 32, at least 34, at least 35, at least 36, at least 38, at least 40, at least 42, at least 44, at least 45, at least 46, at least 48, and / or at least 50, with each question scored on a scale of zero to 10, with zero indicating no symptoms and 10 indicating the worst symptoms imaginable.

[0055] In some embodiments, a symptom is reduced if the symptom score is reduced by at least 50%, such as at least 60%, at least 70%, at least 75%, at least 80%, and / or at least 90%, compared to a baseline score for the symptom. In some embodiments, the baseline score for the symptom is the symptom score prior to administering a BTK inhibitor described herein. In some embodiments, the present disclosure relates to a reduction in the total symptom score. In some embodiments, a total symptom score is reduced if the total symptom score is reduced by at least 50%, such as at least 60%, at least 70%, at least 75%, at least 80%, and / or at least 90%, compared to a baseline total symptom score. In some embodiments, the baseline total symptom score is the total symptom score prior to administering a BTK inhibitor described herein. In some embodiments, the total symptom score refers to an average of the daily total symptom scores, such as a 7-day average of the daily total symptom scores. In some embodiments, a reduction in symptoms and / or total symptom score is obtained after administration of a BTK inhibitor described herein for a period of at least 8 weeks, such as at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, and / or at least 30 weeks.

[0056]

[0054] In some embodiments, administering a BTK inhibitor described herein improves the quality of life of a human subject. In some embodiments, the quality of life is assessed by a Patient Global Impression of Change (PGIC) assessment. The PGIC is a 7-point scale that describes a human subject's overall improvement, and the human subject rates the change as "very improved," "much improved," "slightly improved," "unchanged," "slightly worse," "much worse," or "very worse." In some embodiments, the improved quality of life includes a PGIC rating of "very improved," "much improved," or "slightly improved."

[0057] In some embodiments, night sweats include repeated occurrences of sweating during the sleep of a human subject. In some embodiments, night sweats include repeated occurrences of excessive sweating during the sleep of a human subject.

[0058] In some embodiments, fatigue comprises unexplained and recurrent fatigue in a human subject. In some embodiments, fatigue comprises unexplained, persistent and recurrent fatigue in a human subject.

[0059]

[0057] In some embodiments, the pruritus comprises itching of the skin of a human subject. In some embodiments, the pruritus comprises severe itching of the skin of a human subject.

[0060] In some embodiments, the abdominal pain occurs between the thoracic and pelvic regions and is acute. In some embodiments, the abdominal pain occurs between the thoracic and pelvic regions and is chronic.

[0061] In some embodiments, the subcostal pain occurs on the left side of the human subject and is acute. In some embodiments, the subcostal pain occurs on the left side of the human subject and is chronic.

[0062]

[0060] In some embodiments, the bloating is associated with satiety in a human subject.

[0063] In some embodiments, the bone pain is characterized by tenderness, pain, or other discomfort in one or more bones of the human subject. In some embodiments, the bone pain is characterized by extreme tenderness, pain, or other discomfort in one or more bones of the human subject.

[0064] Combination with JAK2 inhibitors

[0062] In some embodiments, the present disclosure relates to a method for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof, by administering an effective amount of a BTK inhibitor in combination with a JAK2 inhibitor to a human subject in need of treatment. The present disclosure also relates to a method for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof, by administering an effective amount of a BTK inhibitor in combination with a JAK2 inhibitor to a human subject having an MPN. The disclosure herein demonstrates that a desirable therapeutic agent can be selected based on BTK inhibition and JAK2 inhibition. Therefore, without wishing to be bound by a particular mechanism of action, it is expected that BTK inhibition in combination with JAK2 inhibition will alter one or more downstream signaling components (e.g., CXCR-4, CXCL12, VLA-4, VCAM1) to mobilize CD34+ cell migration into the peripheral blood and be useful in treating complications associated with MPNs, particularly in reducing or alleviating symptoms including, but not limited to, night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof.

[0065]

[0063] Thus, the present disclosure relates to a method of reducing or alleviating symptoms associated with MPN in a human subject suffering from MPN, comprising administering to the human a BTK inhibitor compound or a pharma- ceutically acceptable salt thereof in combination with a JAK2 inhibitor compound or a pharma- ceutically acceptable salt thereof. In some embodiments, the JAK2 inhibitor is selected from ruxolitinib, fedratinib, pacritinib, momelotinib, jactinib, irginatinib, or combinations thereof. In some embodiments, the MPN is myelofibrosis (MF). In some embodiments, the MF is primary myelofibrosis, also known as chronic idiopathic myelofibrosis (cIMF). In one embodiment, the primary myelofibrosis is selected from the group consisting of fibrillary / early PMF and fibrotic PMF. In some embodiments, the MF is secondary myelofibrosis. In some embodiments, the MF is myelofibrosis secondary to polycythemia vera or essential thrombocythemia. In some embodiments, the MF is myelofibrosis secondary to chronic myelogenous leukemia (CML). In some embodiments, the MF is idiopathic myelofibrosis. In some embodiments, the MPN is chronic myelogenous leukemia. In some embodiments, the MPN is acute myelogenous leukemia with precursor MPN (also known as blast phase MPN (MPN-BP)). In some embodiments, the MPN is chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, or chronic myelomonocytic leukemia (CMML). In some embodiments, the MPN is idiopathic systemic mastocytosis (SM), chronic eosinophilic leukemia-not otherwise specified (CEL-NOS), myeloproliferative neoplasm unclassifiable (MPN-U), myelodysplastic syndrome (MDS), systemic mast cell disease (SMCD), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplastic / myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0066] In one embodiment, the human is assessed as hydroxyurea (HU) intolerant (unacceptable side effects). In one embodiment, the human subject is assessed as hydroxyurea resistant (inadequate response).

[0067] In some embodiments, the human subject additionally suffers from splenomegaly, hepatomegaly, or hepatosplenomegaly. In one embodiment, the human subject has splenomegaly, hepatomegaly, or hepatosplenomegaly and is phlebotomy dependent. In one embodiment, the human subject is phlebotomy dependent without splenomegaly, hepatomegaly, or hepatosplenomegaly.

[0068] In one embodiment, the BTK inhibitor is any of the compounds in Table 1 or a pharma- ceutically acceptable salt thereof. In one embodiment, the JAK2 inhibitor is ruxolitinib, fedratinib, pacritinib, momelotinib, jactinib, irginatinib, combinations thereof, or pharma- ceutically acceptable salts thereof.

[0069]

[0067] In some embodiments, the JAK2 inhibitor is administered once per day, twice per day, three times per day, four times per day, or five times per day. In one embodiment, the JAK2 inhibitor is 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 560 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID, and 480 mg BID. In one embodiment, the JAK2 inhibitor is administered to a human according to the section entitled Dosages and Dosing Regimens herein.In one embodiment, the BTK inhibitor is 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 560 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200mg BID, 225mg BID, 240mg BID, 250mg BID, 275mg BID, 300mg BID, 325mg BID, 350mg BID, 360mg BID, 375mg BID, and 480mg BID. In one embodiment, the BTK inhibitor is administered to a human according to the section entitled Dosages and Dosing Regimens herein. In some embodiments, the BTK inhibitor and the JAK2 inhibitor are administered simultaneously, sequentially, or intermittently.

[0070]

[0068] In some embodiments, the disclosure encompasses a pharmaceutical combination comprising: (a) a BTK inhibitor; (b) a JAK2 inhibitor; and (c) a pharma- ceutically acceptable excipient. In some embodiments, the combination provides a synergistic therapeutic effect compared to administration of the BTK inhibitor or the JAK2 inhibitor alone. In some embodiments, the combination sensitizes myelofibrosis to the BTK inhibitor. In some embodiments, the combination is in a combined dosage form. In some embodiments, the combination is in a separate dosage form.

[0071]

[0069] In some embodiments, the disclosure encompasses the use of a therapeutically effective amount of a combination comprising a BTK inhibitor and a JAK2 inhibitor to reduce or alleviate symptoms associated with MPNs, such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof, in a human subject with MPNs. In some embodiments, the combination provides a synergistic therapeutic effect compared to administration of a BTK inhibitor or a JAK2 inhibitor alone. In some embodiments, the combination sensitizes malignant CD34+ bone marrow cells to the BTK inhibitor. In some embodiments, the combination sensitizes malignant CD34+ bone marrow cells to the JAK2 inhibitor.

[0072] Combination with MDM2 inhibitors

[0070] In some embodiments, the present disclosure relates to a method for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof, by administering an effective amount of a BTK inhibitor in combination with an MDM2 inhibitor to a human subject in need of treatment. The present disclosure also relates to a method for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof, by administering an effective amount of a BTK inhibitor in combination with an MDM2 inhibitor to a human subject having an MPN. The disclosure herein demonstrates that a desirable therapeutic agent can be selected based on BTK inhibition and MDM2 inhibition. Therefore, without wishing to be bound by a particular mechanism of action, it is expected that BTK inhibition in combination with MDM2 inhibition will alter one or more downstream signaling components (e.g., CXCR-4, CXCL12, VLA-4, VCAM1) to mobilize CD34+ cell migration into the peripheral blood and be useful in treating complications associated with MPNs, particularly in reducing or alleviating symptoms including, but not limited to, night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof.

[0073]

[0071] Thus, the present disclosure relates to a method of reducing or alleviating symptoms associated with MPN in a human subject suffering from MPN, comprising administering to the human a BTK inhibitor compound, or a pharma- ceutically acceptable salt thereof, in combination with an MDM2 inhibitor compound, or a pharma- ceutically acceptable salt thereof. In some embodiments, the MDM2 inhibitor is selected from any of the compounds in Table 3, or a pharma- ceutically acceptable salt thereof.

[0074] [Table 3] TIFF2024526092000039.tif208149 TIFF2024526092000040.tif108149

[0075] In some embodiments, the MPN is myelofibrosis (MF). In some embodiments, the MF is primary myelofibrosis, also known as chronic idiopathic myelofibrosis (cIMF). In one embodiment, the primary myelofibrosis is selected from the group consisting of fibrillary / early PMF and fibrotic PMF. In some embodiments, the MF is myelofibrosis secondary to polycythemia vera or essential thrombocythemia. In some embodiments, the MF is myelofibrosis secondary to chronic myelogenous leukemia (CML). In some embodiments, the MF is idiopathic myelofibrosis. In some embodiments, the MPN is chronic myelogenous leukemia. In some embodiments, the MPN is acute myelogenous leukemia with precursor MPN (also known as blast phase MPN (MPN-BP)). In some embodiments, the MPN is chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, or chronic myelomonocytic leukemia (CMML). In some embodiments, the MPN is idiopathic systemic mastocytosis (SM), chronic eosinophilic leukemia-not otherwise specified (CEL-NOS), myeloproliferative neoplasm unclassifiable (MPN-U), myelodysplastic syndrome (MDS), systemic mast cell disease (SMCD), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplastic / myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0076] In one embodiment, the human is assessed as hydroxyurea (HU) intolerant (unacceptable side effects). In one embodiment, the human subject is assessed as hydroxyurea resistant (inadequate response).

[0077] In some embodiments, the human subject additionally suffers from splenomegaly, hepatomegaly, or hepatosplenomegaly. In one embodiment, the human subject has splenomegaly, hepatomegaly, or hepatosplenomegaly and is phlebotomy dependent. In one embodiment, the human subject is phlebotomy dependent without splenomegaly, hepatomegaly, or hepatosplenomegaly.

[0078] In one embodiment, the BTK inhibitor is any of the compounds in Table 1, or a pharma- ceutically acceptable salt thereof. In one embodiment, the MDM2 inhibitor is any of the compounds in Table 3, a combination thereof, or a pharma- ceutically acceptable salt thereof.

[0079] In some embodiments, the MDM2 inhibitor is administered once per day, twice per day, three times per day, four times per day, or five times per day. In one embodiment, the MDM2 inhibitor is 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 560 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID, and 480 mg BID. In one embodiment, the MDM2 inhibitor is administered to a human according to the section entitled Dosages and Dosing Regimens herein.In one embodiment, the BTK inhibitor is 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 560 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200mg BID, 225mg BID, 240mg BID, 250mg BID, 275mg BID, 300mg BID, 325mg BID, 350mg BID, 360mg BID, 375mg BID, and 480mg BID. In one embodiment, the BTK inhibitor is administered to a human according to the section entitled Dosages and Dosing Regimens herein. In some embodiments, the BTK inhibitor and the MDM2 inhibitor are administered simultaneously, sequentially, or intermittently.

[0080]

[0077] In some embodiments, the disclosure encompasses a pharmaceutical combination comprising: (a) a BTK inhibitor; (b) an MDM2 inhibitor; and (c) a pharma- ceutically acceptable excipient. In some embodiments, the combination provides a synergistic therapeutic effect compared to administration of the BTK inhibitor or the MDM2 inhibitor alone. In some embodiments, the combination sensitizes myelofibrosis to the BTK inhibitor. In some embodiments, the combination is in a combined dosage form. In some embodiments, the combination is in a separate dosage form.

[0081]

[0078] In some embodiments, the disclosure encompasses the use of a therapeutically effective amount of a combination comprising a BTK inhibitor and an MDM2 inhibitor to reduce or alleviate symptoms associated with MPNs, such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, and combinations thereof, in a human subject with MPNs. In some embodiments, the combination provides a synergistic therapeutic effect compared to administration of a BTK inhibitor or an MDM2 inhibitor alone. In some embodiments, the combination sensitizes malignant CD34+ bone marrow cells to the BTK inhibitor. In some embodiments, the combination sensitizes malignant CD34+ bone marrow cells to the MDM2 inhibitor.

[0082] Pharmaceutical Compositions In some embodiments, the disclosure provides a pharmaceutical composition comprising a BTK inhibitor compound or a pharma- ceutically acceptable salt thereof for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof in a human subject with MPN. In some embodiments, the disclosure provides a pharmaceutical composition comprising a BTK inhibitor compound or a pharma- ceutically acceptable salt thereof for reducing or alleviating a symptom selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof in a human subject with MPN. In one embodiment, the MPNs are myelofibrosis, primary myelofibrosis, fibrillary / early PMF, fibrotic PMF, secondary myelofibrosis, myelofibrosis secondary to polycythemia vera or essential thrombocythemia, myelofibrosis secondary to chronic myelogenous leukemia (CML), idiopathic myelofibrosis, chronic myelogenous leukemia, acute myelogenous leukemia with precursor MPN (also known as blast phase MPN (MPN-BP)), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic osteoporosis, ... Selected from myelomonocytic leukemia (CMML), idiopathic systemic mastocytosis (SM), chronic eosinophilic leukemia-not otherwise specified (CEL-NOS), myeloproliferative neoplasm, unclassifiable (MPN-U), myelodysplastic syndrome (MDS), systemic mast cell disease (SMCD), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), or myelodysplastic / myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0083]

[0080] Pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the BTK inhibitor compound or its pharma- ceutically acceptable salt. If desired, the pharmaceutical composition contains its pharma- ceutically acceptable salt and / or coordination complex, as well as one or more pharma- ceutical acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. If desired, other components in addition to the BTK inhibitor or its pharma- ceutical acceptable salt may be mixed into the preparation, or both components may be formulated in separate preparations for use in combination, either separately or simultaneously.

[0084] In selected embodiments, the concentration of the BTK inhibitor or a pharma- ceutical acceptable salt thereof provided in the pharmaceutical composition of the present disclosure may be, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0. 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0085]

[0082] In selected embodiments, the concentration of the BTK inhibitor or a pharma- ceutically acceptable salt thereof provided in the pharmaceutical composition of the present disclosure is independently 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16. 25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8. 25%,8%,7.75%,7.50%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.0 greater than 7%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0086] In selected embodiments, the concentration of the BTK inhibitor or a pharma- ceutically acceptable salt thereof is independently from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, and It is in the range of about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0087] In selected embodiments, the concentration of the BTK inhibitor or a pharma- ceutically acceptable salt thereof is independently in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0088] In selected embodiments, the amount of the BTK inhibitor or a pharma- ceutically acceptable salt thereof may be, independently, 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.2 0.0002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.006g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0089]

[0086] In selected embodiments, the amount of the BTK inhibitor or a pharma- ceutically acceptable salt thereof is independently 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0. 002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.00 65g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0 .025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075 g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.4 More than 5g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g.

[0090]

[0087] The BTK inhibitor compounds and their pharma- ceutically acceptable salts in Table 1 are effective over a wide dosage range. For example, in the treatment of adults, dosages ranging, independently, from 0.01 to 1000 mg per day, from 0.5 to 100 mg, from 1 to 50 mg, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend on the route of administration, the form in which the compound is administered, the sex and age of the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0091]

[0088] Non-limiting exemplary pharmaceutical compositions and methods for preparing pharmaceutical compositions are described below.

[0092] Pharmaceutical Compositions for Oral Administration

[0089] In selected embodiments, the present disclosure provides a pharmaceutical composition for oral administration comprising a BTK inhibitor compound or a pharma- ceutically acceptable salt thereof, and a pharmaceutical excipient suitable for oral administration.

[0093] In selected embodiments, the present disclosure provides a solid pharmaceutical composition for oral administration that contains (i) an effective amount of a BTK inhibitor or a pharma- ceutically acceptable salt thereof in combination and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further contains (iii) an effective amount of at least one additional active ingredient.

[0094]

[0091] In selected embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the present disclosure suitable for oral administration may be presented as discrete dosage forms such as capsules, cachets, or tablets, or as liquids or aerosol sprays, each containing a predetermined amount of the active ingredient in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, as a powder, or in the form of granules, solution, or suspension. Such dosage forms may be prepared by any of the methods, but all methods include the step of bringing into association the active ingredient(s) with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with the liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0095]

[0092] The present disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms, since water can promote the degradation of some compounds. For example, in the pharmaceutical arts, water can be added (e.g., 5%) as a means of simulating long-term storage to determine characteristics such as shelf life or stability of a formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. The pharmaceutical compositions and dosage forms of the present disclosure that contain lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. The anhydrous pharmaceutical compositions can be prepared and stored such that the anhydrous nature of the anhydrous pharmaceutical composition is maintained. Thus, the anhydrous compositions may be packaged using materials known to prevent exposure to water, so that the anhydrous compositions can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, and the like, unit dose containers, blister packs, and strip packs.

[0096]

[0093] The BTK inhibitor or its pharma- ceutically acceptable salt can be combined in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms, depending on the form of preparation desired for administration. In preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be employed as the carrier, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or, for oral solid preparations, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used, in some embodiments without the use of lactose. For example, for solid oral preparations, suitable carriers include powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0097]

[0094] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0098]

[0095] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0099]

[0096] Disintegrants can be used in the compositions of the present disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant can result in tablets that disintegrate in the bottle. Too little can be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredient from the dosage form. Thus, a dosage form of the compound disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient(s). The amount of disintegrant used can vary based on the type of formulation and the mode of administration, and can be readily recognized by one of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0100]

[0097] Lubricants that may be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants may optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0101]

[0098] When aqueous suspensions and / or elixirs are desired for oral administration, the essential active ingredients in the aqueous suspensions and / or elixirs may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, as well as various sweetening or flavoring agents, coloring substances, or dyes, and, if desired, emulsifying and / or suspending agents.

[0102]

[0099] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the digestive tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0103] Surfactants that may be used to form the pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0104]

[0101] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds with HLB values ​​greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​of about 10 or less than about 10. However, the HLB value of a surfactant is only a rough guideline that is commonly used to enable the formulation of industrial, pharmaceutical and cosmetic emulsions.

[0105]

[0102] The hydrophilic surfactant may be either ionic or non-ionic.Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0106]

[0103] Of the above groups, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids, and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0107]

[0104] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic acid esters of fatty acids (lactylic ester), stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0108]

[0105] Hydrophilic nonionic surfactants include alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, polyethylene glycol glycerol fatty acid esters, polyglycerol fatty acid esters, polyethylene glycol sorbitan fatty acid esters, etc. The polyoxyalkylene sorbitan fatty acid esters may include, but are not limited to, polyoxyalkylene sorbitan fatty acid esters of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, polyoxyethylene sterols, derivatives, and analogs thereof, polyoxyethylated vitamins and derivatives thereof, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof, polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0109] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, distearate, PEG-32 Glyceryl Laurate, PEG-40 Stearate, PEG-100 Stearate, PEG-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate , PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols tallow, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0110]

[0107] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of mono- and di-glycerides, hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof. Of this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0111] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the disclosed compound and to minimize precipitation of the disclosed compound. Including a solubilizer may be particularly important for compositions for parenteral use, such as compositions for injection. A solubilizer may be added to increase the solubility of hydrophilic drugs and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0112]

[0109] Examples of suitable solubilizers are: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethylisosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropylmethylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N amides and other nitrogen-containing compounds such as hydroxyalkylpyrrolidone, N-alkyl piperidone, N-alkyl caprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsilon-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as, but not limited to, dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0113]

[0110] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0114]

[0111] The amount of solubilizer that may be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which can be easily determined by one skilled in the art. In some situations, for example to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer that far exceeds the bioacceptable amount, and remove the excess solubilizer using conventional techniques such as distillation or evaporation before providing the composition to the patient. Thus, when present, the solubilizer may be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, may also be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0115] The composition may further comprise one or more pharma- ceutically acceptable additives and excipients, including, but not limited to, detackifiers, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0116]

[0113] Additionally, acids or bases may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharma-ceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases that are salts of pharma- ceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, parabromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Salts of polybasic acids may also be used, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. When the base is a salt, the cation may be any convenient and pharma-ceutically acceptable cation, such as ammonium, alkali metals, and alkaline earth metals. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0117]

[0114] Suitable acids are pharma- ceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, parabromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0118] Injectable pharmaceutical composition

[0115] In selected embodiments, the present disclosure provides a pharmaceutical composition for injection comprising a BTK inhibitor compound or a pharma- ceutically acceptable salt thereof, and a pharmaceutical excipient suitable for injection. The components and amounts of the agents in the composition are as described herein.

[0119]

[0116] Forms in which the compositions of the present disclosure can be incorporated for administration by injection include aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0120]

[0117] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0121]

[0118] Sterile injectable solutions are prepared by incorporating the required amount of BTK inhibitor or its pharma- ceutically acceptable salt in a suitable solvent with various other ingredients as listed above, as required, followed by filtration sterilization. In general, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, one particular preferred method of preparation is vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient + any additional desired ingredients from a previously sterile-filtered solution of the active ingredient + any additional desired ingredients.

[0122]

[0119] Administration of the BTK inhibitors or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions of these compounds, can be accomplished by any method that allows delivery of the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topically (e.g., transdermal application), rectal administration, local delivery by catheter or stent, or by inhalation. The compounds can also be administered intraadiposally or intrathecally.

[0123] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0124] The present disclosure also provides kits. The kits include pharmaceutical compositions containing the BTK inhibitor compounds or pharma- ceutically acceptable salts thereof, alone or in combination in suitable packaging, and written materials, which may include instructions for use, a discussion of clinical studies, and a list of side effects. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of this information, which indicate or define the activity and / or benefits of the composition, and / or describe dosing, administration, side effects, drug interactions, or other information useful to a medical care provider. Such information may be based on the results of various studies, for example, studies using laboratory animals, including in vivo models, and studies based on human clinical trials. The kits may further contain another active pharmaceutical ingredient. Appropriate packaging and additional items for use (e.g., measuring cups for liquid preparations, foil wrapping to minimize exposure to air, etc.) are known in the art and may be included in the kits. The kits described herein may be provided, sold, and / or promoted to medical care providers, including physicians, nurses, pharmacists, formulary pharmacy personnel, and the like. The kits may, in selected embodiments, be sold directly to consumers. In one embodiment, the present disclosure provides a kit comprising a pharmaceutical composition comprising a BTK inhibitor or a pharma- ceutical acceptable salt thereof for use in reducing or alleviating a symptom of a selected MPN (e.g., myelofibrosis), such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof, as described herein.

[0125] Dosage and Dosage Regimen The amount of BTK inhibitor or its pharma- ceutically acceptable salt administered will depend on the person being treated, the severity of the disorder or condition, the rate of administration, the pharmacokinetics of the compound, and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg of body weight per day, e.g., about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, an effective dosage would be about 0.05 to 7 g / day, e.g., about 0.05 to about 2.5 g / day. In some circumstances, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, even larger doses can be employed without causing any toxic side effects, e.g., by dividing such larger doses into several smaller doses for administration throughout the day.

[0126] In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered in a single dose. Multiple doses per day, e.g., twice per day, are also embodied. Typically, such administration is oral; however, other routes may be used, if desired.

[0127] In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered in multiple doses to reduce or alleviate symptoms associated with MPN (e.g., myelofibrosis) selected from night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof. In one embodiment, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered in multiple doses. In one embodiment, dosing may be 1, 2, 3, 4, 5, 6, or more than 7 times per day. In one embodiment, dosing may be selected from the group consisting of once a day, twice a day, three times a day, four times a day, five times a day, six times a day, every other day, once a week, twice a week, three times a week, four times a week, every other week, and once a month. In other embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered from about once per day to about six times per day, for example, from about once per day to about four times per day. In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered once per day, while in other embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered twice per day, and in other embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered three times per day. In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered three times per week, including every Monday, Wednesday, and Friday.

[0128]

[0125] Administration of the BTK inhibitor or a pharma- ceutically acceptable salt thereof may continue for as long as necessary. In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered for more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or more days. In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered for about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, or about 56 days. In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. In another embodiment, administration of the MDM2 inhibitor and the BTK inhibitor continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In some embodiments, administration continues for more than about 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, continuous dosing is achieved and maintained for as long as necessary.

[0129]

[0126] In some embodiments, an effective dosage of a BTK inhibitor or a pharma- ceutically acceptable salt thereof is from about 1 mg to about 600 mg, from about 10 mg to about 500 mg, from about 20 mg to about 450 mg, from about 25 mg to about 200 mg, from about 10 mg to about 200 mg, from about 20 mg to about 150 mg, from about 30 mg to about 120 mg, from about 10 mg to about 90 mg, from about 20 mg to about 80 mg, from about 30 mg to about 70 mg, from about 40 mg to about 60 mg, from about 45 mg to about 55 mg , about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 mg to about 202 mg. In some embodiments, the effective dosage of the BTK inhibitor or a pharma- ceutically acceptable salt thereof is about 15 mg, about 25 mg, about 30 mg, about 50 mg, about 50 mg, about 75 mg, about 90 mg, about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 180 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 360 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 480 mg, or about 500 mg. In some embodiments, the effective dosage of the BTK inhibitor or a pharma- ceutically acceptable salt thereof is 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg.

[0130]

[0127] In some embodiments, an effective dosage of a BTK inhibitor or a pharma- ceutically acceptable salt thereof is from about 0.01 mg / kg to about 4.3 mg / kg, from about 0.15 mg / kg to about 3.6 mg / kg, from about 0.3 mg / kg to about 3.2 mg / kg, from about 0.35 mg / kg to about 2.85 mg / kg, from about 0.15 mg / kg to about 2.85 mg / kg, from about 0.3 mg to about 2.15 mg / kg, from about 0.45 mg / kg to about 1.7 mg / kg, from about 0.15 mg / kg to about 2. Approximately 1.3mg / kg, approximately 0.3mg / kg to approximately 1.15mg / kg, approximately 0.45mg / kg to approximately 1mg / kg, approximately 0.55mg / kg to approximately 0.85mg / kg, approximately 0.65mg / kg to approximately 0.8mg / kg, approximately 0.7mg / k g~about 0.75mg / kg, about 0.7mg / kg~about 2.15mg / kg, about 0.85mg / kg~about 2mg / kg, about 1mg / kg~about 1.85mg / kg, about 1.15mg / kg~about 1.7mg / kg, about 1.3mg / kg In some embodiments, the effective dosage of the BTK inhibitor or a pharma- ceutical acceptable salt thereof is in the range of about 0.35 mg / kg, about 0.7 mg / kg, about 1 mg / kg, about 1.4 mg / kg, about 1.8 mg / kg, about 2.1 mg / kg, about 2.5 mg / kg, about 2.85 mg / kg, about 3.2 mg / kg, or about 3.6 mg / kg.

[0131] In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered in a dosage of 10 to 500 mg BID, including dosages of 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg BID.

[0132] In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered in a dosage of 10 to 600 mg QD, including dosages of 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg QD.

[0133] An effective amount of the BTK inhibitor or a pharma- ceutically acceptable salt thereof may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utility, including buccal, sublingual, and transdermal routes, by intra-arterial injection, intravenously, parenterally, intramuscularly, subcutaneously, or orally.

[0134] In some embodiments, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered to a subject intermittently, known as intermittent dosing. By "intermittent dosing," the term means administration of a therapeutically effective dose of the BTK inhibitor or a pharma- ceutically acceptable salt thereof for a period of time, followed by a period of discontinuance, which is then followed by another dosing period, etc. In each dosing period, the dosing frequency can be independently selected from three times a day, twice a day, daily, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the BTK inhibitor is a compound selected from Table 1 or a pharma- ceutically acceptable salt thereof.

[0135] By "period of discontinuance" or "interruption period" or "rest period," this term refers to the length of time during which administration of a BTK inhibitor or a pharma- ceutically acceptable salt thereof is discontinued. The time of interruption may be longer or shorter than the administration period, or may be the same as the administration period. During the interruption period, other therapeutic agents may be administered other than the BTK inhibitor or a pharma- ceutically acceptable salt thereof. The interruption period may be necessary to alleviate any toxic effects associated with a particular BTK inhibitor compound.

[0136] In one embodiment, a BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered to a human subject in need thereof to reduce or alleviate a symptom associated with an MPN (e.g., myelofibrosis), such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof, for a first dosing period, followed by a discontinuation period, followed by a second dosing period, etc. The first dosing period, the second dosing period, and the discontinuation period are independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, 9 weeks, 10 weeks, 11 weeks, 3 months, 13 weeks, 14 weeks, 15 weeks, a period of more than 4 months, and more days, and the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered to the subject three times per day, twice per day, once per day, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or once per month. In one embodiment, the first administration period is the same length as the second administration period. In one embodiment, the first administration period is shorter than the second administration period. In one embodiment, the first administration period is longer than the second administration period. In one embodiment, the first administration period and the second administration period are about 1 week, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered to the subject daily; the discontinuance period is about 2 weeks. In one embodiment, the first administration period and the second administration period are about 3 weeks, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered to the subject daily; the discontinuance period is about 2 weeks. In one embodiment, the first administration period and the second administration period are about 3 weeks, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered to the subject once a week; the discontinuance period is about 2 weeks. In one embodiment, the first administration period and the second administration period are about 4 weeks, the BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered to the subject daily; the discontinuance period is about 2 weeks. In one embodiment, the first dosing period and the second dosing period are about 4 weeks and the BTK inhibitor, or a pharma- ceutically acceptable salt thereof, is administered to the subject once a week; and the discontinuance period is about 2 weeks.In one embodiment, the BTK inhibitor is a compound selected from Table 1, or a pharma- ceutically acceptable salt thereof.

[0137] In one embodiment, a BTK inhibitor or a pharma- ceutically acceptable salt thereof is administered to reduce or alleviate symptoms associated with MPN (e.g., myelofibrosis), such as night sweats, fatigue, pruritus, abdominal pain, subcostal pain, bloating, bone pain, or a combination thereof, for 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 74 weeks, 76 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, 95 weeks, 96 weeks, 97 weeks, 98 weeks, 99 weeks, 100 weeks, 101 weeks, 102 weeks, 103 weeks, 104 weeks, 105 weeks, 106 weeks, 107 weeks, 108 weeks, 109 weeks, 110 weeks, 111 weeks, 112 weeks, 113 weeks, 114 weeks, 115 weeks, 116 weeks, 117 weeks, 118 weeks, 120 weeks, 122 weeks, 123 weeks, 124 weeks, 125 weeks, 126 weeks, 127 weeks, 128 weeks, 129 weeks, 130 weeks, 131 weeks, 132 weeks, 133 weeks, 5 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138 weeks, 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks, and 156 weeks to a subject in need thereof, wherein the BTK inhibitor is selected from any of the compounds in Table 1 or a pharma- ceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is administered orally at a dose of 100 mg twice daily.

Claims

1. A pharmaceutical composition for reducing symptoms selected from the group consisting of night sweats, fatigue, pruritus, abdominal pain, pain under the ribs, fullness, bone pain, and combinations thereof in a human subject having a myeloproliferative neoplasm (MPN) and comprising a Bruton's tyrosine kinase (BTK) inhibitor.

2. The pharmaceutical composition according to claim 1, wherein the MPN is primary myelofibrosis.

3. The pharmaceutical composition according to claim 1, wherein the MPN is post-polycythemia vera myelofibrosis.

4. The pharmaceutical composition according to claim 1, wherein the MPN is post-essential thrombocythemia myelofibrosis.

5. The pharmaceutical composition according to claim 1, wherein the MPN is chronic myeloid leukemia.

6. The pharmaceutical composition according to claim 1, wherein the MPN is chronic neutrophilic leukemia.

7. The pharmaceutical composition according to claim 1, wherein the MPN is chronic eosinophilic leukemia.

8. The pharmaceutical composition according to claim 1, wherein the MPN is acute myeloid leukemia with a precursor MPN (also known as MPN blast phase (MPN-BP)).

9. The pharmaceutical composition according to claim 1, wherein the MPN is chronic myelomonocytic leukemia.

10. The pharmaceutical composition according to claim 1, wherein the human subject suffers from splenomegaly, hepatomegaly, or hepatosplenomegaly.

11. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is administered in combination with a JAK2 inhibitor.

12. The pharmaceutical composition according to claim 11, wherein the JAK2 inhibitor is ruxolitinib, fedratinib, pacritinib, momelotinib, jakutinib, or elgicinib.

13. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is administered in combination with an MDM2 inhibitor.

14. The pharmaceutical composition according to claim 1, wherein the MPN is a JAK2-V617F myeloproliferative neoplasm.

15. The pharmaceutical composition according to claim 1, wherein the symptom persists for at least 1 day before administration of the BTK inhibitor, for example, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days before administration of the BTK inhibitor.

16. The pharmaceutical composition according to claim 1, wherein the severity of the symptom is assessed before administration of the BTK inhibitor.

17. The pharmaceutical composition according to claim 1, wherein the severity of the symptom is assessed after administration of the BTK inhibitor.

18. The pharmaceutical composition according to claim 1, wherein the severity of the symptom is determined by self-assessment.

19. The pharmaceutical composition according to claim 1, wherein the severity of the symptom is determined by self-report.

20. The pharmaceutical composition according to claim 1, wherein the night sweats include repeated occurrences of excessive sweating during sleep of the human subject, such as repeated occurrences of sweating during sleep of the human subject.

21. The pharmaceutical composition according to claim 1, wherein the fatigue includes unexplained, persistent, and recurrent fatigue of the human subject, such as unexplained and recurrent fatigue of the human subject.

22. The pharmaceutical composition according to claim 1, wherein the pruritus includes itching of the skin of the human subject, such as severe itching of the skin of the human subject.

23. The pharmaceutical composition according to claim 1, wherein the abdominal pain occurs between the chest and the pelvis and is acute or chronic.

24. The pharmaceutical composition according to claim 1, wherein the pain under the rib occurs on the left side of the human subject and is acute or chronic.

25. The pharmaceutical composition according to claim 1, wherein the fullness is associated with a feeling of satiety in the human subject.

26. The pharmaceutical composition according to claim 1, wherein the bone pain is characterized by tenderness, pain, or other discomfort in one or more bones of the human subject, such as extreme tenderness, pain, or other discomfort in one or more bones of the human subject.

27. The pharmaceutical composition according to any one of claims 1 to 26, wherein the BTK inhibitor is selected from the compounds in Table 1 herein or pharmaceutically acceptable salts thereof.

28. The pharmaceutical composition according to any one of claims 1 to 26, wherein the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.