UTILITY PATENT APPLICATION
`
`METHODSOF TREATING AND PREVENTING GRAFT VERSUS HOST DISEASE
`
`WSGRDocket No. 25922-885.201
`
`Inventor(s):
`
`John C. BYRD
`Citizen of the United States of America, Residing at
`1950 Arlington Avenue
`Columbus, OH 43212
`
`Jason A. DUBOVSKY
`Citizen of the United States of America, Residing at
`2505 Avalon Place
`Columbus, OH 43219
`
`Natarajan MUTHUSAMY
`Citizen of India, Residing at
`6129 Glenworth Court
`Galloway, OH 43119
`
`Amy Jo JOHNSON
`Citizen of the United States of America, Residing at
`5396 Winters Run Road
`Dublin, OH 43016
`
`David MIKLOS
`Citizen of United States of America, Residing at
`875 Blake Wilbur Drive, MC 582
`Stanford, CA 94305
`
`Assignee:
`
`Pharmacyclics, Inc.
`995 East Arques Avenue
`Sunnyvale, CA 94085
`
`A Delaware corporation
`
`Entity:
`
`Large Business Concern
`
`WR
`Wilson Sonsini Goodrich & Rosai
`PROFESSIONAL CORPORATION
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(650) 493-9300 (Main)
`(650) 493-6811 (Facsimile)
`Filed Electronically on: October 24, 2014
`
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`

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`WSGRDocket No. 25922-885.201
`
`METHODSOF TREATING AND PREVENTING GRAFT VERSUS HOST DISEASE
`
`CROSS-REFERENCE
`
`[0001] This application claims the benefit of priority of U.S. Provisional Application No.
`
`61/895,981, filed October 25, 2013; U.S. Provisional Application No. 61/910,945, filed December2,
`
`2013; U.S. Provisional Application No. 61/973,173, filed March 31, 2014; and U.S. Provisional
`
`Application No. 61/973,176 filed March 31, 2014, each of which is incorporated herein by reference.
`
`SEQUENCELISTING
`
`[0001.1] The instant application contains a Sequence Listing which has been submitted in ASCII
`
`format via EFS-Webandis hereby incorporated by referencein its entirety. Said ASCII copy,
`
`created on October 20, 2014, is named 25922-885-201SEQ.txt and is 633 bytes in size.
`
`BACKGROUNDOF THE INVENTION
`
`[0002] Chronic graft versus host disease (CGVHD)is the most common long-term complication
`
`following allogeneic stem cell transplant (SCT), affecting 30-70% of patients who survive beyond
`
`the first 100 days. cGVHDandits associated immunedeficiency have been identified as a leading
`
`cause of non-relapse mortality (NRM)in allogeneic SCT survivors. SCT survivors with cGVHDare
`
`4.7 times as likely to develop severeorlife-threatening health conditions compared with healthy
`
`siblings, and patients with active CGVHDare morelikely to report adverse general health, mental
`
`health, functional impairments, activity limitation, and pain than allo-SCT survivors with no history
`
`of cGVHD. Any organ system can be affected, and further morbidity is frequently caused by long-
`
`term exposure to the corticosteroids and calcineurin inhibitors required to treat the condition.
`
`SUMMARYOF THE INVENTION
`
`[0003] Disclosed herein, in some embodiments, are methods of preventing the occurrence ofgraft
`
`versus host disease (GVHD)or reducing the severity of GVHD occurrence in a patient requiring cell
`
`transplantation comprising administration of a therapeutically effective amount of an ACK inhibitor
`
`(e.g., an ITK or BTKinhibitor). In some embodiments, disclosed herein are methods of reducing the
`
`severity of GVHD occurrence in a patient requiring cell transplantation comprising administration of
`
`a therapeutically effective amount of an ACKinhibitor (e.g., an ITK or BTK inhibitor). In some
`
`embodiments the ACKinhibitor is a compound of Formula (A). In some embodiments, disclosed
`
`herein are methods of preventing the occurrence of graft versus host disease (GVHD)or reducing
`
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`WSGRDocket No. 25922-885.201
`
`the severity of GVHD occurrencein a patient requiring cell transplantation, comprising
`
`administration of a therapeutically effective amount of a compound of Formula (A) having the
`
`structure:
`
`R3x, Re
`N
`
`Ry
`
`NOSot
`
`N~
`
`N
`R4
`
`Formula (A);
`
`wherein:
`
`AisN;
`
`R, is phenyl-O-phenylor phenyl-S-pheny];
`
`R, and R; are independently H;
`
`Rg is L3-X-L4-G, wherein,
`
`L3 is optional, and when presentis a bond, optionally substituted or unsubstituted alkyl,
`
`optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl,
`
`optionally substituted or unsubstituted alkynyl;
`
`X is optional, and whenpresentis a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NRo-,
`
`-NHC(O)-, -C(O)NH-, -NRoC(O)-, -C(O)NRo-, -S(=O)2NH-, -NHS(=O)>-, -S(=O)2NRo-, -
`
`NRoS(=O)2-, -OC(O)NH-, -NHC(O)O-, -OC(O)NRo-, -NRoC(O)O-, -CH=NO-, -ON=CH., -
`
`NRjoC(O)NRjo-, heteroaryl-, aryl-, -NRigC(=NRi1)NRio-, -NRiopC(=NR11)-, -C(=NRi)NRio-, -
`
`OC(=NRj1)-, or -C(=NR11)O-;
`
`L,4 is optional, and when presentis a bond, substituted or unsubstituted alkyl, substituted or
`
`unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
`
`substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
`
`heterocycle;
`
`or L3, X and Ly taken together form a nitrogen containing heterocyclic ring;
`O
`Re
`;
`Q, ,0 Re
`Oo
`Re
`mr
`Re
`Z
`-S A
`AAS
`“RAN
`aaAr oF %
`eX
`R20
`Re
`Re
`Re
`Re
`
`Gis
`
`,
`
`e
`
`7
`
`, Or
`
`%y
`
`, wherein,
`
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`WSGRDocket No. 25922-885.201
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`Re, Rz and Rg are independently selected from among H, halogen, CN, OH, substituted or
`
`unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted
`
`cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
`
`substituted or unsubstituted heteroaryl;
`
`each Rois independently selected from among H,substituted or unsubstituted lower alkyl,
`
`and substituted or unsubstituted lower cycloalkyl;
`
`each Rjo is independently H,substituted or unsubstituted loweralkyl, or substituted or
`
`unsubstituted lower cycloalkyl; or
`
`two Rio groups can together form a 5-, 6-, 7-, or 8-memberedheterocyclic ring; or
`
`Rio and Ry; can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or each Ry, is
`
`independently selected from H or substituted or unsubstituted alkyl; or a pharmaceutically
`
`acceptable salt thereof. In some embodiments, L3, X and L, taken together form a nitrogen
`
`containing heterocyclic ring. In some embodiments, the nitrogen containing heterocyclic ring is a
`
`O
`
`Re
`
`oyRy es
`
`Re
`
`or
`
`piperidine group. In some embodiments, G is
`
`° In some embodiments,
`
`the compoundof Formula (A)is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-
`
`1-yl]piperidin- 1-yl]prop-2-en-1-one. In some embodiments, the patient has cancer. In some
`
`embodiments, the patient has a hematological malignancy. In some embodiments, the patient has a
`
`relapsed or refractory hematological malignancy. In some embodiments, the patient has a B-cell
`
`malignancy. In some embodiments, the patient has a T-cell malignancy. In some embodiments, the
`
`patient has a leukemia, a lymphoma, or a myeloma. In some embodiments, the B-cell malignancyis
`
`a non-Hodgkin’s lymphoma. In some embodiments, the B-cell malignancy is chronic lymphocytic
`
`leukemia (CLL). In some embodiments, the B-cell malignancyis a relapsed or refractory B-cell
`
`malignancy. In some embodiments, the B-cell malignancyis a relapsed or refractory non-Hodgkin’s
`
`lymphoma. In some embodiments, the B-cell malignancy is a relapsed or refractory CLL. In some
`
`embodiments, the patient has high risk CLL. In some embodiments, the patient has a 17p
`
`chromosomaldeletion. In some embodiments, the patient has 10%, 20%, 30%, 40%, 50%, 60%,
`
`70%, 80%, 90%, or greater CLL as determined by bone marrow biopsy. In some embodiments, the
`
`patient has received one or more prior anticancer agents. In some embodiments, the anticancer agent
`
`is selected from among alemtuzumab, bendamustine, bortezomib, CAL-101, chlorambucil,
`
`-3-
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`WSGRDocket No. 25922-885.201
`
`cyclophosphamide, dexamethasone,docetaxel, doxorubicin, endostatineverolimus, etoposide,
`
`fludarabine, fostamatinib, hydroxydaunorubicin, ibritumomab, ifosphamide, lenalidomide,
`
`mesalazine, ofatumumab, paclitaxel, pentostatin, prednisone, rituximab, temsirolimus, thalidomide,
`
`tositumomab, vincristine, or a combination thereof. In some embodiments, the anticancer agentis
`
`rituximab. In some embodiments, the anticancer agent is alemtuzumab. In some embodiments, the
`
`anticancer agent is fludarabine, cyclophosphamide, and rituximab (FCR). In some embodiments, the
`
`anticancer agent is oxaliplatin, fludarabine, cytarabine, rituximab (OFAR). In some embodiments,
`
`the amount of the ACK inhibitor compound(e.g., a compound of Formula (A)) prevents or reduces
`
`GVHDwhile maintaining a graft-versus-leukemia (GVL) reaction effective to reduce or eliminate
`
`the numberof cancerouscells in the blood of the patient. In some embodiments, the cell
`
`transplantation is a hematopoietic cell transplantation. In some embodiments, the GVHD is acute
`
`GVHD. In some embodiments, the GVHDis chronic GVHD. In some embodiments, the GVHDis
`
`sclerodermatous GVHD. In some embodiments, the GVHDis steroid resistant GVHD. In some
`
`embodiments, the GVHDis cyclosporin-resistant GVHD. In some embodiments, the GVHDis
`
`refractory GVHD. In some embodiments, the GHVDis oral GVHD. In some embodiments, the oral
`
`GVHDisreticular oral GVHD. In some embodiments, the oral GVHD is erosive oral GVHD. In
`
`some embodiments, the oral GVHDis ulcerative oral GVHD. In some embodiments, the oral
`
`GVHDis GVHDofthe oral cavity. In some embodiments, the oral GVHD is GVHDofthe
`
`oropharyngeal region. In some embodiments, the oral GVHD is GVHDofthe pharyngeal region. In
`
`some embodiments, the oral GVHD is GVHDofthe esophageal region. In some embodiments, the
`
`oral GVHD is acute oral GVHD. In some embodiments, the oral GVHD is chronic oral GVHD. In
`
`some embodiments, the patient exhibits one or more symptoms of GVHD. In some embodiments,
`
`the patient has or will receive an allogeneic bone marrow or hematopoietic stem cell transplant. In
`
`some embodiments, the ACK inhibitor compound (e.g., a compound of Formula (A)) is administered
`
`concurrently with an allogeneic bone marrow or hematopoietic stem cell transplant. In some
`
`embodiments, the ACK inhibitor compound(e.g., a compound of Formula (A)) is administered prior
`
`to an allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the ACK
`
`inhibitor compound(e.g., a compound of Formula (A)) is administered subsequentto an allogeneic
`
`bone marrow or hematopoietic stem cell transplant. In some embodiments, the patient is a candidate
`
`for receiving HLA-mismatched hematopoietic stem cells. In some embodiments, the patient is a
`
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`WSGRDocket No. 25922-885.201
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`candidate for receiving unrelated donor hematopoietic stem cells, umbilical vein hematopoietic stem
`
`cells, or peripheral blood stem cells. In some embodiments, the ACK inhibitor compound (e.g., a
`
`compound of Formula (A)) is administered orally. In some embodiments, the ACK inhibitor
`
`compound(e.g., a compound of Formula (A)) is administered at a dosage of between about0.1
`
`mg/kg per day to about 100 mg/kg per day. In some embodiments, the ACK inhibitor compound
`
`(e.g., a compound of Formula (A)) is administered at a dosage of about 40 mg/day, about 140
`
`mg/day, about 280 mg/day, about 420 mg/day, about 560 mg/day, or about 840 mg/day. In some
`
`embodiments, the ACK inhibitor compound(e.g., a compound of Formula (A)) is administered in
`
`combination with other prophylactic agents. In some embodiments, the ACK inhibitor compound
`
`(e.g., a compound of Formula (A)) is administered from day 1 to about day 120 following allogeneic
`
`bone marrow or hematopoietic stem cell transplant. In some embodiments, the ACKinhibitor
`
`compound(e.g., a compound of Formula (A)) is administered from day | to about day 1000
`
`following allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the
`
`ACKinhibitor compound(e.g., a compound of Formula (A)) is administered in combination with
`
`one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is
`
`a corticosteroid. In some embodiments, the therapeutic agent is cyclosporine (CSA), mycophenolate
`
`mofetil (MMF)or a combination thereof. In some embodiments, the patient has or will receive a
`
`donor lymphocyte infusions (DLI).In some embodiments, the patient is administered one or more
`
`DLIs. In some embodiments, the patient is administered two or more DLIs. In some embodiments,
`
`the DLI comprises CD3+ lymphocytes. In some embodiments, the patient is administered one or
`
`more donor lymphocyte infusions (DLD) following an allogeneic bone marrow or hematopoietic stem
`
`cell transplant. In some embodiments, the ACK inhibitor compound(e.g., a compound of Formula
`
`(A)) is administered concurrently with a DLI following allogeneic bone marrow or hematopoietic
`
`stem cell transplant. In some embodiments, the ACK inhibitor compound(e.g., a compound of
`
`Formula (A)) is administered prior to a DLI following an allogeneic bone marrow or hematopoietic
`
`stem cell transplant. In some embodiments, the ACK inhibitor compound(e.g., a compound of
`
`Formula (A)) is administered following a DLI following an allogeneic bone marrow or
`
`hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound(e.g., a
`
`compound of Formula (A)) is ibrutinib.
`
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`WSGRDocket No. 25922-885.201
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`[0004] Disclosed herein, in some embodiments, are methodsof treating a patient for alleviation of a
`
`bone marrow mediated disease, comprising administering to the patient allogeneic hematopoietic
`
`stem cells and/or allogeneic T-cells, and a therapeutically effective amount of an ACK inhibitor
`
`(e.g., an ITK or BTKinhibitor). In some embodiments, disclosed herein are methodsoftreating a
`
`patient for alleviation of a bone marrow mediated disease, with alleviation of consequently
`
`developed graft versus host disease (GVHD), comprising administering to the patient allogeneic
`
`hematopoietic stem cells and/or allogeneic T-cells, and a therapeutically effective amount of a
`
`compoundof Formula (A):
`
`NR,
`
`N° SyonN
`
`R4
`
`Formula (A);
`
`wherein:
`
`Ais N;
`
`R, is phenyl-O-phenylor phenyl-S-pheny];
`
`R» and R3 are independently H;
`
`Rg is L3-X-L4-G, wherein,
`
`L; is optional, and when presentis a bond, optionally substituted or unsubstituted alkyl,
`
`optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl,
`
`optionally substituted or unsubstituted alkynyl;
`
`X is optional, and whenpresentis a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NRo-,
`
`-NHC(O)-, -C(O)NH-, -NRoC(O)-, -C(O)NRo-, -S(=O)2NH-, -NHS(=O)s-, -S(=O)2NRo-, -
`
`NRoS(=O)2-, -OC(O)NH-, -NHC(O)O-, -OC(O)NRo-, -NRoC(O)O-, -CH=NO-, -ON=CH., -
`
`NRioC(O)NRio-, heteroaryl-, aryl-, -NRioC(=NRi1)NRio-, -NRioC(=NR11)-, -C(=]NRi1)NRio-, -
`
`OC(=NRj1)-, or -C(=NR11)O-;
`
`L4 is optional, and whenpresentis a bond, substituted or unsubstituted alkyl, substituted or
`
`unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
`
`substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
`
`heterocycle;
`
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`WSGRDocket No. 25922-885.201
`
`or L3, X and Ly taken together form a nitrogen containing heterocyclic ring;
`O
`Re
`0
`OP Re
`i
`Re
`m
`Re
`Z
`2X7
`“ wn
`_— yw
`. oe 7 eSR.
`a
`aa
`a
`R2O M
`
`R:
`
`Gis
`
`8
`
`;
`
`;
`
`8
`
`R
`
`7
`
`;
`
`R
`
`7
`
`8
`
`!
`
`, or
`
`8
`
`R
`
`7
`
`, wherein,
`
`Re, Rz and Rg are independently selected from among H, halogen, CN, OH, substituted or
`
`unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted
`
`cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
`
`substituted or unsubstituted heteroaryl;
`
`each Rois independently selected from among H,substituted or unsubstituted lower alkyl,
`
`and substituted or unsubstituted lower cycloalkyl;
`
`each Rjo is independently H,substituted or unsubstituted loweralkyl, or substituted or
`
`unsubstituted lower cycloalkyl; or
`
`two Rio groups can together form a 5-, 6-, 7-, or 8-memberedheterocyclic ring; or
`
`Rio and Ry; can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
`
`each Rj; is independently selected from H or substituted or unsubstituted alkyl; or a
`
`pharmaceutically acceptable salt thereof, is administered prior to, concurrently with, or following the
`
`allogeneic hematopoietic stem cells and/or allogeneic T-cells. In some embodiments, L3, X and L4
`
`taken together form a nitrogen containing heterocyclic ring. In some embodiments, the nitrogen
`
`containing heterocyclic ring is a piperidine group. In some embodiments, G is
`
`O
`
`Re
`
`aen
`Re
`
`or
`
`es
`
`Re In some embodiments, the compound of Formula (A) is 1-[(3R)-3-[4-amino-3-(4-
`phenoxyphenyl)pyrazolo[3,4-d]pyrimidin- l-yl]piperidin-1-yl]prop-2-en-1-one. In some
`
`embodiments, the patient has cancer. In some embodiments, the patient has a hematological
`
`malignancy. In some embodiments, the patient has a relapsed or refractory hematological
`
`malignancy. In some embodiments, the patient has a leukemia, a lymphoma, or a myeloma. In some
`
`embodiments, the patient has a B-cell malignancy. In some embodiments, the B-cell malignancyis a
`
`non-Hodgkin’s lymphoma. In some embodiments, the B-cell malignancy is chronic lymphocytic
`
`leukemia (CLL). In some embodiments, the B-cell malignancyis a relapsed or refractory B-cell
`
`malignancy. In some embodiments, the B-cell malignancyis a relapsed or refractory non-Hodgkin’s
`
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`WSGRDocket No. 25922-885.201
`
`lymphoma. In some embodiments, the B-cell malignancy is a relapsed or refractory CLL. In some
`
`embodiments, the patient has high risk CLL. In some embodiments, the patient has a 17p
`
`chromosomaldeletion. In some embodiments, the patient has 10%, 20%, 30%, 40%, 50%, 60%,
`
`70%, 80%, 90%, or greater CLL as determined by bone marrow biopsy. In some embodiments, the
`
`patient has received one or more prior anticancer agents. In some embodiments, the anticancer agent
`
`is selected from among alemtuzumab, bendamustine, bortezomib, CAL-101, chlorambucil,
`
`cyclophosphamide, dexamethasone,docetaxel, doxorubicin, endostatineverolimus, etoposide,
`
`fludarabine, fostamatinib, hydroxydaunorubicin, ibritumomab, ifosphamide, lenalidomide,
`
`mesalazine, ofatumumab, paclitaxel, pentostatin, prednisone, rituximab, temsirolimus, thalidomide,
`
`tositumomab, vincristine, or a combination thereof. In some embodiments, the anticancer agentis
`
`rituximab. In some embodiments, the anticancer agent is alemtuzumab. In some embodiments, the
`
`anticancer agent is fludarabine, cyclophosphamide, and rituximab (FCR). In some embodiments, the
`
`anticancer agent is oxaliplatin, fludarabine, cytarabine, rituximab (OFAR). In some embodiments,
`
`the amount of the ACK inhibitor compound(e.g., a compound of Formula (A)) prevents or reduces
`
`GVHDwhile maintaining a graft-versus-leukemia (GVL) reaction effective to reduce or eliminate
`
`the numberof cancerouscells in the blood of the patient. In some embodiments, the cell
`
`transplantation is a hematopoietic cell transplantation. In some embodiments, the GVHD is acute
`
`GVHD. In some embodiments, the GVHDis chronic GVHD. In some embodiments, the GVHDis
`
`sclerodermatous GVHD. In some embodiments, the GVHDis steroid resistant GVHD. In some
`
`embodiments, the GVHDis cyclosporin-resistant GVHD. In some embodiments, the GVHDis
`
`refractory GVHD. In some embodiments, the GHVDis oral GVHD. In some embodiments, the oral
`
`GVHDisreticular oral GVHD. In some embodiments, the oral GVHD is erosive oral GVHD. In
`
`some embodiments, the oral GVHDis ulcerative oral GVHD. In some embodiments, the oral
`
`GVHDis GVHDofthe oral cavity. In some embodiments, the oral GVHD is GVHDofthe
`
`oropharyngeal region. In some embodiments, the oral GVHD is GVHDofthe pharyngeal region. In
`
`some embodiments, the oral GVHD is GVHDofthe esophageal region. In some embodiments, the
`
`oral GVHD is acute oral GVHD. In some embodiments, the oral GVHD is chronic oral GVHD. In
`
`some embodiments, the patient exhibits one or more symptoms of GVHD. In some embodiments,
`
`the patient has or will receive an allogeneic bone marrow or hematopoietic stem cell transplant. In
`
`some embodiments, the ACK inhibitor compound (e.g., a compound of Formula (A)) is administered
`
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`WSGRDocket No. 25922-885.201
`
`concurrently with an allogeneic bone marrow or hematopoietic stem cell transplant. In some
`
`embodiments, the ACK inhibitor compound(e.g., a compound of Formula (A)) is administered prior
`
`to an allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the ACK
`
`inhibitor compound(e.g., a compound of Formula (A)) is administered subsequentto an allogeneic
`
`bone marrow or hematopoietic stem cell transplant. In some embodiments, the patient is a candidate
`
`for receiving HLA-mismatched hematopoietic stem cells. In some embodiments, the patient is a
`
`candidate for receiving unrelated donor hematopoietic stem cells, umbilical vein hematopoietic stem
`
`cells, or peripheral blood stem cells. In some embodiments, the ACK inhibitor compound (e.g., a
`
`compound of Formula (A)) is administered at a dosage of between about 0.1 mg/kg per day to about
`
`100 mg/kg per day. In some embodiments, the ACK inhibitor compound(e.g., a compound of
`
`Formula (A)) is administered at a dosage of about 40 mg/day, about 140 mg/day, about 280 mg/day,
`
`about 420 mg/day, about 560 mg/day, or about 840 mg/day. In some embodiments, the ACK
`
`inhibitor compound(e.g., a compound of Formula (A)) is administered orally. In some
`
`embodiments, the ACK inhibitor compound(e.g., a compound of Formula (A)) is administered in
`
`combination with additional therapeutic agents. In some embodiments, the additional therapeutic
`
`agent is a corticosteroid. In some embodiments, the additional therapeutic agent is cyclosporine
`
`(CSA), mycophenolate mofetil (MMF) or a combination thereof. In some embodiments, the ACK
`
`inhibitor compound(e.g., a compound of Formula (A)) is administered from day | to about day 120
`
`following allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the
`
`ACKinhibitor compound(e.g., a compound of Formula (A)) is administered from day | to about
`
`day 1000 following allogeneic bone marrow or hematopoietic stem cell transplant. In some
`
`embodiments, the patient has or will receive a donor lymphocyte infusion (DLI). In some
`
`embodiments, the patient has or will receive two or more donor lymphocyte infusions (DLJ). In
`
`some embodiments, the patient is administered one or more donor lymphocyte infusions (DLJ). In
`
`some embodiments, the DLI comprises CD3+ lymphocytes. In some embodiments, the patientis
`
`administered one or more donor lymphocyte infusions (DLDfollowing an allogeneic bone marrow
`
`or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound(e.g., a
`
`compoundof Formula (A)) is administered concurrently with a DLI following allogeneic bone
`
`marrow or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound
`
`(e.g., a compound of Formula (A)) is administered prior to a DLI following an allogeneic bone
`
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`marrow or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound
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`(e.g., a compound of Formula (A)) is administered following a DLI following an allogeneic bone
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`marrow or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound
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`(e.g., a compound of Formula (A)) is ibrutinib.
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`[0005] In some embodiments, disclosed herein are methods of reducing the severity of GVHD
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`occurrence in a patient requiring cell transplantation comprising administration of a therapeutically
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`effective amountof ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin- l-
`
`yl]piperidin-1-yl]prop-2-en-1-one). In some embodiments, the patient has cancer. In some
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`embodiments, the patient has a hematological malignancy. In some embodiments, the patient has a
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`relapsed or refractory hematological malignancy. In some embodiments, the patient has a B-cell
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`malignancy. In some embodiments, the patient has a T-cell malignancy. In some embodiments, the
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`patient has a leukemia, a lymphoma, or a myeloma. In some embodiments, the B-cell malignancyis
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`a non-Hodgkin’s lymphoma. In some embodiments, the B-cell malignancy is chronic lymphocytic
`
`leukemia (CLL). In some embodiments, the B-cell malignancyis a relapsed or refractory B-cell
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`malignancy. In some embodiments, the B-cell malignancyis a relapsed or refractory non-Hodgkin’s
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`lymphoma. In some embodiments, the B-cell malignancyis a relapsed or refractory CLL. In some
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`embodiments, the patient has high risk CLL. In some embodiments, the patient has a 17p
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`chromosomaldeletion. In some embodiments, the patient has 10%, 20%, 30%, 40%, 50%, 60%,
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`70%, 80%, 90%, or greater CLL as determined by bone marrow biopsy. In some embodiments, the
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`patient has received one or more prior anticancer agents. In some embodiments, the anticancer agent
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`is selected from among alemtuzumab, bendamustine, bortezomib, CAL-101, chlorambucil,
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`cyclophosphamide, dexamethasone,docetaxel, doxorubicin, endostatineverolimus, etoposide,
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`fludarabine, fostamatinib, hydroxydaunorubicin, ibritumomab, ifosphamide, lenalidomide,
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`mesalazine, ofatumumab, paclitaxel, pentostatin, prednisone, rituximab, temsirolimus, thalidomide,
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`tositumomab, vincristine, or a combination thereof. In some embodiments, the anticancer agentis
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`rituximab. In some embodiments, the anticancer agent is alemtuzumab. In some embodiments, the
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`anticancer agent is fludarabine, cyclophosphamide, and rituximab (FCR). In some embodiments, the
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`anticancer agent is oxaliplatin, fludarabine, cytarabine, rituximab (OFAR). In some embodiments,
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`the amountof ibrutinib prevents or reduces GVHD while maintaining a graft-versus-leukemia
`
`(GVL)reaction effective to reduce or eliminate the numberof cancerouscells in the blood of the
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`patient. In some embodiments, the cell transplantation is a hematopoietic cell transplantation. In
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`some embodiments, the GVHDis acute GVHD. In some embodiments, the GVHDis chronic
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`GVHD. In some embodiments, the GVHDis sclerodermatous GVHD. In some embodiments, the
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`GVHDissteroid resistant GVHD. In some embodiments, the GVHDis cyclosporin-resistant
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`GVHD. In some embodiments, the GVHDis refractory GVHD. In some embodiments, the GHVD
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`is oral GVHD. In some embodiments, the oral GVHDisreticular oral GVHD. In some
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`embodiments, the oral GVHD is erosive oral GVHD. In some embodiments, the oral GVHDis
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`ulcerative oral GVHD. In some embodiments, the oral GVHD is GVHDofthe oral cavity. In some
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`embodiments, the oral GVHD is GVHDof the oropharyngeal region. In some embodiments, the oral
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`GVHDis GVHDof the pharyngeal region. In some embodiments, the oral GVHD is GVHDofthe
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`esophageal region. In some embodiments, the oral GVHDis acute oral GVHD. In some
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`embodiments, the oral GVHDis chronic oral GVHD. In some embodiments, the patient exhibits one
`
`or more symptoms of GVHD. In some embodiments, the patient has or will receive an allogeneic
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`bone marrow or hematopoietic stem cell transplant. In some embodiments, the ibrutinib is
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`administered concurrently with an allogeneic bone marrow or hematopoietic stem cell transplant. In
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`some embodiments, the ibrutinib is administered prior to an allogeneic bone marrow or
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`hematopoietic stem cell transplant. In some embodiments, the ibrutinib is administered subsequent to
`
`an allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the patient
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`is a candidate for receiving HLA-mismatched hematopoietic stem cells. In some embodiments, the
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`patient is a candidate for receiving unrelated donor hematopoietic stem cells, umbilical vein
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`hematopoietic stem cells, or peripheral blood stem cells. In some embodiments, the ibrutinib is
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`administered orally. In some embodiments, the ibrutinib is administered at a dosage of between
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`about 0.1 mg/kg per day to about 100 mg/kg per day. In some embodiments, the ibrutinib is
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`administered at a dosage of about 40 mg/day, about 140 mg/day, about 280 mg/day, about 420
`
`mg/day, about 560 mg/day, or about 840 mg/day. In some embodiments, the ibrutinib is
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`administered in combination with other prophylactic agents. In some embodiments, the ibrutinib is
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`administered from day | to about day 120 following allogeneic bone marrow or hematopoietic stem
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`cell transplant. In some embodiments, the ibrutinib is administered from day | to about day 1000
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`following allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the
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`ibrutinib is administered in combination with one or more additional therapeutic agents. In some
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`embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the
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`therapeutic agent is cyclosporine (CSA), mycophenolate mofetil (MMF) or a combination thereof. In
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`some embodiments, the patient has or will receive a donor lymphocyte infusions (DLI).In some
`
`embodiments, the patient is administered one or more DLIs. In some embodiments, the patientis
`
`administered two or more DLIs. In some embodiments, the DLI comprises CD3+ lymphocytes. In
`
`some embodiments, the patient is administered one or more donor lymphocyte infusions (DL
`
`following an allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments,
`
`the ibrutinib is administered concurrently with a DLI following allogeneic bone marrow or
`
`hematopoietic stem cell transplant. In some embodiments, the ibrutinib is administered prior to a
`
`DLIfollowing an allogeneic bone marrow or hematopoietic stem cell transplant. In some
`
`embodiments, the ibrutinib is administered following a DLI following an allogeneic bone marrow or
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`hematopoietic stem cell transplant.
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`INCORPORATION BY REFERENCE
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`[0006] All publications, patents, and patent applications mentioned in this specification are herein
`
`incorporated by reference to the sameextentas if each individual publication, patent, or patent
`
`application wasspecifically and individually indicated to be incorporated by reference.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0007] The novel features of the invention are set forth with particularity in the appended claims. A
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`better understanding of the features and advantages of the present invention will be obtained by
`
`reference to the following detailed description that sets forth illustrative embodiments, in which the
`
`principles of the invention are utilized, and the accompanying drawings of which:
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`[0008] FIG. 1 exemplifies that ibrutinib ameliorates cGVHD symptomatologyafter allotransplant.
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`C57BL/6 mice were engrafted with LP/J bone marrow after 850 cGylethal irradiation. 25 days post-
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`transplant mice were randomly assignedto ibrutinib, vehicle, or cyclosporine groups. Panel A shows
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`images showing external signs ofcCGVHDincluding alopecia, scleroderma, and fibrotic lesions at
`
`day 36 post-transplant. Ibrutinib treatment group displayed few external signs of CGVHD
`
`progression as comparedto vehicle or cyclosporine groups. Panel B showsan analysis of CGVHD
`
`mouse groups using a physical scoring system adapted from Cookeet al., which incorporates weight,
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`posture, coat condition, skin condition, and mobility. Scoring was conducted on day 36 post-
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`transplantation. Panel C shows the LP/J->-C57BL/6 cGVHDscoring. Each category: coat condition,
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`skin condition, weight, posture, mobility, and vitality are individually scored and summedto achieve
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`an overall cGVHDcondition score. Scores are taken by a consistent unbiased observer with no
`
`knowledge of treatment cohorts. Panel D provides images of cGVHD mousegroups at day 39 post-
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`HSCT. Panel E provides images of H&Estained skin preparations of sclerodermatous skin lesions
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`showing levels of dermal fibrosis, epidermal hyperplasia, serocellular crusting, erosion, and
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`lymphohistiocytic infiltration, consistent with cGVHD.
`
`[0009] FIG. 2 exemplifies that Tregs are not inhibited by ibrutinib. Panel A provides a plot of
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`FoxP3+ CD4+ cells in C57BL/6 micetreated with ibrutinib (25mg/kg/day) or vehicle for 9 weeks.
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`The percent FoxP3+ CD4+ cells was analyzed by flow cytometry on peripheral blood. Student’s T-
`
`test indicates no significant difference between the two groups. Panel B provides a plot of CD8 T
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`c