US20240033265A2 - Treatments for mutations in acute myeloid leukemia - Google Patents

Treatments for mutations in acute myeloid leukemia Download PDF

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US20240033265A2
US20240033265A2 US17/263,531 US201917263531A US2024033265A2 US 20240033265 A2 US20240033265 A2 US 20240033265A2 US 201917263531 A US201917263531 A US 201917263531A US 2024033265 A2 US2024033265 A2 US 2024033265A2
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mutation
human
myeloid leukemia
acute myeloid
pharmaceutically acceptable
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US20210235374A1 (en
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Jeffrey W Tyner
Cristina Tognon
Brian J Druker
Daniel Bottomly
Beth Wilmot
Stephen Kurtz
Samantha Savage Stevens
Nicola Long
Anna Reister Schultz
Elie Traer
Shannon K McWeeney
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Oregon Health Science University
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Oregon Health Science University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
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    • C12Q2600/00—Oligonucleotides characterized by their use
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to useful methods of treating Acute Myeloid Leukemia (AML) in a human. Particularly, the invention relates to useful methods of treatment for AML in the presence of gene mutations.
  • AML Acute Myeloid Leukemia
  • AML acute myeloid leukemia
  • Cytogenetic and sequencing analyses have revealed at least 11 genetic classes of AML 3 and over 20 subsets can be assigned when also considering cell differentiation states of the leukemic blasts 4,5 .
  • Deep sequencing of AML by The Cancer Genome Atlas (TCGA) revealed a heterogeneous disease with nearly 2,000 somatically mutated genes observed across 200 patients 6 .
  • Many of the recurrent cytogenetic events and somatic mutations have been shown to carry prognostic significance 3,7,8 .
  • MDS myelodysplastic syndromes
  • MPN myeloproliferative neoplasms
  • a small number of therapies targeted to mutational events have been developed for AML patients, with the current standard of care largely unchanged over the past 30-40 years.
  • the first targeted therapy for AML involved use of all-trans retinoic acid (ATRA) in combination with arsenic trioxide for patients with rearrangement of the retinoic acid receptor 16,17 .
  • ATRA all-trans retinoic acid
  • FLT3 tyrosine kinase inhibitors have been developed for FLT3 mutational events that occur in ⁇ 20-30% of AML patients 18-21 .
  • FLT3 inhibitors deployed as single agents yielded responses of only 2-6 months 22-25 .
  • Midostaurin a broad-spectrum FLT3 inhibitor
  • FLT3-mutated AML patients in combination with standard of care chemotherapy 26 ; however, relapse was still prevalent in this setting.
  • Mechanisms underlying relapse on FLT3 inhibitors include acquisition of secondary mutations of FLT3 27 , mutations in alternative genes/pathways, such as TET2 28 , and tumor-extrinsic signals such as FLT3 ligand and FGF2 29,30 .
  • Targeting of mutant IDH1 and IDH2 31 has shown clinical benefit leading to approval of the IDH2 inhibitor, enasidenib, with approval pending for the IDH1 inhibitor, ivosidenib 32,33
  • Additional proposed strategies have included inhibition of epigenetic modifiers such as EZH2 34 , LSD1 35 , and DOT1L 36 based on direct mutation of these targets or synthetic lethality in the context of drug combinations (ATRA and LSD1 inhibitors) or specific genetic features (KMT2A-gene rearrangement for DOT1L inhibitors).
  • Hypomethylating agents have been employed in AML patients with better responses reported for certain genetic subsets, such as those with mutation of TET2 37 or TP53 38 .
  • the BCL2 inhibitor venetoclax
  • venetoclax showed a ⁇ 20% response rate when used as a single agent in relapsed patients 39 with higher response rates ( ⁇ 60%) reported in combination with hypomethylating agents in newly diagnosed, elderly AML patients 40 .
  • the present invention provides methods of treatment for Acute Myeloid Leukemia in a human, wherein mutations are present in the genes frequently associated in AML, including mutations in one or more genes selected from the group of NPM1, ASXL1, DNMT3A, NRAS, CBF3.MYH11, IDH1, IDH2, FLT3, FLT3-ITD, MLLT3-KMT2A, MYC, CEBPA, PDS5B, SRSF2, BCOR, RUNX1, RUNX1T1, TET2, WT1, U2AF1, KIT, KRSR2, PML.RARA, SMC1A, CELSR2, PML-RARA, TRIO, and MLLT3.KMT2A.
  • FIG. 1 provides a comparison of the whole Beat AML cohort as well as only the de novo cases in Beat AML with TCGA.
  • FIG. 2 reveals significant patterns of mutational co-segregation identified suggesting biological cooperativity of mutational events.
  • FIG. 3 represents the annotated sensitivity or resistance fraction of each case against ELN 2017 classification.
  • FIG. 4 represents the difference in average drug sensitivity of mutant versus WT cases for each drug/mutation pair plotted on the horizontal axis of a volcano plot with a test for statistical significance of the comparison plotted on the vertical axis.
  • FIG. 5 plots the same analysis from the top panel using only cases that were wild type for FLT3.
  • FIG. 6 depicts the AUC of JAK kinase inhibitors tested.
  • FIG. 7 summarizes frequency with which drug families associated with mutation and gene expression clusters in an iterative regression model.
  • AML patients who present with mutations to one or more genes selected from the group of NPM1 (nucleophosmin 1), DNMT3A (DNA Methyltransferase 3 Alpha), NRAS (Neuroblastoma RAS), CBF ⁇ .MYH11 (core-binding factor subunit beta.myosin heavy chain 11 fusion); IDH2 (isocitrate dehydrogenase 2); FLT3 (Fms Related Tyrosine Kinase 3); SRSF2 (Serine and Arginine Rich Splicing Factor 2); BCOR (BCL6 Corepressor); RUNX1 (Runt Related Transcription Factor 1); RUNX1T1 (RUNX1 Translocation Partner 1); TET2 (tet methylcytosine dioxygenase 2); WT1 (Wilmsmin 1), DNMT3A (DNA Methyltransferase 3 Alpha), NRAS (Neuroblastoma RAS), CBF ⁇ .
  • NPM1 Mutations in NPM1 are usually restricted to exon 12, as shown in an analysis of 52 primary AML patients with cytoplasmic NPM1 (NPM1c), where 98% of the patients had exon 12 mutations. To date, >55 unique mutations have been identified in exon 12 of NPM1. Most mutations consist of a (net) 4 bp insertion with >95% of mutations occurring between nucleotides 960 and 961, however, there have also been cases ( ⁇ 5%) that occur within 10 nucleotides up or downstream. The most common mutation is called type A constituting ⁇ 80% of cases; type A mutations involve duplication of TCTG (nucleotides 956-959), creating an insertion at position 960.
  • Type B and D mutations are also fairly common, both producing 4 bp insertions at position 960. Other mutations are rare, occurring in ⁇ 1% of cases. Additionally, the frequency of nonexon 12 mutations is unknown, as most large studies restrict their analysis to exon 12. Discussion of these NPM1 mutations is discussed by Heath et al., Leukemia (2017) 31, pp. 798-807.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of a drug selected from the group of ibrutinib, vandetanib, lenvatinib, sorafenib, regorafenib, cabozantinib, foretinib, and entospletinib, or a pharmaceutically acceptable salt thereof.
  • a drug selected from the group of ibrutinib, vandetanib, lenvatinib, sorafenib, regorafenib, cabozantinib, foretinib, and entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of vandetanib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of lenvatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of regorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of cabozantinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of foretinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a mutation in the NPM1 gene, the method comprising administering to the human in need thereof a therapeutically effective amount of entospletinib, or a pharmaceutically acceptable salt thereof.
  • NPM1 is a mutation comprising an insertion of from one to four base pairs occurring within 10 nucleotides upstream or downstream of between nucleotides 960 and 961.
  • drugs selected from the group of ibrutinib, vandetanib, lenvatinib, sorafenib, regorafenib, cabozantinib, foretinib, and entospletinib, or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the NPM1 gene. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the NPM1 gene and eight separate embodiments herein concern the use of each drug independently for that use.
  • a method of treating acute myeloid leukemia in a human wherein at least two mutations selected from the group of NPM1, DNMT3A, and NRAS mutations are present, the method comprising administering to the human in need thereof a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof where the Acute Myeloid Leukemia is characterized by at least two mutations in genes selected from the group of NPM1, DNMT3A, and NRAS gene, the method comprising the steps of:
  • Acute Myeloid Leukemia in a human in need thereof where the Acute Myeloid Leukemia is characterized by a mutation in each of the NPM1, DNMT3A, and NRAS genes, the method comprising the steps of:
  • ibrutinib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in at least two of the genes selected from the group of NPM1, DNMT3A, and NRAS.
  • ibrutinib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of NPM1, DNMT3A, and NRAS.
  • a method of treating AML in a human comprising administering to the human in need thereof a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof where the Acute Myeloid Leukemia is characterized by a mutation in each of the NPM1 and DNMT3A genes and at least one mutation in a gene selected from the group of NRAS and FLT3, the method comprising the steps of:
  • ibrutinib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of NPM1 and DNMT3A and characterized by a mutation in at least one of the genes selected from the group of NRAS and FLT3
  • ibrutinib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of NPM1, DNMT3A, and FLT3.
  • ibrutinib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of NPM1, DNMT3A, NRAS, and FLT3.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of a drug selected from the group of sorafenib, cabozantinib, and entospletinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of cabozantinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of entospletinib, or a pharmaceutically acceptable salt thereof.
  • drugs selected from the group of sorafenib, cabozantinib, and entospletinib, or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the NPM1 and FLT3 genes. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the NPM1 and FLT3 genes and three separate embodiments herein concern the use of each drug independently for that use.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of vandetanib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of NF-kB activation inhibitor, or a pharmaceutically acceptable salt thereof.
  • drugs selected from the group of vandetanib and NF-kB activation inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the NPM1 and IDH2 genes. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the NPM1 and IDH2 genes and two separate embodiments herein concern the use of each drug, vandetanib and NF-kB activation inhibitor, independently for that use.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of one or more drugs selected from the group of lenvatinib, ibrutinib, saracatinib, and regorafenib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of regorafenib, or a pharmaceutically acceptable salt thereof.
  • drugs selected from the group of lenvatinib, ibrutinib, saracatinib, and regorafenib, or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the NPM1 and DNMT3A genes. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the NPM1 and DNMT3A genes and four separate embodiments herein concern the use of each drug, lenvatinib, ibrutinib, saracatinib, and regorafenib, independently for that use.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • ibrutinib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of NPM1 and TET2.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of trametinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of YM-155, or a pharmaceutically acceptable salt thereof.
  • trametinib and YM-155 are also provided, for use in treating Acute Myeloid Leukemia characterized by a mutation in the CBFB.MYH11 and NRAS genes. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the CBFB.MYH11 and NRAS genes and two separate embodiments herein concern the use of each drug, trametinib and YM-155, independently for that use.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable.
  • sorafenib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of IDH2 and FLT3.
  • crizotinib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of SRSF2 and IDH2.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of a JAK kinase inhibitor, or a pharmaceutically acceptable salt thereof.
  • JAK kinase inhibitor for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of BCOR and RUNX1.
  • the JAK kinase inhibitor is selected from the group of momelotinib, ruxolitinib, tofacitinib, baricitinib, filgotinib (G-146034, GLPG-0634), gandotinib, lestaurtinib (CEP-701), pacritinib (SB1518), PF-04965842, upadacitinib (ABT-494), peficitinib (ASP015K, JNJ-54781532), fedratinib (SAR302503), cucurbitacin (JSI-1214), and CZ868, or a pharmaceutically acceptable salt thereof.
  • the JAK kinase inhibitor is selected from the group of momelotinib, ruxolitinib, and tofacitinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein an NRAS mutation is present comprising administering to the human in need thereof a therapeutically effective amount of one or more drugs selected from the group of selumetinib, trametinib, and flavopiridol, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein an NRAS mutation is present comprising administering to the human in need thereof a therapeutically effective amount of trametinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein an NRAS mutation is present comprising administering to the human in need thereof a therapeutically effective amount of flavopiridol, or a pharmaceutically acceptable salt thereof.
  • drugs selected from the group of selumetinib, trametinib, and flavopiridol, or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the NRAS gene. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the NRAS gene and three separate embodiments herein concern the use of each drug, selumetinib, trametinib, and flavopiridol, independently for that use.
  • RAF265 RAF265
  • RAF265 (CHIR-265), or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the WT1 gene.
  • RAF265 is also known by the chemical name 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of one or more drugs selected from the group of sorafenib, quizartinib, cabozantinib, foretinib, sunitinib, and regorafenib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein a FLT3 mutation is present comprising administering to the human in need thereof a therapeutically effective amount of quizartinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein a FLT3 mutation is present comprising administering to the human in need thereof a therapeutically effective amount of cabozantinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein a FLT3 mutation is present comprising administering to the human in need thereof a therapeutically effective amount of foretinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein a FLT3 mutation is present comprising administering to the human in need thereof a therapeutically effective amount of sunitinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein a FLT3 mutation is present comprising administering to the human in need thereof a therapeutically effective amount of regorafenib, or a pharmaceutically acceptable salt thereof.
  • drugs selected from the group of sorafenib, quizartinib, cabozantinib, foretinib, sunitinib, and regorafenib, or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the FLT3 gene. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the FLT3 gene and six separate embodiments herein concern the use of each drug, sorafenib, quizartinib, cabozantinib, foretinib, sunitinib, and regorafenib, independently for that use.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of one or more drugs selected from the group of crizotinib and lenvatinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human wherein an IDH2 mutation other than a FLT3/ITD mutation is present, the method comprising administering to the human in need thereof a therapeutically effective amount of crizotinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human wherein an IDH2 mutation other than a FLT3/ITD mutation is present, the method comprising administering to the human in need thereof a therapeutically effective amount of lenvatinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of one or more drugs selected from the group of crenolanib, trametinib, saracatinib, and dasatinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human wherein a PML.RARA mutation is present, the method comprising administering to the human in need thereof a therapeutically effective amount of one or more drugs selected from the group of venetoclax, ABT-737, and YM-155, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of pazopanib, or a pharmaceutically acceptable salt thereof.
  • pazopanib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in each of the genes selected from the group of RUNX1 and RUNX1T1.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of lenvatinib, or a pharmaceutically acceptable salt thereof.
  • pazopanib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the DNMT3A gene.
  • a method of treating acute myeloid leukemia in a human, wherein an IDH1 mutation is present comprising administering to the human in need thereof a therapeutically effective amount of YM-155, or a pharmaceutically acceptable salt thereof.
  • YM-155 or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the IDH1 gene.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of cediranib, or a pharmaceutically acceptable salt thereof.
  • cediranib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the U2AF1 gene.
  • a method of treating acute myeloid leukemia in a human, wherein a KIT mutation is present comprising administering to the human in need thereof a therapeutically effective amount of one or more drugs selected from the group of imatinib, sorafenib, and pazopanib, or a pharmaceutically acceptable salt thereof.
  • the drug administered is a) imatinib, b) sorafenib, and c) pazopanib, or a pharmaceutically acceptable salt thereof.
  • drugs selected from the group of imatinib, sorafenib, and pazopanib, or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the KIT gene. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the KIT gene and three separate embodiments herein concern the use of each drug, imatinib, sorafenib, and pazopanib, independently for that use.
  • a method of treating acute myeloid leukemia in a human comprising administering to the human in need thereof a therapeutically effective amount of tofacitinib, or a pharmaceutically acceptable salt thereof.
  • tofacitinib or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the ZRSR2 gene.
  • a method of treating acute myeloid leukemia in a human, wherein a BCOR mutation is present comprising administering to the human in need thereof a therapeutically effective amount of one or more drugs selected from the group of RAF265 and crizotinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein a BCOR mutation is present comprising administering to the human in need thereof a therapeutically effective amount of RAF265, or a pharmaceutically acceptable salt thereof.
  • a method of treating acute myeloid leukemia in a human, wherein a BCOR mutation is present comprising administering to the human in need thereof a therapeutically effective amount of crizotinib, or a pharmaceutically acceptable salt thereof.
  • drugs selected from the group of RAF265 and crizotinib, or a pharmaceutically acceptable salt thereof, for use in treating Acute Myeloid Leukemia characterized by a mutation in the BCOR gene. It is understood that each drug in this list may be used separately for use in treating Acute Myeloid Leukemia characterized by a mutation in the BCOR gene and two separate embodiments herein concern the use of each drug, RAF265 and crizotinib, independently for that use.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a BCOR mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine (also known asRAF265 and CHIR-265), crizotinib, and 3,5,7,8-Tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidin-4-one (XAV-939), or a pharmaceutically acceptable salt thereof.
  • at least one agent selected from the group of 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a BCOR mutation, the method comprising administering to the human a therapeutically effective amount of 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine (also known asRAF265 and CHIR-265), or a pharmaceutically acceptable salt thereof.
  • RAF265 and CHIR-265 also known asRAF265 and CHIR-265
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a BCOR mutation, the method comprising administering to the human a therapeutically effective amount of crizotinib (also known as PF-2341066), or a pharmaceutically acceptable salt thereof.
  • crizotinib also known as PF-2341066
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a BCOR mutation, the method comprising administering to the human a therapeutically effective amount of 3,5,7,8-Tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidin-4-one (also known as XAV-939), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a BCOR mutation and the presence of at least one mutation from the group of an ASXL1 mutation, a DNMT3A mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of 3,5,7,8-Tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidin-4-one (also known as XAV-939), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a BCOR mutation and an ASXL1 mutation, the method comprising administering to the human a therapeutically effective amount of 3,5,7,8-Tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidin-4-one (also known as XAV-939), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a BCOR mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of 3,5,7,8-Tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidin-4-one (also known as XAV-939), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a BCOR mutation and a SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of 3,5,7,8-Tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidin-4-one (also known as XAV-939), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a CBF ⁇ -MYH11 mutation
  • the method comprising administering to the human a therapeutically effective amount of one or more agents selected from the group of crenolanib, trametinib, N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (also known as PLX-4720 and CAS No.: 918505-84-7), and Saracatinib, or a pharmaceutically acceptable salt thereof.
  • crenolanib trametinib
  • N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide also known as PLX
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a CBFB-MYH11 mutation, the method comprising administering to the human a therapeutically effective amount of crenolanib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a CBFB-MYH11 mutation, the method comprising administering to the human a therapeutically effective amount of trametinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a CBFB-MYH11 mutation
  • the method comprising administering to the human a therapeutically effective amount of N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (also known as PLX-4720 and CAS No.: 918505-84-7), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a CBFB-MYH11 mutation, the method comprising administering to the human a therapeutically effective amount of Saracatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a CBFB-MYH11 mutation and a NRAS mutation, the method comprising administering to the human a therapeutically effective amount of 1-(2-methoxyethyl)-2-methyl-3-(pyrazin-2-ylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione (also known as YM-155), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a CELSR2 mutation, the method comprising administering to the human a therapeutically effective amount of Tivozanib (also known as AV-951), or a pharmaceutically acceptable salt thereof.
  • Tivozanib also known as AV-951
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of one or more agents selected from the group of Lenvatinib, ibrutinib, saracatinib, cabozantinib, sorafenib, and entospletinib, and Dasatinib, or a pharmaceutically acceptable salt thereof.
  • agents selected from the group of Lenvatinib, ibrutinib, saracatinib, cabozantinib, sorafenib, and entospletinib, and Dasatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of Lenvatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of saracatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of cabozantinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of, entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of Dasatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a DNMT3A mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation
  • the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of Barasertib (also known as AZD1152-HQPA), bosutinib, roscovitine, 5-(2,6-Dichlorophenyl)-2-[2,4-difluorophenyl)thio]-6H-pyrimido[1,6-b]pyridazin-6-one (also known as Neflamapimod and VX-745), CYT387, saracatinib, and [(3S,5S,6R,7S,8E,10R,11S,12E,14E)-21-(allylamino)-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of Barasertib (also known as AZD1152-HQPA), or a pharmaceutically acceptable salt thereof.
  • Barasertib also known as AZD1152-HQPA
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of tanespimycin (also known as 17AAG), or a pharmaceutically acceptable salt thereof.
  • tanespimycin also known as 17AAG
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of roscovitine, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of VX-745, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of CYT387, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of saracatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an IHD2 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of Barasertib, ruxolitinib, bosutinib, and tanespimycin (a.k.a. 17AAG), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an IHD2 mutation, the method comprising administering to the human a therapeutically effective amount of Barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an IHD2 mutation, the method comprising administering to the human a therapeutically effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an IHD2 mutation, the method comprising administering to the human a therapeutically effective amount of bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an IHD2 mutation, the method comprising administering to the human a therapeutically effective amount of tanespimycin (a.k.a. 17AAG or 17-AAG), or a pharmaceutically acceptable salt thereof.
  • tanespimycin a.k.a. 17AAG or 17-AAG
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an ASXL1 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of Barasertib, 17-AAG, and VX-745, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an ASXL1 mutation, the method comprising administering to the human a therapeutically effective amount of Barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an ASXL1 mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an ASXL1 mutation, the method comprising administering to the human a therapeutically effective amount of VX-745, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of Barasertib, 17-AAG, and bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of Barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of N-[(1S)-2-[[(7S)-6,7-Dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ) and venetoclax, or a pharmaceutically acceptable salt thereof.
  • DBZ N-[(1S)-2-[[(7S)-6,7-Dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-di
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of DBZ, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of venetoclax, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an RUNX1 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of bosutinib and 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an RUNX1 mutation, the method comprising administering to the human a therapeutically effective amount of bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and an RUNX1 mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of barasertib and bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a WT1 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of barasertib and 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a WT1 mutation, the method comprising administering to the human a therapeutically effective amount of barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a FLT3-ITD mutation and a WT1 mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of YM-155, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of crizotinib, GW-2580, Vargetef, Lenvatinib, NVP-TAE684, GSK-1838705A, PHA-665752, DBZ, Foretinib, Masitinib, Entospletinib, and (VX-680), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of crizotinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of GW-2580, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of Vargetef, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of Lenvatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of NVP-TAE684, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of GSK-1838705A, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of PHA-665752, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of DBZ, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of Foretinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of Masitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of Entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a MLLT3-KMT2A mutation, the method comprising administering to the human a therapeutically effective amount of vatalanib (PTK787), or a pharmaceutically acceptable salt thereof.
  • PTK787 vatalanib
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a MYC mutation, the method comprising administering to the human a therapeutically effective amount of saracatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of KW-2449, ibrutinib, vandetanib, lenvatinib, sorafenib, regorafenib, cabozantinib, DBZ, entospletinib, foretinib, sunitinib, dovitinib, quizartinib, ponatinib, barasertib, erlotinib, crenolanib, 17-AAG, Gefitinib, NVP-TAE684, and Vargetef, or a pharmaceutically acceptable salt thereof.
  • at least one agent selected from the group of KW-2449, ibrutinib, vandetanib, lenvatinib,
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of KW-2449, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of vandetanib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of lenvatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of regorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of cabozantinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of DBZ, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of foretinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of sunitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of dovitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of quizartinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of ponatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of erlotinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of crenolanib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of Gefitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of NVP-TAE684, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, the method comprising administering to the human a therapeutically effective amount of Vargetef, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a NPM1 mutation and a CEBPA mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of [4-[2-(1H-Indazol-3-yl)ethenyl]phenyl]-1-piperazinylmethanone (KW-2449), 6-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)thio)quinoline (SGX-523), and crizotinib, or a pharmaceutically acceptable salt thereof.
  • at least one agent selected from the group of [4-[2-(1H-Indazol-3-yl)ethenyl]phenyl]-1-piperazinylmethanone (KW-2449), 6-((6-(1-methyl-1
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a NPM1 mutation and a CEBPA mutation, the method comprising administering to the human a therapeutically effective amount of [4-[2-(1H-Indazol-3-yl)ethenyl]phenyl]-1-piperazinylmethanone (KW-2449), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a NPM1 mutation and a CEBPA mutation, the method comprising administering to the human a therapeutically effective amount of 6-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)thio)quinoline (SGX-523), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a NPM1 mutation and a CEBPA mutation, the method comprising administering to the human a therapeutically effective amount of crizotinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of lenvatinib, ibrutinib, saracatinib, regorafenib, foretinib, cabozantinib, sorafenib, KW-2449, PRT062607, entospletinib, crenolanib, gefitinib, dovitinib, 17-AAG, axitinib, gilteritinib, quizartinib, sunitinib, ponatinib, and 4-((5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl)
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of lenvatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of saracatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of regorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of foretinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of cabozantinib or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of KW-2449, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of PRT062607, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of crenolanib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of gefitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of dovitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of axitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of gilteritinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of quizartinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of sunitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of ponatinib or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of JNJ-7706621, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of barasertib, 17-AAG, cyt387, and bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of cyt387, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a FLT3-ITD mutation, the method comprising administering to the human a therapeutically effective amount of bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a FLT3-ITD mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of 17-AAG, saracatinib, and bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a FLT3-ITD mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a FLT3-ITD mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of saracatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a FLT3-ITD mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of bosutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a FLT3-ITD mutation, and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of 17-AAG, and barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a FLT3-ITD mutation, and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of 17-AAG, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a FLT3-ITD mutation, and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of barasertib, JNJ-7706621, dovitinib, ym-155 (Sepantronium bromide), erlotinib, roscovitine, and entospletinib, or a pharmaceutically acceptable salt thereof.
  • at least one agent selected from the group of barasertib, JNJ-7706621, dovitinib, ym-155 (Sepantronium bromide), erlotinib, roscovitine, and entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of JNJ-7706621, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of dovitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of ym-155 (Sepantronium bromide), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of erlotinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of roscovitine, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH1 mutation, the method comprising administering to the human a therapeutically effective amount of entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of DBZ, KW-2449, MLN120B, vandetanib, NVP-TAE684, vargetef, NF-kB activation inhibitor, GSK-1838705A, SGX-523, GW-2580, ibrutinib, barasertib, ponatinib, lapatinib, gefitinib, gilteritinib, ruxolitinib, palbociclib, sorafenib, erlotinib, VX-745, cabozantinib, entospletinib (GS-9973), quizartinib, lenvatinib,
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of DBZ, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of KW-2449, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of MLN120B, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of vandetanib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of NVP-TAE684, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of vargetef, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of NF-kB activation inhibitor, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of GSK-1838705A, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of SGX-523, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of GW-2580, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of barasertib or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of ponatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of lapatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of gefitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of gilteritinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of palbociclib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of erlotinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of VX-745, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of cabozantinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of entospletinib (GS-9973), or a pharmaceutically acceptable salt thereof.
  • GS-9973 entospletinib
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of quizartinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of lenvatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of regorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of vemurafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of KW-2449, vandetanib, NVP-TAE684, MLN120B, foretinib, sunitinib, Vargetef, barasertib, SGX-523, sorafenib, cabozantinib, entospletinib, NFkB-activation inhibitor, and regorafenib, or a pharmaceutically acceptable salt thereof.
  • at least one agent selected from the group of KW-2449, vandetanib, NVP-TAE684, MLN120B, foretinib, sunitinib, Vargetef, barasertib, SGX-523, sorafen
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of KW-2449, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of vandetanib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of NVP-TAE684, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of foretinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of sunitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of Vargetef, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of barasertib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of SGX-523, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of cabozantinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and an SRSF2 mutation, the method comprising administering to the human a therapeutically effective amount of regorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of ibrutinib, KW-2449, SGX-523, AZD1480, NVP-TAE684, K120227, and DBZ, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of ibrutinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of KW-2449, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of SGX-523, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of AZD1480, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of NVP-TAE684, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of K120227, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation, the method comprising administering to the human a therapeutically effective amount of DBZ, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of sorafenib and sunitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of sorafenib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation and a TET2 mutation, the method comprising administering to the human a therapeutically effective amount of sunitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of regorafenib (BAY 73-4506), cabozantinib, lenvatinib, vargetef, and entospletinib, or a pharmaceutically acceptable salt thereof.
  • regorafenib BAY 73-4506
  • cabozantinib lenvatinib
  • vargetef vargetef
  • entospletinib or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of regorafenib (BAY 73-4506), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of cabozantinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of lenvatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of vargetef, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of entospletinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a NRAS mutation, the method comprising administering to the human a therapeutically effective amount of Flavopiridol, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a PDS5B mutation, the method comprising administering to the human a therapeutically effective amount of N′-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine (BMS-345541), or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a PML-RARA mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of venetoclax, and YM-155, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a PML-RARA mutation, the method comprising administering to the human a therapeutically effective amount of venetoclax, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a PML-RARA mutation, the method comprising administering to the human a therapeutically effective amount of YM-155, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a RUNX1 mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of cediranib and BEZ2345, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a RUNX1 mutation, the method comprising administering to the human a therapeutically effective amount of cediranib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a RUNX1 mutation, the method comprising administering to the human a therapeutically effective amount of BEZ2345, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a RUNX1 mutation and a DNMT3A mutation, the method comprising administering to the human a therapeutically effective amount of MGCD-265, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of at least one agent selected from the group of GDC-0879, vatalanib, GSK-1838705A, BAY 11-7085, masitinib, lapatinib, canertinib, foretinib, and crizotinib, or a pharmaceutically acceptable salt thereof.
  • at least one agent selected from the group of GDC-0879, vatalanib, GSK-1838705A, BAY 11-7085, masitinib, lapatinib, canertinib, foretinib, and crizotinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of GDC-0879, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of vatalanib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount GSK-1838705A, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of BAY 11-7085, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of masitinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of lapatinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of canertinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of foretinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a SMC1A mutation, the method comprising administering to the human a therapeutically effective amount of crizotinib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a TRIO mutation, the method comprising administering to the human a therapeutically effective amount of palbociclib, or a pharmaceutically acceptable salt thereof.
  • Acute Myeloid Leukemia in a human in need thereof, wherein the Acute Myeloid Leukemia is characterized by the presence of a U2AF1 mutation, the method comprising administering to the human a therapeutically effective amount of cediranib (AZD2171), or a pharmaceutically acceptable salt thereof.
  • RAF265 also known as CHIR-265
  • RAF265 also known as CHIR-265
  • entospletinib (GS-9973), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation and an IDH2 mutation; b) an NPM1 mutation and an SRSF2 mutation; c) an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation; d) a DNMT3A mutation; e) a DNMT3A mutation and an IDH2 mutation; f) an IDH2 mutation; g) an NPM1 mutation; h) an NPM1 mutation and a DNMT3A mutation; and i) an NPM1 mutation and an IDH1 mutation.
  • sunitinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation; an NPM1 mutation and a DNMT3A mutation; c) an NPM1 mutation and an SRSF2 mutation; and d) an NPM1 mutation and a TET2 mutation.
  • cabozantinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a DNMT3A mutation.
  • sorafenib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a DNMT3A mutation; b) an NPM1 mutation; c) an NPM1 mutation and a DNMT3A mutation; d) an NPM1 mutation and an IDH2 mutation; e) an NPM1 mutation and an SRSF2 mutation; f) and an NPM1 mutation and a TET2 mutation.
  • crizotinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a BCOR mutation; b) an IDH2 mutation; c) a NPM1 mutation and a CEBPA mutation; and d) a SMC1A mutation.
  • Tivozanib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a CELSR2 mutation.
  • crenolanib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a CBFB-MYH11 mutation; b) an NPM1 mutation; and c) an NPM1 mutation and a DNMT3A mutation.
  • ibrutinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) DNMT3A mutation; b) an NPM1 mutation; c) an NPM1 mutation and a DNMT3A mutation; d) an NPM1 mutation and an IDH2 mutation; and e) an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation.
  • trametinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a CBFB-MYH11 mutation.
  • lenvatinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a DNMT3A mutation; b) an IDH2 mutation; c) an NPM1 mutation; d) an NPM1 mutation and a DNMT3A mutation; e) an NPM1 mutation and an IDH2 mutation; and f) an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation.
  • saracatinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a CBFB-MYH11 mutation; b) a DNMT3A mutation; c) a FLT3-ITD mutation; d) a Myc mutation; e) an NPM1 mutation and a DNMT3A mutation; and f) an NPM1 mutation, a FLT3-ITD mutation, and a DNMT3A mutation.
  • dasatinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a DNMT3A mutation.
  • bosutinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a FLT3-ITD mutation; b) a FLT3-ITD mutation and an IHD2 mutation; c) a FLT3-ITD mutation and a DNMT3A mutation; d) a FLT3-ITD mutation and a TET2 mutation; e) an NPM1 mutation and a FLT3-ITD mutation; and f) an NPM1 mutation, a FLT3-ITD mutation, and a DNMT3A mutation.
  • roscovitine or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a FLT3-ITD mutation; and b) an NPM1 mutation and an IDH1 mutation.
  • ruxolitinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a FLT3-ITD mutation and an IHD2 mutation; and b) an NPM1 mutation and an IDH2 mutation.
  • Vargetef or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an IDH2 mutation; b) an NPM1 mutation and an IDH2 mutation; c) an NPM1 mutation and an SRSF2 mutation; and d) an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation.
  • foretinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an IDH2 mutation; b) an NPM1 mutation; c) an NPM1 mutation and a DNMT3A mutation; d) an NPM1 mutation and an SRSF2 mutation; and e) a SMC1A mutation.
  • Masitinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation selected from the group of: a) an IDH2 mutation and b) a SMC1A mutation.
  • dovitinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation; b) an NPM1 mutation and a DNMT3A mutation; and c) an NPM1 mutation and an IDH1 mutation.
  • regorafenib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation; b) an NPM1 mutation and a DNMT3A mutation; c) an NPM1 mutation and an IDH2 mutation; d) an NPM1 mutation and an SRSF2 mutation; and e) an NPM1 mutation, a TET2 mutation, and a DNMT3A mutation.
  • barasertib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a FLT3-ITD mutation; b) a FLT3-ITD mutation and an IHD2 mutation; c) a FLT3-ITD mutation and an ASXL1 mutation; d) a FLT3-ITD mutation and a DNMT3A mutation; e) a FLT3-ITD mutation and a TET2 mutation; f) a FLT3-ITD mutation and a WT1 mutation; g) an IDH2 mutation; h) an NPM1 mutation; i) an NPM1 mutation and a FLT3-ITD mutation; j) an NPM1 mutation, a FLT3-ITD mutation, and a TET2 mutation;
  • gefitinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation; b) an NPM1 mutation and a DNMT3A mutation; and c) an NPM1 mutation and an IDH2 mutation.
  • gilteritinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation and a DNMT3A mutation; and b) an NPM1 mutation and an IDH2 mutation.
  • ponatinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation; b) an NPM1 mutation and a DNMT3A mutation; and c) an NPM1 mutation and an IDH2 mutation.
  • vemurafenib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by an NPM1 mutation and an IDH2 mutation.
  • DBZ or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a FLT3-ITD mutation and an IDH1 mutation; b) an IDH2 mutation; c) an NPM1 mutation; d) an NPM1 mutation and an IDH2 mutation; and e) an NPM1 mutation, a SRSF2 mutation, and an IDH2 mutation.
  • palbociclib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation and an IDH2 mutation; and b) a TRIO mutation.
  • erlotinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation; b) an NPM1 mutation and an IDH1 mutation; and c) an NPM1 mutation and an IDH2 mutation.
  • lapatinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation and an IDH2 mutation; and b) a SMC1A mutation.
  • venetoclax or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a FLT3-ITD mutation and an IDH1 mutation; and b) a PML-RARA mutation.
  • vandetanib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) an NPM1 mutation; b) an NPM1 mutation and an IDH2 mutation; and c) an NPM1 mutation and an SRSF2 mutation.
  • vatalanib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a MLLT3-KMT2A mutation; and b) a SMC1A mutation.
  • canertinib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by a SMC1A mutation.
  • cediranib or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Acute Myeloid Leukemia in a human, wherein the Acute Myeloid Leukemia is characterized by at least one mutation or combination of mutations selected from the group of: a) a RUNX1 mutation; and b) a U2AF1 mutation.
  • AML acute myeloid leukemia
  • AML refers to a rapidly progressing cancer of the blood and bone marrow that affects a group of white blood cells called the myeloid cells.
  • AML can also be referred to as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia and acute nonlymphocytic leukemia.
  • Binding an association between two substances or molecules such as the association of an antibody with a cell surface marker.
  • stable binding means that a macromolecule such as an antibody can bind to another macromolecule such as a polypeptide in a manner that can be detected. Binding can be detected by any procedure known to one skilled in the art, such as by physical or functional properties. Binding can also be detected by visualization of a label (such as a fluorescent label) conjugated to one of the molecules. Specific binding means that a macromolecule such as an antibody binds to members of a class of macromolecules to the exclusion of macromolecules not in that class (binding to non-specific antibody binding macromolecules such as protein A, Fc receptors, etc. is excepted).
  • Biomarker Molecular, biological or physical attributes that characterize a physiological, cellular, or disease state and that can be objectively measured to detect or define disease progression or predict or quantify therapeutic responses.
  • a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.
  • a biomarker may be any molecular structure produced by a cell or organism.
  • a biomarker may be expressed inside any cell or tissue; accessible on the surface of a tissue or cell; structurally inherent to a cell or tissue such as a structural component, secreted by a cell or tissue, produced by the breakdown of a cell or tissue through processes such as necrosis, apoptosis or the like; or any combination of these.
  • a biomarker may be any protein, carbohydrate, fat, nucleic acid, catalytic site, or any combination of these such as an enzyme, glycoprotein, cell membrane, virus, cell, organ, organelle, or any uni- or multimolecular structure or any other such structure now known or yet to be disclosed whether alone or in combination.
  • a biomarker can also be a discrete cellular entity such as a circulating leukemia cell expressing particular cell surface markers including CD11b or CD58.
  • CLL Chironic lymphocytic leukemia
  • Contacting Placing within an environment where direct physical association occurs, including contacting of a solid with a solid, a liquid with a liquid, a liquid with a solid, or either a liquid or a solid with a cell or tissue, whether in vitro or in vivo. Contacting can occur in vitro with isolated cells or tissue or in vivo by administering to a subject.
  • an “effective amount”, a “therapeutically effective amount”, and/or a “pharmaceutically effective amount” of an agent is an amount that upon administration to a human in need thereof is sufficient to generate a desired response such as reducing or eliminating a sign or symptom of a condition or a disease.
  • An effective amount also encompasses an effective amount of a first agent and an effective amount of a second agent administered in combination with the first agent. In some examples, the effective amount of the two combined agents is less than that of either agent when administered alone.
  • Hematological malignancy a general term for cancers that affects the blood or bone marrow.
  • Label A label can be any substance capable of aiding a machine, detector, sensor, device, column, or enhanced or unenhanced human eye from differentiating a labeled composition from an unlabeled composition. Labels may be used for any of a number of purposes and one skilled in the art will understand how to match the proper label with the proper purpose. Examples of uses of labels include purification of biomolecules, identification of biomolecules, detection of the presence of biomolecules, detection of protein folding, and localization of biomolecules within a cell, tissue, or organism.
  • labels include: radioactive isotopes or chelates thereof; dyes (fluorescent or nonfluorescent), stains, enzymes, nonradioactive metals, magnets, protein tags, fluorescent proteins, any antibody epitope, any specific example of any of these; any combination between any of these, or any label now known or yet to be disclosed.
  • a label may be covalently attached to a biomolecule or bound through hydrogen bonding, Van Der Waals or other forces.
  • a label may be covalently or otherwise bound to the N-terminus, the C-terminus or any amino acid of a polypeptide or the 5′ end, the 3′ end or any nucleic acid residue in the case of a polynucleotide.
  • Myeloproliferative neoplasms or myelodysplastic syndromes blood cancers that are characterized by the overproduction of white blood cells, red blood cell, or platelets.
  • MPNs include polycythemia vera, essential thrombocythemia, and myelofibrosis.
  • MDS Myelodysplastic Syndrome
  • MDS refers to conditions in which blood-forming cells in bone marrow become abnormal or dysplastic, leading to lower numbers of one or more types of blood cells.
  • References herein are understood to include the conditions of MDS with multilineage dysplasia, MDS with single lineage dysplasia (including refractory anemia (RA), refractory neutropenia (RN), and refractory thrombocytopenia (RT)), MDS with ring sideroblasts, MDS with excess blasts (including MDS-EB1 and MDS-EB2), MDS with isolated del(5q), and MDS, unclassified (MDS-U).
  • the methods herein also encompass treatments for the conditions above as primary MDS (cause unknown) and secondary MDS (cause known).
  • Subject or “patient”: A living multicellular vertebrate organism, a category that includes, for example, mammals and birds.
  • a “mammal” includes both human and non-human mammals, such as mice.
  • a subject is a human patient, such as a patient diagnosed with AML, a myeloproliferative neoplasm, or myelodysplastic syndromes.
  • a subject is a human patient yet to be diagnosed with AML, a myeloproliferative neoplasm, or myelodysplastic syndromes.
  • Treatment any therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition.
  • the term “ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of metastases, an improvement in the overall health or well-being of the subject, or by other clinical or physiological parameters associated with a particular disease.
  • a “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology.
  • a “therapeutic” treatment is a treatment administered after the development of significant signs or symptoms of the disease.
  • the terms “for treatment of”, “for use in the treatment of”, “for treating”, “for use in treating” and the like are understood to be synonymous and may be interchanged in describing and claiming the methods herein.
  • “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • Examples of salts may include hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesuflonate (besylate), p-toluenesulfonate (tosylate), 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate (such as acetate, HOOC--(CH.sub.2).sub.n--COOH where n is 0-4).
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts.
  • compositions including therapeutic and prophylactic formulations
  • pharmaceutically acceptable carriers known equivalently as vehicles
  • other therapeutic ingredients include, optionally, other therapeutic ingredients.
  • compositions can formulated for administration to subjects by a variety of mucosal administration modes, including by oral, rectal, intranasal, intrapulmonary, intravitrial, or transdermal delivery, or by topical delivery to other surfaces including the eye.
  • the compositions can be administered by non-mucosal routes, including by intramuscular, subcutaneous, intravenous, intra-arterial, intra-articular, intraperitoneal, intrathecal, intracerebroventricular, or parenteral routes.
  • the compound can be administered ex vivo by direct exposure to cells, tissues or organs originating from a subject.
  • the compound can be combined with various pharmaceutically acceptable additives.
  • Desired additives include, but are not limited to, pH control agents, such as arginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, and the like.
  • local anesthetics for example, benzyl alcohol
  • isotonizing agents for example, sodium chloride, mannitol, sorbitol
  • adsorption inhibitors for example, Tween®-80
  • solubility enhancing agents for example, cyclodextrins and derivatives thereof
  • stabilizers for example, serum albumin
  • reducing agents for example, glutathione
  • the tonicity of the formulation is typically adjusted to a value at which no substantial, irreversible tissue damage will be induced at the site of administration.
  • the tonicity of the solution is adjusted to a value of about 0.3 to about 3.0, such as about 0.5 to about 2.0, or about 0.8 to about 1.7.
  • the compound can be dispersed in any pharmaceutically acceptable carrier, which can include a hydrophilic compound having a capacity to disperse the compound, and any desired additives.
  • the carrier can be selected from a wide range of suitable compounds, including but not limited to, copolymers of polycarboxylic acids or salts thereof, carboxylic anhydrides (for example, maleic anhydride) with other monomers (for example, methyl (meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers, such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives, such as hydroxymethylcellulose, hydroxypropylcellulose and the like, and natural polymers, such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid, and nontoxic metal salts thereof.
  • copolymers of polycarboxylic acids or salts thereof include but not limited to, copolymers of polycarboxylic acids or salts thereof, carboxylic anhydrides (for example, maleic anhydride) with other monomers (for example, methyl (meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers,
  • a biodegradable polymer is selected as a carrier, for example, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyhydroxybutyric acid, poly(hydroxybutyric acidglycolic acid) copolymer and mixtures thereof.
  • synthetic fatty acid esters such as polyglycerin fatty acid esters, sucrose fatty acid esters and the like can be employed as carriers.
  • Hydrophilic polymers and other vehicles can be used alone or in combination, and enhanced structural integrity can be imparted to the vehicle by partial crystallization, ionic bonding, cross-linking and the like.
  • the carrier can be provided in a variety of forms, including fluid or viscous solutions, gels, pastes, powders, microspheres, and films for direct application to a mucosal surface.
  • the compound can be combined with the carrier according to a variety of methods, and release of the compound can be by diffusion, disintegration of the vehicle, or associated formation of water channels.
  • the compound is dispersed in microcapsules (microspheres) or nanoparticles prepared from a suitable polymer, for example,
  • compositions for administering the compound can also be formulated as a solution, microemulsion, or other ordered structure suitable for high concentration of active ingredients.
  • the vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • polyol for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like
  • suitable mixtures thereof for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • Proper fluidity for solutions can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a desired particle size in the case of dispersible formulations, and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols, such as mannitol and sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the compound can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the compound can be administered in a time release formulation, for example in a composition which includes a slow release polymer.
  • a composition which includes a slow release polymer can be prepared with vehicles that will protect against rapid release, for example a controlled release vehicle such as a polymer, microencapsulated delivery system or bioadhesive gel. Prolonged delivery in various compositions of the disclosure can be brought about by including in the composition agents that delay absorption, for example, aluminum monostearate hydrogels and gelatin.
  • controlled release binders suitable for use in accordance with the disclosure include any biocompatible controlled release material which is inert to the active agent and which is capable of incorporating the compound and/or other biologically active agent. Numerous such materials are known in the art.
  • Useful controlled-release binders are materials that are metabolized slowly under physiological conditions following their delivery (for example, at a mucosal surface, or in the presence of bodily fluids).
  • Appropriate binders include, but are not limited to, biocompatible polymers and copolymers well known in the art for use in sustained release formulations.
  • biocompatible compounds are non-toxic and inert to surrounding tissues, and do not trigger significant adverse side effects, such as nasal irritation, immune response, inflammation, or the like. They are metabolized into metabolic products that are also biocompatible and easily eliminated from the body.
  • Exemplary polymeric materials for use in the present disclosure include, but are not limited to, polymeric matrices derived from copolymeric and homopolymeric polyesters having hydrolyzable ester linkages. A number of these are known in the art to be biodegradable and to lead to degradation products having no or low toxicity.
  • Exemplary polymers include polyglycolic acids and polylactic acids, poly(DL-lactic acidco-glycolic acid), poly(D-lactic acid-co-glycolic acid), and poly(L-lactic acid-coglycolic acid).
  • biodegradable or bioerodable polymers include, but are not limited to, such polymers as poly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid), poly(epsilon.-aprolactone-CO-glycolic acid), poly(betahydroxy butyric acid), poly(alkyl-2-cyanoacrilate), hydrogels, such as poly(hydroxyethyl methacrylate), polyamides, poly(amino acids) (for example, L-leucine, glutamic acid, L-aspartic acid and the like), poly(ester urea), poly(2-hydroxyethyl DL-aspartamide), polyacetal polymers, polyorthoesters, polycarbonate, polymaleamides, polysaccharides, and copolymers thereof.
  • polymers such as polymers as poly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid),
  • compositions of the disclosure typically are sterile and stable under conditions of manufacture, storage and use.
  • Sterile solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the compound and/or other biologically active agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
  • methods of preparation include vacuum drying and freeze-drying which yields a powder of the compound plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • compositions described herein can be administered by any appropriate route including orally or parenterally including buccally, sublingually, sublabially, by inhalation, intra-arterially, intravenously, intraventricularly, intramuscularly, subcutaneously, intraspinally, intraorbitally, intracranially or intrathecally.
  • a pharmaceutical composition comprising the disclosed compounds
  • the treatments can be administered to the subject in a single bolus delivery, via continuous delivery (for example, continuous transdermal, mucosal or intravenous delivery) over an extended time period, or in a repeated administration protocol (for example, by an hourly, daily or weekly, repeated administration protocol).
  • the therapeutically effective dosage of the treatments for viral infection can be provided as repeated doses within a prolonged prophylaxis or treatment regimen that will yield clinically significant results to alleviate one or more symptoms or detectable conditions associated with a disease or condition.
  • an effective amount or concentration of the disclosed combinations of compounds can be any amount of the two compounds administered by themselves alone or in combination with additional therapeutic agents, is sufficient to achieve a desired effect in a subject.
  • the effective amount of the agent will be dependent on several factors, including, but not limited to, the subject being treated and the manner of administration of the compositions.
  • a therapeutically effective amount or concentration is one that is sufficient to prevent advancement, delay progression, or to cause regression of a disease or condition, or which is capable of reducing symptoms caused by any disease or condition.
  • a desired effect is to reduce or inhibit one or more symptoms associated with a disease or condition characterized by hematological malignancy.
  • the one or more symptoms do not have to be completely eliminated for the composition to be effective.
  • a composition can decrease the sign or symptom by a desired amount, for example by at least 20%, at least 40%, at least 50%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100%, as compared to how the sign or symptom would have progressed in the absence of the composition or in comparison to currently available treatments.
  • the actual effective amount will vary according to factors such as the type of hematological malignancy to be protected against/therapeutically treated and the particular status of the subject (for example, the subject's age, size, fitness, extent of symptoms, susceptibility factors, and the like) time and route of administration, other drugs or treatments being administered concurrently, as well as the specific pharmacology of treatments for hematological malignancy for eliciting the desired activity or biological response in the subject. Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response.
  • An effective amount is also one in which any toxic or detrimental side effects of the compound and/or other biologically active agent is outweighed in clinical terms by therapeutically beneficial effects.
  • a non-limiting range for a therapeutically effective amount of treatments for hematological malignancy within the methods and formulations of the disclosure is about 0.0001 pg/kg body weight to about 10 mg/kg body weight per dose for one or both compounds in the combination, such as about 0.0001 pg/kg body weight to about 0.001 pg/kg body weight per dose for one or both compounds in the combination, about 0.001 pg/kg body weight to about 0.01 pg/kg body weight per dose for one or both compounds in the combination, about 0.01 pg/kg body weight to about 0.1 pg/kg body weight per dose for one or both compounds in the combination about 0.1 pg/kg body weight to about 10 pg/kg body weight per dose for one or both compounds in the combination, about 1 pg/kg body weight to about 100 pg/kg body weight per dose for
  • crenolanib, crizotinib, entospletinib (GS-9973, 6-(1H-indazol-6-yl)-N-(4-morpholin-4-ylphenyl)imidazo[1,2-a]pyrazin-8-amine), fedratinib (SAR302503, TG101348), filgotinib, ibrutinib (Imbruvica®), momelotinib (GS-0387, CYT387), pacritinib, pazopanib, PF-04965842, sorafenib, vandetanib (CAPRELSA®), venetoclax, the drug, or a pharmaceutically acceptable salt thereof, may be administered to a human patient once or twice daily at individual dosages of from about 50 mg to about 1,200 mg.
  • the individual dosages may be administered once or twice daily at individual dosages of from about 50 mg to about 200 mg; from about 50 mg to about 400 mg; from about 100 mg to about 400 mg; from about 200 mg to about 400 mg; from about 200 mg to about 600 mg; from about 400 mg to about 600 mg; from about 400 mg to about 800 mg; from about 600 mg and about 800 mg; from about 600 mg to about 1,000 mg; from about 800 mg to about 1,000 mg; from about 800 mg to about 1,200 mg; from about 1,000 mg to about 1,200 mg.
  • individual doses given once or twice daily may also be selected from the group of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,100 mg, and 1,200 mg.
  • the drug may be delivered intravenously at dosages of from about 10 mg/m 2 /day to about 20 mg/m 2 /day, with individual dosages falling in the range of from about 10 mg/m 2 /day to about 40 mg/m 2 /day, about 10 mg/m 2 /day to about 60 mg/m 2 /day, about 10 mg/m 2 /day to about 100 mg/m 2 /day, about 50 mg/m 2 /day to about 150 mg/m 2 /day, and about 100 mg/m 2 /day to about 150 mg/m 2 /day.
  • the drug may be administered at from about 0.5 mg to about 40 mg once or more times daily.
  • baracitinib, tofacitinib, trametinib may be administered at dose ranges from about 0.5 mg to about 20 mg; from about 0.5 mg to about 15 mg; from about 0.5 mg to about 10 mg; and about 0.5 mg to about 5 mg.
  • Individual doses administered once or twice daily include 0.5 mg, 1.0 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, and 10 mg.
  • the drug may be administered at from about 0.5 mg to about 250 mg once or more times daily.
  • baracitinib may be administered at dose ranges from about 1 mg to about 20 mg; from about 1 mg to about 40 mg; from about 1 mg to about 60 mg; about 1 mg to about 80 mg; from about 20 mg to about 80 mg; from about 40 mg to about 80 mg; from about 20 mg to about 60 mg; from about 20 mg to about 50 mg; from about 50 mg to about 150 mg; from about 80 mg to about 120 mg; and from about 100 mg to about 200 mg.
  • Individual doses administered once or twice daily include 1.0 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, and 100 mg.
  • Determination of effective amount is typically based on animal model studies followed up by human clinical trials and is guided by administration protocols that significantly reduce the occurrence or severity of targeted disease or condition symptoms in the subject.
  • Suitable models in this regard include, for example, murine, rat, rabbit, porcine, feline, non-human primate, and other accepted animal model subjects known in the arts. Using such models, only ordinary calculations and adjustments are required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the treatments for hematological malignancies.
  • the final, high-confidence variant list revealed a diversity of point mutations and small insertion/deletions, with a range of 1-80 somatic variants (cohort median of 13 somatic variants).
  • Comparison of the top 33 most commonly mutated genes across Beat AML and TCGA 6 showed generally similar frequencies. Higher frequency of mutations in SRSF2 were seen in our Beat AML cohort than in TCGA, and this difference was conserved comparing the whole Beat AML cohort as well as only the de novo cases in Beat AML with TCGA ( FIG. 1 ).
  • RNA sequencing was performed on 451 specimens from 411 patients to understand patterns of gene expression as they relate to clinical parameters of disease, genetic groups, and drug sensitivity profiles. Analysis of the 2,000 most variably expressed genes across the cohort revealed gene expression signatures that clustered strongly with many of the prominent genetic and cytogenetic disease groups, including chromosomal rearrangements causing gene fusion of RUNX1-RUNX1T1, CBFB-MYH11 or PML-RARA, and mutation of NPM1, DNMT3A and/or FLT3-ITD.
  • the library contained small molecule inhibitors with activity against the BCL2 family, BRD4, Hedgehog, HSP90, NOTCH/gamma-secretase, proteasome, survivin, STAT3, and WNT/beta-catenin.
  • Drug sensitivity patterns were analyzed with respect to clinical and genetic features of tumors. We compared the average area-under-the curve (AUC) values for each drug between the de novo and transformed samples via a series of single factor ANOVAs. Generally, transformed cases showed less sensitivity to most drugs than de novo cases. Of the 122 drugs tested, 64 were significantly (FDR ⁇ 0.1) more sensitive in the de novo samples, while only 1 drug Panobinostat (HDAC inhibitor) was significantly more sensitive in the transformed cases.
  • AUC area-under-the curve
  • TP53 or ASXL1 Mutation of several genes, most notably TP53 or ASXL1, were shown to cause a broad pattern of drug resistance. Interestingly, a few drugs trended more sensitive to TP53 mutant (e.g. elesclemol) or ASXL1 mutant (e.g. panobinostat) cases hinting at candidates to explore for these poor prognostic features. Mutation of NRAS or KRAS also correlated largely with resistance to most drugs, though did show the predicted sensitivity to MEK inhibitors. It was interesting to note a stronger association of NRAS than KRAS mutation with MEK sensitivity. IDH2 mutation conferred sensitivity to a broad spectrum of drugs, while mutation of IDH1 conferred resistance to most drugs.
  • Ibrutinib is an inhibitor of BTK and TEC family kinases, although it can exhibit broad off-target effects when maintained in continuous culture with target cells.
  • Another kinase inhibitor with high specificity for SYK kinase, entospletinib showed a similarly significant pattern of sensitivity for cases with FLT3-ITD and NPM1, potentially pointing to an operationally important target for this disease subset.
  • RNA-sequencing was performed using the Agilent SureSelect Strand-Specific RNA Library Preparation Kit. All sequencing was performed on an Illumina HiSeq 2500 System.
  • Ex vivo drug screens were performed on freshly isolated mononuclear cells from AML samples as previously described 41 .
  • FIG. 1 The 33 mutational events that were cumulatively most frequent in the Beat AML and TCGA cohorts (union of 25 most frequent for each cohort) are plotted displaying the frequency of each mutational event in each cohort with the top row representing the full Beat AML cohort and the middle bar representing only the de novo cases in the Beat AML cohort. Note that mutations were summarized by gene as was done by TCGA whereas the internal tandem duplications in FLT3 were kept separate in the rest of the manuscript.
  • FIG. 2 The extent of co-occurrence or exclusivity of the most recurrent mutational events in the Beat AML cohort were assessed and plotted on a dot plot indicating the odds ratio of co-occurrence (blue) or exclusivity (red) using color-coding and circle size as well as asterisks that indicate FDR-corrected statistical significance of the mutational association pattern.
  • FIG. 3 Transcriptomic Landscape of the Beat AML Cohort. 451 specimens from 411 unique AML patients were subjected to RNA-sequencing. The 2,000 genes with greatest differential expression across these unique AML patients are displayed on the heatmap. The heatmap is annotated with disease type, ELN risk stratification groups, genetic, and cytogenetic features of disease as noted in the figure legend.
  • FIG. 4 All mutational and cytogenetic events where at least 5 patient samples with evaluable drug sensitivity data exhibited mutation of the gene were assessed for average difference in area under the curve between mutant and wild type samples. A statistical comparison of the mutant versus wild type drug sensitivity patterns (corrected for multiple comparisons) was also computed. Average difference between mutant and wild type cases is plotted on the horizontal axis with FDR-corrected q-value plotted on the vertical axis.
  • FIG. 5 The same analysis as described above was conducted for the subset of the cohort that was negative for FLT3-ITD. Volcano plots that are specific to each drug or mutant gene in the dataset are available with interactive features in our online data browser (www.vizome.orq) and conditional “by drug” and “by gene”.
  • Mononuclear cells were isolated by Ficoll gradient centrifugation from freshly obtained bone marrow aspirates or peripheral blood draws. Cell pellets were snap frozen in liquid nitrogen for subsequent DNA isolation (Qiagen, DNeasy Blood & Tissue Kit), freshly pelleted cells were lysed immediately in GTC lysate for subsequent RNA isolation (Qiagen, RNeasy Mini Kit), and freshly isolated mononuclear cells were plated into an ex vivo drug sensitivity assays within 24 hours (described in detail below). Skin punch biopsies were collected at the site of Jamshidi needle insertion for subsequent bone marrow biopsies and genomic DNA was isolated for use as matched normal controls for exome sequencing (Qiagen, DNeasy Blood & Tissue Kit).
  • Quantification of capture pools was done using real time PCR (Kapa). Libraries were denatured, flow cells set up using the cBot (Illumina), and run on a HiSeq 2500 using paired end 100 cycle protocols. For the AML tumor samples, 5 or 6 lanes were run per capture group. For the matched skin biopsy samples, 3 lanes (or equivalent) were run per capture group.
  • an 11.9 megabase custom capture library was developed that provided coverage of all variants previously reported in AML as well as all new variants detected from exome sequencing in this study. This capture library was then applied to sequence 96 specimens that had previously been subjected to whole exome sequencing for validation of variant calls.
  • the files contained within the Broad's bundle 2.8 were used including their version of the build 37 human genome (These files were downloaded from: ftp://ftp.broadinstitute.org/bundle/2.8/b37/). The following steps were performed per sample-lane SAM file generated for each CaptureGroup:
  • the resulting BAM files were then aggregated by sample and an additional round of MarkDuplicates was carried out at the sample level.
  • Quality control reports were generated using the ReportingTools 3 and qrqc 4 Bioconductor R packages along with output files from the sequencing core and the alignment output files.
  • Each AML sample BAM was paired with its skin biopsy pair and an additional round of indel realignment was carried out to ensure consistency of genotypes between the two samples. If an AML sample did not have a pair, the indel realignment was instead done at the sample level.
  • each AML/skin biopsy pair was realigned at the sample level and then genotyped for single nucleotide variations using Mutect v1.1.7 5 and Varscan2 v2.4.1 6 . Indels were produced using Varscan2.
  • Each VCF file was annotated using the Variant Effect Predictor v83 against GRCh37 7 .
  • the resulting VCF files were filtered to include only those annotated to a gene and were converted to MAF format using the vcf2maf v1.6.6 tool 8 .
  • Mutect v1.1.7 5 was run using default parameters except that no limit was placed on the number or frequency of the alternative allele frequency in the normal to help address normal contamination.
  • Varscan2 v2.4.1 6 was run in somatic mode with the recommended filtering scheme 9 except as shown in the table below.
  • Indels and SNVs were produced for the tumor-only samples again using Mutect without a specified normal for consistency and VarScan2 in mpileup2indel or mpileup2snp mode respectively.
  • the TCGA AML variants 10 in MAF form were downloaded from the GDC archive site: https://portal.gdc.cancer.gov/legacy-archive/files/c410d927-d49c-4d4f-8356-601bee563ebe.
  • the MAF was converted to VCF files using the vcf2maf suite 11 .
  • the resulting VCF files were lifted over from NCB136 to GRCh37 of the human genome using CrossMap 12 . Only those variants that successfully lifted over were kept.
  • a subset of samples was tested for FLT3-ITD and NPM1 mutation status using an internally run PCR assay and capillary electrophoresis.
  • Genomic DNA was extracted from fresh blood or bone marrow aspirates of AML patients was used to detect the presence or absence of FLT3-ITD and NPM1 4 bp insertion mutations 17,18 .
  • Primers for FLT3 spanned approximately 330 bp to include the common internal duplication site 17 .
  • Primers for NPM1 spanned approximately 170 bp to cover the clustered multiple insertional or insertion/deletion sites 18,19 .
  • Primers were HPLC-purified by the manufacturer.
  • the multiplex PCR reaction solution consisted of 100 ng gDNA, 10 pmol of the respective forward and reverse primers for FLT3 and NPM1, 25 mmol/I MgCl 2 , 2 ⁇ 5 mmol/l dNTP, 5 ⁇ l 10 ⁇ PCR buffer, 0 ⁇ 2 ⁇ l AccuTaq DNA polymerase and water in a total volume of 50 ul 20 .
  • the PCR conditions were: initial denaturing for 5 min at 94° C., followed by 30 cycles at 94° C. for 30 s, 56° C. for 45 s and 72° C. for 30 s with a final cycle of 10 min at 72° C.
  • the PCR products were diluted 1:10 and analyzed by capillary electrophoresis on a QiAxcel high resolution DNA cartridge according to the manufacturer's protocol.
  • Forward Primer FLT3 5′- AGCA ATT TAG GTA TGA AAG CCA GCTA - 3′ Reverse Primer FLT3: 5′ - CTT TCA GCA TTT TGA CGG CAA CC - 3′ Forward Primer NPM1: 5′ - GTT TCT TTT TTT TTT CCA GGC TAT TCA AG - 3′ Reverse Primer NPM1: 5′ - CAC GGT AGG GAA AGT TCT CAC TCT GC - 3′
  • Consensus FLT3-ITD and NPM1 mutation calls were determined by comparing the internal capillary PCR test (internal; method described above), the CLIA/CAP laboratory run test (Sequenome, GeneTrails®, Foundation Medicine, Genoptix, Illumina). The internal test was used for the sample consensus call when available as it was performed on the exact sample that was used for further ex vivo drug sensitivity assays. Where discordance existed between the internal test versus the CLIA lab test results, the sample was flagged for manual review. The trace file for the internal test was visually inspected and if discordance with the CLIA/CAP test results persisted, the whole exome sequencing data was then used to help determine the consensus call.
  • N-terminal and C-terminal mutations have been described to occur on opposing alleles and patients harboring CEBPA biallelic mutations have been shown to fall into a favorable risk category 21 .
  • Patients were scored positive for biallelic CEBPA mutation if described in the clinical notes as biallelic or double positive. Patients were also scored as CEBPA biallelic if both N-terminal and C-terminal mutations were identified in the whole exome sequencing data.
  • RNA samples were sequenced using the Agilent SureSelect Strand-Specific RNA Library Preparation Kit on the Bravo robot (Agilent). Briefly, poly(A)+ RNA was chemically fragmented. Double stranded cDNAs were synthesized using random hexamer priming with 3′ ends of the cDNA adenylated then indexed adaptors were ligated. Library amplification was performed using three-primer PCR using a uracil DNA glycosylase addition for strandedness. Libraries were validated with the Bioanalyzer (Agilent) and combined to run 4 samples per lane, with a targeted yield of 200 million clusters.
  • the FASTQ files were aggregated into single files for read 1 and read 2 (if not already done by the sequencing core). During this process these reads were trimmed by 3 on the 5′ end and 5 on the 3′ end. Alignments of reads was performed using the subjunc aligner (1.5.0-p2) 22 . BAM files obtained from subjunc were used as inputs into featureCounts (1.5.0-p2) 23 and gene-level read counts were produced.
  • the GRCh37 build provided by the Broad as part of the GATK bundle was used. Gene assignments were based on the Ensembl build 75 gene models on GRCh37. See the parameters below for software usage.
  • RNA-sequencing genotyping protocol as of GATK v3.3
  • WES protocol described in the ‘Whole Exome Sequencing’ section including for each sample:
  • the resulting BAM files were used to produce RNA genotypes using the UnifiedGenotyper for the purposes of QC and ethnicity estimation.
  • Gene fusion data was additionally generated using the TopHat-Fusion (v2.0.14) program using default parameters 26 .
  • RNA-sequencing and Data Processing We formed coexpression modules using the WGCNA procedure on the RNA-sequencing data from the ‘RNA-Sequencing and Data Processing’ section. All RNA-sequencing samples were used to form the set of modules. Due to the heterogeneity of clinical expression data we generated ‘signed hybrid’ networks using ‘bicor’ correlation setting the max proportion of outliers to 0.1 27 . We ran the procedure multiple times, varying several parameters to choose the most relevant set for further analysis. The WGCNA procedure was run on datasets formed from the top 2,000 and 5,000 most variable genes. For each dataset we set the ‘power’ variable to either 2 or 3.
  • module detection parameters of dynamicTreeCut 24 namely the deepSplit parameter was set to 0 or 2 and the pamStage parameter was set to TRUE or FALSE.
  • module quality statistics 28 mean correlation, mean adjacency, mean MAR, mean KME, proportion of variability explained and the mean cluster coefficient. Significance of modules was determined by computing a Zscore of each of these values relative to the mean and standard deviation of those from 100 random assignment of modules. We chose the set of modules to use in our analyses as those that were most correlated with the ‘specimentSpecificDx’ using the module quality as a tie-breaker.
  • the UnifiedGenotyper runs for both the WES and RNA-sequencing were combined into a single VCF file using the GATK CombineVCFs functionality.
  • This combined VCF file was converted to a GDS file using SNPRelate (1.12.2) 30 . Note the version is an upper bound as several versions were used across the entire project).
  • the overall similarity of the genotypes of each pair of samples were computed, termed identity by state (IBS) and a hierarchical clustering was performed using one minus this similarity. From this clustering and visualization we had devised hard cutoffs for further inspection based on the types of data being compared.
  • samples not meeting the specified IBS thresholds were subject to manual review. Based on the dendrogram structure as well as the clinical/lab information, samples were either excluded, assigned to a different patient ID or in rare cases assigned to a different sample. It was observed that bone marrow transplants between sample collections produced a noticeable but milder effect in these dendrograms and such samples were flagged for removal in RNA-sequencing analysis and for treatment as tumor-only samples in the WES analysis as is described in the ‘WES Variant Detection’ section.
  • Fusions calls were determined from a consensus of three datatypes, a specific diagnosis categorization at the time of sample acquisition, current set of clinical karyotypes and fusions detected in RNA-sequencing data by TopHat-Fusion. All sources were limited to the same set of known fusions: RUNX1-RUNX1T1, CBFB-MYH11, MLLT3-KMT2A, DEK-NUP214, GATA2-MECOM and PML-RARA.
  • RNA-sequencing calls did not provide additional resolution in detecting these known fusions and was not performed on all the samples so the consensus was limited to the clinical karyotype calls as well as the specific diagnosis categorization (which was determined based on karyotype and other cytogenetic clinical tests). Overall the calls were based on the karyotype data except in 10 cases, 3 where the karyotype and diagnosis was sufficiently complex to warrant a separate ‘Complex’ categorization. The remaining 7 of these cases were set to the specific diagnosis classification. It should be noted there was additional support from the RNA-sequencing data for several of these cases.
  • the combined RNA and WES VCF from the ‘Quality Control’ step was merged with a set of Hapmap genotypes 31 lifted over to build 37.
  • the SNPRelate package was used to convert the VCF to GDS, perform LD pruning using an LD threshold of 0.2, MAF cutoff of 0.05 and allowing a missing rate of 0.3 and calculation of the principal components.
  • the methodology of Zheng and Weir 2015 32 was used to assign admixture proportions relative to the HapMap samples using the principal components. Each sample was assigned to an ethnicity group based on the group with the maximum admixture proportion. If the maximum was 50% or less, we labeled it Admixed.
  • K-means clustering is used to assign samples to 2 clusters with the cluster with the lower mean labeled as the Female cluster.
  • RNA-sequencing counts were converted to counts per million (CPM) after applying the Trimmed Mean of M scaling normalization 33 .
  • CPM counts per million
  • a set of 28 genes chosen to successfully discriminate the genders via DE analysis over multiple studies (data not shown) were used in conjunction with Kmeans clustering to form two clusters.
  • the Female cluster was labeled based on high XIST expression.
  • Karyotypes in the clinical file were first cleaned and parsed into clones/subclones and distinct abnormalities using standard conventions 35 .
  • the current representation was corrected for nomenclature type (e.g. idem vs sl) in a basic manner. For instance, ambiguous events such as chromosomal loss (e.g. ⁇ 15) was not corrected for whether the preceding clone had a counteracting gain. Also, additional +/ ⁇ symbols in conjunction with valid karyotype operators in a separate clone (e.g. +del(12)(q?15) or -del(12)(q?15))) were treated separately with gains (+) being kept in the unique count of events and losses ( ⁇ ) being removed.
  • nomenclature type e.g. idem vs sl
  • ambiguous events such as chromosomal loss (e.g. ⁇ 15) was not corrected for whether the preceding clone had a counteracting gain
  • Abn_17 calls were manually curated from the karyotype data and clinical genotype calls respectively.
  • the determination of ELN 2017 categories proceeds by assigning TRUE/FALSE/NA values to one or more of the 5 columns (3 ELN and 2 ambiguous) in the following way:
  • Ex vivo functional drug screens were performed on freshly isolated mononuclear cells from AML samples. Briefly, 10,000 cells per well were arrayed into three, 384-well plates containing 122 small-molecule inhibitors. Drug plates were created using inhibitors purchased from LC Laboratories and Selleck Chemicals and master stocks were reconstituted in DMSO and stored at ⁇ 80° C.
  • Master plates were created by distributing a single agent per well in a seven-point concentration series, created from three-fold dilutions of the most concentrated stock resulting in a range pf 10 ⁇ M to 0.0137 ⁇ M for each drug (except dasatinib, ponatinib, sunitinib, and YM-155 which were plated at a concentration range of 1 ⁇ M to 0.00137 ⁇ M).
  • DMSO control wells and positive control wells containing a drug combination of Flavopiridol, Staurosporine and Velcade were placed on each plate, with the final concentration of DMSO ⁇ 0.1% in all wells.
  • Daughter plates were created using a V&P Scientific 384-well pin tool head operated by the Caliper Sciclone ALH 3000 and equipped with 0.457 mm diameter, 30 nanoliter, slotted stainless steel pins (cat num: FP1NS30).
  • Daughter and destination plates were sealed with pealable thermal seals using a PlateLoc thermal sealer. Destination plates were stored at ⁇ 20° C. for no more than three months and thawed immediately before use. Primary mononuclear cells were plated across single-agent inhibitor panels within 24 h of collection.
  • Cells were seeded into 384-well assay plates at 10,000 cells per well in RPMI 1640 media supplemented with FBS (10%), 1-glutamine, penicillin/streptomycin, and 3-mercaptoethanol (10-4 M). After 3 d of culture at 37° C. in 5% CO2, MTS reagent (CellTiter96 AQueous One; Promega) was added, optical density was measured at 490 nm, and raw absorbance values were adjusted to a reference blank value and then used to determine cell viability (normalized to untreated control wells).
  • MTS reagent CellTiter96 AQueous One; Promega
  • sensitivity/resistance was determined by the lowest and highest 20% of the AUC values for each drug.
  • Drugs were first filtered requiring greater than two hundred samples per drug. Additional samples were removed accordingly to allow correlations to be computed between all present samples using available AUC data and between all drugs.
  • a binary encoding (1/0) was used for each drug based on same threshold as for the gene signatures (e.g., sensitivity/resistance was determined by the lowest and highest 20% of the AUC values for each drug). Individual scores were computed for resistance and sensitivity separately and represented as the proportion over all drugs screened for each patient sample.
  • the AUC values were pooled for the four JAK inhibitors (CYT387, Tofacitinib (CP-690550), JAK Inhibitor I, Ruxolitinib (INCB018424)) for each gene mutation set (BCOR, BCOR:DNMT3A, BCOR:RUNX1, BCOR:SRSF2). The contrast of the difference between BCOR:RUNX1 samples and the average of the other three mutation groups was tested.
  • Mutations (0/1 encoding) and the module eigengenes from the WGCNA analysis were used separately and combined together in regression models with coefficients selected using the lasso approach 49 as implemented in glmnet 50 .
  • the 3 datasets were initially randomly separated into training (75%) and test (25%) sets. Similar to a previous approach 51 , a bootstrap aggregation approach was used where the 1,000 bootstraps of the training dataset was generated and for each one, the lasso trained using 10 fold cross-validation. Predictions were formed for the test dataset over these bootstrap models and the predicted AUC was averaged. R 2 values were computed for these aggregated predictions relative to the test AUC values. As performance was seen to be dependent on the initial test/training split, we repeated the entire process 100 times, recording the mean and standard deviation of the R 2 value as well as the count non-zero coefficients.
  • the table below represents the relationship of genetic and cytogenetic events with patterns of drug sensitivity in the patient samples. All mutational and cytogenetic events where at least 5 patient samples with evaluable drug sensitivity data exhibited mutation of a gene were assessed for average difference in area under the curve between mutant and wild type samples. A statistical comparison of the mutant versus wild type drug sensitivity patterns (corrected for multiple comparisons) was also computed. The dataset was visualized on Volcano plots specific to each drug or mutant gene, where the average difference in area under the curve between mutant and wild type cases (measure of effect of the drug) was plotted on the horizontal axis and FDR-corrected q-value (statistical significance) was plotted on the vertical axis (for example, see FIG. 5 ). The dataset captured in this table are those found in the top left quadrant of the various volcano plots.
  • a colon “:” between two listed mutations indicates separate mutations, such as BCOR:ASXL1 indicates separate BCOR and ASXL1 mutations present in the same AML experienced by a subject.
  • Two identifiers connected by a hypen “-”, underline “_” ⁇ , or a period “.” represents gene fusion, such as RUNX1-RUNXIT1 and CBFB-MYH11.

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