Certains contenus de cette application ne sont pas disponibles pour le moment.
Si cette situation persiste, veuillez nous contacter àObservations et contact
1. (WO2019006133) MÉTHODES DE RETARDEMENT ET DE PRÉVENTION DE RECHUTE DE LEUCÉMIE AIGUË MYÉLOÏDE
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

WHAT IS CLAIMED IS:

1. A method for improving a survival rate of patients having acute myeloid leukemia (AML), comprising the steps of:

(a) identifying the presence of mutant nucleophosmin 1 (NPM1) in a patient having AML; and

(b) administering to a patient identified as having a mutant NPM1 in step (a) a therapeutically effective amount of IL2 and a therapeutically effective amount of an agent selected from the group consisting of histamine, a histamine structural analog having H2-receptor activities, an endogenous histamine releasing preparation, a non- histamine derivative H2-receptor agonist, and a combination thereof,

wherein the administration of said IL-2 and said agent results in an increase in said survival rate of said patients compared to the untreated patients.

2. A method of preventing and/or delaying the onset of relapse to acute myeloid leukemia (AML) in a patient in complete remission (CR) from AML, comprising the steps of:

(a) identifying the presence of mutant nucleophosmin 1 (NPM1) in a patient in complete remission (CR) from AML; and

(b) administering to a patient identified as having a mutant NPM1 in step (a) a therapeutically effective amount of IL2 and a therapeutically effective amount of an agent selected from the group consisting of histamine, a histamine structural analog having H2-receptor activities, an endogenous histamine releasing preparation, a non- histamine derivative H2-receptor agonist, and a combination thereof,

thereby preventing and/or delaying the onset of relapse to AML in said patient.

3. A method of prolonging remission from acute myeloid leukemia (AML), comprising the steps of:

(a) identifying the presence of mutant nucleophosmin 1 (NPM1) in a patient in remission from AML; and

(b) administering to a patient identified as having a mutant NPM1 in step (a) a therapeutically effective amount of IL2 and a therapeutically effective amount of an agent selected from the group consisting of histamine, a histamine structural analog having H2-receptor activities, an endogenous histamine releasing preparation, a non- histamine derivative H2-receptor agonist, and a combination thereof,

thereby prolonging remission from AML in said patient.

4. A method for improving a survival rate of patients having acute myeloid leukemia (AML), comprising the steps of:

(a) acquiring knowledge of the presence of one or more molecular alterations in a biological sample from an AML patient, wherein said one or more molecular alterations comprises the presence of mutant nucleophosmin 1 (NPM1); and

(b) for a patient known to have a mutant NPM1 in step (a), administering to the patient a therapeutically effective amount of IL2 and a therapeutically effective amount of an agent selected from the group consisting of histamine, a histamine structural analog having H2-receptor activities, an endogenous histamine releasing preparation, a non-histamine derivative H2-receptor agonist, and a combination thereof,

wherein the administration of said IL-2 and said agent results in an increase in said survival rate of said patients compared to the untreated patients.

5. A method of preventing and/or delaying the onset of relapse to acute myeloid leukemia (AML) in a patient in complete remission (CR) from AML, comprising the steps of:

(a) acquiring knowledge of the presence of one or more molecular alterations in a biological sample from an AML patient, wherein said one or more molecular alterations comprises the presence of mutant nucleophosmin 1 (NPM1); and

(b) for a patient known to have a mutant NPM1 in step (a), administering to the patient a therapeutically effective amount of IL2 and a therapeutically effective amount of an agent selected from the group consisting of histamine, a histamine structural analog having H2-receptor activities, an endogenous histamine releasing preparation, a non-histamine derivative H2-receptor agonist, and a combination thereof,

thereby preventing and/or delaying the onset of relapse to AML in said patient known to have a mutant NPM1.

6. A method of prolonging the remission from acute myeloid leukemia (AML), comprising the steps of:

(a) acquiring knowledge of the presence of one or more molecular alterations in a biological sample from an AML patient, wherein said one or more molecular alterations comprises the presence of mutant nucleophosmin 1 (NPM1); and

(b) for a patient known to have a mutant NPM1 in step (a), administering to the patient a therapeutically effective amount of IL2 and a therapeutically effective amount of an agent selected from the group consisting of histamine, a histamine structural analog having H2-receptor activities, an endogenous histamine releasing preparation, a non-histamine derivative H2-receptor agonist, and a combination thereof,

thereby prolonging remission from AML in said patient known to have a mutant NPM1.

7. The method of any one of Claims 1-6, wherein the patient is in complete remission (CR) from AML, wherein the CR comprises less than 5% blast cells in normocellular bone marrow and an absence of extramedullary leukemia.

8. The method of any one of Claims 1-7, wherein said agent is administered twice a day.

9. The method of any one of Claims 1-8, wherein said agent is administered in an amount of about 1 mg/day to about 10 mg/day.

10. The method of any one of Claims 1-9, wherein said agent is histamine.

11. The method of Claim 10, wherein said histamine is histamine dihydrochloride.

12. The method of Claim 10, wherein said histamine is histamine diphosphate.

13. The method of any one of Claims 10-12, wherein the histamine is administered at 0.5 mg twice a day.

14. The method of any one of Claims 1-13, wherein said IL-2 is administered in an amount of about 5,000 U/kg/day to about 300,000 U/kg/day.

15. The method of any one of Claims 1-14, wherein said IL-2 is administered at a dosage of 16,400 U kg twice a day.

16. The method of any one of Claims 1-15, wherein said agent and IL-2 are administered on the same days.

17. The method of any one of Claims 1-16, wherein said agent and IL-2 are administered together.

18. The method of any one of Claims 1-17, wherein the administration of said agent and said IL-2 is performed simultaneously.

19. The method of any one of Claims 1-17, wherein said agent and IL-2 are administered separately.

20. The method of any one of Claims 1-19, wherein the administration of said agent and the administration of said IL-2 are performed within 24 hours.

21. The method of any one of Claims 1-20, wherein the administration of said agent and said IL-2 is accomplished by one or more of intramuscular injection, subcutaneous injection, intradermal injection, intravenous injection, implantation infusion device, inhalation, and transdermal diffusion.

22. The method of any one of Claims 1-21, wherein the administration of said agent and said IL-2 is accomplished by subcutaneous injection.

23. The method of any one of Claims 1-22, wherein said agent and said IL-2 is administered once per day.

24. The method of any one of Claims 1-23, wherein said agent and said IL-2 is administered for at least one cycle.

25. The method of any one of Claims 1-24, wherein said agent and said IL-2 is administered for at least two cycles.

26. The method of any one of Claims 1-25, wherein said agent and said IL-2 is administered for six cycles.

27. The method of any one of Claims 24-26, wherein the at least one cycle comprises 21 consecutive days of treatment.

28. The method of any one of Claims 24-27, wherein an interval between two treatment cycles is at least two weeks.

29. The method of Claim 28, wherein the interval is at least three weeks.

30. The method of Claim 28, wherein the interval is at least six weeks.

31. The method of any one of Claims 1-30, wherein the patient has a de novo AML.

32. The method of any one of Claims 1-30, wherein the patient has a secondary AML.

33. The method of any one of Claims 1-32, wherein the patient has recurrent, relapsing or refractory AML.

34. The method of Claim 33, wherein the recurrent or relapsing AML is caused by minimal residual disease (MRD) or leukemic stem cells.

35. The method of any one of Claims 1-34, wherein the patient has already undergone 2 or more rounds of chemotherapy.

36. The method of any one of Claims 1-35, wherein the patient has already undergone 4 or more rounds of chemotherapy.

37. The method of any one of Claims 1-36, wherein said patient is undergoing immunotherapy for relapse prevention.

38. The method of any one of Claims 1-37, wherein the patient has experienced a partial response or complete response, is in remission, is asymptomatic, has a low number of abnormal cells and/or has a non-detectable disease based on one or more of the following: (i) a total body leukemia burden below approximately 109 cells and/or less than 5% blasts in the marrow and/or no signs or symptoms of leukemia; (ii) a greater than 25% reduction in the serum protein M level; (iii) a greater than 50% reduction in the serum protein M level; (iv) 10% or more plasma cells in the bone marrow, but does not meet the criteria for multiple myeloma (MM); (v) serum M proteins levels greater than or equal to 3 g/dL; (vi) 10% or more plasma cells in the bone marrow with no evidence of end-organ damage; (vii) serum M protein levels greater than or equal to 3 g/dL and has 10% or more plasma cells in the bone marrow; (viii) serum M protein levels greater than or equal to 3 g/dL and has 10% or more plasma cells in the bone marrow and no evidence of end-organ damage; and (ix) less than 10% plasma cells in the bone marrow.

39. The method of any one of Claims 1-38, wherein the patient has completed induction chemotherapy.

40. The method of any one of Claims 1-39, wherein the patient is a patient who relapses from complete remission of AML after induction chemotherapy.

41. The method of any one of Claims 1-40, wherein the patient has completed induction and consolidation chemotherapy.

42. The method of any one of Claims 1-41, wherein said administration of said IL-2 and said agent begins the same day after consolidation chemotherapy is completed.

43. The method of any one of Claims 1-41, wherein said administration of said IL-2 and said agent begins between about 1 day and about 300 days after consolidation chemotherapy is completed.

44. The method of any one of Claims 1-41, wherein said administration of said IL-2 and said agent begins about 200 days after consolidation chemotherapy is completed.

45. The method of any one of Claims 1-41, wherein said administration of said IL-2 and said agent begins about 100 days after consolidation chemotherapy is completed.

46. The method of any one of Claims 1-41, wherein said administration of said IL-2 and said agent begins about 50 days after consolidation chemotherapy is completed.

47. The method of any one of Claims 1-46, wherein said administration of said IL-2 and said agent results in an increase of at least 30% in a survival rate of said patients compared to the untreated patients.

48. The method of any one of Claims 1-47, wherein said administration of said IL-2 and said agent results in an increase of at least 30% in a survival rate of said patients compared to the untreated patients.

49. The method of any one of Claims 1-48, wherein said administration of said IL-2 and said agent results in an increase of at least 50% in a survival rate of said patients compared to the untreated patients.

50. The method of any one of Claims 1, 4, and 7-49, wherein said survival rate is leukemia-free survival rate.

51. The method of any one of Claims 1, 4, and 7-49, wherein said survival rate is overall survival rate.

52. The method of any one of Claims 1-51, wherein said administration of said IL-2 and said agent delays relapse of AML of said patients by at least 3 months compared to the untreated patients.

53. The method of any one of Claims 1-52, wherein said administration of said IL-2 and said agent delays relapse of AML of said patients by at least 6 months compared to the untreated patients.

54. The method of any one of Claims 1-53, wherein said administration of said IL-2 and said agent delays relapse of AML of said patients by at least 12 months compared to the untreated patients.

55. The method of any one of Claims 2, 5, and 7-54, wherein relapse comprises at least 5% blast cells in the bone marrow.

56. The method of any one of Claims 2, 5, and 7-54, wherein relapse comprises extramedullary leukemia.

57. The method of any one of Claims 1-56, wherein said administration of said IL-2 and said agent prolongs remission from AML of said patients by at least 3 months compared to the untreated patients.

58. The method of any one of Claims 1-57, wherein said administration of said IL-2 and said agent prolongs remission from AML of said patients by at least 6 months compared to the untreated patients.

59. The method of any one of Claims 1-58, wherein said administration of said IL-2 and said agent prolongs remission from AML of said patients by at least 12 months compared to the untreated patients.

60. The method of any one of Claims 4-59, wherein said knowledge is acquired from an analytical assay selected from the group consisting of nucleic acid sequencing, polypeptide sequencing, restriction digestion, capillary electrophoresis, nucleic acid amplification-based assays, nucleic acid hybridization assay, comparative genomic hybridization, real-time PCR, quantitative reverse transcription PCR (qRT-PCR), PCR-RFLP assay, HPLC, mass-spectrometric genotyping, fluorescent in-situ hybridization (FISH), next generation sequencing (NGS), a kinase activity assay, and any combination thereof.

61. The method of any one of Claims 4-59, wherein said knowledge is acquired from an antibody-based assay selected from ELISA, immunohistochemistry, western blotting, mass spectrometry, flow cytometry, protein-microarray, immunofluorescence, a multiplex detection assay, or any combination thereof.

62. The method of any one of Claims 4-59, wherein said knowledge is acquired from immunohistochemistry.

63. The method of any one of Claims 1-62, wherein the patient's leukemic cells have a normal karyotype.

64. The method of any one of Claims 1-63, wherein the presence of the mutant NPM1 is determined by identifying a patient nucleic acid encoding the mutant NPM 1.

65. The method of Claim 64, wherein identifying a patient nucleic acid encoding the mutant NPMl comprises amplification of at least a portion of exon 12 of NPMl.

66. The method of Claim 65, wherein said amplification comprises the polymerase chain reaction (PCR).

67. The method of Claim 66, wherein said PCR is real-time PCR (RT-PCR).

68. The method of any one of Claims 64-67, wherein said patient nucleic acid is obtained from an acellular body fluid of said patient.

69. The method of Claim 68, wherein said acellular body fluid is serum or plasma.

70. The method of any one of Claims 64-69, wherein said patient nucleic acid is genomic DNA.

71. The method of any one of Claims 64-69, wherein said patient nucleic acid is mRNA.

72. The method of any one of Claims 1-63, wherein identifying a patient nucleic acid encoding the mutant NPMl comprises using an oligonucleotide probe complimentary to a portion of exon 12 of NPMl.

73. The method of Claim 72, wherein the oligonucleotide probe comprises a label.

74. The method of Claim 73, wherein the label is fluorescent.

75. The method of any one of Claims 1-74, wherein the mutant NPMl comprises one or more mutations in exon 12 NPMl that cause cytoplasmic location of NPMl protein

76. The method of any one of Claims 1-75, wherein the mutant NPMl comprises one or more of the following NPMl mutations: Mutation A, Mutation B, Mutation C, Mutation D, Mutation E or Mutation F.

77. The method of any one of Claims 1-75, wherein the mutant NPMl comprises one or more of the NPMl mutations selected from the group consisting of: Mutation A, Mutation B, Mutation C, Mutation D, Mutation E, Mutation F, Mutation E*, Mutation G*, Mutation H*, Mutation J, Mutation L, Mutation K, Mutation M, Mutation N, Mutation O, Mutation P, Mutation Q, Mutation Gm, Mutation Km, Mutation Lm, Mutation Nm, Mutation Om, Mutation Qm, Mutation 1, Mutation 3, Mutation 4, Mutation 6, Mutation 7, Mutation 12, Mutation 13, Mutation 10, Mutation 14, Mutation G+, Mutation H+, Mutation I+, Mutation J+, Mutation I, and a combination thereof.

78. The method of any one of Claims 1-75, wherein the mutant NPMl comprises a signal motif of nuclear export (NES) in exon 12 of NPMl, wherein the NES comprises the amino acid sequence YxxxYxxYxY, wherein Y is a hydrophobic amino acid selected from the group consisting of leucine, isoleucine, methionine, valine, phenylalanine, and wherein x can be any amino acid.

79. The method of any one of Claims 1-63, wherein the presence of the mutant NPMl is determined by identifying mutant NPMl protein in patient cells.

80. The method of Claim 79, wherein the mutant NPMl protein is identified in the cells by identifying NPMl protein in cytoplasm of the cells.

81. The method of Claim 80, wherein the mutant NPMl protein is identified in cytoplasm of the cells immunohistochemically.

82. The method of Claim 79, wherein the mutant NPMl protein is identified in the cells with an antibody that selectively binds to the mutant NPMl protein but not a wildtype NPMl protein.