METHODS AND COMPOSITIONS FOR THE DIAGNOSIS, PROGNOSIS AND TREATMENT OF ACUTE MYELOID LEUKEMIA

• US 20150031641A1
• Filed: 03/11/2013
• Published: 01/29/2015
• Est. Priority Date: 03/12/2012
• Status: Active Application

• Current Assignee: Memorial Sloan-Kettering Cancer Center
• Original Assignee: Memorial Sloan-Kettering Cancer Center
• Inventors: Levine, Ross L., Abdel-Waheb, Omar, Patel, Jay P., Gonen, Mithat
• Application Number:
  US14/384,580
• Publication Number:
  US 20150031641A1
• Time in Patent Office: Days
• US Class Current: 514/34
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

Gene mutations are associated with the progression of acute myeloid leukemia (AML). The invention relates to methods and systems for evaluating the progression of AML based on these gene mutations. The present invention also relates to methods and compositions for treating AML patients by modulating the expression or activity of certain genes involved in AML progression and/or their encoded proteins. The invention further relates to methods and compositions for determining the responsiveness of an AML patient to induction chemotherapy therapy.

Claims

1. A method of predicting survival of a patient with acute myeloid leukemia (AML), said method comprising:

(a) analyzing a genetic sample isolated from the patient for the presence of cytogenetic abnormalities and a mutation in at least one of FLT3, NPM1, DNMT3A, NRAS, CEBPA, TET2, WT1, IDH1, IDH2, KIT, RUNX1, MLL-PTD, ASXL1, PHF6, KRAS, PTEN, P53, HRAS, and EZH2 genes; and

(b) (i) predicting poor survival of the patient if a mutation is present in at least one of FLT3, MLL-PTD, ASXL1 and PHF6 genes, or (ii) predicting favorable survival of the patient if a mutation is present in IDH2R140 and/or a mutation is present in CEBPA.

2. The method of claim 1, further comprising,

predicting intermediate survival of the patient with cytogenetically-defined intermediate risk AML if:

(i) no mutation is present in any of FLT3-ITD, TET2, MLL-PTD, DNMT3A, ASXL1 or PHF6 genes,

(ii) a mutation in CEBPA and the FLT3-ITD is present, or

(iii) a mutation is present in FLT3-ITD but trisomy 8 is absent.

3. The method of claim 1, further comprising:

predicting unfavorable survival of the patient with cytogenetically-defined intermediate-risk AML if

(i) a mutation in TET2, ASXL1, or PHF6 or an MLL-PTD is present in a patient without the FLT3-ITD mutation, or

(ii) the patient has a FLT3-ITD mutation and a mutation in TET2, DNMT3A, MLL-PTD or trisomy 8.

4. The method of claim 2, wherein intermediate survival the patient is survival of about 18 months to about 30 months.

10. The method of claim 1, wherein poor or unfavorable survival (adverse risk) of the patient is survival of less than or equal to about 10 months.

11. The method of claim 1, wherein favorable survival of the patient is survival of about 32 months or more.

5. A method of predicting survival of a patient with acute myeloid leukemia, said method comprising:

(a) assaying a genetic sample from the patient'"'"'s blood or bone marrow for the presence of a mutation in at least one of genes FLT3, NPM1, DNMT3A, NRAS, CEBPA, TET2, WT1, IDH1, IDH2, KIT, RUNX1, MLL-PTD, ASXL1, PHF6, KRAS, PTEN, P53, HRAS, and EZH2 in said sample; and

(b) predicting a poor survival of the patient if a mutation is present in at least one of genes FLT3-ITD, MLL-PTD, ASXL1, PHF6;

or predicting a favorable survival of the patient if a mutation is present in CEBPA or a mutation is present in IDH2 at R140.

6. The method of claim 5, wherein amongst patients with cytogenetically-defined intermediate-risk acute myeloid leukemia who have FLT3-ITD mutation, at least one of the following:

trisomy 8 or a mutation in TET2, DNMT3A, or the MLL-PTD are associated with an adverse outcome and poor overall survival of the patient.

7. The method of claim 5, wherein amongst patients with cytogenetically-defined intermediate-risk acute myeloid leukemia who have a mutation in FLT3-ITD gene, a mutation in CEBPA gene is associated with improved outcome and overall survival of the patient.

8. The method of claim 5, wherein in a cytogenetically-defined intermediate risk AML patient with both IDH1/IDH2 and NPM1 mutations, the overall survival is improved compared to NPM1-mutant patients wild-type for both IDH1 and IDH2.

9. The method of claim 5, wherein amongst patients with acute myeloid leukemia, IDH2R140 mutations are associated with improved overall survival.

22. The method of claim 5, wherein the patient is characterized as intermediate-risk on the basis of cytogenetic analysis.

12. A method of predicting survival of a patient with acute myeloid leukemia, said method comprising:

(a) assaying a genetic sample from the patient'"'"'s blood or bone marrow for the presence of a mutation in genes ASXL1 and WT1; and

(b) determining the patient has or will develop primary refractory acute myeloid leukemia if mutated ASXL1 and WT1 genes are detected.

13. A method of determining responsiveness of a patient with acute myeloid leukemia to high dose therapy, said method comprising:

(a) analyzing a genetic sample isolated from the patient for the presence of a mutation in genes DNMT3A, and NPM1, and for the presence of a MLL translocation; and

(b) (i) identifying the patient as one who will respond to high dose therapy if a mutation in DNMT3A or NPM1 or an MLL translocation are present;

or

(ii) identifying the patient as one who will not respond to high dose therapy in the absence of mutations in DNMT3A or NPM1 or an MLL translocation.

25. The method of claim 13, wherein the sample is DNA extracted from bone marrow or blood from the patient.

26. The method of claim 13, wherein the genetic sample is DNA isolated from mononuclear cells (MNC) from the patient.

14. A method of predicting whether a patient suffering from acute myeloid leukemia will respond better to high dose chemotherapy than to standard dose chemotherapy, the method comprising:

(a) obtaining a DNA sample obtained from the patient'"'"'s blood or bone marrow;

(b) determining the mutational status of genes DNMT3A and NPM1, and the presence of a MLL translocation; and

(c) predicting that the subject will be more responsive to high dose chemotherapy than standard dose chemotherapy where the sample is positive for a mutation in DNMT3A or NPM1 or an MLL translocation;

or predicting that the subject will be non-responsive to high dose chemotherapy compared to standard dose chemotherapy where the sample is wild type with no mutations in DNMT3a or NPM1 genes and no translocation in MLL.

23. The method of claim 14, wherein the therapy comprises the administration of anthracycline.

24. The method of claim 14 or claim 21, wherein administering high dose therapy comprises administering one or more high dose anthracycline antibiotics selected from the group consisting of Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, and Adriamycin.

15. A method of screening a patient with acute myeloid leukemia for responsiveness to treatment with high dose of Daunorubicin or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising:

obtaining a genetic sample comprising an acute myeloid leukemic cell from said individual; and

assaying the sample and detecting the presence of a mutation in DNMT3A or NPM1 or an MLL translocation; and

correlating a finding of a mutation in DNMT3A or NPM1 or an MLL translocation, as compared to wild type controls where there is no mutation, with said acute myeloid leukemia patient being more sensitive to high dose treatment with Daunorubicin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

16. The method of claim 15, wherein the method further comprises predicting the patient is at a lower risk of relapse of acute myeloid leukemia following chemotherapy if a mutation in DNMT3A or NPM1 or an MLL translocation is detected.

17. A method of determining whether a human has an increased genetic risk for developing or developing a relapse of acute myeloid leukemia, comprising:

(a) analyzing a genetic sample isolated from the human'"'"'s blood or bone marrow for the presence of a mutation in at least one gene from FLT3, NPM1, DNMT3A, NRAS, CEBPA, TET2, WT1, IDH1, IDH2, KIT, RUNX1, MLL-PTD, ASXL1, PHF6, KRAS, PTEN, P53, HRAS, and EZH2; and

(b) determining the individual with cytogenetically-defined intermediate risk AML has an increased genetic risk for developing or developing a relapse of acute myeloid leukemia, relative to a control human with no such gene mutations in said genes, when;

(i) a mutation in at least one of TET2, MLL-PTD, ASXL1 and PHF6 genes is detected when the patient has no FLT3-ITD mutation, or (ii) a mutation in at least one of TET2, MLL-PTD, and DNMT3A genes or trisomy 8 is detected when the patient has a FLT3-ITD mutation.

18. A method for preparing a personalized genomics profile for a patient with acute myeloid leukemia, comprising:

(a) subjecting mononuclear cells extracted from a bone marrow aspirate or blood sample from the patient to gene mutational analysis;

(b) assaying the sample and detecting the presence of a cytogenetic abnormality and one or more mutations in a gene selected from the group consisting of FLT3, NPM1, DNMT3A, NRAS, CEBPA, TET2, WT1, IDH1, IDH2, KIT, RUNX1, MLL-PTD, ASXL1, PHF6, KRAS, PTEN, P53, HRAS, and EZH2 in said cells; and

(c) generating a report of the data obtained by the gene mutation analysis, wherein the report comprises a prediction of the likelihood of survival of the patient or a response to therapy.

19. A kit for determining treatment of a patient with AML, the kit comprising means for detecting a mutation in at least one gene selected from the group consisting of ASXL1, DNMT3A, NPM1, PHF6, WT1, TP53, EZH2, CEBPA, TET2, RUNX1, PTEN, FLT3, HRAS, KRAS, NRAS, KIT, IDH1, and IDH2;

and instructions for recommended treatment based on the presence of a mutation in one or more of said genes.

21. A method of treating, preventing or managing acute myeloid leukemia in a patient, comprising:

(a) analyzing a genetic sample isolated from the patient for the presence of a mutation in genes DNMT3A, and NPM1, and for the presence of a MLL translocation;

(b) identifying the patient as one who will respond to high dose chemotherapy better than standard dose chemotherapy if a mutation in DNMT3A or NPM1 or a MLL translocation are present; and

(c) administering high dose therapy to the patient.

27. The method of claim 21, wherein the high dose administration is Daunorubicin administered at from about 70 mg/m2 to about 140 mg/m2, or Idarubicin administered at from about 10 mg/m2 to about 20 mg/m2.

28-33. -33. (canceled)

34. A method of predicting survival of a patient with acute myeloid leukemia, comprising:

(a) analyzing a sample isolated from the patient for the presence of

(i) a mutation in at least one of FLT3, MLL-PTD, ASXL1, and PHF6 genes, plus optionally one or more of NPM1, DNMT3A, NRAS, CEBPA, TET2, WT1, IDH1, IDH2, KIT, RUNX1, KRAS, PTEN, P53, HRAS, and EZH2 genes;

or

(ii) a mutation in IDH2 and/or CEBPA genes, plus optionally one or more of FLT3, MLL-PTD, ASXL1, PHF6, NPM1, DNMT3A, NRAS, TET2, WT1, IDH1, KIT, RUNX1, KRAS, PTEN, P53, HRAS, and EZH2 genes; and

(b) (i) predicting poor survival of the patient if a mutation is present in at least one of FLT3, MLL-PTD, ASXL1 and PHF6 genes, or (ii) predicting favorable survival of the patient if a mutation is present in IDH2R140 and/or a mutation is present in CEBPA.

35. The method of claim 34, further comprising analyzing the sample for the presence of cytogenetic abnormalities.

36. The method of claim 34, further comprising (ii) predicting favorable survival of the patient if the following mutation is present:

IDH2R140Q.