METHODS OF IDENTIFYING PATIENTS LIKELY TO BENEFIT FROM TREATMENT WITH A TELOMERASE INHIBITOR
This disclosure provides methods of identifying or selecting a patient most likely to benefit from treatment with a telomerase inhibitor, such as e.g. imetelstat, by testing a patient for: a lack of a mutation in each of JAK2, CALR, and MPL; and/or a high-molecular risk (HMR), based on the presence of a mutation in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1/2. The patient may be suffering from myelofibrosis. The disclosure also provides methods of treating myelofibrosis, which include identifying such patients.
1 . A method of treating a patient that has myelofibrosis with a telomerase inhibitor, the method comprising administering the telomerase inhibitor to the patient if the patient is determined to have a triple negative status,
wherein the triple negative status comprises an absence of a mutation in each of the Janus kinase 2 (JAK2), calreticulin (CALR), and thrombopoietin receptor (MPL) genes.
2 . The method of claim 1 , wherein the myelofibrosis is selected from primary myelofibrosis or myelofibrosis that develops post-polycythemia vera (post-PV MF) or myelofibrosis that develops post essential thrombocythemia (post-ET MF).
3 . The method of claim 1 , wherein the patient has not previously received JAK-inhibitor therapy.
4 . The method of claim 1 , wherein the patient:
has previously received JAK-inhibitor therapy and is relapsed;
has previously received JAK-inhibitor therapy and is refractory; or
has previously received JAK-inhibitor therapy and has discontinued JAK-inhibitor therapy due to treatment-related to toxicities or intolerance.
5 . The method of claim 1 , wherein the telomerase inhibitor is imetelstat.
6 . The method of claim 5 , wherein the imetelstat is imetelstat sodium.
7 . The method of claim 5 , wherein the telomerase inhibitor is imetelstat and is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:
intravenous administration of about 7-10 mg/kg imetelstat once every three weeks;
intravenous administration of about 7-10 mg/kg imetelstat once weekly for three weeks;
intravenous administration of about 2.5-10 mg/kg imetelstat once every three weeks; or
intravenous administration of about 0.5-9.4 mg/kg imetelstat once every three weeks.
8 . The method of claim 7 , wherein each dosage cycle comprises intravenous administration of about 7-10 mg/kg imetelstat once every three weeks.
9 . The method of claim 8 , wherein each dosage cycle comprises intravenous administration of about 9.4 mg/kg imetelstat once every three weeks.
10 . The method of claim 1 , further comprising determining average relative telomere length by analyzing the relative length of telomeric nucleic acids in target cells present in a biological sample from the patient.
11 . The method of claim 10 , further comprising selecting a patient identified as having an average relative telomere length in target cells present in a biological sample from the patient determined to be in the 50th percentile or less of a relative telomere length range determined from one or more known standards.
12 . The method of claim 1 , further comprising screening a patient to determine if the patient has a high-molecular risk (HMR), wherein having HMR comprises the presence of a mutation in at least one gene selected from the group consisting of ASXL1, EZH2, SRSF2 and IDH1/2.
13 . The method of claim 1 , further comprising assessing hTERT expression level in a biological sample obtained from the patient after administration of the telomerase inhibitor.
14 . The method of claim 13 , wherein the hTERT expression level is reduced by 50% or more relative to a baseline hTERT expression level prior to administration of the telomerase inhibitor.
15 . The method of claim 14 , further comprising altering the dosage of the telomerase inhibitor, the frequency of dosing, or the course of therapy administered to the subject.
16 . A method of treating a patient that has myelofibrosis with a telomerase inhibitor, the method comprising administering the telomerase inhibitor to the patient if the patient is determined to have a high-molecular risk (HMR), wherein having HMR comprises the presence of a mutation in at least one gene selected from the group consisting of additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), serine and arginine rich splicing factor 2 (SRSF2), and isocitrate dehydrogenase 1/2 (IDH1/2).
17 . The method of claim 16 , wherein the myelofibrosis is selected from primary myelofibrosis or myelofibrosis that develops post-polycythemia vera (post-PV MF) or myelofibrosis that develops post essential thrombocythemia (post-ET MF).
18 . The method of claim 16 , wherein the patient has not previously received JAK-inhibitor therapy.
19 . The method of claim 16 , wherein the patient:
has previously received JAK-inhibitor therapy and is relapsed;
has previously received JAK-inhibitor therapy and is refractory; or has previously received JAK-inhibitor therapy and has discontinued JAK-inhibitor therapy due to treatment-related to toxicities or intolerance.
20 . The method of claim 16 , wherein the telomerase inhibitor is imetelstat.
21 . The method of claim 20 , wherein the imetelstat is imetelstat sodium.
22 . The method of claim 20 , wherein the telomerase inhibitor is imetelstat and is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:
intravenous administration of about 7-10 mg/kg imetelstat once every three weeks;
intravenous administration of about 7-10 mg/kg imetelstat once weekly for three weeks;
intravenous administration of about 2.5-10 mg/kg imetelstat once every three weeks; or
intravenous administration of about 0.5-9.4 mg/kg imetelstat once every three weeks.
23 . The method of claim 22 , wherein each dosage cycle comprises intravenous administration of about 7-10 mg/kg imetelstat once every three weeks.
24 . The method of claim 23 , wherein each dosage cycle comprises intravenous administration of about 9.4 mg/kg imetelstat once every three weeks.
25 . The method of claim 16 , further comprising determining average relative telomere length by analyzing the relative length of telomeric nucleic acids in target cells present in a biological sample from the patient.
26 . The method of claim 25 , further comprising selecting a patient identified as having an average relative telomere length in target cells present in a biological sample from the patient determined to be in the 50th percentile or less of a relative telomere length range determined from one or more known standards.
27 . The method of claim 16 , further comprising screening a patient to determine if the patient is triple negative status, wherein the triple negative status comprises an absence of a mutation in each of the genes selected from the group consisting of JAK2, CALR and MPL.
28 . The method of claim 16 , further comprising assessing hTERT expression level in a biological sample obtained from the patient after administration of the telomerase inhibitor.
29 . The method of claim 28 , wherein the hTERT expression level is reduced by 50% or more relative to a baseline hTERT expression level prior to administration of the telomerase inhibitor.
30 . The method of claim 29 , further comprising altering the dosage of the telomerase inhibitor, the frequency of dosing, or the course of therapy administered to the subject.
31 . A method of treating a patient that has myelofibrosis with a telomerase inhibitor, the method comprising administering the telomerase inhibitor to the patient if cells present in a biological sample from the patient are determined to have average relative telomere length that is determined to be in the 50th percentile or less of a relative telomere length range determined from one or more known standards.
32 . The method of claim 31 , wherein the myelofibrosis is selected from primary myelofibrosis or myelofibrosis that develops post-polycythemia vera (post-PV MF) or myelofibrosis that develops post essential thrombocythemia (post-ET MF).
33 . The method of claim 31 , wherein the patient has not previously received JAK-inhibitor therapy.
34 . The method of claim 31 , wherein the patient:
has previously received JAK-inhibitor therapy and is relapsed;
has previously received JAK-inhibitor therapy and is refractory; or
has previously received JAK-inhibitor therapy and has discontinued JAK-inhibitor therapy due to treatment-related to toxicities or intolerance.
35 . A method of selecting a patient most likely to benefit from treatment with a telomerase inhibitor comprising:
testing a patient for triple negative status, wherein the triple negative status comprises an absence of a mutation in each of the JAK2, CALR and MPL genes; and
selecting the patient if the patient has triple negative status,
wherein the selected patient is most likely to benefit from treatment with a telomerase inhibitor.
36 . The method of claim 35 , wherein the myelofibrosis is selected from primary myelofibrosis or myelofibrosis that develops post-polycythemia vera (post-PV MF) or myelofibrosis that develops post essential thrombocythemia (post-ET MF).
37 . The method of claim 35 , wherein the patient has not previously received JAK-inhibitor therapy.
38 . The method of any one of claim 35 , wherein the patient:
has previously received JAK-inhibitor therapy and is relapsed;
has previously received JAK-inhibitor therapy and is refractory; or
has previously received JAK-inhibitor therapy and has discontinued JAK-inhibitor therapy due to treatment-related to toxicities or intolerance.
39 . The method of claim 35 , further comprising screening a patient to determine if the patient has a high-molecular risk (HMR), wherein having HAIR comprises the presence of a mutation in at least one gene selected from the group consisting of ASXL1, EZH2, SRSF2 and IDH1/2.
40 . The method of claim 35 , further comprising administering the telomerase inhibitor to the patient.
41 . The method of a claim 35 , further comprising obtaining a sample that comprises DNA from the patient.
42 . A method of selecting a patient most likely to benefit from treatment with a telomerase inhibitor comprising:
testing a patient to determine if the patient has a high molecular risk (HMR), wherein having HMR comprises the presence of a mutation in at least one gene selected from the group consisting of ASXL1, EZH2, SRSF2, and IDH1/2; and
selecting the patient if the patient has a high molecular risk (HMR),
wherein the selected patient is most likely to benefit from treatment with a telomerase inhibitor.
43 . The method of claim 42 , wherein the myelofibrosis is selected from primary myelofibrosis or myelofibrosis that develops post-polycythemia vera (post-PV MF) or myelofibrosis that develops post essential thrombocythemia (post-ET MF).
44 . The method of claim 42 , wherein the patient has not previously received JAK-inhibitor therapy.
45 . The method of any one of claim 42 , wherein the patient:
has previously received JAK-inhibitor therapy and is relapsed;
has previously received JAK-inhibitor therapy and is refractory; or
has previously received JAK-inhibitor therapy and has discontinued JAK-inhibitor therapy due to treatment-related to toxicities or intolerance.
46 . The method of claim 42 , further comprising screening a patient to determine if the patient is triple negative status, wherein the triple negative status comprises an absence of a mutation in each of the genes selected from the group consisting of JAK2, CALR and MPL.
47 . The method of claim 42 , further comprising administering the telomerase inhibitor to the patient.
48 . The method of claim 42 , further comprising obtaining a sample that comprises DNA from the patient.
49 . A method of monitoring therapeutic efficacy in a subject with myelofibrosis (MF), the method comprising:
measuring hTERT expression level in a biological sample obtained from the patient after administration of a telomerase inhibitor; and
comparing the hTERT expression level in the biological sample to a baseline hTERT expression level prior to administration of the telomerase inhibitor;
wherein a 50% or greater reduction in hTERT expression level in the biological sample identifies a subject who has an increased likelihood of benefiting from treatment with the telomerase inhibitor.
50 . The method of claim 49 , wherein the hTERT expression level measured or assessed is hTERT RNA expression level.