Use of a Janus kinase inhibitor and a telomerase inhibitor for the treatment of myeloproliferative neoplasms
Aspects of the disclosure include methods for treating a myeloproliferative neoplasm. Methods according to certain embodiments include co-administering to a subject a Janus kinase (JAK) inhibitor and a telomerase inhibitor comprising an oligonucleotide and a lipid moiety linked to the 5′ and/or 3′ end of the oligonucleotide. Methods for inducing apoptosis of a myeloproliferative neoplasm cell by contacting the cell with an amount of a JAK inhibitor and a telomerase inhibitor sufficient to induce apoptosis are also described. Compositions having a JAK inhibitor and a telomerase inhibitor for practicing the subject methods are also provided.
1. A method of treating a subject having a myeloproliferative neoplasm, the method comprising sequentially administering to the subject ruxolitinib or a pharmaceutically acceptable salt thereof, followed by imetelstat or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1 , wherein the method comprises:
administering on a first day a dosage of ruxolitinib or pharmaceutically acceptable salt thereof and a dosage of imetelstat or pharmaceutically acceptable salt thereof; and
administering a dosage of ruxolitinib or pharmaceutically acceptable salt thereof once or twice per day for a duration of from about 20 days to about 27 days after the first day.
3. The method according to claim 2 , wherein the dosage of ruxolitinib or pharmaceutically acceptable salt thereof is administered twice on the first day.
4. The method according to claim 1 , wherein the method comprises:
administering to the subject ruxolitinib or a pharmaceutically acceptable salt thereof once or twice per day for a duration of from about 14 days to 21 days; and
administering to the subject one or more doses of imetelstat or pharmaceutically acceptable salt thereof during the period from about 1 day to about 7 days after the last administered dosage of the ruxolitinib or pharmaceutically acceptable salt thereof.
5. The method according to claim 1 , wherein ruxolitinib or a pharmaceutically acceptable salt thereof is administered to the subject at a dosage of about 10 mg/day to about 400 mg/day.
6. The method according to claim 1 , wherein imetelstat or a pharmaceutically acceptable salt thereof is administered to the subject at a dosage of from about 7.5 mg/kg to about 9.4 mg/kg.
7. The method according to claim 1 , wherein imetelstat or a pharmaceutically acceptable salt thereof is administered to the subject by intravenous infusion over a duration of from about 1 hour to about 3 hours.
8. The method according to claim 1 , wherein ruxolitinib or a pharmaceutically acceptable salt thereof is administered to the subject once per day.
9. The method according to claim 1 , wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is administered to a subject at a dosage of:
5 mg twice per day when the subject has a baseline platelet count of less than about 100×10 9 /L platelets;
15 mg twice per day when the subject has a baseline platelet count of from about 100×10 9 /L platelets to about 200×10 9 /L platelets; and
20 mg twice per day when the subject has a baseline platelet count of greater than about 200×10 9 /L platelets.
10. The method according to claim 1 , wherein the telomerase inhibitor is imetelstat sodium.
11. The method according to claim 1 , wherein the method comprises:
administering to the subject ruxolitinib or a pharmaceutically acceptable salt thereof once or twice per day for a duration of 0 days to 21 days; and
administering to the subject one dose or more of imetelstat or a pharmaceutically acceptable salt thereof within 7 days of the last administered dosage of ruxolitinib or pharmaceutically acceptable salt thereof.
12. The method according to claim 1 , wherein the myeloproliferative neoplasm is selected from myelofibrosis (MF), myelodysplastic syndrome (MDS), Essential Thrombocythemia (ET), Polycythemia vera (PV), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia and acute myeloid leukemia (AML).
13. A method of inducing apoptosis of a myeloproliferative neoplasm cell, the method comprising sequentially contacting the cell with ruxolitinib or a pharmaceutically acceptable salt thereof, followed by imetelstat or a pharmaceutically acceptable salt thereof sufficient to induce apoptosis.
14. The method according to claim 13 , wherein the myeloproliferative neoplasm cell is a myelofibrosis hematopoietic stem cell (HSC) or a malignant hematopoietic progenitor cell (HPC).
15. The method according to claim 13 , wherein the ruxolitinib or a pharmaceutically acceptable salt thereof and the imetelstat or a pharmaceutically acceptable salt thereof are contacted with the myeloproliferative neoplasm cell in vitro.