Treatment of myelodysplastic syndromes

Abstract

To provide methods for treating myelodysplastic syndrome.SOLUTION: The disclosure provides a method for treating myelodysplastic syndrome (MDS) in a subject naive to the treatment with a drug selected from hypomethylating agents (HMA) and lenalidomide or both. The method comprises administering an effective amount of a telomerase inhibitor, e.g., imetelstat or imetelstat sodium to the subject. In some cases, the patient is classified as having low or intermediate-1 IPSS risk MDS, and / or MDS relapsed / refractory to an erythropoiesis-stimulating agent (ESA).SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 538,315, filed July 28, 2017, U.S. Provisional Application No. 62 / 595,329, filed December 6, 2017, and U.S. Provisional Application No. 62 / 685,542, filed June 15, 2018, the entire contents of each of which are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on June 19, 2018, is named JBI5134WOPCTl_SL.txt and is 573 bytes in size.

[0003] This application relates to the treatment of myelodysplastic syndromes (such as IPSS low-risk and intermediate-1 risk non-del(5q) MDS) with a telomerase inhibitor in patients who have not been treated with a hypomethylating agent, lenalidomide, or both. [Background technology]

[0004] A. Myelodysplastic syndrome Myelodysplastic syndromes (MDS) are a group of conditions that include cancers of the blood and bone marrow. They also include diseases such as refractory anemia, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, and chronic myelomonocytic leukemia. MDS is a collection of hematological medical conditions that involve inefficient production of myeloid classes of blood cells. In MDS, immature blood stem cells (blasts) do not develop into healthy red blood cells, white blood cells, or platelets. The blasts die in the bone marrow or die shortly after moving into the blood, leaving less room in the bone marrow for healthy white blood cells, red blood cells, and / or platelets to form.

[0005] MDS primarily affects elderly individuals and is characterized by anemia and other cytopenias, as well as a high risk of leukemic transformation (Cheson et al, Blood 2006;108:419-425). In clinical practice, MDS is suspected when an otherwise unexplained anemia is associated with other cytopenias, elevated mean corpuscular volume, or increased red cell distribution width. Diagnosis includes bone marrow examination and cytogenetic studies. The bone marrow is usually hyperproliferative. Diagnosis is based on the demonstration of erythroid, granulocytic, or megakaryocytic dysplasia in 10% or more of the cells with signaling functions (Vardiman,et al, Blood 2009;114(5):937-951). MDS may progress over time. For example, MDS patients often develop severe anemia, requiring frequent blood transfusions. Risk of bleeding and infection also occurs due to low or dysfunctional levels of platelets and neutrophils, respectively. In some cases, the disease worsens and patients develop cytopenias (reduced blood cell counts) caused by progressive bone marrow failure. In other cases, the disease transforms into acute myeloid leukemia (AML). Transformation to AML is said to have occurred when the overall percentage of bone marrow blasts exceeds certain cutoffs (20% for the World Health Organization (WHO) and 30% for the French-American-British (FAB) subtype). Patients with low-risk MDS who are relapsed or refractory to erythropoiesis-stimulating agents (ESAs) have limited treatment options.

[0006] The standard prognostic tool for assessing MDS is the International Prognostic Scoring System (IPSS), which classifies patients into low-risk, intermediate-1, intermediate-2, and high-risk categories based on several prognostic variables, including bone marrow blasts, cytogenetics, and the presence of cytopenias. The median survival times for these four groups have been estimated to be 5.7, 3.5, 1.2, and 0.4 years, respectively. The median time for 25% of patients in these groups to develop AML was 9.4, 3.3, 1.1, and 0.2 years, respectively (Greenberg et al, Blood 1997;89(6):2079-2088). Patients with low-risk and intermediate-1 risk MDS may be referred to as having "low-risk" disease, while patients with intermediate-2 and high-risk MDS may be referred to as having "high-risk" disease.

[0007] In patients aged ≥70 years in Western countries, the incidence of MDS is conservatively estimated at approximately 30–40 cases per 100,000 population per year. Due to the aging of the population, the number of MDS cases is expected to increase. Despite a declining rate of leukemic transformation in lower-risk patients, most patients are affected by anemia and anemia-related symptoms, which have a significant effect on patient-reported outcomes (Almeida et al, Leukemia Res. 2017;52:50-57). Many anemic patients with MDS eventually develop a dependency on red blood cell ("RBC") transfusions; evidence suggests that iron overload resulting from chronic RBC transfusions may be a contributing factor to the overall mortality of the disease (Malcovati et al, J Clin Oncol 2005;23:7594-7603; Malcovati et al, Haematologica 2006;91:1588-1590; Steensma DP., Mayo Clinic Proc. 2015;90(7):969-983). Analysis of retrospective data from 426 patients diagnosed with MDS according to WHO criteria in Italy between 1992 and 2004 showed that a transfusion requirement of 2 units per month reduces the life expectancy of MDS patients by approximately 50% (Malcovati et al., Haematologica 2006).

[0008] B. Current Treatment of IPSS Low-Risk and Intermediate-1-Risk Non-del(5q) MDS The treatment strategy for MDS is mainly based on the IPSS score. In patients classified as IPSS intermediate 2 or high risk (higher risk MDS) and with a median survival of only about 12 months if untreated, the goal of treatment is to modify the disease course, avoid progression to AML, and prolong survival. In patients classified as IPSS low or intermediate 1 risk (lower risk MDS), survival is longer, but many patients die of causes other than MDS. Treatment for these patients is mainly aimed at improving cytopenias and transfusion outcomes and improving quality of life (Ades et al.,Lancet 2014;383(9936):2239-2252).

[0009] Erythropoiesis Stimulators For patients with low-risk non-del(5q) MDS, first-line treatment of anemia often involves the use of erythropoietin stimulating agents (ESAs) or other hematopoietic growth factors. High-dose ESAs (e.g., epoetin alfa), with or without granulocyte-colony stimulating factor, have produced erythroid response rates ranging from 30% to 50%, with a median duration of 2 years (ibid.). Key favorable prognostic factors for response to ESAs are low or no need for RBC transfusions (<2 packed red blood cell units / month) and low serum erythropoietin levels (≤500 units / L) (Hellstrom-Lindberg et al., Br J Haematol. 2003;120(6):1037-1046). Studies have shown that ESAs do not affect the risk of progression to higher-risk MDS and AML, and strongly suggest that they may even improve survival in low-risk MDS compared with RBC transfusions alone (Garcia-Manero et al., J Clin Oncol. 2011;29(5):516-523). In the absence of concurrent progression to high-risk MDS or AML, patients who were primarily refractory to ESAs or who relapsed within 6 months of achieving a response had a relatively high risk of AML transformation (23.1%) and shorter survival (median 3 years), whereas patients who responded to treatment and relapsed >6 months had a more favorable outcome after failure, with a 9% AML risk at 7 years and a median overall survival of 4.5 years (Kelaidi et al.,Leukemia 2013;27(6):1283-1290).

[0010] In the United States, there are no approved therapies for patients with low-risk non-del(5q) MDS who do not respond to ESAs; treatment options after ESA failure are limited. The majority of patients with lower-risk MDS ultimately require long-term RBC transfusions, which are often accompanied by iron overload (Ades et al., Lancet 2014; Fenaux et al., Blood 2013;121:4280-4286; Steensma et al., Mayo Clinic Proc. 2015). Life expectancy in patients with MDS has been shown to be inversely proportional to RBC transfusion burden (Malcovati et al., Haematologica 2006). Despite frequent RBC transfusions, patients with chronic anemia may be at risk for associated morbidity (e.g., heart failure, falls, fatigue) and reduced quality of life (Crawford et al., Cancer 2002;95:888-895).

[0011] Hypomethylating Agents Hypomethylating agents (HMAs) (e.g., azacitidine and decitabine) are approved for the treatment of all French-American-British (FAB) subtypes, including some patients with lower-risk MDS. Although these agents reduce the need for transfusions in higher-risk patients with MDS, there is no evidence of improved long-term outcomes for lower-risk patients who receive HMAs after ESA failure. In a retrospective study of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs, those who subsequently received HMAs (n=194) after ESA failure did not experience a significant improvement in 5-year overall survival (Park et al, J Clin Oncol. 2017;35(14):1591-1597). Other reports suggest that in cohorts of lower-risk MDS patients who are transfusion-dependent after ESA failure, azacitidine induces RBC-TI in approximately 14% to 33% of patients (Fili et al, Clin Cancer Res. 2013;19:3297-3308; Thepot et al, Haematologica. 2016;101:918-925; Tobiasson et al, Blood Cancer J. 2014:4,el89). Given the limited benefit and observed toxicities (neutropenia, infections), azacitidine cannot be recommended for the treatment of these patients (Tobiasson et al, Blood Cancer J. 2014).

[0012] Lenalidomide The del(5q) chromosomal abnormality is observed in 10% to 15% of patients with MDS and is associated with a good prognosis (Oliva et al., Hematol. 2013;92(l):25-32). Treatment with lenalidomide results in transfusion independence in about two-thirds of such patients (Ades et al., Lancet 2014; Fenaux et al., Blood 2013;121(21):4280-4286). In phase 3 trials, the median duration of TI was not reached (median follow-up, 1.55 years) (Fenaux et al., Blood 2011;118(14):3765-3776). Myelosuppression is the most frequently reported grade 3 or 4 toxicity, and close monitoring of blood counts is required during the first weeks of lenalidomide therapy (ibid.).

[0013] Lenalidomide has also been studied as a treatment for transfusion-dependent non-del(5q) MDS, which accounts for 85%-90% of the MDS population. The majority of these subjects do not respond to lenalidomide. Hematologic toxicity (i.e., neutropenia, and thrombocytopenia) was less severe than in patients with del(5q) MDS (Loiseau et al, Exp Hematol 2014). 2015;43(8):661-72). Similar to HMAs, treatment with lenalidomide after ESA failure has not been shown to significantly improve overall survival when used to treat patients with lower-risk non-del(5q) MDS (Park et al., J. Med. 2015;43(8):661-72). Clin Oncol. 2017).

[0014] Other treatment options Immunosuppressive therapy is a treatment option for certain lower-risk non-del(5q) patients, but no significant effect on transformation-free survival was observed; adverse events, including hematologic toxicity, and associated severe adverse events such as bleeding and infection, have been reported (Almeida et al., Leukemia Res. 2017). Allogeneic stem cell transplantation is typically reserved for medically fit higher-risk MDS patients, but may be considered an option for select lower-risk patients, such as those under 60 to 70 years of age with IPSS intermediate-1 risk MDS, poor-risk cytogenetics, or persistent elevated blasts, when alternative treatment options are ineffective (ibid.). Limited treatment options are currently available for patients with lower-risk non-del(5q) MDS once first-line treatment with ESAs fails and patients become dependent on RBC transfusions. Treatment with HMAs or lenalidomide has limited efficacy in this patient population and has not been shown to significantly impact overall survival. Immunotherapy and allogeneic stem cell transplantation are reserved for small, select subgroups of patients with specific disease and patient characteristics. For lower-risk non-del(5q) MDS patients who are relapsed or refractory to ESA therapy, treatment options that delay or avoid transfusion dependency and associated risks are needed. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Cheson et ah,Blood 2006;108:419-425 [Non-Patent Document 2] Vardiman,et al,Blood 2009;114(5):937-951 [Non-Patent Document 3] Greenberg et al,Blood 1997;89(6):2079-2088 [Non-Patent Document 4] Almeida et al ,Leukemia Res.2017;52:50-57

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[0016] BRIEF SUMMARY OF THE INVETION The present invention provides the use of telomerase inhibitors, such as imetelstat, in the treatment of myelodysplastic syndromes (MDS) in subjects who have not been treated with hypomethylating agents (HMA) or lenalidomide. Accordingly, a method of treating MDS in a subject who has not been treated with HMA, lenalidomide, or both is provided. The method includes administering an effective amount of a telomerase inhibitor to the subject. In some cases, the subject is classified as having low or intermediate 1 IPSS risk MDS and / or MDS that is relapsed / resistant to erythropoiesis stimulating agents (ESA). In some instances, the telomerase inhibitor is imetelstat sodium.

[0017] One embodiment of the present invention is a method of treating myelodysplastic syndrome (MDS), comprising administering an effective amount of a telomerase inhibitor to a subject in need thereof, whereby the subject is not receiving treatment with an agent selected from a hypomethylating agent (HMA), lenalidomide, and combinations thereof. One embodiment of the present invention is a method of treating MDS, comprising administering an effective amount of a telomerase inhibitor to a subject in need thereof, whereby the subject is not receiving treatment with an HMA and lenalidomide. In certain embodiments, the MDS is relapsed or refractory MDS. In one embodiment, the MDS is relapsed / refractory MDS to erythropoiesis stimulating agents (ESAs).

[0018] The subject may be transfusion dependent, hi one embodiment, the transfusion dependent subject has a transfusion requirement of about 4 units or more for the 8 weeks prior to administration of the telomerase inhibitor.

[0019] The subject may also be a non-del5q human patient. The subject may also or alternatively be classified as a low or intermediate 1 IPSS risk MDS subject. In certain embodiments, the subject is classified as a low or intermediate 1 IPSS risk MDS subject and is non-del5q. In some embodiments of the present invention, the MDS is relapsed or refractory MDS, and the subject is classified as a low or intermediate 1 IPSS risk MDS subject.

[0020] In certain embodiments, the subject is not treated with lenalidomide. In other embodiments, the subject is not treated with HMA. HMA can be decitabine, azacitidine, or both. Thus, in one embodiment, the subject is not treated with decitabine. In another embodiment, the subject is not treated with azacitidine (also known as 5-azacytidine or azacitidine).

[0021] Another embodiment of the present invention is a telomerase inhibitor, such as imetelstat, for use in treating myelodysplastic syndromes (MDS) in a subject who has not been treated with an agent selected from a hypomethylating agent (HMA), lenalidomide, and combinations thereof. Alternatively, the subject has not been treated with an agent selected from a hypomethylating agent (HMA) and lenalidomide. In one embodiment, the subject has not been treated with lenalidomide. In another embodiment, the HMA is selected from decitabine and azacitidine, and the subject has not been treated with decitabine or azacitidine. The subject may also not be treated with both decitabine and azacitidine. The MDS may be relapsed or refractory MDS, including MDS that is relapsed / refractory to erythropoiesis stimulating agents (ESAs). In certain embodiments, the subject is classified as a low or intermediate 1 IPSS risk MDS subject. The subject may also be transfusion dependent, a non-del5q human patient, or both. In another embodiment, the subject is a transfusion-dependent subject and has a transfusion requirement of about 4 units or more for 8 weeks prior to administration of the telomerase inhibitor.In another embodiment, the subject is classified as a low or intermediate 1 IPSS risk MDS subject and is non-del5q.Alternatively, the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject.

[0022] Yet another embodiment of the present invention is the use of a telomerase inhibitor, such as imetelstat, for treating myelodysplastic syndrome (MDS) in a subject who has not been treated with a drug selected from hypomethylating agents (HMA), lenalidomide, and combinations thereof. Such use also includes the use of a telomerase inhibitor in the manufacture of a medicament for treating myelodysplastic syndrome (MDS) in a subject who has not been treated with a drug selected from hypomethylating agents (HMA), lenalidomide, and combinations thereof. Yet another embodiment of the present invention is the use of a telomerase inhibitor, such as imetelstat, for treating myelodysplastic syndrome (MDS) in a non-del5q human patient. Such use also includes the use of a telomerase inhibitor in the manufacture of a medicament for treating myelodysplastic syndrome (MDS) in a non-del5q human patient. In a particular embodiment of the use, the subject has not been treated with a drug selected from hypomethylating agents (HMA) and lenalidomide. The HMA can be selected from decitabine and azacitidine. The subject may not have been treated with: (a) lenalidomide, (b) decitabine or azacitidine, (c) decitabine and azacitidine, (d) lenalidomide and decitabine or azacitidine, or both. The MDS may be relapsed or refractory MDS, including MDS relapsed / refractory to erythropoiesis stimulating agents (ESAs). In certain embodiments, the subject may be classified as a low or intermediate 1 IPSS risk MDS subject and may be a transfusion dependent, non-del5q human patient, or both. In other embodiments, the subject is a transfusion dependent subject and has a need for about 4 or more units of transfusion during the 8 weeks prior to administration of the telomerase inhibitor. In additional embodiments, the subject is classified as a low or intermediate 1 IPSS risk MDS subject and is non-del5q. Alternatively, the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject.

[0023] The telomerase inhibitor may be imetelstat or imetelstat sodium. In other embodiments, the telomerase inhibitor is imetelstat and its tautomers, and pharma- ceutically acceptable salts thereof. In certain embodiments, imetelstat is administered in 1, 2, 3, 4, 5, 6, 7, 8, or more than 8 dosing cycles, each cycle comprising intravenous administration of about 7-10 mg / kg imetelstat once every 4 weeks, intravenous administration of about 7-10 mg / kg imetelstat once a week for 4 weeks, intravenous administration of about 2.5-10 mg / kg imetelstat once every 3 weeks, or intravenous administration of about 0.5-9.4 mg / kg imetelstat once every 4 weeks. In one embodiment, each dosing cycle comprises intravenous administration of about 7-10 mg / kg imetelstat once every 4 weeks, or intravenous administration of about 7.5 mg / kg imetelstat.

[0024] In one embodiment of a telomerase inhibitor for use in treating MDS, the telomerase inhibitor is imetelstat. Similarly, in one embodiment of the use of a telomerase inhibitor, the telomerase inhibitor is imetelstat. In any embodiment, the use may include administration of 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles. In this embodiment, the dosing cycle may include intravenous administration of about 7-10 mg / kg of imetelstat once every 4 weeks, intravenous administration of about 7-10 mg / kg of imetelstat once a week for 4 weeks, intravenous administration of about 2.5-10 mg / kg of imetelstat every 3 weeks, or intravenous administration of about 0.5-9.4 mg / kg of imetelstat once every 4 weeks. Thus, in one embodiment, each dosing cycle includes intravenous administration of about 7-10 mg / kg of imetelstat once every 4 weeks. In another embodiment, each dosing cycle comprises about 7.5 mg / kg of imetelstat administered intravenously once every four weeks.

[0025] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, the drawings show embodiments of the invention, but it is to be understood that the invention is not limited to the precise arrangements, examples, and instrumentalities shown. The present invention provides, for example, the following items. (Item 1) A method for treating myelodysplastic syndrome (MDS), comprising administering an effective amount of a telomerase inhibitor to a subject in need thereof, wherein the subject is not currently receiving treatment with an agent selected from a hypomethylating agent (HMA), lenalidomide, and combinations thereof. (Item 2) The method of item 1, wherein the MDS is relapsed or refractory MDS. (Item 3) The method of item 2, wherein the MDS is relapsed / refractory MDS to erythropoiesis stimulating agents (ESAs). (Item 4) 2. The method of claim 1, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject. (Item 5) 2. The method of claim 1, wherein the subject is transfusion dependent. (Item 6) 6. The method of claim 5, wherein the transfusion-dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to the administration of the telomerase inhibitor. (Item 7) The method of claim 1, wherein the subject is a non-del5q human patient. (Item 8) The method of claim 1, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject and is non-del5q. (Item 9) 2. The method of item 1, wherein the subject has not been treated with lenalidomide. (Item 10) The method according to claim 1, wherein the subject is not undergoing treatment with a hypomethylating agent (HMA). 2. The method of claim 1, wherein the subject has not been treated with lenalidomide and a hypomethylating agent (HMA). (Item 12) 11. The method of item 10, wherein the HMA is decitabine. (Item 13) 11. The method of claim 10, wherein the HMA is azacitidine. (Item 14) 2. The method of claim 1, wherein the telomerase inhibitor is imetelstat. (Item 15) 15. The method of claim 14, wherein the imetelstat is imetelstat sodium. (Item 16) the telomerase inhibitor is imetelstat and is administered in 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) Imetelstat administered intravenously at approximately 7-10 mg / kg once every 4 weeks; (b) Imetelstat administered intravenously at approximately 7-10 mg / kg once weekly for 4 weeks; (c) Imetelstat administered intravenously at approximately 2.5 to 10 mg / kg once every 3 weeks; or (d) The method of item 14, comprising intravenous administration of about 0.5 to 9.4 mg / kg of imetelstat once every 4 weeks. (Item 17) 17. The method of item 16, wherein each dosing cycle comprises intravenous administration of about 7-10 mg / kg of imetelstat once every 4 weeks. (Item 18) 18. The method of item 17, wherein each dosing cycle comprises intravenous administration of about 7.5 mg / kg of imetelstat once every 4 weeks. (Item 19) The method of item 1, wherein the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject. (Item 20) 15. The method of claim 14, wherein the subject is transfusion dependent. (Item 21) The method of claim 14, wherein the subject is a non-del5q human patient. (Item 22) A method of treating myelodysplastic syndrome (MDS), comprising administering an effective amount of a telomerase inhibitor to a subject in need thereof, wherein the subject is a non-del5q human patient. (Item 23) 23. The method of item 22, wherein the MDS is relapsed or refractory MDS. (Item 24) 24. The method of item 23, wherein the MDS is relapsed / refractory MDS to erythropoiesis stimulating agents (ESAs). (Item 25) 23. The method of claim 22, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject. (Item 26) 23. The method of claim 22, wherein the subject is transfusion dependent. (Item 27) 27. The method of claim 26, wherein the transfusion-dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to the administration of the telomerase inhibitor. (Item 28) 24. The method of item 23, wherein the subject has not been treated with lenalidomide. (Item 29) 24. The method of claim 23, wherein the subject is not undergoing treatment with a hypomethylating agent (HMA). (Item 30) 24. The method of claim 23, wherein the subject has not been treated with lenalidomide and a hypomethylating agent (HMA). (Item 31) 30. The method of item 29, wherein the HMA is decitabine. (Item 32) 30. The method of claim 29, wherein the HMA is azacitidine. (Item 33) 24. The method of claim 23, wherein the telomerase inhibitor is imetelstat. (Item 34) 34. The method of claim 33, wherein the imetelstat is imetelstat sodium. (Item 35) 34. The method of claim 33, wherein the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject. (Item 36) 34. The method of claim 33, wherein the subject is transfusion dependent. (Item 37) the telomerase inhibitor is imetelstat, and the use comprises administration of 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) Imetelstat administered intravenously at approximately 7-10 mg / kg once every 4 weeks; (b) Imetelstat administered intravenously at approximately 7-10 mg / kg once weekly for 4 weeks; (c) Imetelstat administered intravenously at approximately 2.5 to 10 mg / kg once every 3 weeks; or (d) The method of item 33, comprising intravenous administration of about 0.5 to 9.4 mg / kg of imetelstat once every 4 weeks. (Item 38) 38. The method of item 37, wherein each dosing cycle comprises intravenous administration of about 7 to 10 mg / kg of imetelstat once every 4 weeks. (Item 39) 39. The method of item 38, wherein each dosing cycle comprises intravenous administration of about 7.5 mg / kg of imetelstat once every 4 weeks. [Brief description of the drawings]

[0026] [Figure 1A]Waterfall plots of the longest transfusion-free interval (Figure 1A) and absolute change in transfusion volume at the best 8-week interval (Figure IB) are shown in the study of imetelstat sodium in red blood cell (RBC) transfusion-dependent (TD) patients described in the experimental section. HI-E=Hematologic improvement-based on Hb rise of at least 1.5 g / dL above pretreatment levels for at least 8 weeks, or a reduction of at least 4 units of RBC transfusions per 8 weeks compared to previous RBC transfusion burden (criteria adapted from IWG 2006), HI-E Hb=HI-E with a sustained rise in hemoglobin of at least 1.5 g / dL for 8 weeks, TI=transfusion independence, TR=transfusion reduction of at least 4 units in 8 weeks. [Figure 1B] Same as above. [Diagram 2] FIG. 1 shows a timeline of hematology and imetelstat sodium administration in a typical 24-week transfusion-independent (TI) responder. [Figure 3A] Waterfall plots of the longest transfusion-free interval (Figure 3A) and absolute change in transfusion volume at the best 8-week interval (Figure 3B) are shown in the study of imetelstat sodium in red blood cell (RBC) transfusion-dependent (TD) patients described in the experimental section. HI-E=hematologic improvement-based on Hb rise of at least 1.5 g / dL above pretreatment levels for at least 8 weeks, or a reduction of at least 4 units of RBC transfusions per 8 weeks compared to previous RBC transfusion burden (criteria adapted from IWG 2006), TI=transfusion independence, TR=transfusion reduction of at least 4 units in 8 weeks. [Figure 3B] Same as above. [Figure 4] Efficacy results for EPO and RS subgroups are shown. [Diagram 5] FIG. 1 shows a timeline of hematology and imetelstat sodium dosing for a typical 24-week transfusion independent (TI) responder through 115 weeks. [Figure 6] 1 shows hemoglobin and imetelstat sodium dosing among patients with persistent TI. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The present application provides a method of treating myelodysplastic syndromes (MDS) in subjects not treated with hypomethylating agents (HMA), lenalidomide, or both, by administering an effective amount of a telomerase inhibitor, such as imetelstat. In some cases, the subject being treated is classified as having low IPSS risk MDS, intermediate 1 IPSS risk MDS, MDS relapsed to erythropoiesis stimulating agents (ESA), MDS refractory to MS, or a combination thereof. The subject may be other than del5q. For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into subsections that describe or illustrate certain features, embodiments, or applications of the invention.

[0028] A.Definition As used herein, the term "about" when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of between +20% and +0.1% from the particular value, preferably +20% or +10, more preferably +5%, even more preferably +1%, and even more preferably +0.1%, as such variations are appropriate for carrying out the disclosed methods.

[0029] The term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal (a salt that includes a counterion that has acceptable mammalian safety for a given dosing regimen). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which are derived from a variety of organic and inorganic counterions well known in the art, including, by way of example only, sodium, and the like, and, where the molecule contains a basic functional group, includes salts of organic or inorganic acids, such as hydrochloride. Pharmaceutically acceptable salts of interest include the aluminum, ammonium, arginine, barium, benzathine, calcium, choline acid, ethylenediamine, lysine, lithium, magnesium, meglumine, procaine, potassium, sodium, tromethamine, N-methylglucamine, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, ethanolamine, piperazine, zinc, diisopropylamine, diisopropylethylamine, triethylamine and triethanolamine salts.

[0030] The term "salt thereof" refers to a compound formed when a proton of an acid is replaced with a cation, such as a metal cation or an organic cation. Preferably, the salt is a pharma- ceutically acceptable salt. By way of example, the salt of the present compound includes those in which the compound is protonated with an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt. Salts of interest include, but are not limited to, aluminum, ammonium, arginine, barium, benzathine, calcium, cesium, choline acid, ethylenediamine, lithium, magnesium, meglumine, procaine, N-methylglucamine, piperazine, potassium, sodium, tromethamine, zinc, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, ethanolamine, piperazine, diisopropylamine, diisopropylethylamine, triethylamine, and triethanolamine salts. For any of the oligonucleotide structures shown herein that include a backbone of internucleoside linkages, it is understood that such oligonucleotides may include any convenient salt form. In some embodiments, the acidic form of the internucleoside bond is depicted for simplicity. In some instances, the salt of the subject compound is a monovalent cation salt. In certain instances, the salt of the subject compound is a divalent cation salt. In some instances, the salt of the subject compound is a trivalent cation salt. "Solvate" refers to a complex formed by the combination of a solvent molecule with a molecule or ion of a solute. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.

[0031] "Stereoisomer" and "stereoisomer" refer to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include, for example, cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. With respect to any of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not include any substitutions or substitution patterns that are sterically impractical and / or synthetically impractical. All stereoisomers are intended to be included within the scope of this disclosure.

[0032] Those skilled in the art will recognize that other tautomeric configurations of the groups described herein are possible. It is understood that all tautomeric forms of the subject compounds are encompassed in the depicted structures, even if not specifically shown, as one possible tautomeric configuration of the groups of the compounds.

[0033] Pharmaceutically acceptable salt solvates of the stereoisomeric tautomers of the subject compounds are intended to be included and are intended to be included within the scope of this disclosure.

[0034] Before describing particular embodiments in more detail, it is to be understood that the invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0035] Where a range of values ​​is provided, unless the context clearly indicates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any other stated or intervening value in the stated range is included in the invention. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are included in the invention, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative exemplary methods and materials are described herein.

[0037] All publications and patents cited herein are incorporated by reference herein to disclose and describe the methods and / or materials in connection with which the publications are cited, as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the publication dates provided may be different from the actual publication dates which must be independently confirmed.

[0038] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. It should be further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as a preface for using exclusive terminology, such as "solely," "only," and the like, in connection with the recitation of claim elements or the use of a "negative" limitation.

[0039] Each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0040] As used throughout, "MDS" refers to myelodysplastic syndrome or myelodysplastic syndrome.

[0041] B. Treatment An embodiment of the present disclosure includes a method of treating myelodysplastic syndrome (MDS) with a telomerase inhibitor in a subject who has not been treated with a particular drug, for example, a drug selected from a hypomethylating agent (HMA) and lenalidomide. A subject is considered to be "naive" if the subject has not been treated with a particular disease. Treating MDS patients who are relapsed / resistant to ESA therapy with imetelstat can improve outcomes, including reducing the incidence of anemia.

[0042] The subject is a mammalian animal that needs to be treated for cancer. Generally, the subject is a human patient. In some embodiments of the present invention, the subject may be a non-human mammalian animal, such as a non-human primate, an animal model (e.g., an animal such as a mouse and a rat that is used in screening, characterizing, and evaluating pharmaceutical drugs) and other mammalian animals. As used herein, the terms patient, subject, and individual are used interchangeably.

[0043] As used herein, and as is well understood in the art, "treatment" is an approach to obtain beneficial or desired results, including clinical results. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, reduction in the extent of disease, stable (i.e., not worsening) state of disease, prevention of disease spread, delay or slowing of disease progression, improvement or mitigation of disease state, and remission (partial or total), whether detectable or undetectable. "Treatment" also means prolonging survival compared to expected survival without treatment.

[0044] In certain instances, the subject method provides an enhanced therapeutic response in subjects who have not been previously treated with hypomethylating agents (HMA) or lenalidomide, compared to subjects who have been previously so treated. "Enhanced therapeutic response" refers to a statistically significant improvement in the first and / or second endpoints of MDS therapy, and / or improvement in one or more symptoms of MDS (e.g., as described herein), such as the rate and / or duration of red blood cell (RBC) transfusion independence (TI) or hematological improvement (HI) rate, compared to a suitable control. In some cases, the subject method provides a therapeutic effect of red blood cell (RBC) transfusion independence (TI), which lasts for 4 weeks or more, such as 5 weeks or more, 6 weeks or more, 7 weeks or more, 8 weeks or more, 9 weeks or more, 10 weeks or more, 12 weeks or more, 16 weeks or more, 20 weeks or more, even 24 weeks or more. In some cases, the time to TI and / or the duration of TI are significantly improved. In certain examples, a subject method provides a period of TI of 24 weeks or more, eg, 30 weeks or more, 36 weeks or more, 42 weeks or more, 48 weeks or more, 60 weeks or more, or more.

[0045] Hypomethylating agents (HMA) are agents that inhibit DNA methylation, for example by blocking the activity of DNA methyltransferase (DNA methyltransferase inhibitors / DNMT inhibitors). Interesting HMAs include, but are not limited to, decitabine (CAS Registry Number: 2353-33-5; 5-aza-2'-deoxycytidine) and azacitidine (CAS Registry Number: 320-67-2, 5-azacitidine). In some examples, the subject is not receiving treatment with decitabine. In some examples, the subject is not receiving treatment with azacitidine. In other examples, the subject is not receiving treatment with both decitabine and azacitidine.

[0046] Lenalidomide is a drug used to treat various inflammatory diseases and cancers, including multiple myeloma and MDS. Lenalidomide (CAS Registry Number: 191732-72-6; 2,6-piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-); 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione) is a derivative of thalidomide. Lenalidomide has a variety of mechanisms of action that provide a broad range of biological activity that can be exploited to treat various hematological and solid cancers.

[0047] Deletion 5q (del5q) refers to a chromosomal abnormality found in certain forms of MDS subjects (Adema et al, Haematologica. 2013 Dec;98(12):1819-1821; Sole et al, Haematologica. 2005;90(9):1168-78). In some cases of the subject methods, the subject is a human patient with del5q. In some cases, the subject is a human patient that is not del5q. A non-del5q subject is a subject that does not have a del5q chromosomal abnormality. In certain cases, the non-del5q subject is a human.

[0048] In certain instances, the subject has not been previously treated with either a hypomethylating agent (HMA) or lenalidomide, and does not have a del(5q) chromosomal abnormality (e.g., is non-del5q). In certain instances, the non-del5q subject is a human.

[0049] C. Myelodysplastic syndrome (MDS) Myelodysplastic syndromes ("MDS") are a group of diseases that include blood and bone marrow cancers, and in some cases, are characterized by cytopenias resulting from ineffective hematopoiesis.Various MDS can be treated using the subject method, including but not limited to refractory anemia, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, chronic myelomonocytic leukemia, isolated MDS, del(5q) and unclassified MDS.

[0050] MDS is characterized by clonal myeloproliferation arising from malignant progenitor cell clones with shorter telomeres and multiple clonal genetic abnormalities. Telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) expression are significantly increased in MDS and may play a role in dysregulated cell proliferation, leading to continuous and uncontrolled proliferation of malignant progenitor cell clones. Higher TA and hTERT, as well as shorter telomere length, are poor prognostic features of patients with low-risk MDS, leading to reduced overall survival. There are limited therapeutic options for anemia in lower-risk MDS that have relapsed after or are refractory to ESA therapy. Targeting MDS clones with imetelstat can improve outcomes, including anemia, in MDS patients who are relapsed / resistant to ESA therapy.

[0051] In some embodiments, the subject methods find use in alleviating at least one symptom associated with myelodysplastic syndromes, such as, for example, refractory anemia, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, and chronic myelomonocytic leukemia. In some embodiments, the symptoms include shortness of breath, fatigue, weakness, fainting, nosebleeds, bruising, bleeding from the mouth or gums, bloody stools, petechiae, or stroke.

[0052] In some cases, the subject suffers from relapsed or refractory MDS. "Refractory MDS" refers to a patient who still has MDS cells in the bone marrow after treatment with any convenient MDS-related therapy. "Relapsed MDS" refers to a patient who has MDS cells returning to the bone marrow and normal blood cells decreasing after remission. In certain instances, the subject has relapsed / refractory MDS to erythropoiesis stimulating agents (ESAs). ESAs can increase hemoglobin levels and eliminate transfusion dependency in some cases of MDS for a period of time. ESAs of interest include, but are not limited to, erythropoietin-alpha, erythropoietin-beta, and darbepoetin.

[0053] In certain embodiments of the subject method, the subject is classified as a low or intermediate 1 IPSS risk MDS subject. Myelodysplastic syndrome (MDS) patients can be classified into lower risk groups (low and intermediate 1 / [INT-1] IPSS) in which apoptotic events in the bone marrow are widespread and respond poorly to cytokines (including erythropoietin), and higher risk groups (intermediate 2 / [INT-2] and high IPSS) in which a block in the maturation of bone marrow progenitors is the major change. In some cases, transfusion dependency is a negative prognostic variable. Thus, in certain embodiments of the method, the subject is red blood cell (RBC) transfusion dependent. In some cases, transfusion dependent subjects have had a need for RBC transfusion of about 4 units or more over an 8 week period, or 4-14 units over an 8 week period, or about 6 units or more per 8 weeks prior to administration with the subject method. The unit of packed red blood cells (PRBC) can be about 300 mL / unit. A unit of whole blood may be about 450-500 mL / unit.

[0054] The International Prognostic Scoring System (IPSS) is a system developed to stage MDS. The IPSS evaluates three factors, which are the percentage of leukemic blasts in the bone marrow cells (scored on a scale from 0 to 2), the chromosomal abnormalities, if any, in the bone marrow cells (scored from 0 to 1), and the presence of one or more low blood counts (scored as 0 or 0.5). Each factor is given a score, with the lowest score having the best outlook. The scores of the factors are then summed to create the IPSS score. The IPSS classifies people with MDS into four groups, which are low risk, intermediate 1 risk, intermediate 2 risk, and high risk.

[0055] D. Telomerase inhibitors Any convenient telomerase inhibitor can find use in the subject method.In some embodiments, the telomerase inhibitor is an oligonucleotide having telomerase inhibitory activity, in particular the oligonucleotide defined in WO 2005 / 023994 and / or WO 2014 / 088785, the disclosure of which is incorporated herein by reference in its entirety.In some cases, one or more telomerase inhibitors (e.g., two or three telomerase inhibitors) can be administered to mammal to treat hematological malignancies.

[0056] Imetelstat In certain embodiments, the telomerase inhibitor is imetelstat, including its tautomers and salts thereof, such as pharma- ceutically acceptable salts. Imetelstat is a novel, best-in-class telomerase inhibitor with clinical activity in hematological malignancies (Baerlocher et al, NEJM 2015;373:920-928; Tefferi et al, NEJM 2015;373:908-919) (shown below): [ka] Here, "nps" represents a thiophosphoramidate bond, -NH-P(=0)(SH)-O-, connecting the 3'-carbon of one nucleoside to the 5'-carbon of the adjacent nucleoside.

[0057] In a particular example, the telomerase inhibitor is imetelstat sodium, including its tautomers. Imetelstat sodium is the sodium salt of imetelstat, which is a synthetic lipid-conjugated 13-mer oligonucleotide N3'->P5'-thiophosphoramidate. Imetelstat sodium is a telomerase inhibitor that is a covalently lipidated 13-mer oligonucleotide (shown below) complementary to the human telomerase RNA (hTR) template region. The chemical name of imetelstat sodium is: DNA, d(3'-amino-3'-deoxy-P-thio)(TAGGGTTAGACAA), 5'- / [0- / [2-hydroxy-3-(hexadecanoylamino)propyl]phosphorothioate], sodium salt (1:13) (SEQ ID NO: 1). Imetelstat sodium does not function via an antisense mechanism and therefore lacks the side effects commonly seen with such treatments. [ka]

[0058] Imetelstat Sodium Unless otherwise specified or clear from the context, a reference to imetelstat herein also includes its tautomers and salts, such as pharma- ceutically acceptable salts. As mentioned above, in particular, imetelstat sodium is the sodium salt of imetelstat. Unless otherwise specified or clear from the context, a reference to imetelstat sodium herein also includes all its tautomers.

[0059] Imetelstat and imetelstat sodium can be manufactured, formulated, or obtained as described elsewhere (see, e.g., Asai et al., Cancer Res., 63:3931-3939 (2003), Herbert et al., Oncogene, 24:5262-5268 (2005), and Gryaznov, Chem. Biodivers., 7:477-493 (2010)). Unless otherwise specified or clear from the context, references to imetelstat herein also include salts thereof. As noted above, in particular imetelstat sodium is the sodium salt of imetelstat.

[0060] Imetelstat targets the RNA template of telomerase and inhibits telomerase activity and cell proliferation in various cancer cell lines and tumor xenografts in mice. Phase 1 studies involving patients with breast cancer, non-small cell lung cancer, other solid tumors, multiple myeloma, or chronic lymphocytic leukemia have provided information on the pharmacokinetics and pharmacodynamics of the drug. Subsequent phase 2 studies involving patients with essential thrombocythemia have demonstrated platelet lowering activity with significant reductions in JAK2 V617F and CALR mutant allele burden. Imetelstat sodium is routinely administered intravenously, and it is contemplated that other routes of administration, such as intrathecal administration, intratumoral injection, and oral administration, may also be used in the practice of the subject methods. Imetelstat sodium may be administered at doses comparable to those routinely utilized clinically. In certain embodiments, imetelstat sodium is administered as described elsewhere herein.

[0061] Certain embodiments are according to any one of the other embodiments, wherein the imetelstat is limited to imetelstat sodium.

[0062] E. Pharmaceutical Compositions To facilitate administration, the telomerase inhibitors (e.g., as described herein) may be formulated into various pharmaceutical forms for administration purposes. In some cases, the telomerase inhibitors are administered as pharmaceutical compositions. The carriers or diluents of the pharmaceutical composition must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the recipient thereof. The pharmaceutical composition may be in a unit dosage form suitable for administration, particularly oral, rectal, transdermal, parenteral injection, or inhalation. In some cases, administration may be via intravenous injection. For example, in preparing the composition in oral dosage form, any of the usual pharmaceutical media, e.g., water, glycols, oils, alcohols, etc., may be used in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions, or solid carriers, such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants, etc., may be used in the case of powders, pills, capsules, and tablets. Because of ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case obviously solid pharmaceutical carriers are used. For parenteral compositions, the carrier will usually comprise at least mostly sterile water, although other ingredients, for example to aid solubility, may be included. For example, injectable solutions can be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. For example, injectable solutions can be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable solutions containing the telomerase inhibitors described herein can be formulated in oil for prolonged action. Oils suitable for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these with other oils. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents, and the like can be used. Also included are solid preparations that are intended to be converted to liquid preparations immediately prior to use. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, combined in minor proportions with suitable additives of any nature that do not introduce significant adverse effects on the skin.The additives may facilitate application to the skin and / or aid in preparing the desired composition. The composition may be administered in a variety of ways, for example, as a transdermal patch, a spot-on, an ointment, etc.

[0063] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the above-mentioned pharmaceutical composition in unit dosage form.Unit dosage form as used herein refers to a physically separate unit suitable as unit dosage, each unit containing a predetermined amount of active ingredient calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The example of such unit dosage form is tablet (including divided tablet or coated tablet), capsule, pill, powder packet, wafer, suppository, injection solution or suspension, etc., and separate multiples thereof.

[0064] To enhance the solubility and / or stability of the drugs described herein in the pharmaceutical composition, it may be advantageous to use α-, β- or γ-cyclodextrin or their derivatives, in particular hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-P-cyclodextrin or sulfobutyl-P-cyclodextrin. Also, co-solvents such as alcohols may improve the solubility and / or stability of the telomerase inhibitor in the pharmaceutical composition.

[0065] Depending on the mode of administration, the pharmaceutical compositions preferably contain 0.05-99% by weight, more preferably 0.1-70% by weight, and even more preferably 0.1-50% by weight of a telomerase inhibitor described herein, and 1-99.95% by weight, more preferably 30-99.9% by weight, and even more preferably 50-99.9% by weight of a pharma- ceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0066] F. Administration and Dosing Regimens The frequency of administration can be any frequency that reduces the severity of MDS symptoms (e.g., as described herein) without causing significant toxicity to the subject. For example, the frequency of administration can be about once every two months to about once a week, or about once a month to about twice a month, or about once every six weeks, about once every five weeks, or about once every four weeks, or about once every three weeks, or about once every two weeks, or about once every week. The frequency of administration can remain constant or can be variable during the treatment period. A course of treatment using a composition comprising one or more telomerase inhibitors can include a rest period. For example, a composition comprising a telomerase inhibitor can be administered weekly for a period of three weeks, followed by a rapid period of two weeks, and such a regimen can be repeated multiple times. As with the effective amount, various factors can affect the actual frequency of administration used for a particular application. For example, the effective amount, the duration of treatment, the use of multiple therapeutic agents, the route of administration, and the severity of the MDS and related conditions may require more or less frequent administration.

[0067] The effective period for administering a composition comprising a telomerase inhibitor (e.g., imetelstat or imetelstat sodium) can be any period that reduces the severity of MDS symptoms (e.g., as described herein) without causing significant toxicity to the subject. Thus, the effective period can vary from one month to several months or years (e.g., one month to one year, three months to two years, three months to ten months, or three months to 18 months). In general, the effective period for treating MDS can range from two months to twenty months. In some cases, the effective period can be as long as the individual subject survives. Multiple factors can affect the actual effective period used for a particular treatment. For example, the effective period can vary depending on the frequency of administration, the effective amount, the use of multiple therapeutic agents, the route of administration, and the severity of MDS and related symptoms.

[0068] In certain examples, the progress of treatment and the severity of one or more symptoms associated with MDS can be monitored. Any method can be used to determine whether the severity of the MDS symptoms is reduced. For example, the severity of the MDS symptoms (e.g., as described herein) can be evaluated using biopsy techniques.

[0069] Telomerase inhibitors as used in the subject methods can be administered at any therapeutically effective dose, including doses comparable to those routinely utilized clinically. Specific dosing regimens (e.g., recommended effective amounts) of known and approved anticancer drugs are known to physicians and are provided, for example, in the product descriptions found in the PHYSICIANS'DESK REFERENCE, 2003, 57th Ed., Medical Economics Company, Inc., Oradell, NJ; Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS” 2001, 10th Edition, McGraw-Hill, New York, and / or are available from the Federal Drug Administration and / or are discussed in the medical literature.

[0070] In some embodiments, the dose of the telomerase inhibitor, imetelstat sodium, administered to the subject is about 1.0 mg / kg to about 13.0 mg / kg. In other embodiments, the dose of the telomerase inhibitor is about 4.5 mg / kg to about 11.7 mg / kg, or about 6.0 mg / kg to about 11.7 mg / kg, or about 6.5 mg / kg to about 11.7 mg / kg. In some embodiments, the dose of the telomerase inhibitor is at least about 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 ... mg / kg, 7.3mg / kg, 7.4mg / kg, 7.5mg / kg, 7.6mg / kg, 7.7mg / kg, 7.8mg / kg, 7.9mg / kg, 8mg / kg, 8.1mg / kg, 8.2mg / kg , 8.3mg / kg, 8.4mg / kg, 8.5mg / kg, 8.6mg / kg, 8.7mg / kg, 8.8mg / kg, 8.9mg / kg, 9mg / kg, 9.1mg / kg, 9.2mg / kg, 9.3m g / kg, 9.4mg / kg, 9.5mg / kg, 9.6mg / kg, 9.7mg / kg, 9.8mg / kg, 9.9mg / kg, 10mg / kg, 10.1mg / kg, 10.2mg / kg, 10.3mg / kg, 10.4mg / kg, 10.5mg / kg, 10.6mg / kg, 10.7mg / kg, 10.8mg / kg, 10.9mg / kg, 11mg / kg, 11.1mg / kg, 11.2mg / kg, 1 Contains either 1.3mg / kg, 11.4mg / kg, 11.5mg / kg, 11.6mg / kg, 11.7mg / kg, 11.8mg / kg, 11.9mg / kg, 12mg / kg, 12.1mg / kg, 12.2mg / kg, 12.3mg / kg, 12.4mg / kg, 12.5mg / kg, 12.6mg / kg, 12.7mg / kg, 12.8mg / kg, 12.9mg / kg, or 13mg / kg.

[0071] In some embodiments, the effective amount of the telomerase inhibitor administered to an individual includes at least about any of 1 mg / kg, 2.5 mg / kg, 3.5 mg / kg, 4.7 mg / kg, 5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 9.4 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. In some embodiments, the effective amount of the telomerase inhibitor administered to an individual is at least about any of 1 mg / kg, 2.5 mg / kg, 3.5 mg / kg, 5 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 9.4 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. In various embodiments, the effective amount of a telomerase inhibitor administered to an individual includes less than about 350 mg / kg, 300 mg / kg, 250 mg / kg, 200 mg / kg, 150 mg / kg, 100 mg / kg, 50 mg / kg, 30 mg / kg, 25 mg / kg, 20 mg / kg, 10 mg / kg, 7.5 mg / kg, 6.5 mg / kg, 5 mg / kg, 3.5 mg / kg, 2.5 mg / kg, 1 mg / kg, or 0.5 mg / kg of a telomerase inhibitor.

[0072] Exemplary dosing frequencies of pharmaceutical compositions comprising a telomerase inhibitor include, but are not limited to, daily, every other day, twice a week; three times a week; weekly without a break; weekly for three out of four weeks, once every three weeks; once every two weeks; weekly for two out of three weeks. In some embodiments, the pharmaceutical composition is administered about once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In some embodiments, the composition is administered at least about 1x, 2x, 3x, 4x, 5x, 6x, or 7x (i.e., daily) weekly, or three times daily, twice daily. In some embodiments, the interval between each administration is less than about any of 6 months, 3 months, 1 month, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the interval between each administration is greater than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is less than about 1 week.

[0073] A telomerase inhibitor such as imetelstat (e.g., imetelstat sodium) can be administered using any suitable method. For example, a telomerase inhibitor such as imetelstat (e.g., imetelstat sodium) can be administered intravenously once every four weeks for a period of time (e.g., 1, 2, 3, 4, or 5 hours). In some embodiments, imetelstat is administered intravenously at 7-10 mg / kg for about two hours once a week. In certain embodiments, imetelstat is administered intravenously at 2.5-7 mg / kg for about two hours once every three weeks. In one embodiment, imetelstat is administered intravenously at 0.5-5 mg / kg for about two hours once every four weeks. In one embodiment, imetelstat is administered intravenously at about 2.5-10 mg / kg for about two hours once every three weeks. Alternatively, Imestat is administered intravenously at about 0.5-9.4 mg / kg once every four weeks over a period of about two hours.

[0074] In certain embodiments of the method, imetelstat is administered in 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle being about 7-10 mg / kg imetelstat administered intravenously once every 4 weeks, about 7-10 mg / kg imetelstat administered intravenously once a week for 4 weeks, about 2.5-10 mg / kg imetelstat administered intravenously once every 3 weeks, or about 0.5-9.4 mg / kg imetelstat administered intravenously once every 4 weeks. In certain examples, each dosing cycle comprises about 7-10 mg / kg imetelstat administered intravenously once every 4 weeks. In some cases, each dosing cycle comprises about 7.5 mg / kg imetelstat administered intravenously once every 4 weeks.

[0075] In one embodiment of the invention, imetelstat is administered intravenously at a dosage of about 7-10 mg / kg imetelstat once every four weeks after premedication with an antihistamine, a corticosteroid, or both, hi other embodiments, imetelstat is administered intravenously at a dosage of about 7.5 mg / kg, or alternatively about 7.0 mg / kg to about 7.7 mg / kg, once every four weeks after premedication with an antihistamine, a corticosteroid, or both.

[0076] In certain embodiments, imetelstat is administered at a dose of about 7.5 mg / kg, or alternatively about 7.0 mg / kg to about 7.7 mg / kg, once every 4 weeks for at least three cycles, with subsequent dose escalations. In certain embodiments, the ANC and platelet nadir are each about 1.5×10 9 / L to approx. 75x10 9 If the dose of imetelstat does not decrease between 0.01 mg / kg and 0.1 mg / L and there is no non-hematologic toxicity of grade greater than 3, the dose of imetelstat can be increased to about 9.4 mg / kg, or from about 8.8 mg / kg to about 9.6 mg / kg.

[0077] It is understood that cancer treatment sometimes involves multiple "rounds" or "cycles" of administration of a drug, with each cycle including administration of one or more drugs according to a specified schedule (e.g., three consecutive days every three weeks, once a week, etc.). For example, an anticancer drug can be administered for one to eight cycles, or more. When more than one drug (e.g., two drugs) are administered to a subject, each can be administered according to its own schedule (e.g., weekly, once every three weeks, etc.). It will be apparent that administration of drugs, even those administered in different cycles, can be coordinated such that both drugs are administered on the same day at least some of the time, or are administered on consecutive days at least some of the time.

[0078] As is understood in the art, if toxicity is observed or for the convenience of the patient, treatment with the cancer medicament can be temporarily interrupted and then resumed without departing from the scope of the invention.

[0079] In certain embodiments, the present invention relates to a telomerase inhibitor for use in a method of treating myelodysplastic syndrome (MDS), comprising administering an effective amount of a telomerase inhibitor to a subject in need thereof, wherein the subject has not been treated with an agent selected from a hypomethylating agent (HMA) and lenalidomide. In other embodiments, the present invention relates to a telomerase inhibitor for use in a method of treating myelodysplastic syndrome (MDS), comprising administering an effective amount of a telomerase inhibitor to a subject in need thereof, wherein the subject has not been treated with an agent selected from a HMA, lenalidomide, and combinations thereof.

[0080] In a particular embodiment, the invention relates to a telomerase inhibitor for use in the method defined in any of the other embodiments.

[0081] G. Exemplary Embodiments An exemplary embodiment of the method of treating MDS of the present invention is shown in Table A below, which comprises administering an effective amount of a telomerase inhibitor to a subject in need thereof, whereby the subject has not been treated with an agent selected from a hypomethylating agent (HMA) and lenalidomide.

[0082] Exemplary embodiments include using any of the telomerase inhibitors of Table A to treat any of the types of MDS shown in Table A in any one of the subjects shown in Table A, whereby the subject has not received any of the treatments shown in Table A. In certain embodiments, one of the dosing regimens set forth in Table A is used. In other embodiments, the methods of the invention can be used to treat any of the types of MDS shown in Table A in any one of the subjects shown in Table A using imetelstat (imetelstat sodium), whereby the subject has not received any of the treatments set forth in Table A. When imetelstat (imetelstat sodium) is used, the dosing regimens set forth in Table A can be used. [Table A-1] [Table A-2]

[0083] The following examples are offered by way of illustration and not by way of limitation. EXAMPLES

[0084] Example 1; Efficacy and Safety of Imetelstat in Transfusion-Dependent (TD) Patients with International Prognostic Scoring System (IPSS) Low / Intermediate 1 Risk Myelodysplastic Syndrome Relapsed / Refractory to Erythropoiesis-Stimulating Agent (ESA) Therapy (IMerge™) Introduction IMerge™: An ongoing, two-part comprehensive study of imetelstat sodium in patients with red blood cell (RBC) transfusion-dependent (TD), ESA-relapsed / refractory, and lower-risk MDS. Part 1 consists of an open-label, single-arm design of imetelstat sodium monotherapy. This example provides safety and efficacy findings for 32 patients enrolled in part 1. Subgroup analyses of lenalidomide- and hypomethylating agent (HMA)-naïve and del(5q)-naïve patients are also presented. Results suggest improved efficacy among these patients.

[0085] method Eligibility The eligibility requirements for the study were as follows: Adults diagnosed with MDS; International Prognostic Scoring System (IPSS) Low or Int-1 · Transfusion dependence (TD), defined as red blood cell (RBC) transfusion requirement of more than 4 units over the 8 weeks prior to study enrollment. Relapsed or refractory to ESAs after at least 8 weeks of weekly epoetin alfa 40,000 U or darbepoetin alfa 150 meg (or equivalent) or serum erythropoietin (sEPO) >500 mU / mL Prior therapy (including lenalidomide or HMAs) was permitted. Patients with del(5q) karyotype were able to participate regardless of prior therapy. Eastern Cooperative Oncology Group (ECOG) score 0-2. Absolute neutrophil count (ANC) > 1.5x10 9 / L and platelets >7.5x10 9 / L is independent of growth factors or transfusion support. ·Liver function tests: AST, ALT, and ALP<2.5 times upper limit of normal (xULN), total bilirubin<3xULN and direct bilirubin<2xULN (unless due to Gilbert's syndrome).

[0086] Treatment: Imetelstat sodium was administered as a 2-h IV infusion every 4 weeks at a starting dose of 7.5 mg / kg after premedication with antihistamines and corticosteroids. ANC and platelet nadir were 1.5x10, respectively. 9 / L and 75x10 9 Dose escalation to 9.4 mg / kg was permitted for inadequate response after at least three cycles at the initial dose, provided that serotonin levels did not fall below 9.4 mg / L and there was no non-hematologic toxicity >grade 3. Transfusions and supportive care, including bone marrow growth factors, were permitted as clinically indicated.

[0087] Endpoints and Analysis: Primary endpoint: Proportion of RBC transfusion independence (TI) lasting longer than 8 weeks. Key secondary endpoints: ○ Safety, ○ Proportion of TIs longer than 24 weeks, ○ Time to TI and duration of TI, Hematologic improvement (HI) rate, and - International Working Group (IWG) complete response (CR) and partial response (PR) rates.

[0088] result patient Median baseline RBC transfusion burden, 6 units / 8 weeks (range: 4-14)

[0089] Baseline characteristics are shown in Table 1 below. The following abbreviations are used in Table 1: Eastern Cooperative Oncology Group Performance Status Score 0-1 (ECOG PS 0-1); 0-1”), refractory anemia with ringed sideroblasts (“RARS”), or refractory cytopenia with multilineage dysplasia and ringed sideroblasts (“RCMD-RS”). [Table 1]

[0090] Key hematological criteria: ANC=1,500 and PLT=75,000. Based on baseline RBC transfusion burden, this was a patient in the massive transfusion group.

[0091] Results (first data snapshot) exposure Median follow-up for this analysis: 66.1 weeks Median number of treatment cycles: 6.5 (range: 1-20 cycles) Adverse events led to dose reductions in 16 patients (50%) and cycle delays in 19 patients (59%). Seven patients had their imetelstat sodium dose increased to 9.4 mg / kg

[0092] efficacy Table 2 below shows the key efficacy results. [Table 2]

[0093] The primary endpoint of RBC TI lasting ≥8 weeks was achieved in 12 / 32 (38%) patients.

[0094] 5 / 32 (16%) achieved 24 weeks of TI (see Figure 1A, IB, and Figure 2). These patients also had a sustained increase in hemoglobin of at least 1.5 g / dL (HI-E Hb) for 8 weeks (HI-E Hb = HI-E with a sustained increase in hemoglobin of at least 1.5 g / dL for 8 weeks). The duration of the patients' TI (65.1 weeks) exceeded 1 year.

[0095] 20 / 32 patients (63%) had red blood cell hematological improvement (HI) (see Figure 1A and FIG. IB).

[0096] In the subset of patients not receiving lenalidomide and HMA who lacked del(5q), the 8- and 24-week TI rates were 54% and 31%, respectively (higher than in the overall population) and the erythroid HI rate was 69% (similar to that reported in the overall population). Complete responses (CR) and myeloid CR (mCR) were reported in two patients each, and there were no partial responses (PR), for a CR+PR+mCR rate of 13%.

[0097] One CR and both mCRs were in the subset of patients who did not receive lenalidomide and HMA and lacked del(5q). 8-week TI did not differ based on the presence of ringed sideroblasts (RS), 38% (6 / 16) in RS+ and 38% (6 / 16) in RS-. Responses appeared independent of sEPO level. Of the 30 patients with reported baseline sEPO levels, 41% (7 / 17) achieved ≥8-week TI with sEPO levels ≤500 mU / L and 38% (5 / 13) achieved ≥8-week TI with sEPO levels >500 mU / L.

[0098] safety Cytopenias, particularly neutropenia and thrombocytopenia, were the most frequently reported adverse events overall and in the subset not receiving lenalidomide and HMA and lacking del(5q) (see Table 3 below). This subset of patients had a lower incidence of grade ≥3 neutropenia compared to the overall population, but similar grade ≥3 thrombocytopenia (see Table 4 below). In most cases, grade ≥3 cytopenias were reversible within 4 weeks without clinical sequelae, allowing patients to continue imetelstat sodium treatment following dose modification.

[0099] One patient (of 22 with neutropenia) experienced a neutropenic fever, and two patients (of 18 with thrombocytopenia) had grade 3 thrombocytopenia concomitant with a grade 1 bleeding event. Both of these were thought to be related to imetelstat sodium, and both of these events resolved without sequelae. Twenty-eight patients (88%) had at least one grade increase in liver function tests (LFTs). These events were generally grade 1 or 2 and were reversible. Four patients (including three in the subset of patients not receiving lenalidomide and HMAs and lacking del / [5q]) had grade 3 worsening of aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT), and one of these patients had grade 3 worsening of bilirubin, all of which were reversible.

[0100] Table 3 shows the most common treatment emergent adverse events. Table 4 shows the maximum grade change in cytopenias from baseline. [Table 3] [Table 4] The results in Table 4 are based on the first data snapshot.

[0101] Results (second data snapshot) exposure Median follow-up for this analysis: 95 weeks Median number of treatment cycles: 6.5 (range: 1-28 cycles) Sixteen patients (50%) had dose reductions and 19 patients (59%) had cycle delays Seven patients had their imetelstat sodium dose increased to 9.4 mg / kg

[0102] efficiency Table 5 below shows key efficiency results for the second data snapshot. [Table 5]

[0103] The maximum follow-up from responding patients was 115 weeks or 26 months.

[0104] Of the seven subjects who received dose escalation, one subject achieved an 8-week TI and three subjects achieved HI-E. The median number of treatment cycles in the subgroups was 8 cycles. Median duration of therapy overall and subgroup was 24 weeks and 29 weeks, respectively.

[0105] FIG. 3A shows the longest transfusion-free interval in the second data snapshot. Three of the five patients with a 24-week TI are still on treatment. The data shown in FIG. 3A are summarized in Table 6 below: [Table 6]

[0106] FIG. 3B shows the absolute change in transfusion volume over the best 8 week interval. One patient with a transfusion burden of 10 went to 0. Patients who did not reach TI (HI-E(TR)) had a highly significant reduction in transfusion burden. The data shown in FIG. 3B is summarized in Table 7 below: [Table 7]

[0107] Figure 4 shows efficacy results for EPO and RS subgroups at the second data snapshot. Similar efficacy was observed across these subgroups. Figure 5 shows hematology and imetelstat sodium dosing by patient over time at the second data snapshot. Figure 6 shows hemoglobin and imetelstat sodium dosing in patients with persistent TI. The top three patients in Figure 6 are still on treatment. The top two subjects in Figure 6 have the longest follow-up.

[0108] safety Safety findings in those who were lenalidomide / HMA-naive / non-del(5q) were similar to the overall study population.

[0109] Table 8 shows the most common treatment-emergent adverse events in the second data snapshot. Table 9 shows the occurrence and reversibility of grade 3 / 4 cytopenias. Table 10 shows the maximum post-baseline Common Terminology Criteria for Adverse Events (CTCAE) grade worsening since baseline for cytopenias by population and safety analysis set in the second data snapshot. [Table 8] [Table 9]

[0110] Eleven patients received G-CSF during the study for treatment of adverse events or ongoing medical history (n=10), or as prophylaxis. [Table 10] Observations (based on both data snapshots):

[0111] Safety and efficacy data from the 32 patients in part 1 of the study support continued investigation of imetelstat sodium using the current dosing regimen of 7.5 mg / kg every 4 weeks.

[0112] In the first data snapshot, 8-week RBC TI was demonstrated in 38% of ESA-refractory / relapsed IPSS low / Int-1 RBC transfusion-dependent MDS patients and RBC HI in 63% of them. A sustained 24-week TI with persistently elevated Hb was observed in 16% of patients.

[0113] In the initial data snapshot, 54% of RBC TI was observed in 13 patients without del(5q) and no prior exposure to either lenalidomide or HMAs (compared to 38% in the overall population), and responses were durable (24-week TI rate of 31%).

[0114] Overall, 8-week TI was observed in 34% of all patients, with a 24-week TI rate of 16%. The median time to TI was 8.0 weeks. The median duration of TI was 23.1 weeks.

[0115] For patients who did not receive lenalidomide / HMA and were non-del(5q), the 8-week and 24-week TI rates were 54% and 31%, respectively. In these patients, the median duration of TI was 42.9 weeks.

[0116] Overall, TR(HI-E) was observed in 59% of all patients. The mean relative reduction in RBC transfusion burden from baseline was 60%.

[0117] These results support further study of imetelstat sodium (7.5mg / kg I once weekly) in IPSS low / Int-1, TD, ESA relapsed / refractory MDS. In RBC TD patients with LR-MDS (median: 6U / 8 weeks), imetelstat sodium treatment resulted in red blood cell improvement in the majority of patients.

[0118] The study was repeated in a target population of 13 subjects with non-del(5q) MDS and no prior exposure to either HMAs or lenalidomide. In this target population, 53.8% achieved the primary endpoint of 8 weeks of RBC TI compared with 21.1% of other subjects not in the target population. Responses were more durable in the control population than in other subjects (median duration, 42.9 vs. 13.9 weeks), and more subjects in the target population achieved 24 weeks of RBC TI (30.8% vs. 5.3%). The target population showed a comparable or better safety profile for cytopenias and other adverse events, and cytopenias appeared to resolve faster in the target population.

[0119] Although particular embodiments have been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be readily apparent in light of the teachings of the present invention that certain changes and modifications can be made without departing from the spirit of the invention or the scope of the appended claims.

[0120] Thus, the foregoing merely illustrates the principles of the invention. Although not explicitly described or shown herein, various configurations may be devised which embody the principles of the invention and are within its spirit and scope. Moreover, all examples and conditional language recited herein are intended primarily to aid the reader in understanding the principles of the invention and the concepts the inventors have contributed to furthering the art, and are not intended to be limiting to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention and specific examples thereof are intended to encompass both structural and functional equivalents thereof. Moreover, such equivalents are intended to include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function regardless of structure. Thus, the scope of the invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the invention is embodied by the appended claims.

[0121] Numbered Embodiments of the Invention Exemplary numbered embodiments of the present invention are set forth below. 1. A method of treating myelodysplastic syndromes (MDS), comprising administering an effective amount of a telomerase inhibitor to a subject in need thereof, wherein the subject is not undergoing treatment with an agent selected from a hypomethylating agent (HMA), lenalidomide, and combinations thereof. 2. The method of embodiment 1, wherein said MDS is relapsed or refractory MDS. 3. The method of embodiment 1 or embodiment 2, wherein said MDS is relapsed / refractory to erythropoiesis stimulating agents (ESAs). 4. The method of any one of embodiments 1-3, wherein the subject is classified as a low or moderate 1 IPSS risk MDS subject. 5. The method of any one of embodiments 1-4, wherein the subject is transfusion dependent. 6. The method of embodiment 5, wherein the transfusion-dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to administration of the telomerase inhibitor. 7. The method of any one of embodiments 1-6, wherein the subject is a non-del5q human patient. 8. The method of any one of embodiments 1-7, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject and is non-del5q. 9. The method of any one of embodiments 1-8, wherein the subject has not been treated with lenalidomide. 10. The method of any one of embodiments 1-9, wherein said HMA is selected from the group consisting of decitabine and azacitidine. 11. The method of embodiment 10, wherein the subject has not been treated with decitabine. 12. The method of embodiment 10, wherein the subject has not been treated with azacitidine. 13. The method of any one of embodiments 1-12, wherein the telomerase inhibitor is imetelstat. 14. The method of embodiment 13, wherein said imetelstat is imetelstat sodium. 15. The method of embodiment 13, wherein the telomerase inhibitor is imetelstat and is administered in 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) Imetelstat administered intravenously at approximately 7-10 mg / kg once every 4 weeks; (b) about 7-10 mg / kg of imetelstat administered intravenously once weekly for four weeks; (c) about 2.5-10 mg / kg of imetelstat administered intravenously once every three weeks; or (d) Imetelstat administered intravenously at approximately 0.5 to 9.4 mg / kg once every 4 weeks. 16. The method of embodiment 15, wherein each dosing cycle comprises intravenous administration of about 7-10 mg / kg of imetelstat once every 4 weeks. 17. The method of embodiment 16, wherein each dosing cycle comprises intravenous administration of about 7.5 mg / kg of imetelstat once every 4 weeks. 18. The method of embodiment 1, wherein the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 19. The method of embodiment 18, wherein the subject is transfusion dependent. 20. The method of claim 18, wherein the subject is a non-del5q human patient. 21. The method of any one of embodiments 1-20, wherein the subject has not been treated with an agent selected from a hypomethylating agent (HMA) and lenalidomide. 22. A telomerase inhibitor for use in treating myelodysplastic syndromes (MDS) in a subject not receiving treatment with an agent selected from a hypomethylating agent (HMA), lenalidomide, and combinations thereof. 23. The telomerase inhibitor for use according to embodiment 22, wherein said MDS is relapsed or refractory MDS. 24. The telomerase inhibitor for use according to embodiment 22 or 23, wherein said MDS is MDS that is relapsed / refractory to erythropoiesis stimulating agents (ESAs). 25. The telomerase inhibitor for use according to any one of embodiments 22 to 24, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 26. The telomerase inhibitor for use according to any one of embodiments 22 to 25, wherein the subject is transfusion dependent. 27. The telomerase inhibitor for use according to embodiment 26, wherein said transfusion-dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to administration of the telomerase inhibitor. 28. The telomerase inhibitor for use according to any one of embodiments 22 to 27, wherein the subject is a non-del5q human patient. 29. The telomerase inhibitor for use according to embodiment 22, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject and is non-del5q. 30. The telomerase inhibitor for use according to any one of embodiments 22 to 28, wherein the subject has not been treated with lenalidomide. 31. The telomerase inhibitor for use according to any one of embodiments 22 to 29, or 30, wherein the HMA is selected from the group consisting of decitabine and azacitidine. 32. The telomerase inhibitor for use according to embodiment 31, wherein the subject has not been treated with decitabine. 33. The telomerase inhibitor for use according to embodiment 31, wherein the subject has not been treated with azacitidine. 34. The telomerase inhibitor for use according to any one of embodiments 22 to 33, wherein the telomerase inhibitor is imetelstat. 35. The telomerase inhibitor for use according to embodiment 34, wherein said imetelstat is imetelstat sodium. 36. The telomerase inhibitor for use according to any one of embodiments 22 to 35, wherein the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 37. The telomerase inhibitor for use according to embodiment 36, wherein the subject is transfusion dependent. 38. The telomerase inhibitor for use according to embodiment 36, wherein the subject is a non-del5q human patient. 39. The telomerase inhibitor for use according to any one of embodiments 22 to 36, wherein the telomerase inhibitor is imetelstat and the use comprises administration of 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) Imetelstat administered intravenously at approximately 7-10 mg / kg once every 4 weeks; (b) intravenous administration of approximately 7 to 10 mg / kg of imetelstat once weekly for 4 weeks; (c) approximately 2.5 to 10 mg / kg of imetelstat administered intravenously once every three weeks; or (d) Imetelstat administered intravenously at approximately 0.5 to 9.4 mg / kg once every 4 weeks. 40. The telomerase inhibitor for use according to embodiment 39, wherein each dosing cycle comprises intravenous administration of about 7-10 mg / kg of imetelstat once every 4 weeks. 41. The telomerase inhibitor for use according to embodiment 40, wherein each dosing cycle comprises intravenous administration of about 7.5 mg / kg of imetelstat once every 4 weeks. 42. The telomerase inhibitor for use according to any one of embodiments 22 to 41, wherein the subject has not undergone treatment with an agent selected from a hypomethylating agent (HMA) and lenalidomide. 43. Use of a telomerase inhibitor to treat myelodysplastic syndromes (MDS) in a subject not receiving treatment with an agent selected from a hypomethylating agent (HMA), lenalidomide, and combinations thereof. 44. The use according to embodiment 43, wherein the MDS is relapsed or refractory MDS. 45. The use according to embodiment 43 or 44, wherein said MDS is MDS that is relapsed / refractory to erythropoiesis-stimulating agents (ESAs). 46. ​​The use according to any one of embodiments 43 to 45, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 47. The use according to any one of embodiments 43 to 46, wherein the subject is transfusion dependent. 48. The use according to embodiment 47, wherein the transfusion dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to administration of the telomerase inhibitor. 49. The use according to any one of embodiments 43 to 48, wherein the subject is a non-del5q human patient. 50. The use according to embodiment 43, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject and is non-del5q. 51. The use according to any one of embodiments 43 to 49, wherein the subject has not been treated with lenalidomide. 52. The use according to any one of embodiments 43 to 50, or 51, wherein the HMA is selected from the group consisting of decitabine and azacitidine. 53. The use according to embodiment 52, wherein the subject has not been treated with decitabine. 54. The use according to embodiment 52, wherein the subject has not been treated with azacitidine. 55. The use according to any one of embodiments 43 to 54, wherein the telomerase inhibitor is imetelstat. 56. The use according to embodiment 55, wherein the imetelstat is imetelstat sodium. 57. The use according to any one of embodiments 43 to 56, wherein the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 58. The use according to embodiment 57, wherein the subject is transfusion dependent. 59. The use of embodiment 57, wherein the subject is a non-del5q human patient. 60. The use according to any one of embodiments 43 to 59, wherein the telomerase inhibitor is imetelstat and the use comprises administration of 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) Imetelstat administered intravenously at approximately 7-10 mg / kg once every 4 weeks; (b) intravenous administration of approximately 7 to 10 mg / kg of imetelstat once weekly for 4 weeks; (c) approximately 2.5-10 mg / kg of imetelstat administered intravenously once every three weeks; or (d) Imetelstat administered intravenously at approximately 0.5 to 9.4 mg / kg once every 4 weeks. 61. The use of embodiment 60, wherein each dosing cycle comprises intravenous administration of about 7-10 mg / kg of imetelstat once every 4 weeks. 62. The use of embodiment 61, wherein each dosing cycle comprises intravenous administration of about 7.5 mg / kg of imetelstat once every 4 weeks. 63. The use according to any one of embodiments 43 to 62, wherein the subject has not been treated with an agent selected from a hypomethylating agent (HMA) and lenalidomide. 64. A method of treating myelodysplastic syndrome (MDS), comprising administering an effective amount of a telomerase inhibitor to a subject in need thereof, wherein the subject is a non-del5q human patient. 65. The method of embodiment 64, wherein the MDS is relapsed or refractory MDS. 66. The method of embodiment 64 or embodiment 65, wherein the MDS is relapsed / refractory MDS to erythropoiesis-stimulating agents (ESAs). 67. The method of any one of embodiments 64-66, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 68. The method of any one of embodiments 64-67, wherein the subject is transfusion dependent. 69. The method of embodiment 68, wherein the transfusion dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to administration of the telomerase inhibitor. 70. The method of any one of claims 64 to 69, wherein the telomerase inhibitor is imetelstat. 71. The method of embodiment 70, wherein the imetelstat is imetelstat sodium. 72. The method of embodiment 70, wherein the telomerase inhibitor is imetelstat and is administered in 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) Imetelstat administered intravenously at approximately 7-10 mg / kg once every 4 weeks; (b) intravenous administration of approximately 7 to 10 mg / kg of imetelstat once weekly for 4 weeks; (c) approximately 2.5-10 mg / kg of imetelstat administered intravenously once every three weeks; or (d) Imetelstat administered intravenously at approximately 0.5 to 9.4 mg / kg once every 4 weeks. 73. The method of embodiment 72, wherein each dosing cycle comprises intravenous administration of about 7-10 mg / kg of imetelstat once every 4 weeks. 74. The method of embodiment 73, wherein each dosing cycle comprises intravenous administration of about 7.5 mg / kg of imetelstat once every 4 weeks. 75. The method of embodiment 64, wherein the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 76. The method of embodiment 75, wherein the subject is transfusion dependent. 77. A telomerase inhibitor for use in treating myelodysplastic syndrome (MDS) in a subject who is a non-del5q human patient. 78. The telomerase inhibitor for use according to embodiment 77, wherein the MDS is relapsed or refractory MDS. 79. The telomerase inhibitor for use according to embodiment 77 or embodiment 78, wherein said MDS is relapsed / refractory MDS to erythropoiesis-stimulating agents (ESAs). 80. The telomerase inhibitor for use according to any one of embodiments 77 to 79, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 81. The telomerase inhibitor for use according to any one of embodiments 77 to 80, wherein the subject is transfusion dependent. 82. The telomerase inhibitor for use according to embodiment 81, wherein said transfusion-dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to administration of the telomerase inhibitor. 83. The telomerase inhibitor for use according to any one of embodiments 77 to 82, wherein the telomerase inhibitor is imetelstat. 84. The telomerase inhibitor for use according to embodiment 83, wherein said imetelstat is imetelstat sodium. 85. The telomerase inhibitor for use according to any one of embodiments 77 to 84, wherein the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 86. The telomerase inhibitor for use according to embodiment 85, wherein the subject is transfusion dependent. 87. The telomerase inhibitor for use according to any one of embodiments 77 to 86, wherein the telomerase inhibitor is imetelstat and the use comprises administration of 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) Imetelstat administered intravenously at approximately 7-10 mg / kg once every 4 weeks; (b) intravenous administration of approximately 7 to 10 mg / kg of imetelstat once weekly for 4 weeks; (c) approximately 2.5 to 10 mg / kg of imetelstat administered intravenously once every three weeks; or (d) Imetelstat administered intravenously at approximately 0.5 to 9.4 mg / kg once every 4 weeks. 88. The telomerase inhibitor for use according to embodiment 87, wherein each dosing cycle comprises intravenous administration of about 7-10 mg / kg of imetelstat once every 4 weeks. 89. The telomerase inhibitor for use according to embodiment 88, wherein each dosing cycle comprises intravenous administration of about 7.5 mg / kg of imetelstat once every 4 weeks. 90. Use of a telomerase inhibitor to treat myelodysplastic syndrome (MDS) in a subject who is a non-del5q human patient. 91. The use according to embodiment 90, wherein the MDS is relapsed or refractory MDS. 92. The use according to embodiment 90 or embodiment 91, wherein the MDS is relapsed / refractory MDS to erythropoiesis-stimulating agents (ESAs). 93. The use according to any one of embodiments 90 to 92, wherein the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 94. The use according to any one of embodiments 90 to 93, wherein the subject is transfusion dependent. 95. The use according to embodiment 94, wherein the transfusion dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to administration of the telomerase inhibitor. 96. The use according to any one of embodiments 90 to 95, wherein the telomerase inhibitor is imetelstat. 97. The use according to embodiment 96, wherein the imetelstat is imetelstat sodium. 98. The use according to any one of embodiments 90 to 97, wherein the MDS is relapsed or refractory MDS and the subject is classified as a low or intermediate 1 IPSS risk MDS subject. 99. The use of embodiment 98, wherein the subject is transfusion dependent. 100. The use according to any one of embodiments 90 to 99, wherein the telomerase inhibitor is imetelstat and the use comprises administration of 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) Imetelstat administered intravenously at approximately 7-10 mg / kg once every 4 weeks; (b) intravenous administration of approximately 7 to 10 mg / kg of imetelstat once weekly for 4 weeks; (c) approximately 2.5 to 10 mg / kg of imetelstat administered intravenously once every three weeks; or (d) about 0.5-9.4 mg / kg of imetelstat administered intravenously once every 4 weeks. 10101. The use of embodiment 100, wherein each dosing cycle comprises about 7-10 mg / kg of imetelstat administered intravenously once every 4 weeks. 102. The use of embodiment 101, wherein each dosing cycle comprises intravenous administration of about 7.5 mg / kg of imetelstat once every 4 weeks.

Claims

1. 1. A composition comprising a telomerase inhibitor for use in a method of treating transfusion-dependent anemia in a subject, the method comprising: classifying the subject as having MDS that is relapsed or refractory to erythropoiesis stimulating agents (ESAs), having MDS with low or intermediate 1 IPSS risk, and having transfusion-dependent anemia; selecting the subject for treatment with the composition because the subject has been classified as having MDS that is relapsed or refractory to an erythropoiesis stimulating agent (ESA), MDS with a low or intermediate 1 IPSS risk, and transfusion-dependent anemia; and administering said composition to said subject to treat said transfusion-dependent anemia, wherein said telomerase inhibitor is imetelstat.

2. 2. The composition of claim 1, wherein the subject classified as having transfusion-dependent anemia has a transfusion requirement of about 4 units or more during the 8 weeks prior to administration of the composition.

3. The composition of claim 1 , wherein the subject has not been treated with lenalidomide.

4. The composition of claim 1 , wherein the subject is not undergoing treatment with a hypomethylating agent (HMA).

5. 2. The composition of claim 1, wherein the subject has not been treated with lenalidomide and a hypomethylating agent (HMA).

6. 5. The composition of claim 4, wherein the HMA is decitabine.

7. The composition of claim 4, wherein the HMA is azacytidine.

8. The composition of claim 1 , wherein the subject is a non-del5q human patient.

9. The composition of claim 1 , wherein the imetelstat is imetelstat sodium.

10. The composition is administered in 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles, each cycle comprising: (a) administering the composition intravenously once every four weeks at a dose of about 7-10 mg / kg of imetelstat; (b) administering the composition intravenously once a week for four weeks at a dose of about 7-10 mg / kg of imetelstat; (c) administering the composition intravenously once every three weeks at a dose of about 2.5-10 mg / kg of imetelstat; or (d) the composition of claim 1, comprising intravenous administration of said composition once every four weeks at a dose of about 0.5-9.4 mg / kg of imetelstat.

11. 11. The composition of claim 10, wherein each dosing cycle comprises intravenous administration of the composition once every four weeks at a dose of about 7-10 mg / kg of imetelstat.

12. 12. The composition of claim 11, wherein each dosing cycle comprises intravenous administration of the composition once every four weeks at a dose of about 7.5 mg / kg of imetelstat.

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