Methods of identifying patients likely to benefit from treatment with a telomerase inhibitor

Abstract

This disclosure provides a method for identifying or selecting patients most likely to benefit from treatment with a telomerase inhibitor such as imemenostabdominal, by testing patients who: lack mutations in any of the following: JAK2, CALR, and MPL; and / or have a high molecular weight risk (HMR) for mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2. These patients may have myelofibrosis. This disclosure also provides a method for treating myelofibrosis, which includes identifying such patients.

Description

[Technical Field] Cross-reference of related applications Pursuant to 35 USC §119(e), this application claims priority to the filing dates of U.S. Provisional Patent Application No. 62 / 712,841, filed July 31, 2018, and U.S. Provisional Patent Application No. 62 / 772,849, filed November 29, 2018; the disclosures of the aforementioned applications are incorporated herein by reference. sequence list This application contains a sequence list, which has been submitted electronically in ASCII format and is hereby incorporated by full reference. The ASCII copy is named Sequence_Listing.txt and is 356KB in size. This application relates to a method for identifying patients most likely to benefit from telomerase inhibitor therapy by identifying patients who: lack mutations in each of JAK2, CALR, and MPL; and / or have a high molecular weight risk (HMR) based on mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2. The invention also relates to a method for treating myelofibrosis in individuals in need (i.e., patients) with telomerase inhibitors. [Previous Technology] Foreword Myelofibrosis (MF) is a type of classic BCR-ABL1-negative chronic myeloproliferative neoplasm (MPN), characterized by pure myeloproliferation and dysregulated kinase signaling. Cervantes, Blood, 124(17): 2635-2642 (2014). It is also characterized by cytopenia, systemic symptoms, splenomegaly, and the potential to transform into acute myeloid leukemia. Kuykendall et al., Annals of Hematology, 97: 435-431 (2018). MF is a Philadelphia chromosome-negative myeloproliferative neoplasm with a poor prognosis, for which the JAK1 / JAK2 inhibitor ruxolitinib is currently the approved treatment. Ruxolitinib, a Janus kinase (JAK)-1 and JAK-2 inhibitor, is a first-in-class drug awaiting US approval for the treatment of high- and intermediate-risk myelofibrosis (MF). Pardanani et al., Blood Cancer J.; 4(12): e268 (2014). Several other JAK inhibitors are under development, some of which are currently undergoing Phase 3 clinical trials. Ibid. Other treatment options for MF include allo-SCT, hydroxyurea, interferon, lenalidomide (Revlimid®), and thalidomide. Currently, there are ongoing clinical trials evaluating selective JAK inhibitors, histone deacetase / DNA methyltransferase inhibitors, PI3K inhibitors, hedgehog / mammal rapamycin-targeted (mTOR) inhibitors, antifibrotic agents, immunomodulators, monoclonal antibodies, and immune checkpoint inhibitors for MF. Shreenivas et al., Expert Opinion on Emerg Drugs, 23(1): 37-49 (2018). Other MPNs include essential thrombocythemia (ET) and polycythemia vera (PV). Cervantes (see below). MF may recur (primary MF [PMF]) or occur after a previous ET or PV (post-ET or post-PVMF). Ibid. According to Cervantes, MF is the pure lineage proliferation of pluripotent hematopoietic stem cells, in which abnormal cell populations release several cytokines and growth factors in the bone marrow, leading to myelofibrosis and stromal changes, and colonization of extramedullary organs such as the spleen and liver. Ibid. Myelofibrosis is associated with mutations in the Jenners kinase (JAK)2 gene (such as the V617F mutation), mutations in the thrombopoietin receptor gene (MPL), and mutations in the calcium reticulum protectant protein gene (CALR). Ibid. It primarily affects the elderly, and according to Cervantes, "currently, there is no curative treatment except for allogeneic hematopoietic stem cell transplantation (allo-SCT), which is applicable to a small number of patients." Ibid. In fact, according to Langabeer, "most patients with classic myeloproliferative neoplasms (MPNs) of polycythemia vera, essential thrombocythemia, and essential myelofibrosis have various diseases that drive mutations in the JAK2, CALR, or MPL genes." Langabeer, JAK-STAT, 5: e1248011 (2016). These mutations are known as driver mutations. Exemplary driver mutations include JAK2V617F, accompanied by mutations in JAK2 exon 12, MPL exon 10, and CALR exon 9. Ibid. According to Spiegel, in myelofibrosis (MF), driver mutations in JAK2, MPL, or CALR affect survival and progression to the germline stage, with the greatest risk arising from triple-negative status (i.e., non-mutated JAK2, MPL, and CALR). Spiegel et al., Blood Adv., 1(20): 1729-1738 (2017). In fact, the absence of JAK2 / MPL / CALR mutations (i.e., triple-negative) is associated with the worst outcomes. Pardauani et al., Journal of Blood Cancer; 4(12): e268 (2014); see also Tefferi et al., Blood, 124(16): 2507-13 (2014). Furthermore, mutations in high molecular risk (HMR) genes such as ASXL1, EZH2, IDH1 / 2, and SRSF2 are also associated with poor prognosis. Spiegel et al. The presence of an increasing number of prognostic / high molecular risk mutations (i.e., ASXL1, EZH2, SRSF2 and / or IDH-1 / 2 genes) is leading to progressively worse survival outcomes, which is unrelated to traditional risk factors. Guglielmelli et al., Leukemia, 28(9): 1804-10 (2014). Driver mutations in JAK2, MPL, or CALR, either alone or in combination with subhomologous mutations in genes (such as ASXL1), are associated with differences in overall survival (OS). Spiegel et al. Triple-negative patients lacking typical mutations in JAK2, MPL, or CALR have an increased risk of leukemic transformation and shorter OS. Spiegel observed that in patients with myelofibrosis treated with ruxolitinib or momelotinib (JAK 1 / 2 inhibitors), these mutations were associated with shorter time to treatment failure. Ibid. Similarly, “comparing the clinical characteristics of JAK2-positive, CALR-positive, MPL-positive, and TN MF patients, patients with CALR mutations had significantly lower hemoglobin (mean, 8.6 vs. 10.7 g / dL; P 5.001) and white blood cell count (mean, 11.0 vs. 25 g / dL; p 5.033), a trend reported in other MPN cohorts.” Patel et al., Blood; 126(6): 790-797 (2015). Patel et al. observed an inverse correlation between splenic response and time to treatment discontinuation in patients with the three mutations in [Figure] treated with ruzotinib. Driver mutations or triple-negative (JAK2, MPL, CALR) status were found in myelofibrotic patients who discontinued JAK inhibitor therapy. See, for example, Kuykendall et al. [Summary of the Invention] This invention provides a method for identifying or selecting patients most likely to benefit from treatment with telomerase inhibitors (such as imetelstat), by testing patients for: lack of mutations in each of the Jenners kinase 2 (JAK2), calcium reticulum protectant (CALR), and thrombopoietin receptor (MPL) genes; and / or based on a high molecular weight risk (HMR) of mutations in at least one of the following genes: sex comb-like 1 (ASXL1), zeste gene enhancer homolog 2 (EZH2), serine and arginine splicing factor 2 (SRSF2), and isocitrate dehydrogenase 1 / 2 (IDH1 / 2). Patients requiring treatment may have myelofibrosis. This invention also provides a method for treating myelofibrosis in patients requiring said treatment, comprising the step of identifying such patients. One specific embodiment of the present invention is a method for identifying myelofibrosis patients most likely to benefit from treatment with telomerase inhibitors, comprising: (a) testing patients who: (i) are triple-negative based on the absence of mutations in each of the JAK2, CALR, and MPL genes, and / or (ii) have mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2; and (b) selecting patients who: (i) are triple-negative based on the absence of mutations in each of the JAK2, CALR, and MPL genes, and / or (ii) have a high molecular weight risk (HMR) for mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2, wherein the selected patients are most likely to benefit from treatment with telomerase inhibitors. An alternative embodiment of the present invention is a method for identifying patients most likely to benefit from treatment with a telomerase inhibitor, comprising: (a) testing patients who are triple-negative based on the absence of mutations in each of the JAK2, CALR, and MPL genes; and (b) selecting patients who are triple-negative, wherein the selected patients are most likely to benefit from treatment with a telomerase inhibitor. An alternative embodiment of the present invention is a method for identifying patients most likely to benefit from treatment with a telomerase inhibitor, comprising: (a) testing patients who are high molecular weight risk (HMR) for mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2; and (b) selecting patients who are high molecular weight risk (HMR) for mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2. The present invention further provides a method for treating myelofibrosis in patients with triple-negative and / or HMR conditions with a telomerase inhibitor such as, for example, imesta. Another specific embodiment of the present invention is a method for identifying patients with myelofibrosis who are most likely to benefit from telomerase inhibitor treatment, comprising: (a) obtaining a DNA sample from the patient; (b) testing the DNA sample from the patient against: (i) a triple-negative status based on the absence of mutations in each of the JAK2, CALR, and MPL genes; and / or (ii) a high molecular weight risk (HMR) based on the presence of mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2; and (c) selecting a patient who: (i) is a triple-negative status based on the absence of mutations in each of the JAK2, CALR, and MPL genes; and / or (ii) has a high molecular weight risk (HMR) based on the presence of mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2, wherein the selected patient is most likely to benefit from telomerase inhibitor treatment. In some specific embodiments of the method, the DNA sample is obtained from bone marrow, peripheral blood, or both. DNA samples can be obtained by first obtaining a bone marrow sample, a peripheral blood sample, or both, and then isolating DNA from the bone marrow sample, peripheral blood sample, or both. In one specific embodiment, the step of obtaining a DNA sample from a patient includes: obtaining a bone marrow sample from the patient, isolating cells from the bone marrow sample, and extracting DNA from the isolated cells. In another specific embodiment, the step of obtaining a DNA sample from a patient includes: obtaining a peripheral blood sample from the patient; isolating cells (e.g., granular cells) from the peripheral blood sample; and extracting DNA from the isolated cells. Another specific embodiment of the present invention is a method for identifying patients with myelofibrosis who are most likely to benefit from treatment with telomerase inhibitors, comprising testing patients who: (a) are triple-negative based on the absence of any mutations in the JAK2, CALR, and MPL genes; and (b) have a high molecular weight risk (HMR) of mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2; or (c) both; wherein the presence of (a), (b), or (c) indicates that the patient is most likely to benefit from treatment with telomerase inhibitors. In any of these approaches, the patient may develop myelofibrosis. Myelofibrosis can be: primary myelofibrosis; myelofibrosis following polycythemia vera (MF after PV); or myelofibrosis following essential thrombocythemia (MF after ET). In some specific embodiments, the patient has not previously received JAK inhibitor therapy. In other specific embodiments, the patient has previously received JAK inhibitor therapy and the JAK inhibitor therapy "failed" (i.e., the disease is resistant to the therapy, or the patient is difficult to treat with the therapy, or the disease has relapsed despite an initial response to treatment). In other specific embodiments, the patient has received JAK inhibitor therapy and has discontinued JAK inhibitor therapy due to treatment-related toxicity or intolerance. The method may also include the step of administering a telomerase inhibitor once such patients have been identified. In some specific embodiments, the telomerase inhibitor is imelmata or a pharmaceutically acceptable salt thereof. In other specific embodiments, imelmata is imelmata sodium. When imerestat is used to treat patients identified by these methods, imerestat is administered for 1, 2, 3, 4, 5, 6, 7, 8, or more than 8 dosing cycles, each cycle comprising: an intravenous injection of approximately 7-10 mg / kg imerestat once every three weeks; an intravenous injection of approximately 7-10 mg / kg imerestat once weekly for three weeks; an intravenous injection of approximately 2.5-10 mg / kg imerestat once every three weeks; or an intravenous injection of approximately 0.5-9.4 mg / kg imerestat once every three weeks. In one specific embodiment, each dosing cycle comprises an intravenous injection of approximately 7-10 mg / kg imerestat once every three weeks. In another specific embodiment, each dosing cycle comprises an intravenous injection of approximately 9.4 mg / kg imerestat once every three weeks. When using emelestat sodium to treat patients identified by these methods, emelestat sodium is administered for 1, 2, 3, 4, 5, 6, 7, 8, or more than 8 dosing cycles, each cycle comprising: an intravenous injection of approximately 7-10 mg / kg emelestat sodium once every three weeks; an intravenous injection of approximately 7-10 mg / kg emelestat sodium once weekly for three weeks; an intravenous injection of approximately 2.5-10 mg / kg emelestat sodium once every three weeks; or an intravenous injection of approximately 0.5-9.4 mg / kg emelestat sodium once every three weeks. In one specific embodiment, each dosing cycle comprises an intravenous injection of approximately 7-10 mg / kg emelestat sodium once every three weeks. In another specific embodiment, each dosing cycle comprises an intravenous injection of approximately 9.4 mg / kg emelestat sodium once every three weeks. Another specific embodiment of the present invention is a method for treating a patient with myelofibrosis with a telomerase inhibitor such as imetrostat or imetrostat sodium, comprising: (i) Screening patients to determine whether they have: a triple-negative status based on the absence of mutations in each of JAK2, CALR, and MPL, and / or a high molecular weight risk (HMR) based on the presence of mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2; and (ii) If the patient has a triple-negative status based on the absence of mutations in any of JAK2, CALR, and MPL, and / or a high molecular weight risk (HMR) based on the presence of mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2, then the patient is given a telomerase inhibitor. Myelofibrosis may be: primary myelofibrosis, myelofibrosis following polycythemia vera (MF after PV), or myelofibrosis following essential thrombocythemia (MF after ET). In some specific embodiments, the patient has not previously received JAK inhibitor therapy. In another specific embodiment, the patient has previously received JAK inhibitor therapy and the JAK inhibitor therapy failed, or has previously received JAK inhibitor therapy and discontinued JAK inhibitor therapy due to treatment-related toxicity or intolerance. In certain specific embodiments of the treatment method, the telomerase inhibitor is imemenol, and it is administered for 1, 2, 3, 4, 5, 6, 7, 8, or more than 8 dosing cycles, each cycle comprising: an intravenous injection of approximately 7-10 mg / kg imemenol once every three weeks; an intravenous injection of approximately 7-10 mg / kg imemenol once weekly for three weeks; an intravenous injection of approximately 2.5-10 mg / kg imemenol once every three weeks; or an intravenous injection of approximately 0.5-9.4 mg / kg imemenol once every three weeks. In some specific embodiments, each dosing cycle comprises an intravenous injection of approximately 7-10 mg / kg imemenol once every three weeks. In other specific embodiments, each dosing cycle comprises an intravenous injection of approximately 9.4 mg / kg imemenol once every three weeks. In some specific embodiments of the method for identifying or selecting patients most likely to benefit from treatment with a telomerase inhibitor, the method further includes determining the mean relative telomere length by analyzing the relative length of telomere nucleic acids in target cells present in a biological sample from the patient. In some specific embodiments of the method for identifying or selecting patients most likely to benefit from treatment with a telomerase inhibitor, the method further includes selecting patients identified as having a mean relative telomere length in target cells present in a biological sample from the patient that is determined to be within the 50th percentile or less of a range of relative telomere lengths determined by one or more known criteria. In some specific embodiments, the telomerase inhibitor is imemenol or a pharmaceutically acceptable salt thereof. In other specific embodiments, imemenol is imemenol sodium. This disclosure provides a method of treating a patient with myelofibrosis with a telomerase inhibitor, comprising: administering a telomerase inhibitor to the patient if the patient has a triple-negative status based on the absence of mutations in JAK2, CALR, and MPL. In some embodiments, the telomerase inhibitor is imelmeta or a pharmaceutically acceptable salt thereof. In other embodiments, imelmeta is imelmeta sodium. This disclosure provides a method of treating a patient with myelofibrosis with a telomerase inhibitor, comprising administering a telomerase inhibitor to the patient if the patient has a triple-negative status based on the absence of mutations in each of JAK2, CALR, and MPL, and / or has a high molecular risk (HMR) based on the presence of mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2. This disclosure provides a method for treating a patient with myelofibrosis with a telomerase inhibitor, comprising: administering a telomerase inhibitor to the patient if the patient has one or more of the following characteristics: (a) The mean relative telomere length of target cells in biological samples from an individual is determined to be within the 50th percentile or less of the range of relative telomere lengths determined by one or more known criteria. (b) Based on the absence of mutations in any of the JAK2, CALR, and MPL triple-negative states; and (c) Based on a high molecular weight risk (HMR) of mutations in at least one of the following genes: ASXL1, EZH2, SRSF2, and IDH1 / 2. In some specific embodiments, the telomerase inhibitor is imelmeta or a pharmaceutically acceptable salt thereof. In other specific embodiments, imelmeta is imelmeta sodium. This disclosure provides a method for identifying individuals with myelofibrosis (MF) for treatment with telomerase inhibitors, the method comprising: measuring hTERT expression levels in biological samples obtained from the patient after administration of a telomerase inhibitor; and comparing the hTERT expression levels in the biological samples with baseline hTERT expression levels before administration of the telomerase inhibitor; wherein a decrease in hTERT expression levels in the biological samples identifies patients with an increased likelihood of benefiting from telomerase inhibitor treatment. This disclosure provides a method for treating myelofibrosis (MF), the method comprising: administering an effective amount of a telomerase inhibitor to an individual in need; and assessing the hTERT expression level in a biological sample obtained from the patient after administration of the telomerase inhibitor. In some specific embodiments, the telomerase inhibitor is imelmata or a pharmaceutically acceptable salt thereof. In other specific embodiments, imelmata is imelmata sodium. This disclosure provides a method for monitoring the efficacy of treatment in individuals with myelofibrosis (MF), the method comprising: measuring hTERT expression levels in a biological sample obtained from the patient after administration of a telomerase inhibitor; and comparing the hTERT expression levels in the biological sample with baseline hTERT expression levels before administration of the telomerase inhibitor; wherein a 50% or greater reduction in hTERT expression levels in the biological sample identifies individuals with an increased likelihood of benefiting from telomerase inhibitor treatment. In some specific embodiments, the telomerase inhibitor is imelmeta or a pharmaceutically acceptable salt thereof. In other specific embodiments, imelmeta is imelmeta sodium. This disclosure provides a method for selecting patients most likely to benefit from telomerase inhibitor treatment, comprising: testing the patient’s mean relative telomere length by analyzing the relative length of telomere nucleic acids present in target cells from the patient’s biological sample; and selecting patients who are most likely to benefit from telomerase inhibitor treatment if the mean relative telomere length of the target cells present in the patient’s biological sample is determined to be within the 50th percentile or less of a range of relative telomere lengths determined by one or more known criteria. This disclosure provides a method for identifying patients most likely to benefit from treatment with telomerase inhibitors, comprising: obtaining a biological sample from the patient; determining the mean relative telomere length by analyzing the relative length of telomere nucleic acids present in target cells from the patient's biological sample; and identifying the patient most likely to benefit from treatment with telomerase inhibitors if the mean relative telomere length in the target cells present in the patient's biological sample is determined to be within the 50th percentile or less of a range of relative telomere lengths determined by one or more known criteria. This disclosure provides a method of treating a patient with myelofibrosis with a telomerase inhibitor, comprising: administering a telomerase inhibitor to the patient if the mean relative telomere length in target cells present in a biological sample derived from the patient is determined to be within the 50th percentile or less of a range of relative telomere lengths determined by one or more known criteria. In some specific embodiments, the telomerase inhibitor is imelmata or a pharmaceutically acceptable salt thereof. In other specific embodiments, imelmata is imelmata sodium. This disclosure provides a method for monitoring the efficacy of treatment in individuals with myelofibrosis (MF), the method comprising: measuring hTERT expression levels in a biological sample obtained from the patient after administration of a telomerase inhibitor; and comparing the hTERT expression levels in the biological sample with baseline hTERT expression levels before administration of the telomerase inhibitor; wherein a 50% or greater reduction in hTERT expression levels in the biological sample identifies individuals with an increased likelihood of benefiting from telomerase inhibitor treatment. In some embodiments, the measured or assessed hTERT expression level is hTERT RNA expression level. In some embodiments, the telomerase inhibitor is imelmeta or a pharmaceutically acceptable salt thereof. In other embodiments, imelmeta is imelmeta sodium. This disclosure provides a method for identifying patients with myelofibrosis (MF) for treatment with telomerase inhibitors, the method comprising: measuring hTERT expression levels in biological samples obtained from the patient after administration of a telomerase inhibitor; and comparing the hTERT expression levels in the biological samples with baseline hTERT expression levels before administration of the telomerase inhibitor; wherein a decrease in hTERT expression levels in the biological samples identifies patients with an increased likelihood of benefiting from telomerase inhibitor treatment. This disclosure provides a method for monitoring the efficacy of treatment in individuals with myelofibrosis (MF), the method comprising: measuring telomerase activity in a biological sample obtained from the patient after administration of a telomerase inhibitor; and comparing the telomerase activity in the biological sample with a baseline telomerase activity before administration of the telomerase inhibitor; wherein a 50% or greater reduction in telomerase activity in the biological sample identifies individuals with an increased likelihood of benefiting from telomerase inhibitor treatment. In some specific embodiments, the telomerase inhibitor is imelmeta or a pharmaceutically acceptable salt thereof. In other specific embodiments, imelmeta is imelmeta sodium. [Simplified Explanation of the Diagram] The foregoing description of the invention and the following detailed description will be better understood when read in conjunction with the accompanying drawings. The drawings illustrate embodiments of the invention for illustrative purposes. However, it should be understood that the invention is not limited to the precise configurations, examples, and means shown. Figure 1 shows a waterfall plot of spleen volume reduction (SVR) at week 24 in the 4.7 mg / kg and 9.4 mg / kg treatment groups in Example 1. SVR is shown as a percentage change relative to baseline. Figure 2 shows a waterfall plot of the total symptom score (TSS) reduction at week 24 in the 4.7 mg / kg and 9.4 mg / kg treatment groups in Example 1. TSS is shown as a percentage change relative to baseline. Figure 3 shows the Kaplan-Meier plot of total survival grouped by mutation status of the JAK2 / MPL / CALR genes: for the 4.7 mg / kg group, TN versus non-TN (MUT). Specifically, Figure 3 shows the survival probability as a function of time for patients with triple-negative status (TN) and patients with at least one mutation (MUT). Figure 4 shows the Kaplan-Mel plot of total survival grouped by mutation status of the JAK2 / MPL / CALR genes: TN versus non-TN (MUT) for the 9.4 mg / kg group. Specifically, Figure 4 shows the survival probability as a function of time for patients with triple-negative status (TN) and patients with at least one mutation (MUT) in the 9.4 mg / kg group. Figure 5 shows the Kaplan-Mel plot of total survival as a function of time in the 9.4 mg / kg group versus the 4.7 mg / kg group, based on patient grouping. Figure 6 shows the Kaplan-Mel plot of overall survival (OS) grouped by mutation status of the JAK2 / MPL / CALR genes: TN versus non-TN for the 9.4 mg / kg group. Specifically, Figure 6 shows the survival probability as a function of time for patients with triple-negative status (TN) and patients with at least one mutation (non-TN) in the 9.4 mg / kg group. Figure 7 shows the Kaplan-Mel plot of overall survival (OS) grouped by mutation status of the JAK2 / MPL / CALR genes: TN versus non-TN for the 4.7 mg / kg group. Specifically, Figure 7 shows the survival probability as a function of time for patients with triple-negative status (TN) and patients with at least one mutation (non-TN) in the 4.7 mg / kg group.

Implementation Method

Claims

1. The use of imesta or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating patients with myelofibrosis, wherein: (a) The patient is determined to have a triple-negative status, wherein the triple-negative status includes the absence of mutations in each of the genes for Jenners kinase 2 (JAK2), calcium reticulum protectant (CALR), and thrombopoietin receptor (MPL).

2. The use as described in claim 1, wherein (b) the patient is further identified as having a high molecular risk (HMR), wherein having an HMR includes a mutation in at least one gene selected from the group consisting of extra comb-like 1 (ASXL1), zeste gene enhancer homolog 2 (EZH2), serine and arginine splicing factor 2 (SRSF2), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2); and (c) the patient with myelofibrosis, wherein cells present in biological samples from the patient have been identified as having a mean relative telomere length measured at or below the 50th percentile of a range of relative telomere lengths determined by one or more known criteria.

3. The use as described in claim 1, wherein it is further determined that the patient has a high molecular risk (HMR), wherein having an HMR includes the presence of a mutation in at least one gene selected from the group consisting of ASXL1, EZH2, SRSF2, IDH1 and IDH2.

4. The use as described in claim 1, wherein the patient has myelofibrosis, and wherein cells present in biological samples derived from the patient have been determined to have an average relative telomere length measured to be within the 50th percentile or less of a range of relative telomere lengths determined by one or more known criteria.

5. The use as described in claim 1, wherein the myelofibrosis is selected from the group consisting of: primary myelofibrosis, myelofibrosis following polycythemia vera (MF after PV), and myelofibrosis following essential thrombocythemia (MF after ET).

6. The use as described in claim 1, wherein the patient has not previously received JAK inhibitor therapy.

7. The use as described in claim 1, wherein the patient: has received JAK inhibitor therapy and is difficult to treat with JAK inhibitor therapy; has received JAK inhibitor therapy and has relapsed; or has received JAK inhibitor therapy and discontinued JAK inhibitor therapy due to treatment-related toxicity or intolerance.

8. The use as described in claim 7, wherein the imesta or its pharmaceutically acceptable salt is imesta sodium.

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