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US-20260125485-A1 - DENOSUMAB AND COLCHICINE TO PREVENT BLOOD CANCER AND AGING DISEASE IN PATIENTS WITH CLONAL HEMATOPOIESIS

US20260125485A1US 20260125485 A1US20260125485 A1US 20260125485A1US-20260125485-A1

Abstract

In one aspect, the disclosure relates to a method for treating clonal hematopoiesis of indeterminate potential (CHIP) in a subject, the method including at least the step of administering to the subject a therapeutically effective amount of an inhibitor of receptor activator of nuclear factor κB ligand (RANKL), such as denosumab, a therapeutically effective amount of an anti-inflammatory agent, such as colchicine, or both. In a further aspect, performing the method reduces growth of one or more clones or causes the size of one or more clones to remain constant. In another aspect, each month of performing the method can result in a further reduction of annual clonal growth rate. In a still further aspect, performing the method further treats or prevents a cardiometabolic disease, a cardiovascular disease, or a myeloproliferative disease or disorder. Also disclosed are methods for reducing or maintaining clonal hematopoiesis risk score (CHRS) in a subject.

Inventors

  • Taralynn Mack
  • Yash PERSHAD
  • Alexander Bick

Assignees

  • VANDERBILT UNIVERSITY

Dates

Publication Date
20260507
Application Date
20251028

Claims (20)

  1. 1 . A method for treating clonal hematopoiesis of indeterminate potential (CHIP) in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of receptor activator of nuclear factor κB ligand (RANKL), a therapeutically effective amount of an anti-inflammatory agent, or both.
  2. 2 . The method of claim 1 , wherein the inhibitor of RANKL comprises denosumab.
  3. 3 . The method of claim 2 , wherein the inhibitor of RANKL is administered by injection.
  4. 4 . The method of claim 2 , wherein the inhibitor of RANKL is administered once every six months.
  5. 5 . The method of claim 1 , wherein the anti-inflammatory agent comprises colchicine.
  6. 6 . The method of claim 5 , wherein the anti-inflammatory agent is administered orally.
  7. 7 . The method of claim 5 , wherein the anti-inflammatory agent is administered daily.
  8. 8 . The method of claim 1 , further comprising detecting at least one CHIP mutation in the subject prior to performing the method.
  9. 9 . The method of claim 1 , wherein performing the method reduces growth of one or more clones relative to an untreated control.
  10. 10 . The method of claim 1 , wherein performing the method causes a size of one or more clones to remain constant.
  11. 11 . The method of claim 1 , wherein the method is performed for at least one year.
  12. 12 . The method of claim 11 , wherein each month of performing the method results in a reduction of annual clonal growth rate of from about 2.5% to about 3.5%.
  13. 13 . The method of claim 1 , wherein both an inhibitor of RANKL and an anti-inflammatory agent are administered.
  14. 14 . The method of claim 1 , wherein performing the method further treats or prevents at least one cardiometabolic or cardiovascular disease.
  15. 15 . The method of claim 14 , wherein the at least one cardiometabolic or cardiovascular disease comprises peripheral artery disease, non-alcoholic fatty liver disease (NAFLD), hypertension, hyperlipidemia, or atherosclerosis.
  16. 16 . The method of claim 1 , wherein performing the method further treats or prevents at least one myeloproliferative disease or disorder.
  17. 17 . The method of claim 16 , wherein the at least one myeloproliferative disease or disorder comprises chronic myelomonocytic leukemia, chronic myeloid leukemia, anemia, thrombocytopenia, thrombocytosis, polycythemia, or any combination thereof.
  18. 18 . A method for reducing or maintaining clonal hematopoiesis risk score (CHRS) in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of receptor activator of nuclear factor κB ligand (RANKL), a therapeutically effective amount of an anti-inflammatory agent, or both.
  19. 19 . The method of claim 18 , wherein the inhibitor of RANKL comprises denosumab.
  20. 20 . The method of claim 18 , wherein the anti-inflammatory agent comprises colchicine.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/715,157 filed on Nov. 1, 2024, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant OD029586 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) occurs when a hematopoietic stem cell acquires a somatic driver mutation in a leukemia-associated gene, with a variant allele fraction (VAF) exceeding 2% in peripheral blood. Higher VAF is associated with increased morbidity and mortality risk. Identifying factors influencing clonal expansion rate is crucial for risk stratification in CHIP patients. Recent cost-effective targeted assays have enabled serial sequencing and longitudinal profiling of CHIP dynamics. Despite advances in CHIP research, there is still a scarcity of compounds that are effective in the treatment and/or prevention of cardiovascular, cardiometabolic, and myeloproliferative diseases and disorders associated with CHIP. These needs and other needs are satisfied by the present disclosure. SUMMARY In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to a method for treating clonal hematopoiesis of indeterminate potential (CHIP) in a subject, the method including at least the step of administering to the subject a therapeutically effective amount of an inhibitor of receptor activator of nuclear factor κB ligand (RANKL), such as denosumab, a therapeutically effective amount of an anti-inflammatory agent, such as colchicine, or both. In a further aspect, performing the method reduces growth of one or more clones or causes the size of one or more clones to remain constant. In another aspect, each month of performing the method can result in a further reduction of annual clonal growth rate. In a still further aspect, performing the method further treats or prevents at least one cardiometabolic disease, at least one cardiovascular disease, or at least one myeloproliferative disease or disorder. Also disclosed are methods for reducing or maintaining clonal hematopoiesis risk score (CHRS) in a subject. Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another. BRIEF DESCRIPTION OF THE DRAWINGS Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views. FIGS. 1A-1G show cohort characteristics and co-occurring clonal hematopoiesis of indeterminate potential (CHIP) mutations. (FIG. 1A) The cohort consists of 892 CHIP mutations in 711 individuals. Growth rate was calculated using a compound interest formula for sequencing at two blood draws. (FIG. 1B) Larger bar plot demonstrates the number of CHIP with a mutation in a driver gene. Smaller bar plot shows the number of individuals with 1, 2, 3, and 4 CHIP mutations. (FIG. 1C) Box plot of growth rate, calculated with a compound interest formula, for each CHIP mutation by driver gene with number of individuals with mutations in the driver gene shown below the gene name. Red diamond represents the mean growth rate. Box represents the interquartile range of the growth rate. Middle line in the box represents the median of the growth rate. (FIG. 1D) Theoretical example of possible trajectories for individuals with two CHIP mutations. The mutations can either be in distinct cell populations or the same cell population. Variant allele fraction (VAF) trajectories for each of these scenarios should follow similar trends to this example. Each mutation is represented by color, and the line represents change in VAF between first and second blood draws. (FIG. 1E) Box plot showing the difference in average growth rate of the fastest growing mutations for the 116 individuals grouped into the distinct vs sub-clone categories. T