Statins in Patients With Clonal Cytopenia of Undetermined Significance (CCUS) and Myelodysplastic Syndromes (MDS)

Pilot Study of Statins in Patients With Clonal Cytopenia of Undetermined Significance (CCUS) and Myelodysplastic Syndromes (MDS)

Patients with clonal cytopenia of undetermined significance (CCUS) and lower-risk myelodysplastic syndromes (MDS) have a life expectancy of 5 to 10 years. Mortality in these patients results from progression of disease to higher-risk MDS or acute myeloid leukemia (AML) and cardiovascular events. Currently there are no FDA-approved treatments with the potential to improve survival of patients with CCUS and lower-risk MDS. Statins are an appealing class of drugs to consider in this situation as preclinical data support their potential to suppress progression of myeloid malignancy, and they have a well-established role in prevention of major cardiovascular events. This is a pilot study to explore the role of statins in treatment of patients with CCUS and lower-risk MDS. In this study, change in inflammatory biomarkers and variant allele frequency (VAF) of somatic mutations will be used as a surrogate marker of response to statin therapy. The hypothesis is that the use of statins at diagnosis of CCUS or lower-risk MDS will reduce inflammation and delay or prevent the expected increase in the VAF of somatic mutations over time.

Study Overview

• Status: Recruiting
• Conditions: Myelodysplastic Syndromes; Clonal Cytopenia of Undetermined Significance
• Intervention / Treatment: Drug: Atorvastatin; Drug: Rosuvastatin

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Amber Afzal, M.D., MSCI; Phone Number: 314-273-0564; Email: afzalamber@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Amber Afzal, M.D., MSCI; Phone Number: 314-273-0564; Email: afzalamber@wustl.edu
      • Principal Investigator: Amber Afzal, M.D., MSCI
      • Sub-Investigator: Feng Gao, Ph.D.
      • Sub-Investigator: Meagan Jacoby, M.D., Ph.D.
      • Sub-Investigator: Matthew Walter, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of CCUS or lower-risk MDS as defined below:

  • CCUS is defined as the presence of somatic mutation(s) in recurrently mutated genes identified through the clinical MyeloSeq assay with a VAF ≥ 2% in the absence of bone marrow morphology/cytogenetic changes diagnostic of MDS PLUS unexplained persistent cytopenia in at least one lineage for at least 6 months:

    • Hemoglobin < 11.3 g/dL in females or < 13 g/dL in males
    • ANC < 1.8 x 109/L
    • Platelets < 150 x 109/L
  • MDS is defined using the WHO 2016 definition and classified into lower-risk if IPSS-R score is ≤ 3.5 . Lower-risk MDS will be required to have at least one mutation in a recurrent mutated gene with a VAF ≥ 2%.
• Patient must be transfusion independent.
• At least 18 years of age.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• CCUS patients with cytogenetic change alone.
• Current or prior use of disease-modifying therapy (e.g., lenalidomide, Luspatercept, Imitelstat, HMAs, venetoclax) with any dose within the last 3 months, with the exception of concurrent use of erythropoetin stimulating agents
• Prior use of a statin within 1 year prior to start of treatment.
• A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence active of disease.
• Currently receiving any investigational agent for CCUS/MDS. The minimum interval between the last dose of investigational agent used for CCUS/MDS and Day 1 of this trial should be 5 half-lives of the investigational agent.
• A history of allergic reactions or intolerance attributed to compounds of similar chemical or biologic composition to atorvastatin, rosuvastatin, any other statin, or other agents used in the study.
• Uncontrolled intercurrent illness including, but not limited to, symptomatic infection, sepsis, or active liver disease (acute liver failure, decompensated cirrhosis, or persistent elevation in ALT or AST > 3 x ULN), or any other comorbidity that would preclude statin use based on FDA recommendation.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
• Patients with HIV and HCV are not eligible for the trial if they are concomitantly receiving active treatment for HIV/HCV given the concern for potential drug interactions. The minimum interval between the last dose of antiviral and enrollment into the study should be 28 days or 5 half-lives of the antiviral drug, whichever is longer. The liver function profile of eligible HIV/HCV patients must be within the acceptable limits.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Atorvastatin; Choice of statin is at the discretion of the treating physician and may depend on insurance approval.; Atorvastatin dosing starts at 80 mg once daily.; In the absence of disease progression or intolerable side effects, patients may receive up to 12 months of treatment.; If a patient switches statins due to toxicity, treatment time is still limited to 12 months total (ie, if a patient receives 6 months of atorvastatin and switches to rosuvastatin, the duration of rosuvastatin will be no more than 6 months).	Drug: Atorvastatin; Atorvastatin is commercially available.; Other Names: Lipitor
Experimental: Rosuvastatin; Choice of statin is at the discretion of the treating physician and may depend on insurance approval.; Rosuvastatin dosing starts at 40 mg once daily.; In the absence of disease progression or intolerable side effects, patients may receive up to 12 months of treatment.; If a patient switches statins due to toxicity, treatment time is still limited to 12 months total (ie, if a patient receives 6 months of atorvastatin and switches to rosuvastatin, the duration of rosuvastatin will be no more than 6 months).	Drug: Rosuvastatin; Rosuvastatin is commercially available.; Other Names: Crestor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in hs-CTRP levels in peripheral blood during statin therapy	Pre-treatment, every 3 months while on treatment, end of treatment, 3 months after end of treatment and time of progression (estimated to be 15 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in allele burden (VAF) of somatic mutation	-Assessed by next generation sequencing (NGS) performed on peripheral blood/bone marrow.	Pre-treatment, every 3 months while on treatment, end of treatment, 3 months after end of treatment and time of progression (estimated to be 15 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Amber Afzal, M.D., MSCI, Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2024
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: July 28, 2022
• First Submitted That Met QC Criteria: July 28, 2022
• First Posted (Actual): August 1, 2022

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; MDS; Statins; CCUS
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Blood Platelet Disorders; Precancerous Conditions; Leukocyte Disorders; Syndrome; Myelodysplastic Syndromes; Preleukemia; Anemia; Thrombocytopenia; Leukopenia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium
• Other Study ID Numbers: 202211020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Washington University in St Louis supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required (as a condition of research awards and/or as otherwise required).
• IPD Sharing Time Frame: Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication.
• IPD Sharing Access Criteria: Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No