statins in patients with clonal cytopenia of undetermined significance (ccus) and myelodysplastic syndromes (mds)

Conditions: Clonal Cytopenia of Undetermined Significance; Myelodysplastic Syndromes

Summary: 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.


Eligibility criteria:
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.

Keywords: ccus mds statins inflammation