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

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 variant allele frequency (VAF) of somatic mutations present at diagnosis 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 delay or prevent the expected increase in the VAF of somatic mutations over time.

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.

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.

-Defined as Time from diagnosis of CCUS/lower-risk MDS to development of higher-risk MDS/AML, major cardiovascular events, or all-cause mortality, whichever occurs first

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 cytopenia in at least one lineage: Hemoglobin < 11.3 g/dL in females or < 12.9 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%. 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: Eligible to receive HMAs, lenalidomide, or stem cell transplant at time of enrollment. Prior use of a statin within 6 months prior to enrollment. 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 enrollment into this trial should be 28 days or 5 half-lives of the investigational agent, whichever is longer. 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). 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.

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).

Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication.

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.

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