A multi-site break through cancer pilot study testing the feasibility and safety of therapeutic intervention for patients with high-risk clonal cytopenia of undetermined significance (CCUS) Free

Clonal hematopoiesis (CH), the age-related clonal expansion of blood cells, is often caused by somatic mutations genes associated with myeloid neoplasia (MN). Clonal cytopenia of uncertain significance (CCUS) defines a subset of CH in which somatic mutations occur at a variant allele fraction (VAF) of ≥2%, with persistence of unexplained cytopenia, and without significant morphologic dysplasia. Patients with CCUS are at risk for developing myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or related MNs. The clonal hematopoiesis risk score (CHRS) estimates the risk of malignancy, identifying a high-risk CCUS (HR-CCUS) population with a cumulative risk of MN exceeding 50% at year 10. Standard management for HR-CCUS is observation for asymptomatic individuals and supportive transfusions and/or growth factors for symptomatic cytopenias. Given the life-threatening potential of MNs and the lack of curative therapies beyond allogenic stem cell transplantation, risk-adapted prevention strategies are desirable.

Study Design This open-label, multicenter pilot study (NCT06802146) will investigate the co-primary endpoints of feasibility, safety, and tolerability of pharmacologic intervention in HR-CCUS.

Up to 138 eligible adults with HR-CCUS will be assigned to either observation (Arm A) or a pharmacologic intervention (Arm B) by elicited participant preference. Key eligibility criteria include persistent unexplained cytopenias; ≥ 1 acquired somatic mutation with a VAF of ≥2% identified in peripheral blood or bone marrow; CHRS score of ≥ 12.5; and a screening bone marrow assessment that is diagnostic of CCUS as determined by local pathologist review and confirmed by a central review panel consisting of 4 expert hematopathologists. Exclusion criteria include, concurrent primary malignancy requiring recent, current, or planned management with cytotoxic chemotherapy, immunomodulatory agents, or PARP inhibitors; prior diagnosis of any hematolymphoid malignancy; known inherited bone marrow failure disorders; or known concurrent diagnosis with precursors of lymphoid or plasma cell malignancies.

Participant preference in Arm A or B will be elicited at the time of screening. Once enrolled to their chosen Arm, eligible participants receive standard of care monitoring of HR-CCUS for including peripheral blood and/or bone marrow sampling every 3-6 months. In addition, Arm A participants will receive 1 tablet per day of DEC/CED containing 10mg of decitabine and 100mg cedazuridine for 5 days per 28-day cycle for 12 consecutive cycles. Treatment with DEC/CED will continue until completion of cycle 12, development of unacceptable toxicity, or progression to MN. All participants will be observed for a total of 3 years for evidence of progression to MN.

Study feasibility will be defined by the proportion of HR-CCUS participants electing to participate in early intervention with DEC/CED rather than observation. Using a negative binomial design, the cumulative probability of 30 participants enrolling on Arm A exceeds 0.8 at a total study accrual of 138 participants. Study accrual will continue until enrollment of the 30^th participant to Arm A or the 138^th participant to the study, whichever is earliest. Co-primary endpoints of safety and tolerability apply only to the early therapeutic intervention cohorts. Intervention will be deemed safe if < 33.3% of Arm A participants discontinue DEC/CED due to dose limiting toxicity. Tolerability will be defined by ≥ 50% of Arm A participants completing ≥ 3 cycles of DEC/CED.

Secondary objectives include evaluating participants for hematologic response as defined by 2018 World Health Organization (WHO) International working Group (IWG) MDS response criteria; MN-free survival; changes in somatic driver mutation VAF; changes in serum inflammatory markers; incident comorbidities; and patient reported outcomes.

Conclusions This is the first evaluation of oral DEC/CED in HR-CCUS patients. Successful demonstration of feasibility, safety, and tolerability of DEC/CED in CCUS may pave the way for a larger randomized intervention trials. The study design permits comparison of clinical, laboratory, and PRO responses in observation and early intervention populations. Resulting data may identify reliable biomarkers for response and safety, enabling future clinical development of therapeutic interventions for HR-CCUS.*Drs Stahl and Weeks contributed equally