A Randomized Double-Blind Placebo-Controlled Phase II Multi-Center Study of Inflammation Modification of Canakinumab to Prevent Leukemic Progression of Clonal Cytopenias of Unknown Significance (CCUS): Impact Study

Background and Significance: High-risk Clonal Cytopenia of Undetermined Significance (HR-CCUS) is defined by prolonged cytopenias (> 4 months) in 1 or more cell lineages plus myeloid-disorder-associated mutations. CCUS patients with spliceosome mutations, DNMT3A, TET2, or ASXL1 mutations in combination with at least 2 other somatic mutations appear to have an extremely high rate of progression to myeloid neoplasms (MN) with a 95% 5-year cumulative probability of developing a MN such as MDS, MPN, or AML (13-fold increased risk compared to patients with cytopenia classified). Several studies implicate the inflammasome in CH progression to MDS/AML.

Interleukin (IL)-1β is a key upstream cytokine in the inflammasome that strongly induces IL-6. Mutations in another key protein in the inflammasome, cryopyrin, result in high systemic levels of IL-1β and are associated with auto-inflammatory diseases. We hypothesize that the preclinical and clinical data showing a benefit of IL-1β inhibition in patients with CH, is due to reduced downstream activations of inflammasome proteins.

Canakinumab is a high-affinity human monoclonal anti-human IL-1β antibody- FDA approved for the treatment of IL-1β driven inflammatory and oncologic diseases. By binding specifically to human IL-1β, canakinumab blocks the interaction of IL-1β with the IL-1 receptor, leading to inhibition of its downstream targets, thereby preventing IL-1β-induced gene activation and the production of inflammatory mediators. A phase II clinical trial investigating the use of canakinumab in combination with azacitidine is currently studying the impact canakinumab may have on disease progression in relapsed/refractory low or intermediate risk MDS patients (NCT04239157). This has now been extended to newly diagnosed MDS as new emerging data looks promising [unpublished data]. No significant toxicities have been reported.

Thus, we hypothesize that the treatment of HR-CCUS patients, for whom there is no current disease modifying therapy, with an inflammasome targeting antibody, would prevent or significantly delay development of a MN, improve cytopenias and decrease the clone size as well as prevent further clonal evolution.

Study Design and Methods: This study (NCT05641831) is a Phase II multicenter, randomized, two-arm, double-blind placebo-controlled study in patients with HR-CCUS (Figure 1). Patients with HR-CCUS, no known hematological malignancy, and any mutational combination as deemed appropriate by the inclusion criteria - are randomized to the study Arm or control Arm. Patients assigned to the study arm will be eligible to receive canakinumab, 300 mg subcutaneously every 3 months for 2 years. Patients assigned to the control arm will receive placebo every 3 months for 2 years. Bone marrow biopsies will be done for both arms every 6 months to monitor for disease progression (WHO 2016). PB samples will be collected every 3 months to monitor for disease progression. Patient-reported outcomes will be collected at the time of disease assessment.

Statistical plan: The null hypothesis assumes the time to overt MN (MDS/MPN/CMML/AML) is equal in the control and study arms (H₀: HR=1) versus the alternative hypothesis that the risk of an event is lower in the study arm (H₁: HR<1). Assuming exponential survival, 71 events (overt MN) are required for the final analysis to detect a hazard ratio of 0.55 (median 2 years for the control arm versus 3.636 years for the study arm) using a log-rank test with 80% power and one-sided significance level of 5%. This includes one interim futility analysis when 50% of the targeted number of events (36) have been observed. At the time of the interim analysis, futility will be declared if the hazard ratio is greater than 1 and in favor of the control arm. The futility boundary is statistically non-binding in that there is not a final significance level adjustment. If the futility boundary is crossed, then the study will terminate early; patients randomized to the control arm will continue standard of care off study and patients randomized to the study arm will discontinue treatment with Canakinumab.

Accounting for 5% drop-out, this calculation assumes accrual of 89 patients over 3 years and a minimum follow-up of 5 years (or until withdrawal, death, or study closure; earliest event).

To date, 5 patients have been randomized and enrolled on study (Table 1).