Background: Dysregulated innate immune signaling promotes inflammatory suppression of hematopoietic stem and progenitor cell function, contributing to ineffective erythropoiesis in myelodysplastic neoplasms (MDS). The phase 2, open-label CANFIRE and LUCAS trials aimed to determine the efficacy and safety of canakinumab or emavusertib, respectively, in patients with lower-risk MDS (LR-MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN).
Methods: Patients in CANFIRE were refractory refractory: Not responsive to treatment or cure. For example, refractory anemia is a low red blood cell count that doesn't respond to standard treatments. , intolerant to, or ineligible for erythropoiesis-stimulating agent (ESA) treatment and received canakinumab 200 mg subcutaneously every 21 days for up to eight cycles within the first six months of treatment. Patients in LUCAS were either refractory or intolerant to ESAs (cohort A) or ESA-naïve with serum erythropoietin erythropoietin: (i-rith-row-POY-uh-tun) A protein made by the kidneys. Erythropoietin, also called EPO, is created in response to low oxygen levels in the body (anemia). EPO causes the bone marrow to make more red blood cells. A shortage of EPO can also cause anemia. levels >200 U/L (cohort B); all patients received emavusertib 200-300 mg orally twice daily for 21 days in up to four 28-day cycles. The primary endpoint for both trials was hematologic improvement-erythroid per International Working Group 2018 criteria at the end of the planned treatment period. CANFIRE was registered at ClinicalTrials.gov (NCT05237713; registered January 21, 2022). LUCAS was registered in the EU Clinical Trials Clinical Trials: Clinical research is at the heart of all medical advances, identifying new ways to prevent, detect or treat disease. If you have a bone marrow failure disease, you may want to consider taking part in a clinical trial, also called a research study. Understanding Clinical Trials Clinical… Register (EudraCT 2020-003986-20; registered March 15, 2021) and at ClinicalTrials.gov (NCT05178342; registered November 2, 2021).
Results: Here we show that of 11 patients enrolled in CANFIRE and 36 patients enrolled in LUCAS, no patients in either trial achieved the primary endpoint. Canakinumab treatment was well-tolerated, with no reported serious adverse events (SAEs) and no patients died in the CANFIRE trial. In the LUCAS trial, 15 patients reported SAEs, and four patients died. CANFIRE and LUCAS were terminated early due to inadequate patient recruitment and after a pre-planned interim futility analysis, respectively.
Conclusions: Inhibition of IL-1β or IRAK4 signaling with canakinumab or emavusertib did not result in hematologic improvement in patients with LR-MDS.