A phase I open label study of fostamatinib, a SYK inhibitor, in patients with lower-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.

Lower-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are commonly managed with erythropoiesis-stimulating agents, luspatercept, or hypomethylating agents. Despite this, the disease often becomes refractory and patients develop transfusion dependence. Preclinical evidence suggests that targeting innate immune signaling, including NF-kB activation, may improve hematopoiesis. Fostamatinib, an oral SYK inhibitor approved for immune thrombocytopenia, was evaluated in a phase 1 open-label study in previously treated lower-risk MDS/CMML. Eleven patients received fostamatinib starting at 100 mg twice daily with dose escalation for lack of response. Patients had received a median of 3 prior therapies and most were transfusion-dependent. Over a median of 5 treatment cycles and 14.4 months of follow-up, no objective responses were observed, although all patients achieved stable disease. Transfusion needs remained largely unchanged. There were no dose-limiting toxicities. Although safe, fostamatinib demonstrated no clinical benefit, underscoring the need for alternative strategies to modulate inflammatory signaling in MDS/CMML.