Durable imatinib response in ALK+ PDGFR+ ALCL (WES)

Expression of platelet-derived growth factor receptor (PDGFR) in rare ALK-positive anaplastic large cell lymphomas (ALK+ ALCL) is associated with a dismal prognosis. PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib is a suggested treatment rationale, but has not yet been clinically evaluated. Here we present long-term clinical and molecular characterization of chemotherapy resistant ALK+ ALCL patients who were prospectively treated with imatinib. Four of six patients (67%) achieved and maintained a complete remission with a median follow-up of 7.2 years. Tumor cells of imatinib non-responders demonstrated repressed PDGFR and a consistent mutational signature that was detected in 6/33 independent ALCL cases. In addition to a silent PDGFR signaling, imatinib non-responders demonstrated a dominant IL-18- inflammasome which could successfully be treated in one imatinib resistant patient with PD1 checkpoint inhibition. Together, PDGFR expression in ALK+ ALCL patients discriminates distinct lymphoma subgroups with particular clinical implications.