Elimination Of Minimal Residual Disease (MRD) In AML Patients With a Novel Fc-Optimized FLT3 Antibody (4G8-SDIEM)

Chemotherapeutic treatment induces a morphological complete remission (CR) in the majority of leukemia patients, but minimal residual disease (MRD) remains detectable by sensitive methods and constitutes the basis for relapse. Immunotherapeutic strategies are rarely sufficient to eliminate large tumor burden, but can successfully eliminate MRD. This is exemplified by the efficacy of donor lymphocyte infusion (DLI) and allogeneic stem cell transplantation (SCT) in leukemia. Here we report the first clinical experience with a novel Fc-optimized antibody directed to the receptor tyrosine kinase FLT3 expressed on the surface of leukemia cells. This antibody may potently eliminate MRD after conventional therapy and achieve this goal with less toxicity (i.e. GvHD) than DLI and SCT. After in vitro characterization of the antibody, which revealed its markedly increased ability to mediate antibody dependent cytotoxicity (ADCC), in particular of NK cells, against leukemic cells (Hofmann et al, Leukemia 2012), the antibody (4G8SDIEM) was produced in a university owned unit and applied on a compassionate need basis. Upon application in AML patients with active disease, potent NK cell activation and anti-leukemia activity were observed, but effects were rather short lived, most likely due to unfavorable NK:leukemia cell ratios in the bone marrow. Consecutively we applied 4G8SDIEM to AML patients in morphological CR after SCT which displayed increasing MRD levels (mutNPM1) indicative of imminent relapse and for which no other treatment options were available. In 3 of the 4 patients treated so far, a single application of 4G8SDIEM (in 2 cases followed by treatment with one dose of DLI) resulted in rapid elimination of MRD. The non-responsive patient displayed high titers of preexistent anti-Fab antibodies capable of binding 4G8SDIEM, which provides a potential explanation for the lacking response. One patient that had received subsequent DLI died of complications due to GvHD after reaching and maintaining a molecular CR. The other two patients (1 with, 1 without DLI) remained in molecular CR for at present 17 and 12 months after 4G8-SDIEM application without further specific treatment. No stem cell toxicity was observed. Our results imply that 4G8SDIEM is capable to reduce or eliminate MRD after conventional therapy. Based on these observations, a phase I/II trial enrolling AML patients in CR with detectable MRD is in preparation.