Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia.
Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after(early relapse, ER). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123. This study reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in adults with relapsed/refractory AML. Eighty-eight AML patients were enrolled, 42 in dose-finding and 46 at the recommended phase 2 dose (RP2D) of 500ng/kg/day. Consistent with flotetuzumab's mode of action, the most frequent adverse events were infusion-related reactions (IRR)/cytokine release syndrome (CRS), the majority as grade 1-2. Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability. Clinical benefit accrued to PIF/ER AML patients, who showed an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the CR/CRh rate was 26.7%, with an overall response rate (CR/CRh/CRi) of 30.0%. In PIF/ER patients who achieved CR/CRh, median OS was 10.2 months (range 1.87-27.27), with 6- and 12-month survival rates of 75% (95%CI, 0.450-1.05) and 50% (95%CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted complete responses to flotetuzumab (AUROC=0.904 versus 0.672 for the ELN risk classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956.
Uy, Geoffrey L; Aldoss, Ibrahim; Foster, Matthew C; Sayre, Peter H; Wieduwilt, Matthew J; Advani, Anjali S; Godwin, John E; Arellano, Martha L; Sweet, Kendra; Emadi, Ashkan; Ravandi, Farhad; Erba, Harry P; Byrne, Michael; Michaelis, Laura C; Topp, Max S; Vey, Norbert; Ciceri, Fabio; Carrabba, Matteo Giovanni; Paolini, Stefania; Huls, Gerwin; Jongen-Lavrencic, Mojca; Wermke, Martin; Chevallier, Patrice; Gyan, Emmanuel; Récher, Christian; Stiff, Patrick; Pettit, Kristen; Löwenberg, Bob; Church, Sarah; Anderson, Erica Katherine; Vadakekolathu, Jayakumar; Santaguida, Marianne T; Rettig, Michael P; Muth, John; Curtis, Teia; Fehr, Erin; Guo, Kuo; Zhao, Jian; Bakkacha, Ouiam; Jacobs, Kenneth; Tran, Kathy; Kaminker, Patrick; Kostova, Maya; Bonvini, Ezio; Walter, Roland B; Davidson-Moncada, Jan Kenneth; Rutella, Sergio; and DiPersio, John F, "Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia." (2020). Articles, Abstracts, and Reports. 3742.