Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia. Journal Article

Authors: Uy, GL; Aldoss, I; Foster, MC; Sayre, PH; Wieduwilt, MJ; Advani, AS; Godwin, JE; Arellano, ML; Sweet, K; Emadi, A; Ravandi, F; Erba, HP; Byrne, M; Michaelis, LC; Topp, MS; Vey, N; Ciceri, F; Carrabba, MG; Paolini, S; Huls, G; Jongen-Lavrencic, M; Wermke, M; Chevallier, P; Gyan, E; Récher, C; Stiff, P; Pettit, K; Löwenberg, B; Church, S; Anderson, EK; Vadakekolathu, J; Santaguida, MT; Rettig, MP; Muth, J; Curtis, T; Fehr, E; Guo, K; Zhao, J; Bakkacha, O; Jacobs, K; Tran, K; Kaminker, P; Kostova, M; Bonvini, E; Walter, RB; Davidson-Moncada, JK; Rutella, S; DiPersio, JF
Article Title: Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia.
Abstract: 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 6 months (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 CD3e 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.
Journal Title: Blood
ISSN: 1528-0020; 0006-4971
Publisher: American Society of Hematology  
Date Published: 2020