Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.
(Journal Article;Multicenter Study)
Approximately 50% of acute myeloid leukemia (AML) patients 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 CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [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 CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.
Uy, GL; Aldoss, I; Foster, MC; Sayre, PH; Wieduwilt, MJ; Advani, AS; Godwin, JE; Arellano, ML; Sweet, KL; Emadi, A; Ravandi, F; Erba, HP; Byrne, M; Michaelis, L; Topp, MS; Vey, N; Ciceri, F; Carrabba, MG; Paolini, S; Huls, GA; Jongen-Lavrencic, M; Wermke, M; Chevallier, P; Gyan, E; Récher, C; Stiff, PJ; Pettit, KM; Löwenberg, B; Church, SE; Anderson, E; Vadakekolathu, J; Santaguida, M; 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
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