Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

Uy, G.L., Aldoss, I., Foster, M.C., Sayre, P.H., Wieduwilt, M.J., Advani, A.S., Godwin, J.E., Arellano, M.L., Sweet, K., Emadi, A., Ravandi, F., Erba, H.P., Byrne, M., Michaelis, L.C., Topp, M.S., Vey, N., Ciceri, F., Carrabba, M.G., Paolini, S., Huls, G., Jongen-Lavrencic, M., Wermke, M., Chevallier, P., Gyan, E., Récher, C., Stiff, P., Pettit, K., Löwenberg, B., Church, S., Anderson, E.K., Vadakekolathu, J., Santaguida, M.T., Rettig, M.P., Muth, J., Curtis, T., Fehr, E., Guo, K., Zhao, J., Bakkacha, O., Jacobs, K., Tran, K., Kaminker, P., Kostova, M., Bonvini, E., Walter, R.B., Davidson-Moncada, J.K., Rutella, S. ORCID: 0000-0003-1970-7375 and DiPersio, J.F., 2020. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. ISSN 0006-4971

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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 [less than] 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 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.

Item Type: Journal article
Publication Title: Blood
Creators: Uy, G.L., Aldoss, I., Foster, M.C., Sayre, P.H., Wieduwilt, M.J., Advani, A.S., Godwin, J.E., Arellano, M.L., Sweet, K., Emadi, A., Ravandi, F., Erba, H.P., Byrne, M., Michaelis, L.C., Topp, M.S., Vey, N., Ciceri, F., Carrabba, M.G., Paolini, S., Huls, G., Jongen-Lavrencic, M., Wermke, M., Chevallier, P., Gyan, E., Récher, C., Stiff, P., Pettit, K., Löwenberg, B., Church, S., Anderson, E.K., Vadakekolathu, J., Santaguida, M.T., Rettig, M.P., Muth, J., Curtis, T., Fehr, E., Guo, K., Zhao, J., Bakkacha, O., Jacobs, K., Tran, K., Kaminker, P., Kostova, M., Bonvini, E., Walter, R.B., Davidson-Moncada, J.K., Rutella, S. and DiPersio, J.F.
Publisher: American Society of Hematology
Date: 14 September 2020
ISSN: 0006-4971
Identifiers:
NumberType
10.1182/blood.2020007732DOI
1367471Other
Divisions: Schools > School of Science and Technology
Record created by: Jonathan Gallacher
Date Added: 16 Sep 2020 14:29
Last Modified: 16 Sep 2020 14:29
URI: http://irep.ntu.ac.uk/id/eprint/40753

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