Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

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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. ORCID: 0000-0002-2671-4285, 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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Official URL: https://doi.org/10.1182/blood.2020007732

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: