Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Abstract

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.

• Authors: Geoffrey L Uy, Ibrahim Aldoss, Matthew C Foster, Peter H Sayre, Matthew J Wieduwilt, Anjali S Advani, John E Godwin, Martha L Arellano, Kendra L Sweet, Ashkan Emadi, Farhad Ravandi, Harry P Erba, Michael Byrne, Laura Michaelis, Max S Topp, Norbert Vey, Fabio Ciceri, Matteo Giovanni Carrabba, Stefania Paolini, Gerwin A Huls, Mojca Jongen-Lavrencic, Martin Wermke, Patrice Chevallier, Emmanuel Gyan, Christian Récher, Patrick J Stiff, Kristen M Pettit, Bob Löwenberg, Sarah E Church, Erica Anderson, Jayakumar Vadakekolathu, Marianne Santaguida, Michael P Rettig, John Muth, Teia Curtis, Erin Fehr, Kuo Guo, Jian Zhao, Ouiam Bakkacha, Kenneth Jacobs, Kathy Tran, Patrick Kaminker, Maya Kostova, Ezio Bonvini, Roland B Walter, Jan K Davidson-Moncada, Sergio Rutella, John F DiPersio
• Journal: Blood (Blood) Vol. 137 Issue 6 Pg. 751-762 (02 11 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 32929488 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• tocilizumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents, Immunological (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cytokine Release Syndrome (chemically induced, drug therapy)
• Dose-Response Relationship, Immunologic
• Drug Administration Schedule
• Drug Resistance, Neoplasm
• Female
• Follow-Up Studies
• Hematopoiesis (drug effects)
• Humans
• Immunotherapy
• Leukemia, Myeloid, Acute (drug therapy, therapy)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Nausea (chemically induced)
• Protein Interaction Maps
• Salvage Therapy
• Survival Rate