Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

• Published in: Blood Vol. 137; no. 6; pp. 751 - 762
• Main Authors: Uy, Geoffrey L., Aldoss, Ibrahim, Foster, Matthew C., Sayre, Peter H., Wieduwilt, Matthew J., Advani, Anjali S., Godwin, John E., Arellano, Martha L., Sweet, Kendra L., Emadi, Ashkan, Ravandi, Farhad, Erba, Harry P., Byrne, Michael, Michaelis, Laura, Topp, Max S., Vey, Norbert, Ciceri, Fabio, Carrabba, Matteo Giovanni, Paolini, Stefania, Huls, Gerwin A., Jongen-Lavrencic, Mojca, Wermke, Martin, Chevallier, Patrice, Gyan, Emmanuel, Récher, Christian, Stiff, Patrick J., Pettit, Kristen M., Löwenberg, Bob, Church, Sarah E., Anderson, Erica, Vadakekolathu, Jayakumar, Santaguida, Marianne, Rettig, Michael P., Muth, John, Curtis, Teia, Fehr, Erin, Guo, Kuo, Zhao, Jian, Bakkacha, Ouiam, Jacobs, Kenneth, Tran, Kathy, Kaminker, Patrick, Kostova, Maya, Bonvini, Ezio, Walter, Roland B., Davidson-Moncada, Jan K., Rutella, Sergio, DiPersio, John F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.02.2021; American Society of Hematology
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Clinical Trials and Observations; Cytokine Release Syndrome - chemically induced; Cytokine Release Syndrome - 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; Leukemia, Myeloid, Acute - therapy; Male; Maximum Tolerated Dose; Middle Aged; Nausea - chemically induced; Protein Interaction Maps; Salvage Therapy; Survival Rate
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2020007732

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. •Flotetuzumab is associated with acceptable safety and evidence of activity in AML patients with PIF/ER.•A 10-gene immune signature predicts response to flotetuzumab with greater accuracy than the ELN risk classifier. [Display omitted]