Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.
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
Dose-Response Relationship, Immunologic
Drug Administration Schedule
Drug Resistance, Neoplasm
Female
Follow-Up Studies
Hematopoiesis
/ drug effects
Humans
Immunotherapy
Leukemia, Myeloid, Acute
/ drug therapy
Male
Maximum Tolerated Dose
Middle Aged
Nausea
/ chemically induced
Protein Interaction Maps
Salvage Therapy
Survival Rate
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
11 02 2021
11 02 2021
Historique:
received:
16
06
2020
accepted:
25
08
2020
pubmed:
16
9
2020
medline:
2
7
2021
entrez:
15
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32929488
pii: S0006-4971(21)00263-9
doi: 10.1182/blood.2020007732
pmc: PMC7885824
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents, Immunological
0
tocilizumab
I031V2H011
Banques de données
ClinicalTrials.gov
['NCT02152956']
Types de publication
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
Langues
eng
Sous-ensembles de citation
IM
Pagination
751-762Subventions
Organisme : NCI NIH HHS
ID : P50 CA171963
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA152329
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211466
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
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