Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

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

doi:10.1182/blood.2020007732

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

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. HulsMojca 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

Leukemia

Research output: Contribution to journal › Article › peer-review

181 Scopus citations

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. Key Points: • 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.

Original language	English (US)
Pages (from-to)	751-762
Number of pages	12
Journal	Blood
Volume	137
Issue number	6
DOIs	https://doi.org/10.1182/blood.2020007732
State	Published - Feb 11 2021

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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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. L., Emadi, A., Ravandi, F., Erba, H. P., Byrne, M., Michaelis, L., Topp, M. S., Vey, N., Ciceri, F., Carrabba, M. G., Paolini, S., ... DiPersio, J. F. (2021). Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood, 137(6), 751-762. https://doi.org/10.1182/blood.2020007732

Uy, GL, Aldoss, I, Foster, MC, Sayre, PH, Wieduwilt, MJ, Advani, AS, Godwin, JE, Arellano, ML, Sweet, KL, Emadi, A, Ravandi, F, Erba, HP, Byrne, M, Michaelis, L, Topp, MS, Vey, N, Ciceri, F, Carrabba, MG, Paolini, S, Huls, GA, Jongen-Lavrencic, M, Wermke, M, Chevallier, P, Gyan, E, Récher, C, Stiff, PJ, Pettit, KM, Löwenberg, B, Church, SE, Anderson, E, Vadakekolathu, J, Santaguida, M, Rettig, MP, Muth, J, Curtis, T, Fehr, E, Guo, K, Zhao, J, Bakkacha, O, Jacobs, K, Tran, K, Kaminker, P, Kostova, M, Bonvini, E, Walter, RB, Davidson-Moncada, JK, Rutella, S & DiPersio, JF 2021, 'Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia', Blood, vol. 137, no. 6, pp. 751-762. https://doi.org/10.1182/blood.2020007732

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title = "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. Key Points: • 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.",

author = "Uy, {Geoffrey L.} and Ibrahim Aldoss and Foster, {Matthew C.} and Sayre, {Peter H.} and Wieduwilt, {Matthew J.} and Advani, {Anjali S.} and Godwin, {John E.} and Arellano, {Martha L.} and Sweet, {Kendra L.} and Ashkan Emadi and Farhad Ravandi and Erba, {Harry P.} and Michael Byrne and Laura Michaelis and Topp, {Max S.} and Norbert Vey and Fabio Ciceri and Carrabba, {Matteo Giovanni} and Stefania Paolini and Huls, {Gerwin A.} and Mojca Jongen-Lavrencic and Martin Wermke and Patrice Chevallier and Emmanuel Gyan and Christian R{\'e}cher and Stiff, {Patrick J.} and Pettit, {Kristen M.} and Bob L{\"o}wenberg and Church, {Sarah E.} and Erica Anderson and Jayakumar Vadakekolathu and Marianne Santaguida and Rettig, {Michael P.} and John Muth and Teia Curtis and Erin Fehr and Kuo Guo and Jian Zhao and Ouiam Bakkacha and Kenneth Jacobs and Kathy Tran and Patrick Kaminker and Maya Kostova and Ezio Bonvini and Walter, {Roland B.} and Davidson-Moncada, {Jan K.} and Sergio Rutella and DiPersio, {John F.}",

note = "Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

year = "2021",

month = feb,

day = "11",

doi = "10.1182/blood.2020007732",

language = "English (US)",

volume = "137",

pages = "751--762",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "6",

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TY - JOUR

T1 - Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

AU - Uy, Geoffrey L.

AU - Aldoss, Ibrahim

AU - Foster, Matthew C.

AU - Sayre, Peter H.

AU - Wieduwilt, Matthew J.

AU - Advani, Anjali S.

AU - Godwin, John E.

AU - Arellano, Martha L.

AU - Sweet, Kendra L.

AU - Emadi, Ashkan

AU - Ravandi, Farhad

AU - Erba, Harry P.

AU - Byrne, Michael

AU - Michaelis, Laura

AU - Topp, Max S.

AU - Vey, Norbert

AU - Ciceri, Fabio

AU - Carrabba, Matteo Giovanni

AU - Paolini, Stefania

AU - Huls, Gerwin A.

AU - Jongen-Lavrencic, Mojca

AU - Wermke, Martin

AU - Chevallier, Patrice

AU - Gyan, Emmanuel

AU - Récher, Christian

AU - Stiff, Patrick J.

AU - Pettit, Kristen M.

AU - Löwenberg, Bob

AU - Church, Sarah E.

AU - Anderson, Erica

AU - Vadakekolathu, Jayakumar

AU - Santaguida, Marianne

AU - Rettig, Michael P.

AU - Muth, John

AU - Curtis, Teia

AU - Fehr, Erin

AU - Guo, Kuo

AU - Zhao, Jian

AU - Bakkacha, Ouiam

AU - Jacobs, Kenneth

AU - Tran, Kathy

AU - Kaminker, Patrick

AU - Kostova, Maya

AU - Bonvini, Ezio

AU - Walter, Roland B.

AU - Davidson-Moncada, Jan K.

AU - Rutella, Sergio

AU - DiPersio, John F.

PY - 2021/2/11

Y1 - 2021/2/11

N2 - 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. Key Points: • 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.

AB - 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. Key Points: • 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.

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U2 - 10.1182/blood.2020007732

DO - 10.1182/blood.2020007732

M3 - Article

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SN - 0006-4971

VL - 137

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EP - 762

JO - Blood

JF - Blood

IS - 6

ER -

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

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