Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

GL Uy; I Aldoss; MC Foster; PH Sayre; MJ Wieduwilt; AS Advani; JE Godwin; ML Arellano; KL Sweet; A Emadi; F Ravandi; HP Erba; M Byrne; L Michaelis; MS Topp; N Vey; F Ciceri; MG Carrabba; S Paolini; GA Huls; Mojca Jongen - Lavrencic; M Wermke; P Chevallier; E Gyan; C Récher; PJ Stiff; KM Pettit; Bob Löwenberg; SE Church; E Anderson; J Vadakekolathu; M Santaguida; MP Rettig; J Muth; T Curtis; E Fehr; K Guo; J Zhao; O Bakkacha; K Jacobs; K Tran; P Kaminker; M Kostova; E Bonvini; RB Walter; JK Davidson-Moncada; S Rutella; JF DiPersio

doi:10.1182/blood.2020007732

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

GL Uy, I Aldoss, MC Foster, PH Sayre, MJ Wieduwilt, AS Advani, JE Godwin, ML Arellano, KL Sweet, A Emadi, F Ravandi, HP Erba, M Byrne, L Michaelis, MS Topp, N Vey, F Ciceri, MG Carrabba, S Paolini, GA HulsMojca Jongen - Lavrencic, M Wermke, P Chevallier, E Gyan, C Récher, PJ Stiff, KM Pettit, Bob Löwenberg, SE Church, E Anderson, J Vadakekolathu, M Santaguida, MP Rettig, J Muth, T Curtis, E Fehr, K Guo, J Zhao, O Bakkacha, K Jacobs, K Tran, P Kaminker, M Kostova, E Bonvini, RB Walter, JK Davidson-Moncada, S Rutella, JF DiPersio

Hematology

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

Bibliographical note

Funding Information:
M.P.R. was supported by National Institutes of Health/National Cancer Institute grant R50 CA211466. J.F.D. was supported by National Institutes of Health/National Cancer Institute grants R01 CA152329, P50 CA171963, and R35 CA210084. S.R. was supported by Qatar National Research Fund grant NPRP8-2297-3-494.

Funding Information:
The authors thank Barbara Shepherd for providing medical writing support. M.P.R. was supported by National Institutes of Health/National Cancer Institute grant R50 CA211466. J.F.D. was supported by National Institutes of Health/National Cancer Institute grants R01 CA152329, P50 CA171963, and R35 CA210084. S.R. was supported by Qatar National Research Fund grant NPRP8-2297-3-494. Patents: Bispecific CD123 ? CD3 Diabodies for the Treatment of Hematologic Malignancies [International Patent Publication No. WO 2020/0942404]. Bi-Specific Diabodies That Are Capable of Binding CD123 and CD3 and Uses Thereof [US Patent No. 9 822 181].

Publisher Copyright:
© 2021 American Society of Hematology

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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., ... DiPersio, JF. (2021). Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood, 137(6), 751-762. https://doi.org/10.1182/blood.2020007732

@article{a0b8315381da433b9ca4f54d99742f04,

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 = "GL Uy and I Aldoss and MC Foster and PH Sayre and MJ Wieduwilt and AS Advani and JE Godwin and ML Arellano and KL Sweet and A Emadi and F Ravandi and HP Erba and M Byrne and L Michaelis and MS Topp and N Vey and F Ciceri and MG Carrabba and S Paolini and GA Huls and {Jongen - Lavrencic}, Mojca and M Wermke and P Chevallier and E Gyan and C R{\'e}cher and PJ Stiff and KM Pettit and Bob L{\"o}wenberg and SE Church and E Anderson and J Vadakekolathu and M Santaguida and MP Rettig and J Muth and T Curtis and E Fehr and K Guo and J Zhao and O Bakkacha and K Jacobs and K Tran and P Kaminker and M Kostova and E Bonvini and RB Walter and JK Davidson-Moncada and S Rutella and JF DiPersio",

note = "Funding Information: M.P.R. was supported by National Institutes of Health/National Cancer Institute grant R50 CA211466. J.F.D. was supported by National Institutes of Health/National Cancer Institute grants R01 CA152329, P50 CA171963, and R35 CA210084. S.R. was supported by Qatar National Research Fund grant NPRP8-2297-3-494. Funding Information: The authors thank Barbara Shepherd for providing medical writing support. M.P.R. was supported by National Institutes of Health/National Cancer Institute grant R50 CA211466. J.F.D. was supported by National Institutes of Health/National Cancer Institute grants R01 CA152329, P50 CA171963, and R35 CA210084. S.R. was supported by Qatar National Research Fund grant NPRP8-2297-3-494. Patents: Bispecific CD123 ? CD3 Diabodies for the Treatment of Hematologic Malignancies [International Patent Publication No. WO 2020/0942404]. Bi-Specific Diabodies That Are Capable of Binding CD123 and CD3 and Uses Thereof [US Patent No. 9 822 181]. Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

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doi = "10.1182/blood.2020007732",

language = "English",

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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

TY - JOUR

T1 - Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

AU - Uy, GL

AU - Aldoss, I

AU - Foster, MC

AU - Sayre, PH

AU - Wieduwilt, MJ

AU - Advani, AS

AU - Godwin, JE

AU - Arellano, ML

AU - Sweet, KL

AU - Emadi, A

AU - Ravandi, F

AU - Erba, HP

AU - Byrne, M

AU - Michaelis, L

AU - Topp, MS

AU - Vey, N

AU - Ciceri, F

AU - Carrabba, MG

AU - Paolini, S

AU - Huls, GA

AU - Jongen - Lavrencic, Mojca

AU - Wermke, M

AU - Chevallier, P

AU - Gyan, E

AU - Récher, C

AU - Stiff, PJ

AU - Pettit, KM

AU - Löwenberg, Bob

AU - Church, SE

AU - Anderson, E

AU - Vadakekolathu, J

AU - Santaguida, M

AU - Rettig, MP

AU - Muth, J

AU - Curtis, T

AU - Fehr, E

AU - Guo, K

AU - Zhao, J

AU - Bakkacha, O

AU - Jacobs, K

AU - Tran, K

AU - Kaminker, P

AU - Kostova, M

AU - Bonvini, E

AU - Walter, RB

AU - Davidson-Moncada, JK

AU - Rutella, S

AU - DiPersio, JF

N1 - Funding Information: M.P.R. was supported by National Institutes of Health/National Cancer Institute grant R50 CA211466. J.F.D. was supported by National Institutes of Health/National Cancer Institute grants R01 CA152329, P50 CA171963, and R35 CA210084. S.R. was supported by Qatar National Research Fund grant NPRP8-2297-3-494. Funding Information: The authors thank Barbara Shepherd for providing medical writing support. M.P.R. was supported by National Institutes of Health/National Cancer Institute grant R50 CA211466. J.F.D. was supported by National Institutes of Health/National Cancer Institute grants R01 CA152329, P50 CA171963, and R35 CA210084. S.R. was supported by Qatar National Research Fund grant NPRP8-2297-3-494. Patents: Bispecific CD123 ? CD3 Diabodies for the Treatment of Hematologic Malignancies [International Patent Publication No. WO 2020/0942404]. Bi-Specific Diabodies That Are Capable of Binding CD123 and CD3 and Uses Thereof [US Patent No. 9 822 181]. Publisher Copyright: © 2021 American Society of Hematology

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.

UR - http://www.scopus.com/inward/record.url?scp=85100648634&partnerID=8YFLogxK

U2 - 10.1182/blood.2020007732

DO - 10.1182/blood.2020007732

M3 - Article

C2 - 32929488

SN - 0006-4971

VL - 137

SP - 751

EP - 762

JO - Blood

JF - Blood

IS - 6

ER -

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

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