Improvement in Cytokine Release Syndrome Management for the Treatment of AML Patients with Flotetuzumab, a CD123 x CD3 Bispecific Dart® Molecule for T-Cell Redirected Therapy
Authors: Bakkacha Ouiam , Uy Geoffrey L. , Aldoss Ibrahim , Foster Matthew C , Sallman David A , Sweet Kendra L. , Rizzieri David A. , Sayre Peter H. , Advani Anjali S. , Emadi Ashkan , Wieduwilt Matthew J. , Vey Norbert , Ciceri Fabio , Carrabba Matteo Giovanni , Moyo Tamara , Arellano Martha L. , Godwin John E. , Löwenberg Bob , Huls Gerwin , Ravandi Farhad , Tran Kathy , Muth John , Baughman Jan , Jongen-Lavrencic Mojca , Timmeny Erin , Topp Max S. , Paolini Stefania , Guo Kuo , Curtis Teia , Zhao Jian , Wigginton Jon , Bonvini Ezio , Walter Roland B. , Davidson Jan , DiPersio John F. , Jacobs Kenneth 
Published: November 2019

Background: Cytokine release syndrome (CRS) management in acute myeloid leukemia (AML) patients treated with flotetuzumab, an investigational CD123xCD3 bispecific DART® molecule for T cell redirected therapy. CRS is a hallmark of T cell activating therapy and can be correlated with efficacy, specifically, with CAR-T cells(1). Identification of patients at risk for high grade CRS will help guide CRS management. Flotetuzumab (MGD006) is anovel CD123xCD3 bispecific DART® molecule in Phase 1/2 testing in patients with relapsed/ refractory AML. Several strategies have been successfully employed to mitigate CRS severity, some have been previously reported (2, 3). Here we report on further refinement of CRS management and subsequent investigation of potentiel predictive biomarkers of severity.
Methods: The recommended phase 2 dose (RP2D) of flotetuzumab is 500ng/kg/d CIV. Week 1 comprises a step-wise lead-in dose (LID) (1-step: 100 ng/kg/day days 1-4; 2-step: 30ng/kg/d for 3days, 100ng/kg/d for 4days, or multi-step (MS) LID at 30, 60, 100, 200, 300, 400 and 500 ng/kg/day each for 24 hours) in order to improve flotetuzumab tolerability. Tocilizumab usage recommended early in CRS management. The relationships between immune cells (T-cell subsets, monocytes) and tumor burden (percent CD123+ AML blasts, CD123 expression) were further interrogated as potential determinants of CRS.
Results: 50 patients have been treated at the RP2D. While almost all patients experienced IRR/CRS events, the majority of these patients experienced IRR/CRS that were mild-moderate in severity (28% Grade(G)1, 62% G2, and 8% G3), of short duration (median 1 day for G1, 2 days G2, 2.5 days G3), and resolved completely with no clinical sequalae reported. Most CRS events occured in the first week of treatment (38.3%) and gradually decreased with continuous dosing (24.8%, 7.4%, and 4.3% during weeks 2-4, respectively). Several key interventions have helped mitigate CRS severity. Sequential increment in steps of LID schedules (1 step, 2-step or multi-step LID) have successfully decreased CRS severity and incidence. For example, CRS mean grade±SEM for week 1 was 2.0±0.26 vs 1.4±0.72 vs 1.5±0.63 and for week 4, 0.67±0.42 vs 0.2 ±0.50 vs 0.1 ±0.50 (1 step, 2-step or multi-step LID, respectively). Moreover, LID improved overall tolerability. Introduction of early use of tocilizumab has helped forestall CRS development; 27 patients received tocilizumab (10 doses for G1, 27 for G2, and 2 for G3 events), only 5 pts have required steroids (4 for G2 and 1 for G3), and no pts have required vasopressor support. Blunting of CRS events did not impact antileukemic activity. CRS severity showed a relationship with baseline frequency of circulating CD4+ cells (mean 0.2 K/µL in patients with no CRS vs. 1.0 K/µL in G1 vs 1.6 K/µL in G ≥2, p < 0.000.1), and peak CRS grade in week 1.
Conclusion: Like other T-cell activating therapies, flotetuzumab is associated with CRS. Several mitigating factors have helped to blunt the severity of CRS, including lead-in dosing and early tocilizumab usage. Circulating CD4+ cells at baseline continues to be associated with CRS risk, and may be a helpful marker to identify patients at increased risk for CRS.
1. Maude, SL. et al. Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies. Cancer J. 2014; 20(2): 119-122.
2. Jacobs, K, et al.Lead-in Dose Optimization to Mitigate Cytokine Release Syndrome in AML and MDS Patients Treated with Flotetuzumab, a CD123 x CD3 Dart® Molecule for T-Cell Redirected Therapy. Blood 2017 130:3856.
3. Jacobs, K, et al.Management of Cytokine Release Syndrome in AML Patients Treated with Flotetuzumab, a CD123 x CD3 Bispecific Dart® Molecule for T-Cell Redirected Therapy. Blood 2018 132:2738.

Disclosures
Bakkacha: Macrogenics,Inc: Employment, Equity Ownership. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Aldoss:Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; AUTO1: Consultancy; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria. Foster:Bellicum Pharmaceuticals, Inc: Research Funding; Daiichi Sankyo: Consultancy; MacroGenics: Research Funding; Celgene: Research Funding. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Sweet:Pfizer: Consultancy; Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Consultancy; Jazz: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Emadi:Genentech: Consultancy, Honoraria; KinaRx: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder and Scientific Advisor, Patents & Royalties; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wieduwilt:Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Arellano:Gilead: Consultancy. Löwenberg:Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ravandi:Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding. Tran:MacroGenics: Employment. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Baughman:MacroGenics, Inc.: Employment, Equity Ownership. Timmeny:MacroGenics, Inc.: Employment, Other: Stock Ownership. Topp:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:Macrogenics: Employment. Zhao:MacroGenics, Inc.: Employment. Wigginton:macrogenics: Employment, Equity Ownership; western oncolytics: Consultancy, Other: consultancy. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Walter:Daiichi Sankyo: Consultancy; Amgen: Consultancy; Agios: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy. Davidson:Macrogenics,Inc: Employment, Equity Ownership. DiPersio:Incyte: Consultancy, Research Funding; Celgene: Consultancy; Karyopharm Therapeutics: Consultancy; Bioline Rx: Research Funding, Speakers Bureau; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Equity Ownership; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau. Jacobs:Macrogenics,Inc: Employment, Equity Ownership.