Prophylactic Ruxolitinib for Cytokine Release Syndrome in Relapse/Refractory AML Patients Treated with Flotetuzumab.

Document Type


Publication Date


Publication Title

62nd ASH Annual Meeting and Exposition


oregon; portland; chiles


2817 Prophylactic Ruxolitinib for Cytokine Release Syndrome (CRS) in Relapse/Refractory (R/R) AML Patients Treated with Flotetuzumab

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
AML, antibodies, Biological, CRS, Adult, Diseases, Therapies, Adverse Events, Biological Processes, Study Population, Myeloid Malignancies, Clinically relevant, TKI Monday, December 7, 2020, 7:00 AM-3:30 PM

Geoffrey L Uy, MD1, Michael P. Rettig, PhD2, Stephanie Christ, MS3*, Ibrahim Aldoss, MD4, Michael T. Byrne, DO5, Harry P. Erba, MD, PhD6, Martha L. Arellano, MD7, Matthew C Foster, MD8, John E. Godwin, MD9, Farhad Ravandi, MBBS10, Peter H. Sayre, MD, PhD11, Anjali S Advani, MD12, Matthew J. Wieduwilt, MD, PhD13, Ashkan Emadi, M.D., Ph.D.14, Laura C. Michaelis, MD15, Patrick J. Stiff, MD16, Martin Wermke17*, Norbert Vey, MD18, Patrice Chevalier, MD, PhD19*, Emmanuel Gyan, MD, PhD20, Christian Recher, MD, PhD21, Fabio Ciceri, MD22*, Matteo Giovanni Carrabba, MD23*, Antonio Curti, MD PhD24, Geert Huls, MD, PhD25, Max S. Topp, MD26, Mojca Jongen-Lavrencic, MD, PhD27, John Muth, MS28*, Teia Curtis29*, Mary Beth Collins30*, Erin Timmeny31*, Kuo Guo, MSc32*, Jian Zhao, PhD32*, Kathy Tran28*, Patrick Kaminker, PhD33*, Priyanka Patel, PharmD30*, Ouiam Bakkacha, MD34*, Kenneth Jacobs, MD35*, Maya Kostova, PhD32*, Jennifer Seiler, PhD, RAC30*, Bob Lowenberg, MD, PhD36, Sergio Rutella, MD, PhD, FRCPath37, Roland B. Walter, MD, PhD, MS38, Ezio Bonvini, MD33, Jan K Davidson-Moncada, MD, PhD39 and John F. DiPersio, MD1

1Washington University School of Medicine, Saint Louis, MO
2Department of Internal Medicine, Division of Oncology, Washington Univ. School of Med., Saint Louis, MO
3Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO
4Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA
5Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN
6University of Alabama at Birmingham, Birmingham, AL
7Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
8Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, Chapel Hill, NC
9Providence Portland Medical Center, Portland, OR
10Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
11University of California, San Francisco, San Francisco, CA
12Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH
13Moores Cancer Center, University of California, San Diego, La Jolla, CA
14University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
15Division of Hematology/Oncology, Department of Medicine, The Medical College of Wisconsin Inc., Milwaukee, WI
16Loyola University Chicago Stritch School of Medicine, Maywood, IL
17NCT/UCC Early Clinical Trial Unit, University Hospital Carl Gustav Carus, Dresden, Germany
18Hematologie clinique, Institut Paoli Clamettes, Marseille, France
19Department of Hematology and Cell Therapy, CHU Nantes, Nantes, France
20CHU de Tours - Hôpital Bretonneau, Tours, France
21Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
22Haematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
23Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
24Hematology/Oncology "L. e A. Seràgnoli", Sant’Orsola-Malpighi University Hospital, Bologna, Bologna, Italy
25Department of Hematology, University Medical Center Groningen, Groningen, GZ, Netherlands
26Medizinische Klinik Und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
27Erasmus University Medical Center, Rotterdam, Netherlands
28MacroGenics, Inc., Rockville, MD
29MacroGenics, Inc., Frederick, MD
30MacroGenics, Rockville
31MacroGenics, Inc., ROCKVILLE, MD
32MacroGenics, Rockville, MD
33Macrogenics, Rockville, MD
34Macrogenics,Inc, ROCKVILLE, MD
35MacroGenics, Inc, Rockville, MD
36Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
37John van Geest Cancer Centre School of Science and Technology, Nottingham Trent University, Nottingham, ENG, United Kingdom
38Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
39MacroGenics, Inc., Washington, DC Introduction: CRS is a potentially life-threatening toxicity observed following T cell-redirecting therapies. CRS is associated with elevated cytokines, including IL6, IFNγ, TNFα, IL2 and GM-CSF. Glucocorticosteroids (GC) and the IL6 receptor blocking antibody tocilizumab (TCZ) can reduce CRS severity; however, CRS may still occur and limit the therapeutic window of novel immunotherapeutic agents. Disruption of cytokine signaling via Janus kinase (JAK) pathway interference may represent a complementary approach to blocking CRS. Ruxolitinib (RUX), an oral JAK1/2 inhibitor approved for the treatment of myelofibrosis and polycythemia vera, interferes with signaling of several cytokines, including IFNγ and IL6, via blockade of the JAK/STAT pathway. We hypothesized that RUX may reduce the frequency and severity of CRS in R/R AML patients (pts) undergoing treatment with flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule.

Methods: Relapse/refractory (including primary induction failure, early relapse and late relapse) AML pts were included in this study. RUX pts were treated at a single site, Washington University, St. Louis, MO. RUX was dosed at 10 mg or 20mg BID days -1 through 14. Comparator (non-RUX) pts (n=23) were treated at other clinical sites. FLZ was administered at 500 ng/kg/day continuously in 28-day cycles following multi-step lead-in dosing in week 1 of cycle 1. CRS was graded per Lee criteria1.

Results: As of July 1st, 2020, 10 R/R AML pts, median age 65 (range 40-82) years, have been enrolled and treated in the RUX cohort (6 at 10mg, 4 at 20 mg of RUX). All pts had non-favorable risk by ELN 2017 criteria (8 adverse and 2 intermediate); 1 (10.0%) pt had secondary AML; pt characteristics in the RUX and non-RUX cohorts were balanced, except for median baseline BM blasts which was higher in non-RUX pts: 15% (range 5-72) vs (40% (range 7-84), RUX and non-RUX pts respectively. Cytokine analysis showed statistically significant (p<0.05) lower levels of IL4, IL12p70, IL13, IL15, IL17A, IFNα2, but higher levels of GM-CSF were measured in RUX vs non-RUX pts, specifically during co-administration with FLZ (Fig. 1). However, incidence and severity of CRS events were similar. In the RUX cohort, 9 (90%) pts experienced mild to moderate (grade ≤ 2; 48.6% of events were grade 1) CRS events whereas no grade ≥ 3 CRS were reported; in the non-RUX cohort, 23 (100%) pts experienced mild to moderate (grade ≤ 2; 73.1% of events were grade 1) CRS events, 1 (4.3%) grade ≥ 3 CRS was reported. Most CRS events occurred in the first 2 weeks of FLZ administration (75% and 92%, respectively). No differences in duration of CRS events were noted. However, more CRS-directed treatment was used in the RUX cohort. Five (50%) pts received a total of 12 doses of TCZ, 1 (10%) pt received GC and 1 (10%) pts received vasopressors in the RUX cohort. In the non-RUX cohort, 5 (21.7%) pts received 8 doses of TCZ, 3 (13.0%) pts received GC and 1 (3.7%) pt received vasopressors. Dose intensity (DI) at FLZ dose of 500 ng/kg/day was comparable, with median DI of 97.6% and 98.0% in RUX and non-RUX cohorts, respectively. Time to first response (TTFR; BM < 5% blasts) and time on treatment (ToT) were similar between both groups. Median TTFR was 1 cycle for both groups (range 1-2 cycles), and median ToT was 1.4 (range 0.9-5.1) and 1.8 (range 1.3-5.1) months, for RUX and non-RUX pts, respectively. Complete response rate (BM < 5% blasts) was similar: 4 (40%) in RUX pts, and 8 (34.8%) in non-RUX pts; 2 RUX (50%) and 5 non-RUX (62.5%) responders transitioned to stem cell transplant.

Conclusion: Prophylactic RUX produced a clear difference in cytokine profiles but no discernable improvement in clinical CRS or response rates in FLZ treated patients. A larger study may be required to determine the prophylactic role of RUX in CRS.

Clinical Institute



Earle A. Chiles Research Institute