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2816 Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or Icans after CAR T-Cell Therapy

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Clinical: Poster II
Hematology Disease Topics & Pathways:
Biological therapies, Adults, Workforce, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diversity, Equity, Inclusion, and Accessibility (DEI/DEIA) , Pediatric, Real World Evidence, Therapies, Immunotherapy, Study Population
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Nicolas Gazeau1*, Pere Barba, MD, PhD2*, Gloria Iacoboni, MD3,4*, Mi Kwon, MD, PhD5,6*, Rebeca Bailen7,8*, Juan Luis Reguera9*, Lucía López Corral, MD10*, Rafael Hernani, MD11*, Valentín Ortiz-Maldonado, MD, PhD12*, Antonio Perez-Martinez, MD, PhD13*, Richard T. Maziarz, MD14, Staci Williamson, MS14*, Eneida R. Nemecek, MD, MBA, MSc15, Mazyar Shadman, MD16, Andrew Coman17*, Damian J. Green, MD18, Victor A. Chow, MD19, Alexandre V. Hirayama, MD18, David G. Maloney, MD, PhD18, Cameron J. Turtle, MBBS, PhD20 and Jordan Gauthier, MD19,20,21

1Clinical Research Division, Fred Hutchinson Cancer Research center, Seattle, WA
2Hospital Universitari Vall d’Hebron and Universitat Autonoma de Barcelona, Barcelona, Spain
3Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
4Vall d’Hebron University Hospital, Barcelona, Spain
5Hematology Department, Gregorio Marañón General University Hospital, Madrid, Spain
6Department of Hematology, Hospital General Universitario Gregorio Marañón, Gregorio Marañon Health Research Institute, Madrid, Spain
7Hospital General Universitario Gregorio Marañón, Gregorio Marañon Health Research Institute, Madrid, Spain
8Department of Hematology, Gregorio Marañón General University Hospital, Madrid, Spain
9Hospital Universitario Virgen del Rocío, Sevilla, Spain
10Hematology Department, Hospital Clínico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain
11Department of Hematology, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
12Department of Hematology, Hospital Clinic de Barcelona, Barcelona, Spain
13Department of Hematologia-Oncologia, Hospital Universitario La Paz, Madrid, Spain
14Knight Cancer Institute, Oregon Health and Science University, Portland, OR
15Pediatric Hematology/Oncology & Bone Marrow Transplantation, Oregon Health & Science University, Knight Cancer Institute Doernbecher Children's Hospital, Portland, OR
16University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA
17Department of Medicine, University of Washington, Seattle, WA
18Fred Hutchinson Cancer Research Center, Seattle, WA
19Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
20Clinical Research Division, Fred Hutchinson Cancer Research Ctr., Seattle, WA
21University of Washington, Seattle Cancer Care Alliance, Seattle, WA

Background:

Chimeric antigen receptor-engineered (CAR) T-cell therapy remains associated with significant toxicities including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Recently, the recombinant IL-1 receptor antagonist anakinra has emerged as a promising approach after failure of tocilizumab and corticosteroids to treat CRS/ICANS (Norelli, Nat Med 2018; Giavridis, Nat Med 2018). Here, we describe the safety and efficacy of two anakinra dose regimens to treat refractory CRS and/or ICANS after CAR T-cell therapy.

Methods:

We retrospectively analyzed data from 26 patients with B-cell or plasma cell malignancies treated at 9 institutions with anakinra for CRS and/or ICANS after CAR T-cell therapy. Details regarding CAR T-cell product and disease type are shown in the Table. CRS/ICANS grade was determined by applying the ASTCT criteria at the time of peak symptom severity. We defined response to anakinra as an improvement in CRS and/or ICANS symptoms per the attending physician’s evaluation.

Results:

Patients, disease, and CAR T-cell product are shown in the Table. Anakinra was administered at 100-200mg/day subcutaneously (SC) in 13 patients (pts) (50%; low-dose), or at 8mg/kg/day SC or intravenously (IV) in 13 pts (50%; high-dose). Most pts were treated with anakinra for steroid-refractory ICANS (n=23); two pts were treated for tocilizumab-refractory CRS (n=2) and one for both (n=1). All but one patient received anakinra concurrently with corticosteroids.

Median peak CRS and ICANS grade by ASTCT criteria was 2 (range, 1-4), and 4 (range, 0-5), respectively. Median CRS and ICANS duration was 5 days (range, 1-10) and 15.5 days (range, 1-38), respectively. Median time from CAR T-cell infusion to anakinra initiation was 9 days (range, 5-31). The median duration of anakinra treatment was 8.5 days (range, 1-47). The median time to anakinra initiation from CRS or ICANS onset was comparable in pts receiving high-dose compared to low-dose anakinra (4 versus 4 days, respectively; p=0.8). Comparable peak CRS (median grade, 2 versus 2, p=0.9) and ICANS (median grade, 4 versus 4, p=0.2) were measured in both groups. Other toxicity-directed therapies were administered in 8 pts receiving low-dose anakinra (siltuximab, n=8; intrathecal chemotherapy, n=2, etoposide n=1).

The only infectious event reported after anakinra initiation was HHV6 encephalitis (n=1). Two pts with infections confirmed prior to anakinra initiation died after anakinra treatment: CMV pneumonia (n=1), Escherichia coli bacteremia (n=1). In one patient the anakinra administration route was changed from SC to IV due to a subcutaneous hematoma; in one patient anakinra was discontinued due to elevated liver enzymes. We observed anti-tumor responses (partial or complete) to CAR T-cell therapy in 15 pts (58%; B-ALL, n=1/1; DLBCL, n=9/15; MCL, n=3/4; MM; n=1/1; PMBCL, n=1/3), including complete responses in 11 pts (42%). In high-dose anakinra pts, the ORR was 77% (complete response, 53%).

CRS/ICANS improvement was observed after anakinra initiation in 73% of pts with a median duration of treatment of 3 days (range 1-7). Higher response rates were seen in pts who received high-dose compared to low-dose anakinra (100% versus 46%, respectively; p=0.005) and the non-relapse mortality rate at day 30 was significantly lower in pts treated with high-dose anakinra compared to low-dose anakinra (0% versus 69%; p=0.001%).

In addition, a shorter time to anakinra initiation from CRS or ICANS onset was associated with CRS/ICANS improvement (median, 2 versus 5 days in responders versus non-responders, respectively; p=0.04).

Conclusion

After failure of tocilizumab and/or corticosteroids, early administration of high-dose anakinra (8mg/kg/day IV or SC) was associated with rapid resolution of CRS/ICANS symptoms after use of tocilizumab and/or corticosteroids, with a manageable toxicity profile, and with a non-relapse mortality rate at day 30 of 0%. In contrast, 38% of patients treated with low-dose anakinra died from infections. We observed complete responses to CAR T-cell therapy in pts treated with high-dose anakinra, suggesting limited impact on in vivo CAR-T cell function. In summary, high-dose anakinra is a feasible and promising approach after failure of conventional CRS and ICANS-directed therapies. Prospective trials of anakinra to prevent or treat CRS and ICANS are ongoing.

Disclosures: Barba: Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding; Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Bailen: Gilead, Pfizer: Speakers Bureau. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Corral: Gilead: Consultancy; Novartis: Consultancy; Gileqd: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Maziarz: Allovir: Consultancy, Research Funding; Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Vor Pharma: Other: Data and Safety Monitoring Board; Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; Artiva Therapeutics: Consultancy; CRISPR Therapeutics: Consultancy; Intellia: Honoraria; Omeros: Research Funding; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Incyte Corporation: Consultancy, Honoraria. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Chow: ADC Therapeutics: Current equity holder in publicly-traded company, Research Funding; AstraZeneca: Research Funding. Hirayama: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Maloney: Kite, a Gilead Company, Juno, and Celgene: Research Funding; A2 Biotherapeutics: Consultancy; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Juno: Patents & Royalties. Turtle: AstraZeneca: Consultancy, Research Funding; Nektar Therapeutics: Consultancy, Research Funding; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; T-CURX: Other: Scientific Advisory Board; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Asher Bio: Consultancy; Amgen: Consultancy; PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; Allogene: Consultancy. Gauthier: JMP: Consultancy; Larvol: Consultancy; Multerra Bio: Consultancy; Eusapharma: Consultancy; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, A BMS Company: Research Funding; Celgene, a BMS Company: Research Funding.

*signifies non-member of ASH