Anakinra for the Prevention of Cytokine Release Syndrome and Neurotoxicity in Patients With B-Cell Non-Hodgkin Lymphoma Receiving CD19-Targeted CAR-T Cell Therapy

OUTLINE:

Patients receive anakinra intravenously (IV) \[previously subcutaneously (SC) for some patients\] over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, positron emission tomography/computed tomography (PET/CT) or CT, bone marrow aspirate (BMA) and biopsy (if clinically indicated), and lumbar puncture (if clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.

After completion of lisocabtagene maraleucel infusion, patients are followed up periodically for up to 90 days.

• Anakinra (Biological), also known as Kinaret, Kineret, rIL-1ra, rIL1RN, 143090-92-0: Given IV (previously SC)
• X-Ray Imaging (Procedure), also known as Conventional X-Ray, Diagnostic Radiology, Medical Imaging, Radiographic Imaging: Undergo x-ray
• Positron Emission Tomography (Procedure), also known as Medical Imaging, PET scan: Undergo PET/CT
• Computed Tomography (Procedure), also known as CAT Scan, Computed Axial Tomography, CT scan: Undergo PET/CT or CT
• Bone Marrow Aspiration (Procedure): Undergo BMA
• Bone Marrow Biopsy (Procedure): Undergo bone marrow biopsy
• Lumbar Puncture (Procedure), also known as LP, spinal tap: Undergo lumbar puncture
• Biospecimen Collection (Procedure), also known as Biological Sample Collection: Undergo blood sample collection

Primary outcomes

• Absence of Any Grade Cytokine Release Syndrome (CRS) [Up to 28 days after lisocabtagene maraleucel (liso-cel) infusion]: Will assess the efficacy of anakinra in preventing the occurrence of any grade CRS using the Bayesian optimal phase 2 design. Assessed based on the ASTCT Consensus Grading for CRS and Neurotoxicity Associated with Immune Effector Cell.

Secondary outcomes

• CRS Grade [Up to 28 days after liso-cel infusion]: CRS severity was graded per American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria (Lee et al, Biol Blood Marrow Transplant, 2019) based on the presence and severity of fever, hypotension, and hypoxia: grade 1, fever ≥38°C without hypotension or hypoxia; grade 2, hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen; grade 3, hypotension requiring a single vasopressor or hypoxia requiring high-flow oxygen; grade 4, life-threatening hypotension requiring multiple vasopressors and/or hypoxia requiring positive-pressure ventilation; grade 5, death.
• ICANS Grade [Up to 28 days after liso-cel infusion]: ICANS severity was graded per American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria (Lee et al, Biol Blood Marrow Transplant, 2019): grade 1, immune effector cell-associated encephalopathy (ICE, overall score range 0-10, higher score = better condition) score 7-9, awakens spontaneously; grade 2, ICE score 3-6, awakens to voice; grade 3, ICE score 0-2, awakens only to tactile stimulus, any clinical seizure that resolves rapidly or non-convulsive seizures on EEG that resolve with intervention, focal/local oedema on neuroimaging; grade 4, ICE 0, unarousable and unable to perform ICE, unarousable or requires vigorous or repetitive tactile stimuli to arouse, stupor or coma, life-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between, deep focal motor weakness such as hemiparesis or paraparesis, diffuse cerebral oedema on neuroimaging, decerebrate or decorticate posturing, or cranial nerve VI
• Rate of Hospitalization After Liso-cel Treatment [Up to 28 days after liso-cel infusion]: Number of patients hospitalized after liso-cel treatment.
• Duration of Hospitalization After Liso-cel Treatment [Up to 28 days after liso-cel infusion]: Duration of hospitalization measured in days following liso-cel administration.
• Corticosteroid Usage After Liso-cel Treatment [Up to 28 days after liso-cel infusion]: Number of patients who received corticosteroids within 28 days after liso-cel infusion.
• Disease Response to Liso-cel [Approximately 90 days after liso-cel infusion]: Best response within approximately 90 days post liso-cel infusion will be assessed based on institutional standard using physical examination, imaging (CT or PET-CT), and if necessary, bone marrow biopsies, in patients with measurable disease prior to treatment.
• Adverse Events (AEs) [Up to 28 days after liso-cel infusion]: Grade 3 or greater AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Subjects must be 18 years of age or older
* Karnofsky performance status of >= 60%
* Patients with B-cell non-Hodgkin lymphoma (B-NHL) and eligible for treatment with liso-cel. Patients treated with non-conforming (out-of-specification) liso-cell may remain on study.
* Negative serum pregnancy test within 2 weeks of enrollment for women of childbearing potential, defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year
* Fertile male and female subjects must be willing to use an effective contraceptive method before, during, and for at least 4 months after the last dose of anakinra
* Ability to understand and provide informed consent

Exclusion Criteria:

* Subjects requiring ongoing daily corticosteroid therapy at a dose of > 15 mg of prednisone per day (or equivalent). Pulsed corticosteroid use for disease control is acceptable
* Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the principal investigator (PI)
* Known hypersensitivity to Escherichia € coli-derived proteins, anakinra, or to any component of the product
* Major organ dysfunction defined as:

  * Serum creatinine > 2.5 mg/dL
  * Significant hepatic dysfunction (Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 5x upper limit of normal; bilirubin > 3.0 mg/dL) unless due to malignancy or Gilbert's syndrome in the opinion of the PI or designee
  * Subjects with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing. Those with a forced expiratory volume in 1 second (FEV1) of < 50% of predicted or diffusion capacity of the lung for carbon monoxide (DLCO) (corrected) < 40% will be excluded
  * Significant cardiovascular abnormalities as defined by any one of the following: New York Heart Association (NYHA) class III or IV congestive heart failure, clinically significant hypotension, uncontrolled symptomatic coronary artery disease, or a documented ejection fraction of < 35%
* Uncontrolled serious and active infection

Participant flow

Outcome results

• Absence of Any Grade Cytokine Release Syndrome (CRS) (Primary), Count of participants, Participants: Prevention (anakinra, lisocabtagene maraleucel) 16
• CRS Grade (Secondary), Count of participants, Participants: Prevention (anakinra, lisocabtagene maraleucel) 9
• ICANS Grade (Secondary), Count of participants, Participants: Prevention (anakinra, lisocabtagene maraleucel) 16
• Rate of Hospitalization After Liso-cel Treatment (Secondary), Count of participants, Participants: Prevention (anakinra, lisocabtagene maraleucel) 18
• Duration of Hospitalization After Liso-cel Treatment (Secondary), Median, days: Prevention (anakinra, lisocabtagene maraleucel) 6 (0 to 10)
• Corticosteroid Usage After Liso-cel Treatment (Secondary), Count of participants, Participants: Prevention (anakinra, lisocabtagene maraleucel) 10
• Disease Response to Liso-cel (Secondary), Count of participants, Participants: Prevention (anakinra, lisocabtagene maraleucel) 8
• Adverse Events (AEs) (Secondary), Count of participants, Participants: Prevention (anakinra, lisocabtagene maraleucel) 25

Adverse events

Time frame: All-Cause Mortality was assessed from date of infusion to date off study, up to 32 months; serious adverse events and other (not including serious) adverse events were assessed from the date of consent until stabilization or resolution, up to 36 days after infusion of liso-cel.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2024-06-05)
• Informed Consent Form (PDF, 2024-04-15)

• Jordan Gauthier, Principal investigator, Fred Hutch/University of Washington Cancer Consortium