B-Acute Lymphoblastic Leukemia, CAR-T Cell Therapy, Cytokine Release Syndrome, Immune Effector Cell Associated Hemophagocytic Lymphohistiocytosis-like Syndrome, Immune Effector Cell Associated Neurotoxicity Syndrome
Conditions
Keywords
Anakinra, Cytokine Release Syndrome, CAR-T Therapy, Pediatric, B-acute lymphoblastic leukemia, Prophylaxis, Inflammatory Toxicity, Immune Effector Cell Associated Neurotoxicity Syndrome
Brief summary
Objectives: The primary objective of this study will be to evaluate the impact of pre-emptive use of anakinra on the rate of severe cytokine release syndrome (CRS) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for B-acute lymphoblastic leukemia (B-ALL) in children and young adults. Patient Population: Children and young adults \<25 years of age undergoing CAR T-cell therapy for B-ALL with bone marrow disease burden of ≥5% involvement or detectable peripheral blasts within 2 weeks of the initiation of lymphodepleting chemotherapy. Study Design: This is a pilot single arm study. The investigators will inquire into the efficacy and safety of using anakinra pre-emptively to reduce the rate of severe CRS in patients with \>/=5% bone marrow blasts or lymphoblasts in the peripheral blood. Treatment Plan: This is a single arm unblinded study in which patients will receive anakinra, 2.5 mg/kg (max 100mg), IV every 12 hours starting at the onset of persistent fever (fever \>38.5⁰ C x 2 occurrences separated by at least 4 hours in a 24 hour period). If there is persistence or progression of CRS, anakinra frequency will be increased to 2.5mg/kg IV (max 100mg), every 6 hours. Anakinra will be continued until 48 hours after resolution of CRS and ICANS, and at least 7 days post-CAR T infusion. If dose and frequency of anakinra is increased, the increased dose of anakinra will be continued until 48 hours after resolution of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) and at least 7 days post-CAR T infusion. For CRS worsening beyond dose escalation of anakinra, CRS will be managed as per standard of care management. Participants will be followed for 12 months following enrollment in the study and disease evaluations will be performed as per routine clinical care following CAR T-cell therapy.
Interventions
Pre-emptive Anakinra at the initial onset of CRS.
Sponsors
Kevin McNerney
National Center for Advancing Translational Sciences (NCATS)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
• Patient consent and parental assent will be obtained. NOTE: Signed consent form must be obtained prior to any study procedures. Labs, marrows or other procedures obtained during routine clinical care maybe used for eligibility if obtained within the protocol required windows. * Patients or their parents/legally authorized representatives (LARs) must have the ability to understand and the willingness to sign a written informed consent document. * The effects of Anakinra on the developing human fetus are largely unknown. For this reason, patients of child-bearing potential (POCBP) and their partners with sperm-producing reproductive capacity must agree to use adequate contraception from time of informed consent, for the duration of study participation, and for 90 days following completion of Anakinra therapy. Should a POCBP become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. Patients with sperm-producing reproductive capacity (PWSPRC) treated or enrolled on this protocol must also agree to use adequate contraception with partners of childbearing potential from time of informed consent, for the duration of study participation, and 90 days after completion of administration. Note: A POCBP is any patient (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) with an egg-producing reproductive tract who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) * POCBP must have a negative serum or urine pregnancy test (women who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential) * Patients who are between the age of 1 to 26 years * Relapsed or refractory B-acute lymphoblastic leukemia * 2nd or greater marrow relapse OR * Central nervous system (CNS) relapse OR * Any relapse after allogeneic hematopoietic stem cell transplant (HSCT) OR * Refractory disease defined by not achieving an minimal residual disease (MRD)-negative complete remission (CR) after ≥ 2 chemotherapy cycles (1 cycle for relapsed patients) OR * Ineligible for allogeneic HSCT because of: * Comorbid disease * Other contraindications to allogeneic HSCT conditioning * No suitable donor * Prior HSCT * Declines HSCT as the therapeutic option after documented discussion, with expected outcomes, about the role of HSCT with a HSCT physician * Documentation of CD19+ tumor expression in the bone marrow, peripheral blood, cerebrospinal fluid (CSF), or tumor tissue by flow cytometry at relapse, or a recent sample in the case of refractory disease. If the patient has received CD19-directed Pre-emptive anakinra for severe CRS prevention therapy, the flow cytometry should be obtained after this therapy to show CD19 expression. * Adequate organ function defined as: * Alanine aminotransferase (ALT) \< 500 U/L * Bilirubin ≤2.0 mg/dL * Minimum pulmonary reserve defined as ≤Grade 1 dyspnea, pulse oximetry \>92% on room air; diffusing capacity of the lungs for carbon monoxide (DLCO) ≥40% (corrected for anemia) if pulmonary function tests (PFTs) are clinically appropriate as determined by the treating investigator. * Left ventricular shortening fraction ≥ 28% or ejection fraction ≥40% confirmed by echocardiography (ECHO), or adequate ventricular function documented by imaging or a cardiologist. * Serum creatinine below the values in the below table, based on age/sex assigned at birth: Maximum Serum Creatinine (mg/dL) Age (years) Male Female 1 to \<2 0.6 0.6 2 to \<6 0.8 0.8 6 to \<10 1.0 1.0 10 to \<13 1.2 1.2 13 to \<16 1.5 1.4 ≥16 1.7 1.4 * Bone marrow disease burden of ≥5% or peripheral blasts within 2 weeks of the start of lymphodepleting chemotherapy * Receiving commercially available tisagenlecleucel
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Severe CRS within 30 days of CAR T-cell infusion | 30 days of CAR-T infusion | The rate of severe CRS, grade ≥3 CRS, as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) consensus guidelines. Participants will have CRS grading each day of hospitalization and every clinical visit within the first 30 days of CAR T-cell infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Rate | 28-35 days post CAR-T infusion | 1\. Complete Remission Rate at day 28-35 post-CAR-T |
| Overall and event-free survival | Up to 12 months post CAR-T infusion | 6- and 12-month overall and event-free survival |
| CRS and ICANS Severity | Up to 12 months post CAR-T infusion | Rate and any grade of CRS, any grade ICANS, severe (grade \>/=3) ICANS, any grade IEC-HS |
| Immune effector cell-associated hematotoxicity (ICAHT) Severity | Up to 12 months post CAR-T infusion | Rate of any grade and grade \>/=3 ICAHT as defined by European Hematology Association (EHA)/European Society for Blood and Marrow Transplantation (EBMT) guidelines |
| Use of tocilizumab or steroids | Within 30 days post CAR T infusion | Use of tocilizumab and steroids in the treatment of CRS, ICANS, or Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) |
| Infection severity | Within 30 days post CAR T infusion | Rate of severe infections (as defined by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade \>/=3) |
| Inflammatory markers and cell turnover | Within 30 days post CAR T infusion | Inflammatory markers (C-reactive protein, ferritin) and markers of cell turnover (lactate dehydrogenase and uric acid) |
| Cell expansion and plasma cytokine profiles | Within 35 days post CAR T infusion | CAR T-cell expansion and plasma cytokine profiles |
Countries
United States
Outcome results
None listed