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Understanding and Optimizing CAR T-Cell Therapy for Patients With B-Cell Malignancies

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i3 Health is pleased to make the clinician's resource guide available for use as a nonaccredited self-study or teaching resource.

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Understanding and Optimizing CAR T-Cell Therapy for Patients With B-Cell Malignancies

  1. 1. Clinical Tools and Resources for Self-Study and Patient Education CAR T-CELL THERAPY REFERENCE GUIDE The clinical tools and resources contained herein are provided as educational adjuncts to the CE-approved online activity Understanding and Optimizing CAR T-Cell Therapy for Patients with B-Cell Malignancies. To access the activity and earn CE credit, visit: https://www.i3Health.com/CAR-T-Therapy CONTENTS I: Most Common Types of B-Cell MAlignancies...............................................................2 II: CAR T-Cell Therapy Workflow......................................................................................4 III: FDA-Approved CAR T-Cell Therapies.........................................................................5 IV: Adverse Events of CAR T-Cell Therapy.......................................................................6 V: PRinciples of Patient Monitoring..................................................................................7 VI: Cytokine Release Syndrome Guidelines .....................................................................8 VII: CAR T-Cell Related Neurotoxicity..............................................................................9 VIII: Neurotoxicity: Treatment by Grade ........................................................................10 IX: Mini-Mental State Examination (MMSE)....................................................................11
  2. 2. 088CART Reference Guide I Page 2 of 11 www.i3Health.com I: MOST COMMON TYPES OF B-CELL MALIGNANCIES Malignancy Type Characteristics Diffuse large B-cell lymphoma (DLBCL) • Most common; accounts for 1 in 3 lymphomas • Average age at diagnosis is around mid 60s • Subtype: primary mediastinal B-cell lymphoma o Occurs mostly in young women Follicular lymphoma (FL) • Slow growing • Responds well to treatment but is hard to cure • Average age at diagnosis is 60 B-cell acute lymphocytic leukemia (ALL) • Most common cancer in children aged >15 years • Aggressive Chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) • Closely related diseases • Same type of cancer cell for both types • CLL affects blood and bone marrow • SLL affects lymph nodes and spleen • Slow growing Marginal zone lymphoma • Accounts for 5%-10% of lymphomas • Slow growing • Three subtypes o Extranodal marginal zone B-cell lymphoma/mucosa- associated lymphoid tissue (MALT) lymphoma o Nodal marginal zone B-cell lymphoma o Splenic marginal zone B-cell lymphoma Mantle cell lymphoma • Accounts for 5% of lymphomas • More common in men and patients over 60 • Grows faster than indolent lymphomas but doesn’t respond to treatment as well as aggressive lymphomas Burkitt lymphoma • Rare; accounts for 1%-2% of all adult lymphomas • More common in children and males Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) • Rare; accounts for 1%-2% of all lymphoma cases • Lymphoma cells are small and are found in bone marrow, lymph nodes, and spleen Hairy cell leukemia • Rare • Small B lymphocytes with tiny hair-like projections • Found in bone marrow, spleen, and blood • Slow growing
  3. 3. 088CART Reference Guide I Page 3 of 11 www.i3Health.com Malignancy Type Characteristics Primary central nervous system leukemia • Rare; more common in elderly patients with weakened immune systems • Patients develop headaches, confusion, and sometimes seizures American Cancer Society (2019). Types of B-cell lymphoma. Available at: https://www.cancer.org/ National Cancer Institute (2018). Childhood acute lymphoblastic leukemia treatment (PDQ®)—health professional version. Available at: https://www.cancer.gov
  4. 4. 088CART Reference Guide I Page 4 of 11 www.i3Health.com II: CAR T-CELL THERAPY WORKFLOW National Cancer Institute (2019). CAR T-cell therapy infographic. Available at: https://www.cancer.gov
  5. 5. 088CART Reference Guide I Page 5 of 11 www.i3Health.com III: FDA-APPROVED CAR T-CELL THERAPIES Treatment Description and Indications Tisagenlecleucel (Kymriah™) • CD19-directed genetically modified autologous T-cell immunotherapy • FDA approved for patients ≤25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse • Also approved as third-line or later systemic therapy for adults with several types of relapsed/refractory large B-cell lymphoma: o DLBCL-not otherwise specified (NOS) o High-grade B-cell lymphoma o DLBCL arising from FL • Contraindicated in primary central nervous system (CNS) lymphoma Axicabtagene ciloleucel (Yescarta™) • CD19-directed genetically modified autologous T-cell immunotherapy • FDA approved as third-line or later systemic therapy for adults with several types of relapsed/refractory large B-cell lymphoma: o DLBCL-NOS o Primary mediastinal large B-cell lymphoma o High-grade B-cell lymphoma o DLBCL arising from FL • Contraindicated in primary CNS lymphoma Leukemia & Lymphoma Society (2019). Chimeric antigen receptor (CAR) T-cell therapy. Available at: https://www.lls.org/
  6. 6. 088CART Reference Guide I Page 6 of 11 www.i3Health.com IV: ADVERSE EVENTS OF CAR T-CELL THERAPY Adverse Event Characteristics Cytokine release syndrome (CRS) • Cytokines (chemical messengers that help the T cells carry out their functions) are produced when the CAR T cells multiply in the body and kill the cancer cells • Symptoms range from mild flulike symptoms (nausea, fatigue, headache, chills, fever) to more serious symptoms: low blood pressure, tachycardia, capillary leakage, cardiac arrest, cardiac arrhythmias, cardiac failure, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), hypoxia, renal insufficiency, poor lung oxygenation, multiple organ failure Neurologic toxicities • Frequency, severity, and nature of neurological effects vary between CAR T products • Symptoms: language impairment (aphasia), confusion, delirium, involuntary muscle twitching, hallucinations, unresponsiveness, seizures B-cell aplasia • Because CAR T-cell therapy targeting antigens found on the surface of B cells not only destroys cancerous B cells but also normal B cells, B-cell aplasia (low numbers of B cells or absent B cells) is an expected result of successful CD19-specific CAR T-cell treatment and has served as a useful indicator of ongoing CAR T-cell activity • This effect results in less ability to make the antibodies that protect against infection • Intravenous or subcutaneous immunoglobulin replacement therapy may be given with the aim of preventing infection Tumor lysis syndrome (TLS) • Group of metabolic complications that can occur due to the breakdown of dying cells • Usually occurs at the onset of toxic cancer treatments but can be delayed; may occur ≥1 month after CAR T-cell therapy • Can cause organ damage • Can be a life-threatening complication of any treatment, including CAR T, that causes breakdown of cancer cells • Managed by standard supportive therapy Anaphylaxis • There is potential for a patient receiving CAR T-cell therapy to have an overwhelming immune response against the CAR itself • Symptoms: hives, facial swelling, low blood pressure, respiratory distress • There have been few reports of acute anaphylaxis • Thorough monitoring and immediate treatment of this life-threatening side effect are critical Leukemia & Lymphoma Society (2019). Chimeric antigen receptor (CAR) T-cell therapy. Available at: https://www.lls.org
  7. 7. 088CART Reference Guide I Page 7 of 11 www.i3Health.com V: PRINCIPLES OF PATIENT MONITORING Patient Monitoring Before and During CAR T-Cell Infusion • Perform central venous access, preferably with double or triple lumen catheter, for intravenous (IV) fluid and other infusions in case of toxicities • Perform cardiac monitoring at the onset of grade ≥2 CRS until resolution to grade £1 and additionally as clinically indicated • Tumor lysis precautions are recommended for patients with large tumor burden and aggressive histologies per institutional guidelines • For CAR T-cell therapies known to cause neurotoxicity, start seizure prophylaxis (eg, levetiracetam 500-700 mg orally every 12 hours for 30 days) on the day of infusion • Consider baseline brain magnetic resonance imaging (MRI) Patient Monitoring After CAR T-Cell Infusion • Close monitoring in the hospital is preferable with current products used for adults, but extremely close outpatient monitoring may be possible at centers with CAR T- cell transplant or outpatient transplant experience • Hospitalization is warranted for patients with CRS • Monitor complete blood count (CBC), complete metabolic panel (including magnesium and phosphorous), and coagulation profile • Check baseline C-reactive protein (CRP) and ferritin; recheck at least 3 times per week for 2 weeks post infusion. Consider daily checks during CRS. C-reactive protein can normalize prior to the onset of neurotoxicity • During the peak window of CRS risk, assessment for CRS should be done at least twice daily or when the patient’s status changes • During the peak window of neurotoxicity risk, neurotoxicity assessment should be done at least twice daily or when the patient’s status changes. If neurologic concern develops, assess cognitive function and motor weakness at least every 8 hours National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: management of immunotherapy-related toxicities. Version 1.2019. Available at: http://www.nccn.org
  8. 8. 088CART Reference Guide I Page 8 of 11 www.i3Health.com VI: CYTOKINE RELEASE SYNDROME GUIDELINES CRS Grade Anti–IL-6 Therapy Corticosteroids Additional Supportive Care Grade 1: Fever with or without constitutional symptoms For prolonged CRS (>3 days) in patients with significant symptoms and/or comorbidities, consider tocilizumab per Grade 2 N/A • Empiric broad-spectrum antibiotics • If neutropenic, consider granulocyte colony-stimulating factor (G-CSF) • Maintenance IV fluids for hydration • Symptomatic management of organ toxicities Grade 2: Hypotension responding to fluids; hypoxia responding to <40% O2 Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg/dose). Repeat in 8 hours if no improvement; no more than 3 doses in 24 hours, with a maximum of 4 doses in total For persistent refractory hypotension after 1- 2 doses of anti–IL-6 therapy: dexamethasone 10 mg IV every 6 hours (or equivalent) • IV fluid bolus as needed • For persistent refractory hypotension after 2 fluid boluses and anti–IL-6 therapy: o Start vasopressors o Consider transfer to ICU o Consider echocardiogram o Initiate hemodynamic monitoring • Symptomatic management of organ toxicities Grade 3: Hypotension managed with one pressor; hypoxia returning with ³40% O2 Anti–IL-6 therapy per Grade 2 if maximum dose not reached within 24- hour period Dexamethasone 10 mg IV every 6 hours (or equivalent). If refractory, manage as grade 4 • Transfer to ICU, obtain echocardiogram, and perform hemodynamic monitoring • Supplemental oxygen, including high-flow oxygen delivery and noninvasive positive pressure ventilation • IV fluid bolus and vasopressors as needed • Symptomatic management of organ toxicities Grade 4: Life-threatening consequences; requires ventilator support or vasopressor- refractory shock Anti–IL-6 therapy per Grade 2 if maximum dose not reached within 24- hour period Dexamethasone 10 mg IV every 6 hours (or equivalent). If refractory, consider methylprednisolone 1,000 mg/day IV • ICU care and hemodynamic monitoring • Mechanical ventilation as needed • IV fluid bolus and vasopressors as needed • Symptomatic management of organ toxicities National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: management of immunotherapy-related toxicities. Version 1.2019. Available at: http://www.nccn.org
  9. 9. 088CART Reference Guide I Page 9 of 11 www.i3Health.com VII: CAR T-CELL RELATED NEUROTOXICITY Assessment and Supportive Care Recommendations (All Grades) • Neurologic assessment and grading, include cognitive assessment and motor weakness, at least twice a day • Neurology consultation at first sign of neurotoxicity • For neurotoxicity ³ grade 2: o MRI of the brain with and without contrast (or brain computed tomography (CT) if MRI is not feasible) o Electroencephalogram (EEG) for seizure activity • Aspiration precautions • IV hydration • Use caution when prescribing medications that can cause CNS depression (aside from those needed for seizure prophylaxis/treatment) National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: management of immunotherapy-related toxicities. Version 1.2019. Available at: http://www.nccn.org
  10. 10. 088CART Reference Guide I Page 10 of 11 www.i3Health.com VIII: NEUROTOXICITY: TREATMENT BY GRADE Neurologic Toxicity: Assessment and Supportive Care Recommendations (All Grades) Grade No Concurrent CRS Additional Therapy if Concurrent CRS Grade 1 Mild impact on activities of daily living (ADLs) • Supportive Care Tocilizumab 8 mg/kg IV over 1 hour (≤800 mg/dose) Grade 2 Moderate impact on ADLs • Supportive Care • Dexamethasone 10 mg IV x 1; can repeat every 6 hours or methylprednisolone 1 mg/kg IV every 12 hours if symptoms worsen Anti–IL-6 therapy per Grade 1 Grade 3 Severe impact on ADLs; seizure; signs of elevated intracranial pressure (eg, papilledema, Cushing’s triad, hypertension, bradycardia) • ICU care is recommended • Dexamethasone 10 mg IV every 6 hours or methylprednisolone 1 mg/kg IV every 12 hours • Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent grade ³3 neurotoxicity Anti–IL-6 therapy per Grade 1 Grade 4 Patient in critical condition and/or obtunded; cannot perform assessment of tasks; life-threatening seizures or repetitive seizures without return to baseline • ICU care; consider mechanical ventilation for airway protection • High-dose corticosteroids • Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent grade ³3 neurotoxicity • Treat convulsive status epilepticus per institutional guidelines Anti–IL-6 therapy per Grade 1 National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: management of immunotherapy-related toxicities. Version 1.2019. Available at: http://www.nccn.org
  11. 11. 088CART Reference Guide I Page 11 of 11 www.i3Health.com IX: MINI-MENTAL STATE EXAMINATION (MMSE) Maximum Score Patient’s Score Questions 5 “What is the year? Season? Date? Day of the week? Month?” 5 “Where are we now: State? County? Town/city? Hospital? Floor?” 3 The examiner names three unrelated objects clearly and slowly, then asks the patient to name all three of them. The patient’s response is used for scoring. The examiner repeats them until patient learns all of them, if possible. Number of trials: 5 “I would like you to count backward from 100 by sevens.” (93, 86, 79, 72, 65, …) Stop after five answers. Alternative: “Spell WORLD backwards.” (D-L-R-O-W) 3 “Earlier I told you the names of three things. Can you tell me what those were?” 2 Show the patient two simple objects, such as a wristwatch and a pencil, and ask the patient to name them. 1 “Repeat the phrase: ‘No ifs, ands, or buts.’” 3 “Take the paper in your right hand, fold it in half, and put it on the floor.” (The examiner gives the patient a piece of blank paper.) 1 “Please read this and do what it says.” (Written instruction is “Close your eyes.”) 1 “Make up and write a sentence about anything.” (This sentence must contain a noun and a verb.) 1 “Please copy this picture.” (The examiner gives the patient a blank piece of paper and asks him/her to draw the symbol below. All 10 angles must be present and two must intersect.) 30 Total Rovner BW & Folstein MF (1987). Mini-mental state exam in clinical practice. Hosp Pract (Off Ed), 22(1A):99, 103, 106, 110.

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