Secondary Logo

Journal Logo

Nursing management for adult recipients of CAR T-19 therapy

Morrison, Felicia, MSN, MBA, RN-BC

doi: 10.1097/01.CCN.0000553079.71775.62
Feature
Free

Abstract: With limited cancer treatment options available for patients with certain types of advanced or recurrent acute lymphoblastic leukemia and certain types of non-Hodgkin lymphoma, the recent FDA approvals of tisagenlecleucel (Kymriah, formerly known as CTL019), and axicabtagene ciloleucel (Yescarta), CAR T-cell therapy provides a new opportunity to achieve cancer remission for many patients.1,2 These genetically enhanced T cells can destroy cancer cells. This article explores the science behind CAR T-cell therapy and ways critical care nurses can recognize and intervene in potentially life-threatening adverse reactions associated with this new therapy: cytokine release syndrome and CAR T-cell-related encephalopathy syndrome.3

The recent FDA approvals of tisagenlecleucel and axicabtagene ciloleucel, have given patients with certain types of advanced or recurrent acute lymphoblastic leukemia and certain types of non-Hodgkin lymphoma new therapy options. This article explores the science behind CAR T-cell therapy and nursing management considerations for two life-threatening adverse reactions associated with this new therapy.

Felicia Morrison is a clinical nurse at The Hospital of the University of Pennsylvania, Philadelphia, Pa.

The author has disclosed no financial relationships related to this article.

Figure

Figure

Acute lymphoblastic leukemia (ALL), also called acute lymphocytic leukemia, is an aggressive type of leukemia characterized by the presence of too many lymphoblasts or lymphocytes in the bone marrow and peripheral blood. It can spread to the lymph nodes, spleen, liver, central nervous system (CNS), and other organs. Without treatment, ALL usually progresses quickly.4 In 2018, the National Cancer Institute (NCI) estimated that there were 5,960 new cases and 1,470 deaths from ALL in the US.4

The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. NHL usually originates in lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a greater chance of dissemination to extranodal sites. Prognosis depends on the histologic type, stage, and treatment.5 In 2018, the NCI estimated that there were 74,680 new cases and 19,910 deaths from NHL in the US.5

With limited cancer treatments available, patients with ALL and certain types of NHL have had few options to fight their disease.

Back to Top | Article Outline

Chemotherapy challenges

Historically, chemotherapy has been used to treat both ALL and certain types of NHL. Chemotherapeutic agents can be used individually, concurrently, or in combination with other treatment options (such as surgery or radiation therapy) but cannot distinguish between rapidly growing normal cells and cancer cells. This means chemotherapy damages normal cells along with the cancer cells, causing adverse reactions such as nausea, anorexia, oral mucositis, malaise, infection, and alopecia.

Even the most potent chemotherapy has left many patients with ALL and NHL without a cure, and many patients have relapsed.6 However, advances in science, technology, immunotherapy, and genetic engineering have widened the scope of cancer treatment, giving healthcare providers the ability to use a patient's immune system to destroy cancer cells.7

Back to Top | Article Outline

FDA approvals

Until 2017, CAR T-cell therapy was used in clinical trials. In August 2017, the FDA approved the first gene therapy—tisagenlecleucel (Kymriah).8 Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy currently indicated for two patient populations:9

  • patients up to age 25 with B-cell precursor ALL that is refractory or in second or later relapse
  • adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

In October 2017, the FDA approved the second CD19-directed genetically modified autologous T cell immunotherapy axicabtagene ciloleucel (Yescarta), which is indicated for the treatment of:10

  • adult patients with (r/r) large B-cell lymphoma after two or more lines of systemic therapy
  • DLBCL not otherwise specified
  • primary mediastinal large B-cell lymphoma
  • high-grade B-cell lymphoma
  • DLBCL arising from follicular lymphoma.
Back to Top | Article Outline

CAR T-cell therapy process

The patient undergoes leukapheresis, in which white blood cells (WBCs) are collected and separated. T cells are extracted from the WBCs, and the remaining blood components are returned to the patient. T lymphocytes (T cells) are WBCs that are a part of the immune system. (See Understanding lymphocytes.) This process takes about 4 hours. The patient's immune system is not compromised because only approximately 1% of a patient's T cells are removed (see Bonus content).6 When this process is complete, the patient's cells are modified with a lentivirus in which a patient's T cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells.11 (See CAR T-cell therapy.) Within 24 hours, the leukapheresis material is cryopreserved. Cryopreservation allows for convenient scheduling of leukapheresis at a time that is in the best interest of the patient.12

About 2 to 14 days before CAR T-cell therapy infusion, the patient will receive a course of low-dose lymphodepleting chemotherapy over 4 days unless the patient's WBC count is less than or equal to 1 × 109/L (normal, 4.5 to 11.0 × 109/L) within 1 week before the infusion. Lymphodepletion helps prepare the patient for incoming cells and may help promote their proliferation.12 The engineered T cells are the patient's own (autologous) T cells, so a donor is not needed and patients are at little risk for adverse reactions related to reinfusion. Produced in about 5 to 10 days, the T cells metamorphose into CAR T cells. In approximately 2 to 4 weeks after collection—depending on the patient's clinical status—the patient receives his or her own genetically modified T cells via a single I.V. infusion in a process that takes about 20 to 30 minutes.13

Back to Top | Article Outline

Clinical trials

In clinical trials, cytokine release syndrome (CRS) and CAR T-cell-related encephalopathy syndrome (CRES) were the most commonly reported adverse events. In the 2018 ELIANA study of the safety and efficacy of tisagenlecleucel in pediatric and young adult patients with r/r B-cell ALL, 77% of patients developed CRS of any grade and 46% developed CRS of grade 3 or 4; 40% of patients developed neurologic toxicities of any grade and 13% of patients developed neurologic toxicities of grade 3. There were no grade 4 incidences.14

In the 2017 JULIET study of tisagenlecleucel, when administered to adult patients with r/r DLBCL, 58% of patients developed CRS of any grade and 23% developed grade 3 or 4; 21% of patients developed neurologic toxicities of any grade and 12% of patients developed neurologic toxicities of grade 3 or 4.15

In clinical trials, 94% of patients receiving axicabtagene ciloleucel developed CRS of any grade and 13% developed CRS of grade 3 or higher; 57% developed any grade of encephalopathy and 29% developed grade 3 or higher.16

Because of the serious risks associated with the use of CAR T therapy, the FDA requires hospitals and clinics that disburse and/or administer the drug to have certification prior to treating patients. To obtain certification, all employees who will administer and/or dispense CAR T therapy must successfully complete a Risk Evaluation and Mitigation Strategy program. This program ensures organizations know how to manage known or potential adverse reactions, such as CRS and CRES.17,18 As of January 2019, there were 76 tisagenlecleucel-certified facilities in the US.19

Back to Top | Article Outline

Cytokine-release syndrome

CRS is a severe immune reaction that leads to a progressive elevation in inflammatory cytokines by T lymphocytes. CRS onset typically occurs within the first 3 weeks of treatment.3 CRS is characterized by fever (temperature of 100.4° F [38° C] or higher), hypotension (systolic BP less than 90 mm Hg), hypoxemia (supplemental oxygen needed to maintain oxygen saturation greater than 90%), fatigue, immunosuppression, destruction of normal B cells, rash, arthralgia, nausea, vomiting, diarrhea, and myalgia.18

CRS is managed according to a grading scale algorithm from 1 to 4. The scale distinguishes between life-threatening and non-life-threatening clinical manifestations of CRS and required levels of care.3

It is recommended that patients' CRS grade be determined twice daily and any time there is a change in the patient's status.3

  • Grade 1 CRS: these patients will have a fever with or without constitutional symptoms, such as nausea, myalgia, and/or a headache. Treatment is supportive with the use of acetaminophen and hypothermia blanket as needed for fever; ibuprofen if fever is not controlled with earlier measures; use ibuprofen with caution or avoid it if the patient has thrombocytopenia; assess for infection with blood and urine cultures, and chest X-ray; consider antibiotics and filgrastim (if neutropenic); I.V. fluids as needed; symptomatic management of constitutional symptoms and organ toxicities; consider IL-6 antagonist (tocilizumab) for persistent (more than 3 days) or refractory fever. (See CRS antidote: Tocilizumab.)
  • Grade 2 CRS: these patients exhibit hypotension that responds to fluids or one low-dose vasopressor and hypoxemia that responds to supplemental oxygen (FiO2 less than 40%).3 Treatment includes managing fever and constitutional symptoms as in Grade 1 CRS; I.V. fluid bolus of 500-1,000 mL normal saline repeated as necessary to maintain systolic BP greater than 90 mm Hg; consider an IL-6 receptor antagonist (tocilizumab) for hypotension refractory to fluid boluses; if hypotension persists after two fluid boluses and IL-6 antagonist, start vasopressors, transfer patient to the ICU, and obtain an echocardiogram. In patients at high risk for severe CRS, if hypotension persists after IL-6 antagonist, if there are signs of hypoperfusion, or if there is rapid deterioration in the opinion of the clinician, I.V. dexamethasone may be used.3
  • Grade 3 CRS: these patients exhibit oliguria (less than 0.5 mL/kg/h) and poor lactate clearance (less than 10%) despite adequate fluid resuscitation. These patients require supplemental oxygen greater than or equal to 40% FiO2, a vasopressor or multiple vasopressors to treat hypotension, and/or bilevel positive airway pressure (BPAP). Treatment is aggressive and includes grade 2 therapies, IL-6 antagonist if not administered previously, along with the use of I.V. dexamethasone, and management of organ toxicity. In grade 3, steroids are continued and tapered until the events return to grade 1 or less. Manage fever and constitutional symptoms as in grade 1 CRS.3
  • Grade 4 CRS: these patients have life-threatening signs and symptoms requiring endotracheal intubation, mechanical ventilation, and renal replacement therapy. Treatment is aggressive and includes grade 2 and grade 3 therapies, I.V. fluids, IL-6 antagonist, vasopressors, and hemodynamic monitoring; supportive care; and high-dose I.V. methylprednisolone until CRS improvement to grade 1.3
Back to Top | Article Outline

CAR T-cell-related encephalopathy syndrome

CRES is a neurologic toxicity that can occur concurrently with or after CRS. It is characterized by encephalopathy, language disturbance, impaired handwriting, delirium, seizures, headache, anxiety, dizziness, aphasia, sleep disorders, dysphasia, incontinence or motor weakness, dysgraphia, intracranial hypertension, and/or cerebral edema.3 The majority of CRES occurs within 8 weeks following CAR T-cell therapy.

Similar to CRS, CRES is managed according to a grading scale algorithm ranging from 1 to 4. The scale distinguishes between life-threatening and non-life-threatening adverse events and outlines the required levels of care for patients with CRES.3

Using a 10-point CAR T-cell therapy-associated toxicity assessment tool (CARTOX 10), patients are asked a series of 10 simple questions and given 1 point for each correct answer. These questions include orientation to year, month, city, hospital, President (5 points); identifying 3 objects; point to clock, pen, button (3 points); writing a standard sentence, such as, “Our national bird is the bald eagle” (1 point); and counting backward from 100 by 10s (1 point). A score of 10 is normal.

  • Grade 1 CRES is considered mild (CARTOX score of 7 to 9). Treatment involves supportive care, daily CARTOX 10-point neurologic assessment, I.V. hydration, swallowing assessment, low doses of I.V. lorazepam or haloperidol for agitation, a neurology consultation (fundoscopic exam, MRI of brain, daily EEG, lumbar puncture, head CT), avoidance of medications that cause CNS depression, and consideration of IL-6 antagonist (tocilizumab) if associated with concurrent CRS.
  • Grade 2 CRES is considered moderate (CARTOX score of 3 to 6). Treatment includes IL-6 antagonist (tocilizumab) if associated with concurrent CRS, along with ICU transfer, neurologic workup, supportive care, dexamethasone or methylprednisolone for CRES not associated with concurrent CRS or if refractory to IL-6 antagonist therapy.
  • Grade 3 CRES is considered severe (CARTOX score of 0 to 2). In grade 3, low-grade papilledema is present with a cerebral spinal fluid (CSF) opening pressure of less than 20 mm Hg, as well as partial seizures, and/or nonconvulsive seizures on EEG responding to benzodiazepine. Treatment includes transferring the patient to the ICU, a neurologic workup, supportive care, IL-6 antagonist (tocilizumab) if associated with concurrent CRS and not previously given, dexamethasone or methylprednisolone around the clock if symptoms persist despite dose of tocilizumab or for CRES without concurrent CRS. Continue corticosteroids until improvement to grade 1, along with possible CT or MRI every 2 to 3 days if persistent CRES greater than or equal to grade 3.
  • Grade 4 CRES is considered critical (CARTOX score of 0). Papilledema is present along with a CSF opening pressure 20 mm Hg or greater, cerebral edema, generalized seizures, convulsive or nonconvulsive status epilepticus, or new motor weakness. Management includes grade 3 interventions, possible endotracheal intubation and mechanical ventilation, and high-dose methylprednisolone administration. Interventions for convulsive status epilepticus include high-flow supplemental O2, I.V. lorazepam, and I.V. levetiracetam. If seizures persist, I.V. phenobarbital and continuous EEG if seizures are refractory.3 Measures to treat intracranial hypertension with or without cerebral edema include head-of-bed elevation, high-dose I.V. corticosteroids, hyperventilation to achieve target PaCO2 of 28-30 mm Hg for no more than 24 hours, hyperosmolar therapy with either mannitol 20% or hypertonic saline, neurosurgery consultation, I.V. anesthetics for burst-suppression EEG activity, metabolic profile every 6 hours, and daily head CT.3
Back to Top | Article Outline

Patient education

Providing adequate education to patients and caregivers before, during, and immediately following treatment is important for patient safety. Critical care nurses can provide resources and teach patients regarding their treatment. Instruct patients and their caregivers to keep a wallet card displaying the signs and symptoms requiring immediate medical attention with them at all times. After CAR T-cell therapy, patients must stay within 2 hours of the treatment facility for at least 4 weeks and should refrain from driving and engaging in hazardous occupations or activities for at least 8 weeks while receiving CAR T-cell therapy. Patients will be monitored for adverse reactions and cancer reoccurrences for the rest of their lives. It is important for nurses to advise recipients not to receive steroids or cytotoxic medications without consent of their treating oncologist, as those treatments could theoretically negatively impact the effectiveness of CAR T-cell therapy.8

Back to Top | Article Outline

Conclusion

With the advent of targeted immunotherapy, tremendous progress continues to be made in the fight against cancer. One of the most exciting areas of progress involves genetically enhanced T-cell therapy. Critical care nurses must be prepared to identify and rapidly intervene for potentially severe adverse reactions associated with CAR T-cell therapies, especially CRS and CRES.

Back to Top | Article Outline

Understanding lymphocytes

Lymphocytes are the most common of the agranulocytes, accounting for approximately 30% of the total blood leukocytes. They originate in the bone marrow from lymphoid stem cells and migrate through the peripheral lymphoid organs, where they recognize antigens and participate in immune responses.

There are three types of lymphocytes: B lymphocytes, T lymphocytes, and natural killer cells. The B lymphocytes differentiate to form antibody-producing plasma cells and are involved in humoral-mediated immunity. The T lymphocytes differentiate in the thymus. They activate other cells of the immune system (helper T cells) and are involved in cell-mediated immunity (cytotoxic T cells). Natural killer cells participate in innate or natural immunity and their function is to destroy foreign cells.

The lymphocytes of the three different subsets have unique surface markers that can be identified and used to define their function and diagnose disease. Although all lymphocytes are morphologically similar, they comprise elements that vary in terms of lineage, cell membrane molecules and receptors, function, and response to antigen. These cells are often distinguished by surface proteins that can be identified using panels of monoclonal antibodies. These identified proteins are then correlated with cell functions. The standard nomenclature for these proteins is the “CD” (clusters of differentiation) numeric designation (CD4, CD8), which is used to delineate surface proteins that define a particular cell type or stage of cell differentiation and are recognized by a cluster or group of antibodies. Although this nomenclature was originally developed for lymphocytes, it is now common practice to apply it to blood cells other than lymphocytes.

Figure

Figure

Sources: Hinkle JL, Cheever KH. Brunner & Suddarth's Textbook of Medical-Surgical Nursing. Philadelphia, PA; Wolters Kluwer: 2017. Porth CM. Essentials of Pathophysiology: Concepts of Altered Health States. 4th ed. Philadelphia, PA: Wolters Kluwer Health; 2014.

Back to Top | Article Outline

CAR T-cell therapy

Chimeric antigen receptor (CAR)-modified T cells are engineered to express a chimeric protein combining an antibody receptor with a T cell receptor and costimulatory molecule.

Figure

Figure

Source: Greer JP, Arber DA, Glader BE, List AF, Means RT, Rodgers GM. Wintrobe's Clinical Hematology. 14th ed. Philadelphia, PA; Wolters Kluwer: 2019.

Back to Top | Article Outline

Bonus content

Head to www.nursingcriticalcare.com for an animation illustrating the immune response, including how T cells help transform B cells into antibody-secreting cells.

Back to Top | Article Outline

CRS antidote: Tocilizumab20,21

Tocilizumab is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of adults and pediatric patients age 2 and older with CAR T-cell-induced severe or life-threatening CRS. Tocilizumab administration immediately stops cytokine activation and reverses signs and symptoms of CRS.

Back to Top | Article Outline

REFERENCES

1. National Cancer Institute at the National Institutes of Health. NCI Dictionary of Cancer Terms. Kymriah. 2019. http://www.cancer.gov/publications/dictionaries/cancer-terms/def/kymriah.
    3. The University of Texas MD Anderson Cancer Center. Chimeric Antigen Receptor (CAR) Cell Therapy Toxicity Assessment and Management – Adult. 2017. http://www.mdanderson.org/documents/for-physicians/algorithms/clinical-management/clin-management-cytokine-release-web-algorithm.pdf.
    4. National Cancer Institute at the National Institutes of Health. Adult Acute Lymphoblastic Leukemia Treatment (PDQ)–Health Professional Version. 2019. http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq.
    5. National Cancer Institute at the National Institutes of Health. Adult Non-Hodgkin Lymphoma Teatment (PDQ)–Health Professional Version. 2019. http://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq.
    6. D Porter. CART Therapy for CLL [Video]. New York, NY: YouTube. Lymphoma & Myeloma 2013: An International Congress on Hematologic Malignancies. 2013. http://www.youtube.com/watch?feature=player_detailpage&v=nlMh9ieG58E.
    8. Novartis receives first ever FDA approval for a CAR-T cell therapy, Kymriah (CTL019), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice [press release]. Basel, Switzerland: Novartis; August 30, 2017.
    9. Kymriah (tisagenlecleucel) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018.
    10. U.S. Food and Drug Administration. YESCARTA (axicabtagene ciloleucel). 2018. http://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm581222.htm.
    11. Tisagenlecleucel drug information. UpToDate. 2019. http://www.uptodate.com.
    13. Fesnak AD, June CH, Levine BL. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer. 2016;16(9):566–581
    15. Primary analysis results from Novartis pivotal JULIET trial show Kymriah (tisagenlecleucel) sustained complete responses at six months in adults with r/r DLBCL, a difficult-to-treat cancer [press release]. Basel, Switzerland: Novartis; December 10, 2017.
    16. YESCARTA (axicabtagene ciloleucel) [package insert]. Santa Monica, CA: Kite Pharma, Inc.; 2017.
    17. Assessment, Grading and Management of Acute Toxicities From CAR-T-Cell Therapy [press release]. Lugano, Switzerland: European Society for Medical Oncology; November 9, 2017.
    18. FDA approval brings first gene therapy to the United States: CAR T-cell therapy approved to treat certain children and young adults with B-cell acute lymphoblastic leukemia [press release]. Silver Spring, MD: U.S. Food and Drug Administration; August 30, 2017.
    19. Kymriah (tisagenlecleucel). Find a KYMRIAH Treatment Center [press release]. 2019. http://www.us.kymriah.com/treatment-center-locator.
    20. ACTEMRA (tocilizumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2018.
    21. Leukemia and Lymphoma Society. Chimeric Antigen Receptor (CAR) T-Cell Therapy. 2019. http://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy.
    Keywords:

    acute lymphoblastic leukemia (ALL); axicabtagene ciloleucel; CAR T-cell-related encephalopathy syndrome (CRES); CAR T cells; chemotherapy; chimeric antigen receptor; cytokine-release syndrome (CRS); neurologic toxicities; non-Hodgkin lymphoma; tisagenlecleucel

    Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved