Version May 2024
The FDA has received reports of T-cell malignancies in patients treated with BCMA-directed or CD19-directed autologous CAR T cell immunotherapies. Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.
Further information may be found at https://www.fda.gov/safety/medical-product-safety-information/bcma-directed-or-cd19-directed-autologous-chimeric-antigen-receptor-car-t-cell-immunotherapies-fda.
Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel. Do not administer axicabtagene ciloleucel to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurological toxicities, including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with axicabtagene ciloleucel. Provide supportive care and/or corticosteroids as needed.
Axicabtagene ciloleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.
For autologous use only; confirm patient identity matches cassette and infusion bag prior to infusion.
Note: A treatment course consists of lymphodepleting chemotherapy (with fludarabine and cyclophosphamide) on the fifth, fourth, and third day prior to axicabtagene ciloleucel infusion (confirm availability of autologous axicabtagene ciloleucel prior to initiating lymphodepleting chemotherapy). Ensure tocilizumab (2 doses) and emergency equipment are available prior to axicabtagene ciloleucel infusion and during recovery period. Begin infection prophylaxis according to local guidelines prior to initiating axicabtagene ciloleucel. Do not administer axicabtagene ciloleucel to patients with active infection (clinically significant) or inflammatory disorders.
Premedication: Premedicate with acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV or orally ~60 minutes prior to axicabtagene ciloleucel infusion. Consider the use of prophylactic systemic corticosteroids after assessing potential risks/benefits.
Follicular lymphoma, relapsed or refractory: IV: Target dose: 2 × 106 chimeric antigen receptor (CAR)-positive viable T cells per kg body weight (Ref); maximum dose: 2 × 108 CAR-positive viable T cells.
Large B-cell lymphoma, relapsed or refractory: IV: Target dose: 2 × 106 CAR-positive viable T cells per kg body weight (Ref); maximum dose: 2 × 108 CAR-positive viable T cells.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Cytokine release syndrome: Note: Evaluate patients immediately at the first sign of cytokine release syndrome (CRS). Monitor patients with ≥ grade 2 CRS with continuous cardiac telemetry and pulse oximetry. Consider obtaining an echocardiogram in patients with severe CRS; severe or life-threatening CRS may require intensive care supportive therapy.
|
CRS grade |
Tocilizumabb |
Corticosteroids |
|---|---|---|
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a CRS = cytokine release syndrome. | ||
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b Also see Tocilizumab monograph. | ||
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c Refer to table below for management of neurologic toxicity. | ||
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d Alternate therapy may include (but is not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, IV immune globulin, and antithymocyte globulin. | ||
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Grade 1 (symptoms require symptomatic treatment only) Fever, nausea, fatigue, headache, myalgia, malaise |
If symptoms do not improve after 24 hours, consider managing as per grade 2. |
If not improving after 3 days, administer 1 dose of dexamethasone 10 mg IV. |
|
Grade 2 (symptoms require and respond to moderate interventions) Oxygen requirement <40% FiO2 or hypotension responsive to fluids or low-dose of 1 vasopressor or grade 2 organ toxicityc |
Administer tocilizumab 8 mg/kg IV (maximum: 800 mg/dose); if no clinical improvement in CRS signs/symptoms, repeat tocilizumab every 8 hours as needed (maximum: 3 doses in 24 hours, maximum total of 4 doses). If improving, discontinue tocilizumab. |
Administer dexamethasone 10 mg IV once daily. If improving, manage as per grade 1 and continue corticosteroids until severity is ≤ grade 1, then quickly taper as clinically appropriate. If not improving, manage as appropriate grade below. |
|
Grade 3 (symptoms require and respond to aggressive intervention) Oxygen requirement ≥40% FiO2 or hypotension requiring high-dose or multiple vasopressors or grade 3 organ toxicityc or grade 4 transaminitis |
Per grade 2; if improving, manage as appropriate grade above. |
Administer dexamethasone 10 mg IV 3 times daily. If improving, manage as appropriate grade above and continue corticosteroids until severity is ≤ grade 1, then quickly taper as clinically appropriate. If not improving, manage as per grade 4. |
|
Grade 4 (life-threatening symptoms) Requirements for ventilator support, CVVHD, or grade 4 organ toxicity (excluding transaminitis) |
Per grade 2; if improving, manage as appropriate grade above. |
Administer methylprednisolone 1 g IV once daily for 3 days. If improving, manage as appropriate grade above and continue corticosteroids until severity is ≤ grade 1, then quickly taper as clinically appropriate. If not improving, consider methylprednisolone 1 g two to three times daily, or alternate therapy.d |
Neurologic toxicity: Note: Manage promptly if neurologic toxicities occur. Patients with ≥ grade 2 neurologic toxicity should be monitored with continuous cardiac telemetry and pulse oximetry. Severe or life-threatening neurologic toxicity may require intensive care supportive therapy. Consider levetiracetam for seizure prophylaxis for any grade of neurologic toxicity.
|
Grading assessment |
Concurrent CRSa |
No concurrent CRS |
|---|---|---|
|
a CRS = cytokine release syndrome. | ||
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b Alternate therapy may include (but is not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, IV immune globulin, and antithymocyte globulin. | ||
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Grade 1 |
Administer tocilizumab per previous table for management of grade 1 CRS. In addition, administer 1 dose of dexamethasone 10 mg IV. If not improving after 2 days, repeat dexamethasone 10 mg IV. |
Administer 1 dose of dexamethasone 10 mg IV. If not improving after 2 days, repeat dexamethasone 10 mg IV. |
|
Consider levetiracetam for seizure prophylaxis. | ||
|
Grade 2 |
Administer tocilizumab per previous table for management of grade 2 CRS. In addition, administer dexamethasone 10 mg IV 4 times daily. If improving, continue corticosteroids until severity is ≤ grade 1, then quickly taper as clinically appropriate. If not improving, manage as appropriate grade below. |
Administer dexamethasone 10 mg IV 4 times daily. If improving, continue corticosteroids until severity is ≤ grade 1, then quickly taper as clinically appropriate. If not improving, manage as appropriate grade below. |
|
Consider levetiracetam for seizure prophylaxis. | ||
|
Grade 3 |
Administer tocilizumab per previous table for management of grade 2 CRS. In addition, administer methylprednisolone 1 g IV once daily. If improving, manage as appropriate grade above and continue corticosteroids until severity is ≤ grade 1, then taper as clinically appropriate. If not improving, manage as grade 4. |
Administer methylprednisolone 1 g IV once daily. If improving, manage as appropriate grade above and continue corticosteroids until severity is ≤ grade 1, then taper as clinically appropriate. If not improving, manage as grade 4. |
|
Consider levetiracetam for seizure prophylaxis. | ||
|
Grade 4 |
Administer tocilizumab per previous table for management of grade 2 CRS. In addition, administer methylprednisolone 1 g IV twice daily. If improving, manage as appropriate grade above and continue corticosteroids until severity is ≤ grade 1, then taper as clinically appropriate. If not improving, consider methylprednisolone 1 g IV 3 times daily or alternate therapy.b |
Administer methylprednisolone 1 g IV twice daily. If improving, manage as appropriate grade above and continue corticosteroids until severity is ≤ grade 1, then taper as clinically appropriate. If not improving, consider methylprednisolone 1 g IV 3 times daily or alternate therapy.b |
|
Consider levetiracetam for seizure prophylaxis. | ||
Other adverse reactions:
Hypogammaglobulinemia: Manage hypogammaglobulinemia with infection precautions, antibiotic prophylaxis, and IV immunoglobulin treatment (per standard replacement guidelines) as indicated.
Infection: Administer prophylactic antimicrobials prior to axicabtagene ciloleucel according to standard institutional guidelines. Manage infection (before and after axicabtagene ciloleucel) appropriately.
Neutropenic fever: Evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as clinically indicated.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Cardiac arrhythmia (14% to 23%), edema (13% to 23%), hypertension (9% to 15%), hypotension (47% to 57%), tachycardia (43% to 57%), thrombosis (7% to 12%, including deep vein thrombosis, embolism, peripheral ischemia, pulmonary embolism, and splenic infarction)
Dermatologic: Skin rash (9% to 19%, including Stevens-Johnson syndrome)
Endocrine & metabolic: Decreased serum albumin (grades 3/4: 19%), decreased serum glucose (grades 3/4: 10% to 11%), decreased serum phosphate (grades 3/4: 25% to 52%), decreased serum potassium (grades 3/4: 11%), decreased serum sodium (grades 3/4: 10% to 19%), dehydration (11%), increased uric acid (grades 3/4: 13%), weight loss (16%)
Gastrointestinal: Abdominal pain (14% to 20%), constipation (20% to 28%), decreased appetite (24% to 44%), diarrhea (29% to 42%; grades ≥3: 1% to 4%), nausea (34% to 40%; grades ≥3: 2%), vomiting (20% to 26%; grades ≥3: 1%), xerostomia (10% to 11%)
Hematologic & oncologic: Decreased hemoglobin (grades 3/4: 32% to 60%), decreased neutrophils (grades 3/4: 92% to 94%), decreased platelet count (grades 3/4: 26% to 56%), febrile neutropenia (31% to 41%; grades ≥3: 31% to 41%), hypogammaglobulinemia (11% to 18%; grades ≥3: 1%), leukopenia (grades 3/4: 94% to 96%), lymphocytopenia (grades 3/4: 94% to 96%)
Hepatic: Increased direct serum bilirubin (grades 3/4: 14%)
Hypersensitivity: Cytokine release syndrome (84% to 94%)
Infection: Bacterial infection (8% to 13%), fungal infection (5% to 12%), infection (25% to 45%, including serious infection and pulmonary infection), viral infection (13% to 16%)
Nervous system: Aphasia (14% to 20%), chills (28% to 40%), delirium (12% to 17%), dizziness (20% to 25%), encephalopathy (46% to 57%; can last up to 173 days), fatigue (46% to 52%), headache (41% to 45%), insomnia (10% to 16%), motor dysfunction (15% to 19%), peripheral neuropathy (11% to 12%; grades ≥3: 2%), tremor (25% to 31%)
Neuromuscular & skeletal: Back pain (15%), limb pain (17%), musculoskeletal pain (40%), myalgia (14%)
Renal: Renal insufficiency (8% to 12%)
Respiratory: Cough (25% to 30%), dyspnea (8% to 19%), hypoxia (21% to 32%), pleural effusion (6% to 13%), pneumonia (8% to 13%)
Miscellaneous: Fever (85% to 93%)
1% to 10%:
Cardiovascular: Capillary leak syndrome (3%), heart failure (1% to 6%)
Endocrine & metabolic: Decreased serum calcium (grades 3/4: 10%)
Gastrointestinal: Clostridioides difficile-associated diarrhea (serious: >2%), dysphagia (6%)
Genitourinary: Urinary tract infection (serious: >2%)
Hematologic & oncologic: Disorder of hemostatic components of blood (2% to 9%), hemophagocytic lymphohistiocytosis (1%, including macrophage activation syndrome), hemorrhage (8%)
Hypersensitivity: Hypersensitivity reaction (1%), multi-organ hypersensitivity reaction (dysfunction: 1%)
Immunologic: Antibody development (1% to 2%)
Infection: Herpes virus infection (4%), sepsis (2% to 4%)
Nervous system: Ataxia (6% to 10%), cognitive dysfunction (comprehending mathematics: 2%), facial nerve paralysis (2%), hemiparesis (2%), ischemic stroke (1%), myoclonus (2%), paresis (2%), psychological disorder (affective disorder: 10%, including anxiety, depression, impulsivity, mania, and panic attack), seizure (2% to 4%)
Neuromuscular & skeletal: Arthralgia (10%), muscle injury (1%)
Ophthalmic: Blindness (1%), visual impairment (5% to 7%)
Respiratory: Nasal congestion (10%), pulmonary edema (9%), respiratory failure (1% to 2%)
Frequency not defined:
Infection: Reactivation of HBV
Nervous system: Brain edema, dysarthria, lethargy, leukoencephalopathy
Postmarketing:
Hematologic & oncologic: Hematologic malignancy (T-cell) FDA Safety Communication 2023)
Infection: Aspergillosis (can be disseminated), disseminated candidiasis
Nervous system: Herpes meningoencephalitis, progressive multifocal leukoencephalopathy, quadriplegia, spinal cord injury (spinal cord edema), status epilepticus
Neuromuscular & skeletal: Myelitis
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to axicabtagene ciloleucel or any component of the formulation.
Concerns related to adverse effects:
• Cytokine release syndrome: Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel. Grade 3 or 4 CRS reactions have occurred. Manage severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. The median time to onset of CRS was 2 to 4 days (range: 1 to 20 days); the median duration of CRS was 6 to 7 days (range: 1 to 58 days). Key manifestations of CRS include fever, hypotension, tachycardia, hypoxia, chills, headache, nausea, vomiting, increased C-reactive protein, and fatigue. Cardiac arrhythmias (eg, atrial fibrillation, ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, multiorgan failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome may be associated with CRS (may be serious). Patients should seek immediate medical attention if signs or symptoms of CRS occur at any time. Evaluate patients immediately at the first sign of CRS; hospitalize and begin supportive care, tocilizumab, and/or corticosteroids as indicated.
• Cytopenias: Prolonged cytopenias may occur several weeks after lymphodepleting chemotherapy and axicabtagene ciloleucel infusion. Unresolved (by day 30 following axicabtagene ciloleucel treatment) grade 3 and 4 cytopenias included neutropenia, thrombocytopenia, and anemia.
• Hepatitis B virus reactivation: Hepatitis B virus (HBV) reactivation (sometimes resulting in fulminant hepatitis, hepatic failure, and death) may occur in patients treated with medications directed against B cells.
• Hypersensitivity: Allergic reactions may occur with axicabtagene ciloleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may occur due to the dimethyl sulfoxide (DMSO) or residual gentamicin in axicabtagene ciloleucel.
• Hypogammaglobulinemia: Hypogammaglobulinemia and B-cell aplasia may occur in patients receiving axicabtagene ciloleucel.
• Infection: Serious infections (including life-threatening infections) occurred in patients after axicabtagene ciloleucel infusion, including ≥ grades 3 infections. Viral, bacterial, and fungal infections were reported as well as infections due to unknown pathogens. Neutropenic fever has been observed after axicabtagene ciloleucel infusion and may occur concurrently with CRS. Life-threatening and fatal opportunistic infections can occur in patients who are immunosuppressed, including those who have received axicabtagene ciloleucel. Opportunistic infections reported include disseminated fungal infections (eg, candida sepsis and aspergillus infections) and viral reactivation (eg, human herpes virus-6 [HHV-6] encephalitis and John Cunningham virus progressive multifocal leukoencephalopathy [PML]). Consider the possibility of HHV-6 encephalitis and PML in immunosuppressed patients with neurologic events and perform appropriate diagnostic evaluations.
• Neurological toxicities: Neurological toxicities, including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel, including concurrently with CRS or after CRS resolution. Most neurological toxicities occurred within the first 8 weeks following axicabtagene ciloleucel infusion; the median time to onset was 4 to 6 days (range: 1 to 133 days). The median duration of neurologic toxicities was 8 to 17 days (range: 1 to 144 days). Grade 3 or higher neurologic toxicities have occurred. The most common neurological toxicities were encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, and anxiety. Prolonged encephalopathy (lasting up to 173 days) was observed. Fatal and serious cases of cerebral edema have occurred; other serious events included leukoencephalopathy, seizures, and a rare report of fatal late-onset toxic/metabolic encephalopathy. Due to the potential for neurologic events, including altered mental status or seizures, patients receiving axicabtagene ciloleucel are at risk for altered or decreased consciousness or coordination in the 8 weeks following administration; during this initial period, advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery.
• Secondary malignancy: Patients treated with axicabtagene ciloleucel may develop secondary malignancies or leukemia recurrence. If a secondary malignancy occurs, contact the manufacturer (1-844-454-KITE) to obtain patient sampling instructions for testing.
Concurrent drug therapy issues:
• Immunizations: Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during axicabtagene ciloleucel treatment, and until immune recovery following treatment. The safety of immunization with live viral vaccines during or following axicabtagene ciloleucel treatment has not been studied.
• Prophylactic corticosteroids: The use of prophylactic corticosteroids was assessed in a limited number of patients. Patients who received prophylactic corticosteroids for 3 days (beginning on the day of axicabtagene ciloleucel infusion) experienced a slightly lower incidence of CRS, which was managed with tocilizumab and/or therapeutic corticosteroid doses; the median time to onset of CRS was 5 days (range: 1 to 15 days) and the median duration of CRS was 4 days (range: 1 to 10 days). The median time to onset of neurologic toxicities was 6 days (range: 1 to 274 days) and the median duration of neurologic toxicities was 12 days (range: 1 to 107 days). Prophylactic corticosteroids may result in higher grades or prolongation of neurotoxicity, while delaying the onset and decreasing the duration of CRS. Consider the potential risks/benefits of the use of prophylactic corticosteroids within the context of individual patient comorbidities and the potential grade 4 and/or prolonged neurologic toxicities.
Special populations:
• Older age: A subgroup analysis from a refractory large B-cell lymphoma trial found that patients ≥65 years of age experienced a higher incidence of neurologic toxicities (compared to patients <65 years of age), although other serious adverse effects, including CRS, occurred at similar rates between the groups (Neelapu 2020).
Other warnings/precautions:
• Appropriate use: For autologous use only. Confirm patient identity and match to patient identifiers on the cassette and infusion bag prior to infusion. Administer in a health care facility; patients should remain within proximity of the facility for at least 4 weeks after infusion.
• REMS program: Axicabtagene ciloleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program. Information is available at https://www.YescartaTecartusREMS.com or 1-844-454-5483.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intravenous [preservative free]:
Yescarta: Up to 200 million autologous anti-CD19 CAR T cells in approximately 68 mL (1 ea) [contains albumin human, dimethyl sulfoxide]
No
Suspension (Yescarta Intravenous)
200000000CELLS (per each): $0.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intravenous:
Yescarta: Up to 200 million autologous anti-CD19 CAR T cells in approximately 68 mL (1 ea) [contains albumin human, dimethyl sulfoxide]
IV: For IV use only. Administer in a health care facility. Coordinate the timing of administration with thawing (may be stored for up to 3 hours at room temperature after thawing); infusion start time may need to be adjusted based on thawing.
Prime the tubing with NS prior to infusion. Infuse entire contents of bag within 30 minutes either by gravity or a peristaltic pump (infusion bag volume is ~68 mL). A central line is preferred for infusion. Gently agitate the bag during infusion to prevent cell clumping. After completion of the infusion, rinse the tubing with NS at the same infusion rate to ensure cell product delivery. Do not use a lymphocyte depleting filter.
Prior to administration: Ensure tocilizumab and emergency equipment are available prior to infusion and during recovery period. Premedicate with acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV or orally ~60 minutes prior to axicabtagene ciloleucel infusion. Consider the use of prophylactic systemic corticosteroids after assessing potential risks/benefits. Confirm patient identity and match to patient identifiers on the infusion cassette and bag. Inspect the contents of the thawed infusion bag for visible cell clumps; if visible cell clumps remain, gently mix the contents of the bag (small clumps of cellular material should disperse with gentle manual mixing). Do not infuse if clumps are not dispersed, if the infusion bag is damaged or leaking, or if it otherwise appears to be compromised. Apply universal precautions for product handling.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Yescarta: https://www.gilead.com/-/media/files/pdfs/medicines/oncology/yescarta/yescarta_medguide.pdf
Follicular lymphoma, relapsed or refractory: Treatment of relapsed or refractory follicular lymphoma in adults after ≥2 lines of systemic therapy.
Large B-cell lymphoma, relapsed or refractory: Treatment of large B-cell lymphoma in adults that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy; treatment of relapsed or refractory large B-cell lymphoma in adults after ≥2 lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Limitations of use: Not indicated for the treatment of patients with primary CNS lymphoma.
Axicabtagene ciloleucel may be confused with betibeglogene autotemcel, brexucabtagene autoleucel, ciltacabtagene autoleucel, elivaldogene autotemcel, idecabtagene vicleucel, lisocabtagene maraleucel, sipuleucel-T, tisagenlecleucel.
Yescarta may be confused with Tecartus, Yervoy.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Antithymocyte Globulin (Equine): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Chikungunya Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): May enhance the adverse/toxic effect of CAR-T Cell Immunotherapy. Specifically, the severity and duration of neurologic toxicities may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of CAR-T Cell Immunotherapy. Management: Avoid use of corticosteroids as premedication before treatment with CAR-T cell immunotherapy agents. Corticosteroids are indicated and may be required for treatment of toxicities such as cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): CAR-T Cell Immunotherapy may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: The CDC recommends that CAR-T-cell recipients who received COVID-19 vaccine prior to or during treatment with CAR-T-cell therapy should be revaccinated with a primary mRNA vaccine series at least 3 months (12 weeks) after CAR-T-cell therapy. Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): CAR-T Cell Immunotherapy may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: The CDC recommends that CAR-T-cell recipients who received COVID-19 vaccine prior to or during treatment with CAR-T-cell therapy should be revaccinated with a primary vaccine series at least 3 months (12 weeks) after CAR-T-cell therapy. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Mumps- Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Evaluate pregnancy status prior to therapy in patients who could become pregnant; sexually active patients who could become pregnant should have a pregnancy test prior to starting treatment with axicabtagene ciloleucel. Refer to the cyclophosphamide and fludarabine monographs for information related to use of effective contraception in patients using these medications for lymphodepleting chemotherapy. The duration of contraception needed following axicabtagene ciloleucel administration is not known. Potential pregnancies (following treatment) should be discussed with the prescriber.
Treatment with axicabtagene ciloleucel is not recommended during pregnancy. If placental transfer were to occur, fetal toxicity, including B-cell lymphocytopenia, may occur.
Potential pregnancies (following treatment) should be discussed with the prescriber.
It is not known if axicabtagene ciloleucel is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Screen for hepatitis B virus (HBV), hepatitis C virus, and HIV (prior to collection of cells for manufacturing). Monitor blood counts. Monitor immunoglobulin levels and blood counts (after treatment). Evaluate pregnancy status prior to therapy (in patients who could become pregnant).
Monitor for signs/symptoms of cytokine release syndrome (CRS) and neurological toxicities for at least 4 weeks after treatment (monitor daily for the first 7 days after infusion at the health care facility; patients with ≥ grade 2 CRS and/or ≥ grade 2 neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry). Monitor for hypersensitivity reactions and for signs/symptoms of infection (consider the possibility of human herpes virus 6 [HHV-6] encephalitis and progressive multifocal leukoencephalopathy [PML] in immunosuppressed patients with neurologic events and perform appropriate diagnostic evaluations). Monitor (life-long) for secondary malignancies.
The American Society of Clinical Oncology HBV screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Obtain baseline ECG, natriuretic peptides, and troponins; a baseline echocardiography is recommended in patients with preexisting cardiovascular disease; consider baseline echocardiography in all patients; for patients who develop ≥ grade 2 cytokine release syndrome, assess natriuretic peptides and troponins, and obtain echocardiography (ESC [Lyon 2022]). Refer to a cardiologist when clinically indicated.
Axicabtagene ciloleucel is a CD19-directed genetically modified autologous T cell immunotherapy 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. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 and is fused to CD28 and CD3 zeta. CD3 zeta is a critical component for initiating T-cell activation and antitumor activity. After binding to CD19-expressing cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades, which results in T cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines, leading to destruction of CD19-expressing cells. Axicabtagene ciloleucel is prepared from the patient's peripheral blood cells obtained via leukapheresis.
Note: The number of anti-CD19 CAR T cells in the blood was positively associated with objective response (complete remission or partial remission). The median anti-CD19 CAR T cell Cmax levels in patients with refractory large B-cell lymphoma who responded to therapy were 205% higher compared with the levels in nonresponding patients.
Onset: Median time to response: 1 month (range: 0.8 to 6 months) (Neelapu 2017).
Duration: Anti-CD19 CAR T cells displayed an initial rapid expansion followed by a decline to near baseline levels by 3 months post axicabtagene ciloleucel infusion.
Time to peak: Peak levels of anti-CD19 CAR T cells occurred within the first 7 to 14 days after infusion.
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