Axicabtagene Ciloleucel – Uses, Dosage, Side Effects, Interaction

Mechanism of action
Indications
Contraindications
Dosage
Side Effects
Drug Interaction
Pregnancy and Lactation

Axicabtagene ciloleucel is a CAR T-cell therapy used to treat adults with large B-cell lymphomas and follicular lymphoma.

Axicabtagene ciloleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. The drug has a unique mechanism of action, as it utilizes the patient’s own T cells, which play a central role in the immune response to cancer.^[rx] Once T-cells are collected from the patient, they are genetically engineered to express anti-CD19 CARs that recognize and kill cancer cells, and are infused back into the patient.² Each dose of axicabtagene ciloleucel represent the patient’s genetically modified T-cells.^[rx] The development of resulted from early preclinical studies conducted by a group of researchers at the National Cancer Institute (NCI), who demonstrated that T cells expressing an anti-CD19 CAR can produce cytokines that efficiently kill leukemic cells in vitro.^[rx]

Axicabtagene ciloleucel was approved by the FDA on October 18th, 2017. It is marketed under the brand name Yescarta and is used to treat large B-cell lymphomas and follicular lymphoma in adults.^[rx] Axicabtagene ciloleucel was later approved by the EMA on August 23, 2018.^[rx]

Mechanism of action

The CD 19 antigen is an integral membrane glycoprotein normally expressed in B cells during differentiation; however, it is often aberrantly expressed on B cells that have undergone a neoplastic transformation. Distinctive expression of CD19 in lymphomas and leukemias makes this glycoprotein a good immunotherapeutic target.^[rx]

Axicabtagene ciloleucel is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy. It consists of genetically modified T cells of the patient receiving the immunotherapy. The manufacturing of axicabtagene ciloleucel begins with the collection of peripheral blood mononuclear cells from the patient, followed by the harvesting and genetic modification of T cells ex vivo. Retroviral transduction is used to express a CAR on T cells, creating anti-CD19 CAR T cells that are then expanded. Axicabtagene ciloleucel, a suspension of anti-CD19 CAR T cells, is infused back into the patient during treatment.^[rx] Axicabtagene ciloleucel is made up of two components: a single-chain variable fragment targets the CD19 proteins, and there are intracellular domains – CD28 and CD3-zeta co-stimulatory domains – that signal T-cell activation.^[rx,rx] Once administered into the patient’s bloodstream, axicabtagene ciloleucel recognizes the CD19-expressing target cells and the intracellular domains of the drug activate the downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines that kill cancer cells.^[rx] Axicabtagene ciloleucel binds to CD19-expressing cancer cells and normal B cells.^[rx]

Indications

In the US, axicabtagene ciloleucel is indicated for the treatment of adults with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.^[rx]
In the US and Europe, it is used to treat adults with relapsed or refractory large B-cell lymphoma after two or more 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.^[rx,rx]
Axicabtagene ciloleucel is also used to treat adults with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy in the US,^[rx], or three or more lines of systemic therapy in Europe.^[rx]
Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Refractory Follicular Lymphoma
Refractory Large B-cell Lymphoma
Relapsed Diffuse Large B-cell Lymphoma (DLBCL)
Relapsed Follicular Lymphoma
Refractory High-Grade B-cell Lymphoma (HGBCL)
Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL)
Relapsed High-Grade B-cell Lymphoma (HGBCL)
Relapsed Primary Mediastinal Large B-Cell Lymphoma (PMBCL)
B Cell Lymphoma
Diffuse Large B-Cell Lymphoma
Follicular Lymphoma

Use in Cancer

Axicabtagene ciloleucel is approved to treat adults with:

B-cell non-Hodgkin lymphoma (NHL), including the following types:
- Diffuse large B-cell lymphoma (DLBCL).
- DLBCL in patients who had follicular lymphoma.
- Follicular lymphoma.¹
- Primary mediastinal large B-cell lymphoma.
- High-grade B-cell lymphoma.
  It is used in adults whose cancer relapsed (came back) or did not get better after at least two other systemic therapies.
DLBCL that did not respond to first-line chemoimmunotherapy or that relapsed within 12 months of first-line chemoimmunotherapy.

Axicabtagene ciloleucel is only available as part of a special program called Yescarta REMS (Risk Evaluation and Mitigation Strategies).

¹This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that axicabtagene ciloleucel provides a clinical benefit in these patients.

Axicabtagene ciloleucel is also being studied in the treatment of other types of cancer.

Contraindications

The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:

a bad infection
a type of blood disorder with a decrease in all types of blood cells called pancytopenia
leukoencephalopathy is a disease of the white matter of the brain
pregnancy
resolved hepatitis B
reactivation of hepatitis B infection

Dosage

Lymphoma

2 x 10(6) chimeric antigen receptor (CAR)-positive viable T cells IV per kg body weight via IV infusion; infuse within 30 minutes
Maximum Dose: 2 x 10(8) CAR-positive viable T cells

Dose Adjustments

CYTOKINE RELEASE SYNDROME (CRS):

Identify CRS based on clinical presentation.
Evaluate for and treat other causes of fever, hypoxia, and hypotension.
If CRS is suspected, manage according to CRS grading.
Patients who experience Grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry.
For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function.
For severe or life-threatening CRS, consider intensive care supportive therapy.

CRS GRADING

GRADE 1 (symptoms require symptomatic treatment only [e.g., fever, nausea, fatigue, headache, myalgia, malaise]): No adjustment recommended.
GRADE 2 (symptoms require and respond to moderate intervention; oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity:

Tocilizumab: Administer 8 mg/kg IV over 1 hour (not to exceed 800 mg) every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen; limit to a maximum of 3 doses in 24 hours; maximum total of 4 doses.
Corticosteroids: Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab.

GRADE 3 (symptoms require and respond to aggressive intervention; oxygen requirement greater than or equal to 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis:

Tocilizumab: Administer 8 mg/kg IV over 1 hour (not to exceed 800 mg) every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen; limit to a maximum of 3 doses in 24 hours; maximum total of 4 doses.
Corticosteroids: Administer methylprednisolone 1 mg/kg IV 2 times a day or equivalent dexamethasone (e.g., 10 mg IV every 6 hours); continue corticosteroids use until the event is Grade 1 or less, then taper over 3 days.

GRADE 4 (life-threatening symptoms; requirements for ventilator support, continuous venovenous hemodialysis (CVVHD) or Grade 4 organ toxicity (excluding transaminitis):

Tocilizumab: Administer 8 mg/kg IV over 1 hour (not to exceed 800 mg) every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen; limit to a maximum of 3 doses in 24 hours; maximum total of 4 doses.
Corticosteroids: Administer methylprednisolone 1000 mg IV daily for 3 days; if improves, then manage as detailed for Grade 3.

NEUROLOGIC TOXICITY
Grade 2 or Higher:

Monitor patients for neurologic toxicities (Table 2).
Rule out other causes of neurologic symptoms.
Patients who experience Grade 2 or higher neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry.
Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis for any Grade 2 or higher neurologic toxicities.

NEUROLOGIC TOXICITY GRADING AND MANAGEMENT GUIDANCE:
GRADE 2:

Concurrent CRS: Administer tocilizumab per Table 1 for management of Grade 2 CRS; if no improvement within 24 hours after starting tocilizumab, administer dexamethasone 10 mg IV every 6 hours if not already taking other corticosteroids; continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days; consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
No concurrent CRS: Administer dexamethasone 10 mg IV every 6 hours; continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days; consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

GRADE 3:

Concurrent CRS: Administer tocilizumab per Table 1 for management of Grade 2 CRS; in addition, administer dexamethasone 10 mg IV with the first dose of tocilizumab and repeat every 6 hours; continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days; consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
No concurrent CRS: Administer dexamethasone 10 mg IV every 6 hours; continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days; consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

GRADE 4:

Concurrent CRS: Administer tocilizumab per Table 1 for management of Grade 2 CRS; administer methylprednisolone 1000 mg IV per day with first dose of tocilizumab and continue methylprednisolone 1000 mg IV per day for 2 more days; if improves, then manage as above; consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
No concurrent CRS: Administer methylprednisolone 1000 mg IV per day for 3 days; if improves, then manage as above; consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

Side Effects

The Most Common

constipation
stomach pain
back pain
joint or muscle pain
dry mouth
loss of appetite
weight loss
blood in urine
bleeding more easily than normal
fever, sore throat, chills, or other signs of infection
decreased urination frequency or amount
pale skin
fatigue
swelling of the eyes, face, lips, tongue, throat, arms, hands, feet, ankles, or lower legs
difficulty swallowing
rash
hives
itching

More Common

headaches, dizziness;
tremors, anxiety, trouble sleeping;
unusual thoughts or behavior;
trouble speaking or understanding what is said to you; or
low blood cell counts–fever, chills, tiredness, flu-like symptoms, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed or short of breath.
nausea, diarrhea;
low blood cells;
confusion; or
fast heartbeats.

Rare

Cardiovascular: Cardiac arrhythmia (23%), edema (19%), hypertension (15%), hypotension (57%), tachycardia (57%)
Endocrine & metabolic: Dehydration (11%), hyponatremia (grades 3/4: 19%), hypophosphatemia (grades 3/4: 50%), increased uric acid (grades 3/4: 13%), weight loss (16%)
Gastrointestinal: Abdominal pain (14%), constipation (23%), decreased appetite (44%), diarrhea (38%), nausea (34%), vomiting (26%), xerostomia (11%)
Hematologic & oncologic: Anemia (grades 3/4: 66%), febrile neutropenia (34% to 36%; grade ≥3: 31%), hypogammaglobulinemia (15%), leukopenia (grades 3/4: 96%), lymphocytopenia (grades 3/4: 100%), neutropenia (grades 3/4: 93%), thrombocytopenia (grades 3/4: 58%)
Hepatic: Increased direct serum bilirubin (grades 3/4: 13%)
Hypersensitivity: Cytokine release syndrome (94%)
Infection: Bacterial infection (13%), infection (26% to 38%, including serious infection; fungal infection: 5%), viral infection (16%)
Nervous system: Aphasia (18%), chills (40%), delirium (17%), dizziness (21%), encephalopathy (57%; can last up to 173 days), fatigue (46%), headache (44% to 45%), motor dysfunction (19%)
Neuromuscular & skeletal: Back pain (15%), limb pain (17%), myalgia (14%), tremor (31%)
Renal: Renal insufficiency (12%)
Respiratory: Cough (30%), dyspnea (19%), hypoxia (32%), pleural effusion (13%)
Miscellaneous: Fever (86%)

Drug Interaction

DRUG	INTERACTION
Articaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Articaine.
Benzocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Benzocaine.
Benzyl alcohol	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Benzyl alcohol.
Bupivacaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Bupivacaine.
Butacaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Butacaine.
Butamben	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Butamben.
Capsaicin	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Capsaicin.
Chloroprocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Chloroprocaine.
Cinchocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Cinchocaine.
Cocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Cocaine.
Darbepoetin alfa	The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Axicabtagene ciloleucel.
Diphenhydramine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Diphenhydramine.
Dyclonine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Dyclonine.
Erythropoietin	The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Axicabtagene ciloleucel.
Ethyl chloride	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Ethyl chloride.
Etidocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Etidocaine.
Levobupivacaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Levobupivacaine.
Lidocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Lidocaine.
Meloxicam	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Meloxicam.
Mepivacaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Mepivacaine.
Methoxy polyethylene glycol-epoetin beta	The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Axicabtagene ciloleucel.
Oxetacaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Oxetacaine.
Oxybuprocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Oxybuprocaine.
Peginesatide	The risk or severity of Thrombosis can be increased when Peginesatide is combined with Axicabtagene ciloleucel.
Phenol	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Phenol.
Pramocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Pramocaine.
Prilocaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Prilocaine.
Procaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Procaine.
Proparacaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Proparacaine.
Propoxycaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Propoxycaine.
Ropivacaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Ropivacaine.
Tetracaine	The risk or severity of methemoglobinemia can be increased when Axicabtagene ciloleucel is combined with Tetracaine.

Pregnancy and Lactation

US FDA pregnancy category Not Assigned

Pregnancy

The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.