Axicabtagene Ciloleucel - Indication, Dosage, Precautions, and Pharmacological Aspects

Overview:

Axicabtagene Ciloleucel is a medicine designed to treat certain types of rare blood cancers in adults, including high-grade B-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma. It is intended for patients whose cancer has returned or no longer responds to previous treatments. Axicabtagene Ciloleucel is unique since it falls under the category of gene therapy. It works by introducing modified genes into the body. The blood cancers Axicabtagene Ciloleucel targets are uncommon, and the medication was recognized as an orphan medicine (drugs that address needs in public health but are not created by the pharmaceutical industry for financial gain) for specific types of lymphomas. Axicabtagene Ciloleucel is the key component of genetically modified white blood cells. The Food and Drug Administration (FDA) approved Axicabtagene Ciloleucel on October 18, 2017.

Drug Group:

Axicabtagene Ciloleucel injection is used for a specific type of lymphoma that has returned or does not respond to other treatments. It is a type of immunotherapy that uses the patient's cells to boost the immune system and fight cancer cells. It is in a class of medications called autologous cellular immunotherapy, which is a type of medication prepared using the cells from a patient's blood.

Available Doses and Dosage Forms:

Axicabtagene Ciloleucel is available as a cell suspension for infusion and can only be administered in a certified healthcare facility. The medication is made up of a suspension containing a specific number of CAR (chimeric antigen receptor)-positive, viable T cells, with the recommended dose being based on the patient's body weight. The goal is to administer 2 × 106 CAR-positive viable T cells per kilogram of body weight, up to a maximum of 2 × 108 CAR-positive viable T cells, in a volume of approximately 68 ml (milliliter).

For Patients:

What Is Non-Hodgkin’s Lymphoma (B-Cell Lymphoma)?

Non-Hodgkin's lymphoma is a cancer that starts in the lymphatic system, a crucial part of the body's defense against germs. In this type of cancer, a specific kind of white blood cell, called lymphocytes, starts to grow unusually, forming tumors that can spread throughout the body.

How Does Axicabtagene Ciloleucel Work?

Axicabtagene Ciloleucel includes the patient's T cells, a type of white blood cell. These cells are altered in a lab to produce a special protein called chimeric antigen receptor (CAR). This CAR protein can stick to another protein, CD19, found on the surface of cancer cells. When Axicabtagene Ciloleucel is administered to the patient, these modified T cells connect to the cancer cells and eliminate them. Therefore, Axicabtagene Ciloleucel works by using the patient's modified immune cells to target and destroy the cancer cells, aiding in the removal of cancer from the body.

What Is the Dosage of Axicabtagene Ciloleucel?

This treatment is specifically focused on the individual it is taken from; make sure the patient's identity matches the treatment materials before administering. For those with a certain type of large B-cell lymphoma that has relapsed or not responded to previous treatments, the process involves receiving lymphodepleting chemotherapy a few days before getting Axicabtagene Ciloleucel. Make sure medications and emergency equipment are ready before and after the Axicabtagene Ciloleucel infusion. Before the infusion, give the patient Acetaminophen and Diphenhydramine as a preventive measure. It is important not to use corticosteroids unless necessary, as they may interfere with the effectiveness of Axicabtagene Ciloleucel. The infusion is given intravenously, with the amount based on the patient's weight. Special attention is needed for possible drug interactions. Individual doses of this treatment contain a certain number of T cells tailored to the patient's weight. It is like a customized infusion bag with around 2 million to 200 million T cells that have a specific feature, and this all fits into a small volume of liquid, roughly 68 milliliters.

What Are the Things to Inform the Doctor Before Taking the Axicabtagene Ciloleucel?

Consider the advantages and disadvantages of this medication with the doctor. Inform them about allergies and discuss their use in children, the elderly, and during breastfeeding.

How Is Axicabtagene Ciloleucel Administered?

Axicabtagene Ciloleucel injection is given as a liquid into a vein by a doctor or nurse in a medical setting. The process usually takes up to 30 minutes for a one-time dose. Before getting this injection, the individual will receive other medications to prepare the body. Before the injection, a sample of the white blood cells will be collected at a special center using a procedure called leukapheresis, where white blood cells are removed from the body. Since this medication is personalized using the cells, it is crucial to attend all the scheduled appointments. Plan to stay close to the treatment location for at least four weeks after the dose. The healthcare provider will assess the treatment's effectiveness and watch for any potential side effects. If the person has questions about the preparation and what to expect during and after leukapheresis, discuss them with the doctor.

What Are the Side Effects of Axicabtagene Ciloleucel?

1. Common Side Effects: Axicabtagene Ciloleucel may cause mild side effects. Inform the doctor if experiencing:

• Constipation.

• Stomach pain.

• Back pain.

• Joint or muscle pain.

• Dry mouth.

• Loss of appetite.

• Weight loss.

2. Serious Side Effects: Some side effects may be serious. Contact the doctor immediately if one notices:

• Blood in urine.

• Unusual bleeding.

• Signs of infection (fever, sore throat, chills).

• Reduced urination.

• Pale skin.

• Fatigue.

• Swelling in various body parts.

• Difficulty swallowing.

• Skin rash, hives, itching.

3. Cancer Risk: Axicabtagene Ciloleucel may increase the risk of certain cancers. Discuss these risks with the doctor before starting the medication.

4. Other Side Effects: Report any unusual problems to the doctor while receiving this medication.

Dietary Considerations:

Continue the normal diet unless the physician advises taking any special considerations.

Missed Dose:

If a dosage is missed, inform the physician about the missed dose. Do not take an extra dose or the missed dose without informing and suggesting the physician.

Storage:

Keep the frozen suspension in the extremely cold vapor phase of liquid nitrogen (colder than -150 degrees Celsius). Once thawed, it can be stored at room temperature (between 20 and 25 degrees Celsius) for up to three hours.

For Doctors:

Indication:

• Axicabtagene Ciloleucel is indicated in the United States (U.S.) for treating adults with large B-cell lymphoma refractory to first-line chemoimmunotherapy or relapsing within 12 months of the initial treatment.

• In the U.S. and Europe, it is used for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including various subtypes such as diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

• Axicabtagene Ciloleucel is employed for adults with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy in the U.S. or three or more lines of systemic therapy in Europe.

• It is approved for adults with B-cell non-Hodgkin lymphoma (NHL), covering DLBCL, DLBCL in patients with prior follicular lymphoma, follicular lymphoma, primary mediastinal large B-cell lymphoma, and high-grade B-cell lymphoma.

• Axicabtagene Ciloleucel is administered to adults whose cancer relapsed or did not respond to at least two prior systemic therapies, specifically for DLBCL that did not respond to initial chemoimmunotherapy or relapsed within 12 months.

• The drug is only available through the Yescarta REMS (Risk Evaluation and Mitigation Strategies) program.

• Some uses of Axicabtagene Ciloleucel are granted under the FDA's Accelerated Approval Program, with confirmatory trials required to demonstrate clinical benefits in specific patient groups.

• Ongoing research is exploring the potential of Axicabtagene Ciloleucel in treating other types of cancer.

Dose:

Dosing Considerations:

Individual doses are tailored to the patient's body weight and come in single-dose units. These units contain a precise quantity of T cells suspended in a patient-specific infusion bag. The dosage is calculated as 2 x 106 CAR-positive viable T cells per kilogram of body weight, with a maximum of 2 x 108 CAR-positive viable T cells, all within an approximate volume of 68 mL (milliliter).

Dosing and Administration:

The infusion is based on the number of chimeric antigen receptors (CAR)-positive, viable T cells. The recommended dose is 2 x 106 CAR-positive viable T cells per kilogram of body weight, not exceeding 2 x 108 CAR-positive viable T cells. Administered intravenously in a weight-based, autologously prepared infusion over approximately 30 minutes using gravity or a peristaltic pump. A leukocyte-depletion filter should not be used during the process.

What Are the Pharmacological Aspects of Axicabtagene Ciloleucel?

• Pharmacodynamics: Axicabtagene Ciloleucel leads to a temporary rise in chemokine levels, including IL-6 (interleukin), IL-8, IL-10, IL-15, TNF-α (tumor necrosis factor), IFN-γ (interferon), and sIL2Rα (soluble interleukin). The highest levels are typically observed within the initial 14 days post-infusion, and concentrations generally revert to baseline within 28 days. Additionally, as an unintended effect, Axicabtagene Ciloleucel has the potential to induce B-cell aplasia.

• Mechanism of Action: Axicabtagene Ciloleucel is a genetically modified, autologous (using the patient's cells), anti-CD19 CAR T-cell therapy. It has received approval from the U.S. Food & Drug Administration (FDA) for treating relapsed or refractory large B-cell lymphoma in adults, excluding cases of primary central nervous system lymphoma, after at least two prior systemic therapies. The therapy targets CD19, an antigen present in both malignant and normal B cells but not in other normal cells. Axi-cel, upon binding to CD19-positive cells, activates T cells through CD28 and CD3ζ costimulatory domains, leading to T-cell activation, proliferation, and secretion of inflammatory cytokines. This process destroys CD19-positive cells. Cytokine levels peak within the first two weeks post-infusion and generally decrease within 28 days. Evidence suggests that CARs can persist in circulation post-infusion, contributing to sustained remissions, a concept known as persistence, which may vary based on disease characteristics and CAR design. Manufacturing of Axicabtagene Ciloleucel involves obtaining T cells from the patient's peripheral blood through leukapheresis. These activated T cells are then genetically modified using an incompetent retroviral vector and further expanded. The recommended dose is 2 × 106 CAR-positive viable T cells per kg of body weight, with a maximum of 2 × 108 CAR-positive viable T cells. To enhance expansion, lymphodepleting therapy with cyclophosphamide (500 mg/m2(milligram/meter square)) and fludarabine (30 mg/m2) is administered on the fifth, fourth, and third days before CAR T-cell infusion.

• Pharmacokinetics: After Axicabtagene Ciloleucel infusion, anti-CD19 CAR T cells experienced an initial rapid expansion, peaking within seven to 14 days and declining to near baseline levels by three months. Age and gender did not significantly impact Axicabtagene Ciloleucel exposure. In the ZUMA-7 study for large B-cell lymphoma (LBCL), higher levels of anti-CD19 CAR T cells in the blood were positively linked to objective responses. Responders exhibited 275 % higher Cmax and 418 % higher AUC (area under the curve) Day 0 - 28 compared to nonresponders. In the ZUMA-1 study for LBCL, similar associations were observed, with responders showing 205 % higher Cmax and 251 % higher AUC Day zero to 28 compared to nonresponders. For follicular lymphoma (FL) in the ZUMA-5 study, responding patients had higher median Cmax (40.1 cells/μL(microliter)) and AUC Day zero to 28 (465.8 days × cells/μL) compared to nonresponders. Management of cytokine release syndrome (CRS) and neurologic toxicities often required Tocilizumab and corticosteroids. Patients receiving Tocilizumab had 262 % higher anti-CD19 CAR T cells (AUC Day 0 - 28) and 232 % higher Cmax, while corticosteroid-treated patients had 217 % higher AUC Day 0 - 28 and 155 % higher Cmax. Hepatic and renal impairment studies for Axicabtagene Ciloleucel were not conducted.

Toxicity:

Cytokine Release Syndrome (CRS): Improved signaling in CAR-T cell therapy has enhanced T-cell activation and efficacy but also increased the risk of CRS. CRS symptoms, such as fever, low blood pressure, respiratory issues, and capillary leak syndrome, vary in severity. The American Society for Transplantation and Cellular Therapy (ASTCT) provides consensus guidelines for grading CRS. Early detection, appropriate grading, and supportive care are crucial for effective CRS management. At the onset of CRS, immediate supportive care measures are recommended, including antibiotics, vasopressors, and fluids. Tocilizumab, an interleukin 6 receptor antagonist, and corticosteroids like Dexamethasone or Methylprednisolone may be administered. The Axicabtagene Ciloleucel REMS requires the availability of at least two doses of Tocilizumab on-site before Axicabtagene Ciloleucel infusion. Tocilizumab is generally reserved for grade 2 or higher CRS without apparent neurotoxicity concerns. Dosing recommendations for Tocilizumab depend on patient weight, with subsequent dosing options. The interval between doses should be at least eight hours, and a maximum of four doses is recommended. Doses exceeding 800 mg per infusion are discouraged. Corticosteroids, such as Methylprednisolone or Dexamethasone, may be considered if neurologic symptoms are present or if CRS does not respond to Tocilizumab. A gradual taper over several days follows treatment, with the duration based on clinical improvement.

Neurotoxicity (NTX): The ASTCT has defined and graded neurologic toxicity, now referred to as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). This syndrome may include symptoms like delirium, tremors, seizures, aphasia, or encephalopathy. NTX can occur independently, concurrently, or following CRS resolution. High-dose corticosteroids, prophylactic antiepileptic medications, and general supportive care are recommended for managing NTX.

Clinical Studies:

FDA approval was granted based on ZUMA-1, a phase II trial for patients with relapsed or refractory DLBCL (diffuse large B-cell lymphoma), PMBCL (primary mediastinal large B-cell lymphoma), or TFL (transformed follicular lymphoma). Two cohorts were formed (DLBCL, N = 77; PMBCL/TFL, N = 24). Patients underwent conditioning with cyclophosphamide and fludarabine, followed by axi-cel at 2 × 106 CAR T (chimeric antigen receptor) cells/kg. Primary endpoint: ORR (tumor objective response rate); key secondary endpoints: DOR (diminished ovarian reserve), OS (overall survival), AE (adverse events). The primary analysis included 101 patients. ITT ORR was 82 %, CR rate 54 %, and PR rate 28 %. Median time to respond: ~1 month. The overall median DOR was 8.1 months. Median OS not reached, with rates of 78 % at 6 months, 59 % at 12 months, and 52 % at 18 months. Responses were consistent across covariates.

Common grade ≥ 3 AEs: Neutropenia (78 %), anemia (43 %), thrombocytopenia (38 %). Grade ≥ 3 CRS and NTX in 13 % and 28 %, respectively. 27 % received glucocorticoids, and 43 % received Tocilizumab for CRS/NTX management. Three deaths were attributed to axi-cel (two CRS-related, one pulmonary embolism).

As of August 11, 2018, 101 patients followed for a median of 27.1 months. 83 % showed an objective response. The median DOR for all patients was 11.1 months. Median PFS: 5.9 months. Safety profile at 2-year mark similar. Grade ≥ 3 CRS in 11 %, grade ≥ 3 neurologic events in 32 %. 17 % had grade ≥ 3 cytopenias. B cells were detected in 61 % at 9 months and 75 % at 24 months. 50 deaths from disease progression; no new axi-cel-related deaths since initial analysis. Axi-cel proves effective in refractory NHL, offering rapid, durable responses with manageable safety. Further analysis is needed to confirm reported OS results and impact on quality of life.

Warnings and Precautions:

• Cytokine Release Syndrome (CRS) and Neurological Toxicities: CRS, potentially fatal, occurs in most treated patients. Neurological toxicities, including severe or life-threatening cases, can occur post-treatment. Prophylactic corticosteroids for CRS and neurologic toxicities may increase neurologic toxicity grade; evaluate risks and benefits, considering pre-existing conditions.

• Restricted Access Program: Available exclusively through a restricted access program due to safety concerns.

• Allergic Reactions: Allergic reactions, including anaphylaxis, may occur during infusion and are possibly linked to product components.

• Serious Infections: Serious, potentially fatal infections reported; follow local guidelines for infection prophylaxis; monitor and treat infections as needed.

• Viral Reactivation: Viral reactivation is possible, including hepatitis B virus (HBV); screen for HBV, hepatitis C virus (HCV), and HIV (human immunodeficiency virus) before cell collection.

• Prolonged Cytopenias: Prolonged cytopenias may persist for weeks post-lymphodepletion chemotherapy and infusion; monitor blood counts.

• B-cell Aplasia and Hypogammaglobulinemia: B-cell aplasia and hypogammaglobulinemia may occur; monitor immunoglobulin levels and manage according to guidelines.

• Secondary Malignancies: There is a risk of secondary malignancies; hence, lifelong monitoring is recommended.

• Neurological Events Post-Treatment: Patients at risk for altered mental status or seizures in 8 weeks post-treatment are advised against driving or engaging in hazardous activities.

• FDA MedWatch Alert (November 28, 2023): Reports of T-cell malignancies, including CAR-positive lymphoma, in patients receiving BCMA- or CD19-directed CAR-T cell therapies. FDA investigating risk; benefits still outweigh risks for approved uses. Lifelong monitoring for new malignancies is recommended; report occurrences to the manufacturer.

• Immunization With Live Viral Vaccines: Safety not studied; avoid live-virus vaccines for at least six weeks before lymphodepleting chemotherapy, during treatment, and until immune recovery.

What Are the Drug Interactions of Axicabtagene Ciloleucel?

• Baricitinib: Combination with potent immunosuppressants like Azathioprine or Cyclosporine is not recommended. Concurrent use with antirheumatic doses of Methotrexate or nonbiologic disease-modifying antirheumatic drugs (DMARDs) is permitted.

• BCG (Bacille Calmette-Guerin): Avoid combination with immunosuppressants.

• Cladribine: Avoid combination as it may enhance the immunosuppressive effect of immunosuppressants.

• Coccidioides Immitis Skin Test: Monitoring of diagnostic effects is necessary.

• Corticosteroids (Systemic): Avoid corticosteroids as premedication before Axicabtagene Ciloleucel. They may be required for treatment of cytokine release syndrome or neurologic toxicity.

• Denosumab: Enhanced adverse effects risk; monitor therapy.

• Echinacea: Consider avoiding Echinacea in patients on immunosuppressants.

• Fingolimod: Avoid concomitant use with other immunosuppressants; monitor patients closely.

• Inebilizumab: Monitor immunosuppressive effect.

• Leflunomide: Risk of hematologic toxicity may be increased; monitor bone marrow suppression.

• Natalizumab: Avoid combination due to increased risk of concurrent infection.

• Nivolumab: Avoid immunosuppressants before initiation of nivolumab.

• Ocrelizumab: Monitor immunosuppressive effect.

• Ozanimod: Monitor immunosuppressive effect.

• Pidotimod: Monitor therapeutic effect.

• Pimecrolimus: Avoid combinations.

• Roflumilast: Consider avoiding concomitant use with immunosuppressants.

• Siponimod: Monitor immunosuppressive effect.

• Sipuleucel-T: Evaluate the appropriateness of reducing or discontinuing immunosuppressants before initiating sipuleucel-T therapy.

• Tacrolimus (Topical): Avoid combination.

• Talimogene Laherparepvec: Avoid combination; risk of disseminated herpetic infection.

• Tertomotide: Monitor therapeutic effect.

• Tofacitinib: Concomitant use with antirheumatic doses of methotrexate or nonbiologic DMARDs is permitted.

• Upadacitinib: Avoid combination with potent immunosuppressants.

• Vaccines (Inactivated): Complete all age-appropriate vaccinations at least two weeks before starting an immunosuppressant.

• Vaccines (Live): Avoid live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least three months after immunosuppressant discontinuation.

• Vaccines (Live): Axicabtagene Ciloleucel may enhance the adverse or toxic effect of live vaccines; avoid them for at least six weeks before initiating lymphodepleting therapy, during Axicabtagene Ciloleucel infusion, and after treatment until full immune recovery is achieved.

Specific Considerations:

1. Pregnancy: No available pregnancy data; no reproductive toxicity studies conducted in animals. Due to potential fetal toxicity, especially B-cell lymphocytopenia, Axicabtagene Ciloleucel is not recommended during pregnancy. Discuss pregnancy considerations with the treating physician post-infusion. Verify pregnancy status in females of reproductive potential; perform a pregnancy test before treatment initiation.

2. Lactation: Distribution in human breast milk unknown. Consider breastfeeding benefits against the drug's potential impact on the infant and the mother's clinical needs. Evaluate potential adverse effects on the breastfed infant from the drug or maternal condition.