Axicabtagene ciloleucel interacts in the following cases:
The safety of immunisation with live viral vaccines during or following axicabtagene ciloleucel treatment has not been studied. 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 with axicabtagene ciloleucel.
B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with axicabtagene ciloleucel. Hypogammaglobulinaemia has been very commonly observed in patients treated with axicabtagene ciloleucel. Immunoglobulin levels should be monitored after treatment with axicabtagene ciloleucel and managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.
Tumour lysis syndrome (TLS), which may be severe, has occasionally been observed. To minimise risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to axicabtagene ciloleucel infusion. Signs and symptoms of TLS should be monitored and events managed according to standard guidelines.
Serious infections have been very commonly observed with axicabtagene ciloleucel. Patients should be monitored for signs and symptoms of infection before, during, and after axicabtagene ciloleucel infusion and treated appropriately. Prophylactic anti-microbials should be administered according to standard institutional guidelines.
Febrile neutropenia has been observed in patients after axicabtagene ciloleucel infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Screening for HBV, HCV, and HIV should be performed in accordance with clinical guidelines before collection of cells for manufacturing of axicabtagene ciloleucel.
Nearly all patients experienced some degree of CRS. Severe CRS, including life-threatening and fatal reactions, was very commonly observed with axicabtagene ciloleucel with a time to onset of 1 to 12 days.
Ensure that a minimum of 4 doses of tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, are available for each patient prior to infusion of axicabtagene ciloleucel.
Monitor patients daily for signs and symptoms of CRS for at least 10 days following infusion at the qualified clinical facility. After the first 10 days following infusion, the patient should be monitored at the physician’s discretion.
Counsel patients to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of CRS occur. Treatment algorithms have been developed to ameliorate some of the CRS symptoms experienced by patients on axicabtagene ciloleucel. These include the use of tocilizumab or tocilizumab and corticosteroids for moderate, severe, or life-threatening CRS as summarised in Table 1. 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.
Axicabtagene ciloleucel should not be administered to patients with active infections or inflammatory disease until these conditions have resolved.
CRS has been known to be associated with end organ dysfunction (e.g. hepatic, renal, cardiac, and pulmonary). In addition worsening of underlying organ pathologies can occur in the setting of CRS. Patients with medically significant cardiac dysfunction should be managed by standards of critical care and measures such as echocardiography should be considered.
Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.
Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) should be considered in patients with severe or unresponsive CRS.
Axicabtagene ciloleucel continues to expand and persist following administration of tocilizumab and corticosteroids. Tumour necrosis factor (TNF) antagonists are not recommended for management of axicabtagene ciloleucel-associated CRS.
CRS grading and management guidance:
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and axicabtagene ciloleucel infusion. Grade 3 or higher prolonged cytopenias following axicabtagene ciloleucel infusion occurred very commonly and included thrombocytopenia, neutropenia, and anaemia. Monitor blood counts after axicabtagene ciloleucel infusion.
Severe neurologic adverse reactions have been very commonly observed in patients treated with axicabtagene ciloleucel, which could be life-threatening or fatal. Patients with a history of CNS disorders such as seizures or cerebrovascular ischaemia may be at increased risk. Fatal and serious cases of cerebral oedema have been reported in patients treated with axicabtagene ciloleucel. Patients should be monitored for signs and symptoms of neurologic adverse reactions (table). Patients should be monitored at least daily for 10 days at the qualified healthcare facility following infusion for signs and symptoms of neurologic toxicity. After the first 10 days following the infusion, the patient should be monitored at the physician’s discretion. Counsel patients to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of neurologic toxicity occur. Monitoring of vital signs and organ functions should be considered depending on the severity of the reaction.
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. Non-sedating, anti-seizure medicines should be considered as clinically indicated for Grade 2 or higher adverse reactions. Treatment algorithms have been developed to ameliorate the neurologic adverse reactions experienced by patients on axicabtagene ciloleucel. These include the use of tocilizumab (if concurrent CRS) and/or corticosteroids for moderate, severe, or life-threatening neurologic adverse reactions as summarised in the following table.
Neurologic adverse reaction grading and management guidance:
There are no available data with axicabtagene ciloleucel use in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with axicabtagene ciloleucel to assess whether it can cause foetal harm when administered to a pregnant woman.
It is not known if axicabtagene ciloleucel has the potential to be transferred to the foetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-cell lymphocytopenia. Therefore, axicabtagene ciloleucel is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after axicabtagene ciloleucel therapy should be discussed with the treating physician.
Assessment of immunoglobulin levels and B-cells in newborns of mothers treated with axicabtagene ciloleucel should be considered.
It is unknown whether axicabtagene ciloleucel is excreted in human milk or transferred to the breast-feeding child. Breast-feeding women should be advised of the potential risk to the breast-fed child.
The pregnancy status of women of child bearing potential must be verified before starting axicabtagene ciloleucel treatment.
See the prescribing information for lymphodepleting chemotherapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with axicabtagene ciloleucel.
No clinical data on the effect of axicabtagene ciloleucel on fertility are available. Effects on male and female fertility have not been evaluated in animal studies.
ฮxicabtagene ciloleucel has major influence on the ability to drive and use machines. Due to the potential for neurologic events, including altered mental status or seizures, patients should refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.
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