Ciltacabtagene autoleucel

Ciltacabtagene autoleucel approved for the treatment of patients with relapsed or refractory multiple myeloma. 

It is a BCMA directed CAR– T immunotherapy.

A BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express the B-cell maturation antigen (BCMA). 

BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells. 

The Ciltacabtagene autoleucel CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. 

Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.

Trade name CARVYKTI

In the pivotal clinical study, 98 percent of patients with relapsed or refractory multiple myeloma responded to a one-time treatment with ciltacabtagene autoleucel and 78 percent of patients who responded experienced a stringent complete response

Approved CARVYKTI for the treatment of adults with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

The CARTITUDE-1 study, which included patients who had received a median of six prior treatment regimens and had previously received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

It is a chimeric antigen receptor T-cell (CAR-T) therapy featuring two B-cell maturation antigen (BCMA)-targeting single domain antibodies.

CARTITUDE-1 study a median of 18 months follow-up, median duration of response (DOR) was 21.8 months.

A single Cilta-cel infusion resulted in the lower risk of disease progression or death than standard care in lenalidomide refractory patients with multiple myeloma, who had received 1 to 3 previous therapies (CARTRITUDE-4 trial),

Has a Boxed Warning regarding Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and prolonged and/or recurrent cytopenias.

Warnings and Precautions: prolonged and recurrent cytopenias, infections, hypogammaglobulinemia, hypersensitivity reactions, secondary malignancies, and effects on ability to drive and use machines.

The most common adverse reactions (≥20 percent) are pyrexia, Cytokine Release Syndrome (CRS), hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.

Responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up.

98 percent of patients treated with ciltacabtagene autoleucel for RRMM responded to therapy and a majority of patients achieving sustained depth of response with 83 percent of patients achieving an stringent complete response at the 22-month follow-up.

Should not be administered  to patients with active infection or inflammatory disorders. 

Severe or life-threatening CRS is treated with tocilizumab or tocilizumab and corticosteroids.

Neurotoxicity Syndrome (ICANS), may be fatal or life-threatening.

Parkinsonism and Guillain-Barré syndrome resulting in fatal or life-threatening reactions have occurred following treatment with ciltacabtagene autoleucel.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, can occur with CRS or neurologic toxicities.

Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment.

It is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) Program.

Cytokine Release Syndrome (CRS) including fatal or life-threatening reactions, occurred following treatment in 95% of patients receiving ciltacabtagene autoleucel. 

However, Grade 3 or higher CRS occurred in 5% of patients, with Grade 5 CRS reported in 1 patient. 

The median time to onset of CRS was 7 days.

The most common manifestations of CRS included fever (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (14%) and sinus tachycardia (11%). 

Grade 3 or higher events associated with CRS include; increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS)/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

71% patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. 

At the first sign of CRS, treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids are initiated.

Neurologic toxicities with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, peripheral neuropathies, and cranial nerve palsies can occur.

All patients with neurotoxicity have CRS. 

The most frequent manifestations of neurotoxicity include: encephalopathy, aphasia and headache.

Neurologic toxicity is managed with supportive care and/or corticosteroids as needed.

About 20% of patients with neurotoxicity have several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome.

The median onset of parkinsonism in the patients was 43 days 

Peripheral neuropathies present as sensory, motor or sensorimotor neuropathies, with a median time of onset of symptoms of  62 days, and  a median duration of peripheral neuropathies was 256 days.

3.1% of patients experienced cranial nerve palsies.

All three patients had 7th a cranial nerve palsy: other cranial nerves may be involved.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation syndrome was preceded by prolonged CRS lasting 97 days. 

HLH/MAS symptoms include, hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction. 

Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and Ciltacabtagene autoleucel infusion. 

30% of patients experienced prolonged Grade 3 or 4 neutropenia and 41% of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and anemia were seen in 63%, 18%, 60%, and 37% after recovery from initial Grade 3 or 4 cytopenia following infusion. 

After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. 

Ciltacabtagene should not be administered to patients with active infection or inflammatory disorders, as severe, life-threatening or fatal infections occurred in patients after drug infusion.

Infections occurred in 59% patients. 

Grade 3 or 4 infections occurred in 23% of patients.

Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion, and may be concurrent with CRS. 

Hypogammaglobulinemia was reported as an adverse event in 12% of patients, and IgG levels fell below 500 mg/dL after infusion in 92% of patients. 

Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ciltacabtagene treatment, and until immune recovery following treatment with ciltacabtagene.

Hypersensitivity Reactions have occurred in 5% of patients following ciltacabtagene autoleucel infusion. 

Serious hypersensitivity reactions may be due to the dimethyl sulfoxide (DMSO) in  ciltacabtagene.

Patients may develop secondary malignancies. 

It has the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion. 

The most common non-laboratory adverse reactions with an incidence greater than 20%, are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. 

The most common laboratory adverse reactions with an incidence greater than or equal to 50% include: thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia.


Leave a Reply

Your email address will not be published. Required fields are marked *