The European Commission ( EC ) has approved Kymriah ( Tisagenlecleucel, formerly CTL019 ). The approved indications are for the treatment of pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia ( ALL ) that is refractory, in relapse post-transplant or in second or later relapse; and for the treatment of adult patients with relapsed or refractory ( r/r ) diffuse large B-cell lymphoma ( DLBCL ) after two or more lines of systemic therapy.
Kymriah, developed in collaboration with the University of Pennsylvania, is a ground-breaking one-time treatment that uses a patient's own T cells to fight cancer, and the only chimeric antigen receptor T cell ( CAR-T ) therapy to receive regulatory approval in the EU for these two distinct B-cell malignancies.
Kymriah was also the first CAR-T cell therapy ever approved by the US Food and Drug Administration ( FDA ).
This approval was based on the review of the only two global registration CAR-T clinical trials, JULIET and ELIANA, which included patients from eight European countries.
In these trials, Kymriah demonstrated strong and durable response rates and a consistent safety profile in two difficult-to-treat patient populations.
The EC approval of Kymriah in pediatric and young adult patients with r/r B-cell ALL is based on the pivotal phase II ELIANA clinical trial, the first pediatric global CAR-T cell therapy registration study for Kymriah in children and young adults with r/r B-cell ALL.
ELIANA was conducted in collaboration with the University of Pennsylvania and Children's Hospital of Philadelphia, evaluating Kymriah in patients in 25 Centers in the US, Canada, Australia, Japan, and in Europe, in Austria, Belgium, France, Germany, Italy, Norway and Spain.
In this global, multi-center study evaluating 75 patients infused with Kymriah with three or more months of follow-up, 81% of patients achieved overall remission ( 95% CI: 71% - 89% ) with 80% of responders still in remission at 6 months.
Sixty percent of patients achieved complete response ( CR ) and 21% of patients achieved CR with incomplete blood count recovery ( CRi ). Of those patients in remission, 100% had no minimal residual disease ( MRD ) detected in the bone marrow.
Overall survival ( OS ) was 90% at six months, and 76% at 12 months. Median OS was 19.1 months ( 95% CI: 15.2 - NE ) in this difficult-to-treat patient population.
In ELIANA, 47% of patients experienced grade 3 or 4 cytokine release syndrome ( CRS ).
Cytokine release syndrome was managed according to the global CRS management protocol at clinical sites adequately trained for the safe administration and management of Kymriah. T
here were two deaths within 30 days of Kymriah infusion: one due to progressive disease with CRS and one death with resolving CRS from intracranial hemorrhage.
Within eight weeks of treatment, 13% of patients experienced grade 3 or 4 neurological events. The most common severe ( grade 3 or 4 ) neurological events were encephalopathy and/or delirium.
Severe ( grade 3 or 4 ) febrile neutropenia and infection occurred in 36% and 44% of patients, respectively.
The EC approval of Kymriah in adult patients with r/r DLBCL is based on the pivotal phase II JULIET clinical trial, the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL.
JULIET was conducted in collaboration with the University of Pennsylvania, and is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan, and Europe in Austria, France, Germany, Italy, Norway and the Netherlands.
In the JULIET trial, patients were infused in the inpatient and outpatient setting.
In this global, multi-center study, among 93 evaluable patients who were followed for at least three months or discontinued earlier, Kymriah demonstrated an overall response rate ( ORR ) of 52% ( 95% CI, 41% - 62% ), with 40% achieving a complete response ( CR ) and 12% achieving a partial response ( PR ).
The relapse-free probability at 6 and 12 months was 68% and 65%, respectively; and the median duration of response was not reached at the time of data cut-off, indicating sustainability of response.
The overall survival rate at 12 months was 49% and median OS was 11.7 months among all infused patients ( n=111 ) ( 95% CI, 6.6-NE ).
In JULIET, 22% of all treated patients experienced grade 3 or 4 CRS within eight weeks of infusion with Kymriah, as defined by the Penn Grading Scale, a rigorous scale for grading CRS.
Cytokine release syndrome was successfully managed globally using site education on implementation of the CRS treatment protocol.
Twelve percent of patients had grade 3 or 4 neurologic adverse events, which were managed with supportive care.
Grade 3 or 4 cytopenias lasting more than 28 days were reported based on laboratory findings and included thrombocytopenia ( 41% ), lymphopenia ( 28% ), neutropenia ( 24% ), leukopenia ( 21% ) and anemia ( 14% ), grade 3 or 4 infections and grade 3 or 4 febrile neutropenia occurred in 32% and 15% of patients, respectively.
Important safety information
Kymriah must not be administered in case of hypersensitivity to the active substance or to any of the excipients of the product.
In addition, contraindications of the lymphodepleting chemotherapy that is usually preceding the Kymriah infusion to prepare the patient's body, must be considered.
Kymriah treatment should be delayed, if a patient has any of the following conditions: unresolved serious adverse reactions ( especially pulmonary reactions, cardiac reactions or hypotension ) from preceding chemotherapies; active uncontrolled infection; active graft-versus-host disease ( GVHD ); significant clinical worsening of leukemia burden or lymphoma following lymphodepleting chemotheraty.
Kymriah may cause side effects that could be severe, life-threatening or fatal. Therefore, patients should be monitored daily for the first 10 days following infusion for signs and symptoms of potential cytokine release syndrome, neurological events and other toxicities.
Physicians should consider hospitalization for the first 10 days post infusion or at the first signs / symptoms of cytokine release syndrome and/or neurological events.
After the first 10 days following the infusion, the patient should be monitored at the physician's discretion.
Patients should be instructed to remain within proximity ( i.e., 2 hours of travel ) of a qualified clinical facility for at least 4 weeks following infusion.
They should be advised to contact their healthcare provider right away, if they experience any of signs and symptoms of cytokine release syndrome, neurological events, infections and tumor lysis syndrome or if other severe or serious side effects occur.
Patients are advised to take their body temperature twice a day for 3-4 weeks after treatment with Kymriah, and if the temperature is high to contact their doctor immediately.
Kymriah may cause side effects that could be severe, life-threatening or fatal. They usually happen in the first eight weeks after the infusion, but can also develop later. The following main side effects can occur after Kymriah infusion:
a) Cytokine release syndrome has been frequently observed and almost always occurred within the first 10 days after Kymriah infusion. Patients may experience high fever, chills, difficulty breathing, nausea, vomiting, diarrhea, muscle pain, joint pain, low blood pressure, dizziness/light headedness, and issues with blood coagulation. Adverse reactions of multiple body organs, such as the heart, the liver or kidney, may occur.
b) Neurological events, in particular encephalopathy, confusional state or delirium, can occur frequently with Kymriah. Other manifestations can also include altered or decreased consciousness, agitation, seizures, difficulty speaking, understanding speech, or loss of balance. The majority of neurological events occurred within eight weeks following Kymriah infusion and were transient. Because of the risk of neurological side effects, patients should not drive, operate heavy machinery, or do other activities that require alertness for eight weeks after receiving Kymriah.
c) Infections can occur frequently after Kymriah infusion. As appropriate, prophylactic antibiotics should be administered and surveillance testing should be employed prior to and during treatment with Kymriah. Infections are known to complicate the course and management of concurrent cytokine release syndrome. Vaccination with live virus vaccines is not recommended at least six weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and until immune recovery following treatment with Kymriah.
d) Febrile neutropenia was frequently observed in patients after Kymriah infusion. In the event of febrile neutropenia, infection should be evaluated and managed appropriately with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.
e) Tumor lysis syndrome is a rapid breakdown of tumor cells and release of their contents into the bloodstream. This can interfere with the workings of various body organs, especially the kidneys, heart and nervous system. To minimize risk of tumor lysis syndrome, patients with elevated uric acid or high tumor burden should receive allopurinol, or an alternative prophylaxis, prior to Kymriah infusion.
f) Prolonged cytopenias, which is a low count of one or more types of blood cells such as red blood cells, white blood cells, or platelets, can persist for several weeks following Kymriah. The majority of patients who had cytopenias at day 28 following Kymriah treatment improved or resolved within three months after treatment. Prolonged neutropenia has been associated with increased risk of infection.
g) Hypogammaglobulinemia or agammaglobulinemia, a condition in which the level of immunoglobulins ( antibodies ) in the blood is low and the risk of infections is increased, can occur in patients treated with Kymriah. Infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be managed per age and standard guidelines.
h) Secondary malignancies: After treatment with Kymriah, patients will be monitored life-long by their healthcare provider, as they may develop secondary cancers.
i) Pregnancy and breast-feeding: It is not known, whether Kymriah has the potential to be transferred to the fetus via the placenta and could cause fetal toxicity, including B-cell lymphocytopenia. Kymriah is not recommended during pregnancy and in women of childbearing potential not using contraception. It is unknown, whether Kymriah is excreted in human milk. A risk to the breast-fed infant cannot be excluded. Women, who are breast-feeding, should be advised of the potential risk to the breast-fed infant.
l) Blood, organ, tissue and cell donation: Patients treated with Kymriah should not donate blood, organs, tissues and cells for transplantation. ( Xagena )
Source: Novartis, 2018