Important Safety Information


WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

  • Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not admini…+
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Indication
KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.

Treatment Process

About CAR-T Cell Therapy

CAR-T cell therapy is a targeted, personalized therapy that contains patients’ autologous T cells reengineered to fight cancer. KYMRIAH® (tisagenlecleucel) is a CAR-T cell therapy genetically modified to identify and eliminate CD19-expressing malignant and normal cells. Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the KYMRIAH cells.1

Prior to CAR-T cell therapy, patients with r/r DLBCL had limited treatment options and substantially reduced survival. Planning ahead and identifying the right patient for KYMRIAH is critical in optimizing CAR-T treatment outcomes.

Nearly 90% of patients with r/r DLBCL do not achieve long-term remission when treated with traditional therapies and autologous transplant2



Patient Identification

KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.1

Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.1

‭KYMRIAH can be considered for adults with r/r DLBCL who have received 2 or more systemic therapies with any of the following ‭clinical characteristics3:

  • Have not gone into remission (refractory after second line of therapy)
  • ‭Have relapsed (after second line of chemotherapy)
  • Have relapsed following autologous stem cell transplant (ASCT)
  • ‭Have challenges with stem cell collection after salvage chemotherapy‬‬‬‬‬‬‬‬‬‬
  • Are ineligible or not a candidate for ASCT owing to inability to achieve complete remission (CR) or are unlikely to achieve CR after salvage therapy‬‬‬‬‬‬‬‬‬‬

MORE THAN 5000 CLINICAL AND COMMERCIAL PATIENTS HAVE RECEIVED KYMRIAH4

Contact a treatment center early if considering KYMRIAH for a patient. Communication between the primary physician and the treatment center is integral to the treatment process. Find a KYMRIAH Treatment Center


Steps for Patients to Receive KYMRIAH

Diagram showing the steps in the KYMRIAH® (tisagenlecleucel) treatment
Cell Collection and Cryopreservation

The patient’s T cells are collected from the blood (leukapheresis). The material is cryopreserved, allowing leukapheresis to be scheduled at a time that is in the best interest of the patient.1,a

Manufacturing

The patient’s cryopreserved cells are shipped to a Novartis FDA-registered and -approved manufacturing facility, where they are genetically reprogrammed into KYMRIAH CAR-T cells.1

Infusion

The patient may receive lymphodepleting chemotherapy to prepare the body for KYMRIAH.1 KYMRIAH is administered in either an inpatient or outpatient hospital setting at the treating physician’s discretion.5

Monitoring

The patient should stay within proximity of their KYMRIAH Treatment Center for at least 4 weeks after KYMRIAH infusion.1 Patients should be encouraged to participate in a 15-year long-term follow-up registry.

  1. Leukapheresis material from a previous collection may be used if it was collected within 30 months at a Novartis-approved apheresis collection facility.6

The KYMRIAH CAR-T Cell Therapy Manufacturing Process

The KYMRIAH manufacturing process utilizes cryopreservation, which allows for:


Flexibility for patient scheduling6
You can schedule collections as soon as a patient is identified

Optimal timing for leukapheresis6
Leukapheresis material collected at a Novartis-approved apheresis collection facility can be cryopreserved for up to 30 months before manufacturing begins, if you decide that is the best treatment course for your patient.b KYMRIAH is the only commercially available CAR-T cell therapy that allows for early leukapheresis and extended storage of cryopreserved leukapheresis material

Shipping7
The charged Dewar is validated to maintain cryogenic temperatures for 10 days, keeping the cryopreserved leukapheresis material frozen, and providing a safeguard against weather- and/or logistic-related delays

Storage of excess cells6
It may be possible for excess cells to be retained at your facility for potential future use, if a collection yields greater than 4 x 109 CD3+ cells and subject to certain storage requirements

  1. KYMRIAH is individually manufactured for each patient; it is important to keep in mind that not all patients’ cells can be successfully manufactured into KYMRIAH CAR-T cells.

 

References: 1. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. 2. Friedberg JW. Relapsed/refractory diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program. 2011;2011:498-505. 3. Data on file. CTL019C2201 Oncology Clinical Trial Protocol. March 11, 2015. Novartis Pharmaceuticals Corp; 2015. 4. [Data on file. US Commercial Report – Patient Volume – February 2021]. Novartis Pharmaceuticals Corp; February 2021. 5. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. 6. Data on file. Novartis CTL019 leukapheresis reference manual: leukapheresis collection. Novartis Pharmaceuticals Corp; 2016. 7. Data on file. PVR5135-7A Shipping Validation Report: CTL019 pALL. Novartis Pharmaceuticals Corp; 2016.

 

 

Indication

KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.

Important Safety Information for KYMRIAH® (tisagenlecleucel)

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

  • Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab, or tocilizumab and corticosteroids
  • Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed
  • KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS

Warnings and Precautions

Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 85 (74%) of the 115 patients with r/r DLBCL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 23% of patients with r/r DLBCL. In KYMRIAH clinical trials, the median times to onset and resolution were 3 days (range:1-51; 1 patient with onset after Day 10) and 7 days (range: 2-30), respectively.

Of the 85 patients with r/r DLBCL who had CRS, 19 (22%) received systemic tocilizumab or corticosteroids. Seven (8%) received a single dose of tocilizumab, 11 (13%) received 2 doses of tocilizumab, and 11 (13%) received corticosteroids in addition to tocilizumab. One patient with r/r DLBCL received corticosteroids for CRS without concomitant tocilizumab, and 2 patients received corticosteroids for persistent neurotoxicity after resolution of CRS.

Three deaths occurred in patients with r/r DLBCL within 30 days of KYMRIAH infusion. Of these 3 patients, all had a history of CRS in the setting of stable to progressive underlying disease, 1 of whom developed bowel necrosis. Among patients with r/r DLBCL who had CRS, key manifestations included fever (85%), hypotension (45%), hypoxia (35%), and tachycardia (13%). CRS may be associated with hepatic, renal and cardiac dysfunction, and coagulopathy.

Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies, active uncontrolled infection, or active graft vs host disease.

Ensure that at least 2 doses of tocilizumab are available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS 2 to 3 times during the first week, then for at least 4 weeks after treatment. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated. 

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 69 (60%) of the 115 patients with r/r DLBCL following treatment with KYMRIAH, including ≥ grade 3 in 19% of patients. Among KYMRIAH clinical trial patients who had a neurological toxicity, 83% occurred within 8 weeks following KYMRIAH infusion. Median time to the first event was 5 days from infusion (range: 1-368), and the median duration was 17 days for patients with r/r DLBCL. Resolution occurred within 3 weeks in 50% of patients with r/r DLBCL. Encephalopathy lasting up to 50 days was noted. The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

The most common neurological toxicities observed in patients with r/r DLBCL included headache (21%), encephalopathy (16%), delirium (5%), anxiety (10%), sleep disorders (10%), dizziness (12%), tremor (6%), and peripheral neuropathy (12%). Other manifestations included seizures and aphasia.

Monitor patients for neurological events, specifically 2 to 3 times during the first week following KYMRIAH infusion, and exclude other causes for neurological symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events.

KYMRIAH REMS to Mitigate CRS and Neurological Toxicities: Because of the risk of CRS and neurological toxicities, KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH (1-844-459-6742).

Hypersensitivity Reactions: Allergic reactions may occur with KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH. Observe patients for hypersensitivity reactions during the infusion.

Serious Infections: Infections, including life-threatening or fatal infections, occurred in 125 (64%) of 194 KYMRIAH clinical trial patients after KYMRIAH infusion. Seventy-seven patients (40%) experienced ≥ grade 3 infections, including fatal infections in 1 patient (1%) with r/r DLBCL. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Patients with active uncontrolled infection should not start KYMRIAH treatment until the infection is resolved. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately.

Febrile neutropenia (≥ grade 3) was also observed in 17% of patients with r/r DLBCL after KYMRIAH 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.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. There is no experience with manufacturing KYMRIAH for patients with a positive test for HIV or with active HBV or active HCV. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. In patients with r/r DLBCL, ≥ grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included thrombocytopenia (39%) and neutropenia (25%) among 115 treated patients. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.

Hypogammaglobulinemia: Hypogammaglobulinemia and agammaglobulinemia related to B-cell aplasia can occur in patients after KYMRIAH infusion. Hypogammaglobulinemia was reported in 17% of patients with r/r DLBCL. Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines.

The safety of immunization with live vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH.

Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH.

Secondary Malignancies: Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their cancer. Monitor lifelong for secondary malignancies. If a secondary malignancy occurs, call 1-844-4KYMRIAH to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurological events, including altered mental status or seizures, patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Drug Interactions
HIV and the lentivirus used to make KYMRIAH have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false positive results in patients who have received KYMRIAH.

Pregnancy, Lactation, Females and Males of Reproductive Potential
No data are available of KYMRIAH use in pregnant or lactating women. Therefore, KYMRIAH is not recommended for women who are pregnant or breastfeeding. A risk to the breastfed infant cannot be excluded. Pregnancy after KYMRIAH administration should be discussed with the treating physician. Pregnancy status of females of reproductive potential should be verified with a pregnancy test prior to starting treatment with KYMRIAH. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682.

Adverse Reactions
The most common adverse reactions (>20%) reported in patients with r/r DLBCL were cytokine release syndrome, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, bleeding episodes, dyspnea, and headache.

Please see full Prescribing Information for KYMRIAH, including Boxed WARNING, and Medication Guide.