For:
Pediatric and Young Adult B-cell ALL
Important Safety Information


WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

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Indication
KYMRIAH is a CD19‑directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B‑cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

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 KYMRIAH CAR-T cell therapy, pediatric and young adult patients with r/r ALL had limited treatment options and low survival rates.2 Planning ahead and identifying the right patient for KYMRIAH is critical in optimizing CAR-T treatment outcomes.

5-year survival rates are ≤40% after allogeneic stem cell transplant (SCT) in children who were in their second or later remission2

ALL, acute lymphoblastic leukemia; CAR-T, chimeric antigen receptor T cell; r/r, relapsed/refractory.


Patient Identification

Consider KYMRIAH for pediatric and young adult patients with any of the following clinical characteristics1:

  • Have not gone into remission following frontline treatment (primary refractory)
  • Have relapsed and cannot achieve remission (chemorefractory)
  • Have had second or subsequent relapse following complete remission or SCT

MORE THAN 5000 CLINICAL AND COMMERCIAL PATIENTS HAVE RECEIVED KYMRIAH3

As soon as you have identified a patient who may be a candidate for KYMRIAH, contact a treatment center to discuss eligibility, current treatments, and next steps, as ongoing chemotherapy can lead to T-cell depletion,4 which may affect the quality of the final cell product. The treatment center physicians will coordinate with you to ensure the appropriate patients receive KYMRIAH therapy. For more information on the initial KYMRIAH process, download the Starting Your Patients on KYMRIAH guide.

KYMRIAH therapy is available at select treatment centers across the United States. Please call KYMRIAH CARES™ at 1‑844‑4KYMRIAH (1-844-459-6742) for more information about KYMRIAH Treatment Centers, the ordering process, product information, and patient support. Find a KYMRIAH Treatment Center


Steps for Patients to Receive KYMRIAH

KYMRIAH treatment process
Cell Collection and Cryopreservation

Leukapheresis, when a patient’s own T cells are collected from the blood, occurs over 3 to 6 hours. Within 24 hours, the leukapheresis material is cryopreserved.1,5,a

Manufacturing

The patient’s cryopreserved cells are shipped via specialized courier to the Novartis FDA-approved manufacturing facility, where the patient's cells are genetically reprogrammed into KYMRIAH CAR-T cells.

Infusion

The patient may receive lymphodepleting chemotherapy to prepare the body for KYMRIAH CAR-T cells.1 The patient receives their reprogrammed KYMRIAH CAR-T cells during a single infusion. KYMRIAH can be administered in either an inpatient or outpatient setting at the treating physician’s discretion.

Monitoring

Monitor the patient 2 to 3 times during the first week following infusion. The patient should stay within proximity of their KYMRIAH Treatment Center for at least 4 weeks after KYMRIAH infusion to monitor and be treated for potential side effects.1 Routine long-term monitoring is recommended. Patients should be informed about, and encouraged to participate in, the KYMRIAH registry.

aLeukapheresis material from a previous collection may be used if it was collected within 30 months at a Novartis-approved apheresis collection facility.5


The KYMRIAH CAR-T Cell Therapy Manufacturing Process

THE KYMRIAH MANUFACTURING PROCESS UTILIZES CRYOPRESERVATION, WHICH ALLOWS FOR:

 

Flexibility for patient scheduling5
You can schedule collection as soon as a patient is identified

Optimal timing for leukapheresis5
Leukapheresis material collected at the 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

Shipping assurance6
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 cells5
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

bKYMRIAH 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. Bondarenko SN, Moiseev IS, Slesarchuk OA, et al. Allogeneic hematopoietic stem cell transplantation in children and adults with acute lymphoblastic leukemia. Cell Ther Transplant. 2016;5(2):12-20. 3. Data on file. US Commercial Report – Patient Volume – August 2021. Novartis Pharmaceuticals Corp; Aug 2021. 4. Haining WN, Neuberg DS, Keczkemethy HL, et al. Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia. Blood. 2005;106(5):1749-1754. 5. Data on file. Novartis CTL019 leukapheresis reference manual: leukapheresis collection. Novartis Pharmaceuticals Corp; Dec 2016. 6. Data on file. PVR5135-7A Shipping Validation Report: CTL019 pALL. Novartis Pharmaceuticals Corp; Oct 2016.

Indication

KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

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 61 (77%) of the 79 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 48% of patients. The median times to onset and resolution of CRS for patients with r/r ALL were 3 days (range: 1-22; 1 patient with onset after Day 10) and 8 days (range: 1-36), respectively.

Of the 61 patients with r/r ALL who had CRS, 31 (51%) received tocilizumab; 10 (16%) patients received 2 doses of tocilizumab, 3 (5%) patients received 3 doses of tocilizumab, and 17 (28%) patients received addition of corticosteroids (eg, methylprednisolone).

Two deaths occurred in patients with r/r ALL within 30 days of KYMRIAH infusion. One patient died with CRS and progressive leukemia, and 1 patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Among patients with r/r ALL who had CRS, key manifestations included fever (93%), hypotension (69%), hypoxia (57%), and tachycardia (26%). 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 including pulmonary toxicity, cardiac toxicity, or hypotension, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden.

Ensure 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 remain within proximity of the health care facility for at least 4 weeks following infusion, and 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.

Risk factors for severe CRS are high pre-infusion tumor burden (>50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 56 (71%) of the 79 patients with r/r ALL following treatment with KYMRIAH including ≥ grade 3 in 22% of patients. Among patients who had a neurological toxicity, 83% occurred within 8 weeks after KYMRIAH infusion. Median time to the first event was 6 days from infusion (range: 1-301), and the median duration was 7 days. Resolution occurred within 3 weeks in 71% of patients. 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 r/r ALL studies included headache (35%), encephalopathy (30%), delirium (19%), anxiety (16%), sleep disorders (11%), dizziness (5%), tremor (8%), and peripheral neuropathy (4%). 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 patients after KYMRIAH infusion. Seventy-seven patients (40%) experienced ≥ grade 3 infections, including fatal infections in 2 patients (3%) with r/r ALL after KYMRIAH infusion. 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 34% of patients with r/r ALL 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 evidence 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 ALL, ≥ grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%) and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had ≥ grade 3 neutropenia or thrombocytopenia, respectively. 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 53% of patients with r/r ALL. 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 second malignancy occurs, call 1‑844‑4KYMRIAH (1-844-459-6742) 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%) in patients with r/r ALL were cytokine release syndrome, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, bleeding episodes, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, fatigue, acute kidney injury, and arrhythmia.

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