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) follicular lymphoma (FL) after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Break free from the cycle. A single infusion. A chance at lasting remission.

Why KYMRIAH

KYMRIAH is a potentially definitive, single-infusion therapy that may break the perpetual treatment cycle for adult patients with r/r FL1-6

KYMRIAH may break the perpetual cycle of traditional FL treatments with a single infusion

KYMRIAH is now FDA approved for r/r FL in adult patients after two or more lines of systemic therapy1

Efficacy

ELARA Study Design

ELARA was a pivotal, global, open-label, multicenter, single-arm, phase II trial of tisagenlecleucel in 97 adult patients with r/r FL.1,7

  • Patients in the trial were refractory to or relapsed within 6 months after completion of 2 or more lines of systemic therapy, relapsed during or within 6 months after completion of an anti-CD20 antibody maintenance therapy following at least 2 lines of therapy, or relapsed after autologous hematopoietic stem cell transplant (HSCT)
  • The trial excluded patients with active or serious infections, transformed lymphoma or other aggressive lymphomas, prior allogeneic HSCT, or disease with active CNS involvement
  • Most patients had bulky disease (64%), advanced-stage disease (86%), or a Follicular Lymphoma International Prognostic Index (FLIPI) score of ≥3 at study entry (60%)—all of which are risk factors for poor outcomes
  • Patients in the trial had a median of 4 prior lines of therapy (range: 2 to 13)
  • More than half of the patients had progression of disease within 24 months (POD24) of initiating their first anti-CD20 mAb-containing therapy
  • One week before infusion of KYMRIAH, all patients in the trial received one cycle of lymphodepleting chemotherapy. Patients could receive either fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2) IV daily for 3 days or bendamustine (90 mg/m2) IV daily for 2 days

KYMRIAH has the flexibility to be administered in the outpatient or inpatient setting7,8

Among the 97 patients who received KYMRIAH in the ELARA study, 18% were infused in an outpatient setting and 82% were admitted for inpatient infusion.7,8

 

The primary end point of the ELARA trial was complete response rate by an independent review committee at 3 months. Key secondary end points included overall response rate, duration of response, progression-free survival, overall survival, safety, and cellular kinetics.7

KYMRIAH is a single-infusion that delivered strong efficacy with durable responses1,7

The majority of patients responded to KYMRIAH in the ELARA (USPI) 17-month analysis1,a

Overall response rate in ELARA clinical trial

aThis included the first 90 patients with measurable disease who received KYMRIAH consecutively and had at least 9 months' follow-up from first objective response or discontinued earlier.1
bTwo patients with best overall response of CR had their disease relapse more than 6 months after the last line of therapy.1
cOf the 30 patients who initially achieved a PR, 14 patients (47%) converted to a CR, including 10 patients at the next subsequent visit and within 6 months post infusion.1
dPatients removed from analysis (n=3) with a follow-up of less than 6 months.7
eCRR was a primary end point in the ELARA trial; ORR was a secondary end point.7


Duration of Response
DOR was a secondary end point in the ELARA trial.7

71% OF PATIENTS STILL IN RESPONSE AT 12 MONTHS1

  • Among patients whose best response was CR, 85% were estimated to remain in response at 12 months1
  • Median DOR was not reached in ELARA (USPI) with 9.1-month median follow-up for DOR1,f


Progression-Free Survival

PFS was a secondary end point in the ELARA trial.7

67% OF PATIENTS WERE ALIVE AND PROGRESSION FREE AT 12 MONTHS7

PFS data should be interpreted with caution in a single-arm trial as the statistical significance is unknown.


Overall Survival

OS was a secondary end point in the ELARA trial.7

95% OF PATIENTS WERE STILL ALIVE AT 12 MONTHS9

OS data should be interpreted with caution in a single-arm trial as the statistical significance is unknown.

fThe first disease assessment was scheduled to be performed at Month 3 post-infusion. The median follow up is the time from first objective response to last disease assessment.


Safety

KYMRIAH has a well-characterized safety profile 

 

Cytokine Release Syndrome 

KYMRIAH DEMONSTRATED NO GRADE ≥3 CRS IN ELARA1,7

 

Rates of CRS in ELARA clinical trial
  • Nearly all CRS events observed in the ELARA study occurred within the first 8 weeks post-infusion9
  • Ensure that at least 2 doses of tocilizumab are available on site prior to infusion of KYMRIAH1
    • Of the 51 patients who had CRS, 15 (29%) received systemic tocilizumab, and 2 (4%) received corticosteroids in addition to tocilizumab
  • CRS management in ELARA allowed for the use of tocilizumab and corticosteroids as early as grade 21,10
    • In ELARA, all CRS events resolved with appropriate management9,11
  • Monitor patients 2 to 3 times during the first week and for at least 4 weeks following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of CRS. Instruct patients to remain within proximity of the certified health care facility for at least 4 weeks following infusion1


Neurological Events

RATES OF NEs IN ELARA WERE MAINLY GRADE 1 OR 21,7

 

Rates of NEs in ELARA clinical trial


  • The most common NE observed with KYMRIAH was headache (25%)1
  • Onset of NEs can be concurrent with CRS, following resolution of CRS, or in the absence of CRS1
  • The majority of the KYMRIAH-related NEs required no specific protocol-defined intervention other than supportive care9
    • All NEs resolved with appropriate management11
    • There were no fatalities attributed to NEs7

The reported rates of CRS and NEs vary between the 16.6-month analysis and the USPI due to differences in the criteria and clinical manifestations by which they are defined.


g
Percentages reported reflect ≤8 weeks after infusion.7

Adverse Reactions

The most common adverse reactions (incidence ≥20%) in ELARA were CRS, infections-pathogens unspecified, fatigue, musculoskeletal pain, headache, and diarrhea. Below are selected adverse reactions that were reported anytime following treatment with KYMRIAH in ≥10% of adult patients with r/r FL.1

Adverse reactions All grades, % Grade ≥3
Blood and lymphatic disorders Febrile neutropenia 13 13
Gastrointestinal disorders Diarrhea 24 2
Nausea 16 2
Constipation 16 0
Abdominal painh 10 1
General disorders and administration site conditions Fatiguei 27 3
Fever 19 1
Immune system disorders Cytokine release syndrome 53 0
Hypogammaglobulinemiaj 18 1
Infections and infestations Infections - pathogen unspecified 38 12
Viral infectious disorders 18 5
Musculoskeletal and connective tissue disorders Musculoskeletal paink 25 1
Arthralgia 10 0
Nervous system disorders Headachel 25 2
Respiratory, thoracic, and mediastinal disorders Coughm 19 0
Skin and subcutaneous tissue disorders Rashn 10 0
Adverse reactions All grades, % Grade ≥3
Blood and lymphatic disorders    
Febrile neutropenia 13 13
Gastrointestinal disorders    
Diarrhea 24 2
Nausea 16 2
Constipation 16 0
Abdominal painh 10 1
General disorders and administration site conditions    
Fatiguei 27 3
Fever 19 1
Immune system disorders    
Cytokine release syndrome 53 0
Hypogammaglobulinemiaj 18 1
Infections and infestations    
Infections - pathogen unspecified 38 12
Viral infectious disorders 18 5
Musculoskeletal and connective tissue disorders    
Musculoskeletal paink 25 1
Arthralgia 10 0
Nervous system disorders    
Headachel 25 2
Respiratory, thoracic, and mediastinal disorders    
Coughm 19 0
Skin and subcutaneous tissue disorders    
Rashn 10 0

 

hAbdominal pain included abdominal pain and abdominal pain upper.
iFatigue included asthenia, fatigue, and malaise.
jHypogammaglobulinemia included blood immunoglobulin G decreased and hypogammaglobulinemia.
kMusculoskeletal pain included back pain, bone pain, flank pain, muscle discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and non-cardiac chest pain.
lHeadache included headache and migraine.
mCough included cough and productive cough.
nRash included rash, rash maculo-papular, and rash papular.


Patient Identification

Patient health and referral timing are important considerations

KYMRIAH may be appropriate for adults with r/r FL who have received two or more lines of systemic therapy and1:

  • Have not gone into remission (refractory after second line of therapy)
  • Have relapsed (after second line of chemotherapy or following ASCT)
Timely referral is critical. Prior treatments may impact the overall quality of the patient’s T cells, which are used to manufacture KYMRIAH12

Treatment Process

With a single infusion of KYMRIAH, a patient’s own reprogrammed T cells are reinfused to target CD19-expressing cells and fight FL1

First step: cell collection and cryopreservation. Second step: manufacturing. Third step: infusion. Fourth step: monitoring.
 

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,o

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.7,8

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.13

oLeukapheresis material from a previous collection may be used if it was collected within 30 months at a Novartis-approved apheresis collection facility.14


KYMRIAH Treatment Centers

Use the treatment locator to find the KYMRIAH Treatment Center nearest to you.

ASCT, autologous stem cells transplantation; CAR-T, chimeric antigen receptor T cell; CNS, central nervous system; CR, complete response; CRS, cytokine release syndrome; DOR, duration of response; FL, follicular lymphoma; ICANS, immune effector cell-associated neurotoxicity syndrome; NE, neurological event; ORR, overall response rate; OS, overall survival; PR, partial response; REMS, Risk Evaluation and Mitigation Strategy; r/r, relapsed or refractory; USPI, United States Prescribing Information.

 

References: 1. Kymriah [prescribing information]. Novartis Pharmaceuticals Corp; 2022. 2. Aliqopa [prescribing information]. Bayer HealthCare Pharmaceuticals Inc.; 2021. 3. Copiktra [prescribing information]. Verastem, Inc.; 2021. 4. Zydelig [prescribing information]. Gilead Sciences, Inc.; 2020. 5. Revlimid [prescribing information]. Celgene Corp; 2021. 6. Rituxan [prescribing information]. Genentech, Inc.; 2021. 7. Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. 2022;28(2):325-332. 8. Fowler NH, Dickinson M, Ghosh M, et al. 3533 Assessment of healthcare resource utilization and costs in patients with relapsed or refractory follicular lymphoma undergoing CAR-T cell therapy with tisagenlecleucel: results from the Elara study. Presented at: 63rd American Society of Hematology Annual Meeting; December, 2021; Atlanta, GA. https://ash.confex.com/ash/2021/webprogram/Paper145741.html 9. Data on file. CCTL019E2202_Clinical Study Report_v01. Novartis Pharmaceuticals Corp; 2021. 10. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195. 11. Schuster SJ et al. Presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021; Chicago, IL. Abstract 7508. 12. Das RK, Vernau L, Grupp SA, Barrett DM. Naïve T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers. Cancer Discov. 2019;9(4):492-499. 13. Data on file. CCTL019B2401_Clinical Trial Protocol. Novartis Pharmaceuticals Corp; 2018. 14. Data on file. Novartis CTL019 leukapheresis reference manual: leukapheresis collection. Novartis Pharmaceuticals Corp; 2021.

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) follicular lymphoma (FL) after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

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 51 (53%) of the 97 adult patients with r/r FL receiving KYMRIAH. The median times to onset and resolution of CRS were 4 days (range: 1-14) and 4 days (range: 1-13), respectively. Of the 51 patients with CRS, 15 (29%) received systemic anticytokine treatment with tocilizumab. Three (6%) patients required 3 dosages of tocilizumab, 4 (8%) patients required 2 dosages, and 8 (16%) patients required a single dose of tocilizumab. Two (4%) patients received corticosteroids in addition to tocilizumab.

Among patients with r/r FL with CRS, key manifestations included fever (92%), hypotension (40%), hypoxia (19%), and tachycardia (2%). 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, active graft vs host disease, or worsening of leukemia burden.

Ensure that a minimum of 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH. Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred following treatment with KYMRIAH. Neurological toxicities occurred in 42 (43%) of the 97 patients with r/r FL, including ≥ grade 3 in 6%. The median times to the first event and duration were 8 days (range: 1-345) and 5 days, respectively.

Among KYMRIAH patients who had a neurological toxicity, 84% occurred within 8 weeks following KYMRIAH infusion. Resolution occurred within 3 weeks in 74% of patients with
r/r FL.

Encephalopathy lasting up to 70 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 FL included headache (25%), encephalopathy (3%), delirium (1%), anxiety (2%), sleep disorders (6%), dizziness (7%), tremor (3%), and peripheral neuropathy (7%). Other manifestations included seizures and aphasia.

Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of neurological toxicities. Rule out other causes of neurological symptoms. Monitor patients for signs or symptoms of neurological toxicities for at least 4 weeks after infusion and treat promptly. Neurological toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms of neurological toxicity occur at any time. 

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. The required components of the KYMRIAH REMS are:

  • Health care facilities that dispense and administer KYMRIAH must be enrolled in the program and comply with the REMS requirements
  • Certified health care facilities must have on-site, immediate access to tocilizumab and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hours after KYMRIAH infusion, if needed for treatment of CRS
  • Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer KYMRIAH are trained in the management of CRS and neurological toxicities.

Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH (1-844-459-6742).

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS, which can be life-threatening or fatal, has occurred following treatment with KYMRIAH. One patient (1%) with r/r FL developed HLH with a fatal outcome >1 year after receiving KYMRIAH. The patient did not have CRS during or immediately preceding HLH. Treatment of HLH should be administered as per institutional standards.

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 50 (52%) of the 97 patients with r/r FL; 20 patients (21%) experienced ≥ grade 3 infections, including fatal infection in 1 patient (1%). 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 13% of patients with r/r FL 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 hepatitis C virus (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 FL, ≥ grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included thrombocytopenia (17%) and neutropenia (16%) among 97 treated patients. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly granulocyte-macrophage colony-stimulating factor, 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 18% of patients with r/r FL. 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 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 FL were CRS, infections-pathogen unspecified, fatigue, musculoskeletal pain, headache, and diarrhea.

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