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.

Efficacy

JULIET Trial Design

Study characteristics of the global, phase 2 pivotal trial1,2
JULIET was an open-label, multicenter, single-arm trial conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia.1 This trial included adult patients with relapsed/refractory (r/r) DLBCL who received 2 or more lines of chemotherapy.2 Baseline study characteristics for the JULIET trial were consistent across USPI and 14-month (NEJM) analyses.1,2

Patient Demographics (JULIET 14-month [NEJM] analysis, N=93)1
• Aged 22-76 years (median, 56 years)
• Progressive disease after autologous stem cell transplant (ASCT) or were ineligible for transplant (49% underwent ASCT)

Inclusion/Exclusion Criteria1
• Histologically confirmed DLBCL (79% DLBCL not otherwise specified [NOS], 19% transformed follicular lymphoma [tFL]), 2% other
• ≥2 prior lines of therapy (median, 3)
   – 55% of patients had refractory disease and 45% relapsed after their last therapy
• No prior anti-CD19 therapy or active central nervous system (CNS) involvement

End Points1
Primary: Best overall response rate (ORR) (complete response [CR] + partial response [PR])*
Key secondary: Duration of response (DOR), overall survival (OS), safety

Chemotherapy1,2
Bridging: 92% of patients
Lymphodepleting: 93% (103/111) of patients
   – Recommended regimen: Fludarabine (25 mg/m2 intravenous [IV] daily for 3 days) and cyclophosphamide (250 mg/m2 IV daily for 3 days, starting with the first dose of fludarabine)
   – Alternative regimen: Bendamustine 90 mg/m2 IV daily for 2 days

JULIET trial patient disposition1,2

Flow chart of efficacy analysis data set size Flow chart of efficacy analysis data set size

EAS, efficacy analysis set; NEJM, New England Journal of Medicine; USPI, United States Prescribing Information.
*Independent review committee (IRC) response based on the Lugano Classification with a null hypothesis of ORR ≤20%.1
aThe full analysis set and safety set were made up of all the patients who received an infusion, including those treated with KYMRIAH manufactured in the United States (main cohort) and in the European Union (cohort A).1
bPatients in this data set either had no bridging chemotherapy or had imaging that showed measurable disease after completion of bridging chemotherapy and before KYMRIAH infusion.2
cPatients pending infusion at the time of data cutoff: September 6, 2017.3
dThe first 92 patients who received KYMRIAH manufactured in the United States and completed at least 3 months’ follow-up or discontinued earlier.2
ePatients were identified and excluded from the analysis because the treatment effect of KYMRIAH alone could not be determined.2

Overall Response Rate

JULIET 14-MONTH NEJM ANALYSIS1

Overall response rate in JULIET clinical trial at 14 months Overall response rate in JULIET clinical trial at 14 months

 

JULIET 9.4-MONTH (USPI) ANALYSIS2
50% overall response rate at 3 months (n=34/68)
  – 32% complete response (n=22/68)
  – 18% partial response (n=12/68)

 

Persistence based on pharmacokinetics2
In adult patients with r/r DLBCL who achieved a CR, KYMRIAH® (tisagenlecleucel) was present for up to 18 months in peripheral blood and 9 months in bone marrow.

 

Consistent response rates seen regardless of clinical characteristics1

Overall response rate by subgroup chart Overall response rate by subgroup chart

• KYMRIAH demonstrated consistent response rates across high-risk patient subgroup1,3

HSCT, hematopoietic stem cell transplantation; NR, not reported.

Duration of Response

Durable treatment for patients who achieve a complete response1,2

The majority of responders were still in ongoing response at JULIET 14-month (NEJM) and 9.4-month (USPI) analyses.

JULIET 14-MONTH NEJM ANALYSIS1

Median DOR was not reached (95% CI, 10-NE).

Duration of response in JULIET clinical trial at 14 months Duration of response in JULIET clinical trial at 14 months

CR + PR.
DOR was measured from date of first objective response to date of progression or death from relapse.1

JULIET 9.4-MONTH USPI ANALYSIS2

Median DOR was not reached. For patients who achieved a PR, median DOR was 3.4 months.

Overall Survival

Median OS was not reached in patients who achieved a CR1

There was a 90% estimated probability of survival at 12 months in patients who achieved a CR.

Overall survival in JULIET clinical trial at 14 months Overall survival in JULIET clinical trial at 14 months

• OS was a secondary efficacy end point of the global phase 2 pivotal trial
• Median OS of 12 months for all infused patients (95% CI, 7-NE)
• OS data are not in the USPI and should be interpreted with caution in a single-arm trial. The statistical significance of OS is not known

NE, not evaluable.

References: 1. 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. 2. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 3. Data on file. CTD Clinical Study Document 2.7.3 Summary of Clinical Efficacy 30-day Update. Novartis Pharmaceuticals Corp; 2017.

 

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 78 (74%) of the 106 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 time to onset was 3 days (range: 1-51), and in only 2 patients was onset after Day 10. The median time to resolution was 8 days (range: 1-36).

Of the 78 patients with r/r DLBCL who had CRS, 16 (21%) received systemic tocilizumab or corticosteroids. Six (8%) received a single dose of tocilizumab, 10 (13%) received 2 doses of tocilizumab, and 10 (13%) received corticosteroids in addition to tocilizumab. Two patients 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 history of CRS in the setting of stable to progressive underlying disease, 1 of whom developed bowel necrosis. Among r/r DLBCL patients with CRS, key manifestations included fever (90%), hypotension (47%), hypoxia (35%), and tachycardia (14%). 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 2 doses of tocilizumab are available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS 2-3 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. Risk factors for developing severe CRS in r/r DLBCL are unknown.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 62 (58%) of the 106 patients with r/r DLBCL following treatment with KYMRIAH, including ≥ grade 3 in 18% of patients. Among KYMRIAH clinical trial patients who had a neurological toxicity, 88% occurred within 8 weeks following KYMRIAH infusion. Median time to the first event was 6 days from infusion (range: 1-359), and the median duration was 14 days for patients with r/r DLBCL. Resolution occurred within 3 weeks in 61% 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 (6%), anxiety (9%), sleep disorders (9%), dizziness (11%), tremor (7%), and peripheral neuropathy (8%). Other manifestations included seizures, mutism, and aphasia.

Monitor patients for neurological events, specifically 2-3 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.

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

Serious Infections: Infections, including life-threatening or fatal infections, occurred in 95 (55%) of 174 KYMRIAH clinical trial patients after KYMRIAH infusion. Fifty-eight patients (33%) 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. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before cell collection 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 (40%) and neutropenia (25%) among 106 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 (IgG) related to B-cell aplasia can occur in patients with a complete remission after KYMRIAH infusion. Hypogammaglobulinemia was reported in 14% 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 viral vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live virus 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 (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. 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, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache. 

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