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 Study Design

JULIET was an open-label, multicenter, single-arm, global Phase II trial of tisagenlecleucel in 115 adult patients with DLBCL who have relapsed or are refractory to ≥2 prior lines of therapy (NCT02445248).1,2


JULIET Baseline Characteristics

PATIENT BASELINE CHARACTERISTICS WERE CONSISTENT ACROSS THE USPI AND UPDATED ANALYSES1-3,5

Patient Demographics (JULIET 9.4 month analysis, N=68)1
• Aged 22-74 years (median, 56 years)
• Progressive disease after autologous stem cell transplant (ASCT) or were ineligible for transplant (49% underwent ASCT)

Inclusion/Exclusion Criteria1,2
• Histologically confirmed DLBCL (78% DLBCL not otherwise specified [NOS], 22% transformed follicular lymphoma [tFL])
• ≥2 prior lines of therapy (median, 3)
   – 56% of patients had refractory disease and 44% relapsed after their last therapy
• No prior anti-CD19 therapy or active central nervous system (CNS) involvement

End Points2
Primary: Best overall response rate (ORR) (complete response [CR] + partial response [PR])a
Key secondary: Duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety

Chemotherapy1
Bridging: 90% of patients
Lymphodepleting: 93% (107/115) 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 disposition1-3,6,7

Flow chart of efficacy analysis data set size

EAS, efficacy analysis set; FAS, full analysis set; NEJM, New England Journal of Medicine; USPI, United States Prescribing Information.

  1. Independent review committee (IRC) responses based on the Lugano Classification with a null hypothesis of ORR ≤20%.1
  2. At the 32.6-month data cut, the enrollment was completed, and there were no infusions pending.3
  3. The 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) with a data cutoff date of July 1, 2019.3
  4. Patients 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.1
  5. The first 92 patients who received KYMRIAH manufactured in the United States and completed at least 3 months’ follow-up or discontinued earlier.1
  6. Patients pending infusion at the time of data cutoff, September 6, 2017.7
  7. Patients were identified and excluded from the analysis because the treatment effect of KYMRIAH alone could not be determined.1

Overall Response Rate

KYMRIAH DELIVERS STRONG EFFICACY WITH DURABLE RESPONSES IN PATIENTS WITH R/R DLBCL1

Overall response rate in JULIET clinical trial at 40.3

 

Persistence based on pharmacokinetics1
In adult patients with r/r DLBCL who achieved a CR, KYMRIAH was present for up to 18 months in peripheral blood and 9 months in bone marrow.


Duration of Response

KYMRIAH IS A DURABLE TREATMENT WITH 60% OF PATIENTS STILL IN RESPONSE AT MONTH 40.37

The median duration of response has not been reached in both the overall and CR patient population in the 40.3-month analysis.7

Duration of response in JULIET clinical trial at 40.3 months
  1. CR + PR.
  2. DOR was measured from date of first objective response to date of progression or death from relapse.1


JULIET 9.4-MONTH USPI ANALYSIS1

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


Progression-Free Survival

MORE THAN 60% OF PATIENTS WHO REACHED A CR AT MONTH 3 WITH KYMRIAH (n=37) WERE PROGRESSION-FREE AT 3 YEARS

Progression-free survival in JULIET clinical trial at 40.3 months

PFS was a secondary efficacy end point of the JULIET trial, and is not included in the Prescribing Information3. PFS data should be interpreted with caution in a single arm trial, as the statistical significance is unknown.

  • Median PFS was not reached for patients achieving complete response at Month 3 (n=37)6
  • Median PFS was 2.9 months (95% CI, 2.3–5.2) for all infused patients8
  • In a JULIET post hoc analysis, 38.2% of patients who received Flu/Cy (n=85) lymphodepleting chemotherapy were progression free at 2 years9
  • Alternate lymphodepleting chemotherapy (bendamustine 90mg/m2 IV daily for 2 days) was used if a patient experienced a previous grade 4 hemorrhagic cystitis or demonstrated resistance to a previous Cy-containing regimen10,k
  1. 115 patients were infused with KYMRIAH (99 in the main cohort and 16 in cohort A), for this data cut n=115 patients.3,8
  2. Eight patients in JULIET received no lymphodepleting chemotherapy.10

Overall Survival

MEDIAN OS WAS NOT REACHED FOR PATIENTS WITH A COMPLETE RESPONSE IN THE 40.3 MONTH ANALYSIS7

36% of all patients infused with KYMRIAH are still alive at 3 years.7

Overall survival in JULIET clinical trial at 40.3 months

OS was a secondary end point of the JULIET trial and is not included in the Prescribing Information. OS data should be interpreted with caution in a single arm trial, as the statistical significance is unknown

• Median time of survival from infusion was 11.1 months (95% CI: 6.64, 23.85) at 40.3 months (n=115) for all patients and not reached for patients in CR

  1. 115 patients were infused with KYMRIAH (99 in the main cohort and 16 in cohort A); for this data cut n=115 patients.3

 

KYMRIAH DEMONSTRATED CONSISTENT RESPONSE RATES REGARDLESS OF CLINICAL CHARACTERISTICS2,7

KYMRIAH demonstrated consistent response rates across high-risk patient subgroups with non-Hodgkin lymphoma that have relapsed or are refractory after ≥2 lines of systemic therapy.2,7

Overall response rate by subgroup chart

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

References: 1. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. 2. 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. 3. Data on file. CTL019C2201. 30 month follow-up report. Novartis Pharmaceuticals Corp; December 11, 2019. 4. Data on file. CTL019B2202 Interim Clinical Study Report. Novartis Pharmaceuticals Corp; September 22, 2017. 5. Bachanova V, Westin J, Tam C, et al. Correlative analyses of cytokine release syndrome and neurological events in tisagenlecleucel-treated relapsed/refractory diffuse large B-cell lymphoma patients. Presented at: International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 254. 6. Jaeger U, Bishop MR, Salles G, et al. Myc expression and tumor-infiltrating T cells are associated with response in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) treated with tisagenlecleucel in the JULIET Trial. Presented at: 62nd American Society of Hematology Annual Meeting; December 5-8, 2020; Poster 1194. 7. Data on file. CTD Clinical Study Document 2.7.4 Summary of Clinical Efficacy 30-day Update. Study C2201. Novartis Pharmaceuticals Corp; 2017. 8. Data on file. CTL019C2201. Progression Free Survival Data Cut. Novartis Pharmaceuticals Corp; July 1, 2019. 9. Jaeger U, Bishop MR, Salles G, et al. Myc expression and tumor-infiltrating T cells are associated with response in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) treated with tisagenlecleucel in the JULIET Trial. Presented at: Transplantation and Cellular Therapy Annual Meeting; February 8-12, 2021; Poster 212. 10. Andreadis C, Tam CS, Borchmann P, et al. Correlation of bridging and lymphodepleting chemotherapy with clinical outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma treated with tisagenlecleucel. 61st American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Poster 2883.

 

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.