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.

Efficacy

Clinical Trial Design

The efficacy and safety of KYMRIAH™ (tisagenlecleucel) was established in a global phase 2 clinical trial (ELIANA) of 68 children and young adult patients. 

GLOBAL PHASE 2 PIVOTAL TRIAL (ELIANA)1
(N=68)
Initiated 20152

  • 68 patients were infused and 63 were evaluable for response at 3 months
  • Enrolled patients between 3 and 23 years of age (median age, 12 years)
  • 10% of participants had primary refractory disease
  • Patients received a median of 3 prior therapies,3 with 48% having received 1 stem cell transplant (SCT) and 8% having received 2 SCTs
  • Median time from most recent relapse to KYMRIAH infusion was 3.4 months3

Primary end point: Overall remission rate (ORR)* within 3 months postinfusion

*The trial required remission status to be maintained for at least 28 days without clinical evidence of relapse.

Overall Remission Rate

KYMRIAH helped the majority of patients achieve remission in the global phase 2 pivotal trial. Moreover, 100% of patients who achieved remission were minimal residual disease negative (MRD–), which is a strong marker for positive prognosis.1,4

GLOBAL PHASE 2 PIVOTAL TRIAL1
Primary End Point: ORR at 3 Months

100% of patients in remission (n=52) were MRD–

96% of responders (n=52) achieved remission between Days 26 and 31, with a median time of 29 days

MRD– was defined as MRD by flow cytometry <0.01%.

ORR consisted of complete remission (CR) and complete remission with incomplete blood count recovery (CRi defined as less than 5% of blasts in the bone marrow, no evidence of extramedullary disease, and without full recovery of peripheral blood counts with or without blood transfusion). Remission status was required to be maintained for at least 28 days without clinical evidence of relapse.

§5 patients who were infused with KYMRIAH were excluded from the efficacy set. The efficacy analysis set (N=63) is a subset of the full analysis set which consists of all patients treated with KYMRIAH at least 3 months prior to data cut-off.1,3

 

REMISSION WAS ACHIEVABLE WITH KYMRIAH REGARDLESS OF PATIENTS’ CLINICAL CHARACTERISTICS3

aThe area of each box is proportional to the number of patients in the particular grouping. The 95% CIs are exact Clopper-Pearson CIs calculated for each subgroup.

Duration of Remission and Overall Survival

After treatment with KYMRIAH, 88% of responders did not proceed to SCT.1,3 KYMRIAH is a potentially definitive treatment for patients.

DURATION OF REMISSION3

 

ǁDuration of remission (DOR) was defined as time since onset of CR or CRi to relapse or death due to underlying cancer, whichever is earlier, censoring for new cancer therapy including SCT (n=52).

OVERALL SURVIVAL3

  • Median follow-up of 6.2 months3
  • Overall survival was a secondary efficacy end point of the global phase 2 pivotal trial2
  • Median overall survival data is not in the Prescribing Information, and should be interpreted with caution in a single-arm trial. The statistical significance of overall survival is not known3
  • Approximately 84% (57/68) of patients were still alive (censored) at the data cut-off, and only 2 patients were at risk beyond 16 months3

Overall survival analysis was conducted on full analysis set (n=68).

Patient-Reported Quality of Life

As early as 3 months after KYMRIAH infusion, patients experienced an increase in health-related quality of life. These improvements were sustained through 6 months postinfusion in the global phase 2 pivotal trial.3

QUALITY-OF-LIFE IMPROVEMENTS WERE SUSTAINED THROUGH 6 MONTHSa

  • KYMRIAH led to a decrease in severity of problems related to mobility, self-care, usual activities, pain/discomfort, and anxiety/depression at Months 3 and 6 compared to baseline as assessed via the EQ-5D questionnaire3
  • The quality-of-life study is not part of the Prescribing Information. The PedsQL and EQ VAS models were evaluated and validated in a patient population other than pediatric ALL and, therefore, should be interpreted cautiously

aPatient-reported outcome results are mean values from a study population of patients ≥8 years of age (n=48). Population at each time point is the number of patients with nonmissing score at that time point.3

 

References: 1. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017. 2. Data on file. Study CTL019B2202. Novartis Pharmaceuticals Corp; Sept 2017. 3. Data on file. Study CTL019B. Novartis Pharmaceuticals Corp; Feb 2017. 4. Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual ‭disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood. 2015;126(8):964-971. 5. Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL™* 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr. 2003;3(6):329-341. 6. Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer. Health Qual Life Outcomes. 2007;5:70.‬‬

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.
  • 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.

 

Contraindications

None


Warnings and Precautions

Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. In Study 1, CRS occurred in 79% (54/68) of patients receiving KYMRIAH, including grade 3 or 4 (Penn grading system) CRS in 49% (33/68) of patients. The median time to onset of CRS was 3 days (range: 1-22 days). Of the 54 patients with CRS, 27 (50%) received tocilizumab; 7 (13%) patients received 2 doses of tocilizumab, 3 (6%) patients received 3 doses of tocilizumab and 14 (26%) patients received addition of corticosteroids (e.g. methylprednisolone). The median time to resolution of CRS was 8 days (range: 1-36 days).

Key manifestations of CRS may include high fever, lower than normal blood pressure, difficulty breathing, and may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. Risk factors for severe CRS are high pre-infusion tumor burden, uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes. 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 tocilizumab is available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur. 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, which may be severe or life-threatening, can occur following treatment with KYMRIAH. The majority of neurological toxicities occurred within 8 weeks following KYMRIAH infusion. In Study 1, neurological toxicities within 8 weeks after KYMRIAH infusion occurred in 65% of patients, including grade 3 or 4 neurological toxicities in 18% of patients, and 75% of events resolved within 12 days. The most common neurological toxicities were headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%), and tremor (9%). Other manifestations of neurological toxicities included disturbances in consciousness, disorientation, confusion, agitation, seizures, mutism and aphasia. Monitor patients for neurological events and exclude other causes for 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.

Serious Infections: Serious infections, including life-threatening or fatal infections, occurred in patients after KYMRIAH infusion. In Study 1, infections (all grades) after KYMRIAH infusion occurred in 40 patients (59%), including 24 patients (35%) with grade 3 and 4 infections and 2 patients (3%) with fatal infections. Infections with an unknown pathogen occurred in 41% of patients, viral infections in 26%, bacterial infections in 19%, and fungal infections in 13%. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately. Febrile neutropenia (grade 3 or 4) was also observed in 37% of patients 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. HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis. 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. Grades 3 and 4 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 grades 3 and 4 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 (IgG) can occur in patients with a complete remission after KYMRIAH infusion. In Study 1, 43% of patients had hypogammaglobulinemia. B-cell aplasia is an on-target effect of KYMRIAH and therefore a patient may experience hypogammaglobulinemia for as long as KYMRIAH persists. 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 2 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 leukemia. Monitor life-long 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, 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 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
There are no available data 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 (incidence greater than 20%) are cytokine release syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, bleeding, hypotension, tachycardia, nausea, diarrhea, vomiting, viral infection disorders, hypoxia, fatigue, acute kidney injury, and delirium.

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