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…+
The efficacy and safety of KYMRIAH® (tisagenlecleucel) was evaluated in an open-label, multicenter, single-arm trial (JULIET; NCT02445248). Eligible patients were ≥18 years of age with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL), who received ≥2 lines of chemotherapy, including rituximab and anthracycline, or relapsed following autologous hematopoietic stem cell transplantation (HSCT). The study excluded patients with active central nervous system malignancy, prior allogenic HSCT, an ECOG performance status ≥2, a creatinine clearance <60, alanine aminotransferase >5 times normal, cardiac ejection fraction <45%, or absolute lymphocyte concentration less than 300/µL.
Following 2 to 11 days after completion of lymphodepleting (LD) chemotherapy consisting of either fludarabine (25 mg/m2 IV daily for 3 days) and cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine) or bendamustine (90 mg/m2 IV daily for 2 days), KYMRIAH was administered as a single intravenous infusion. Bridging chemotherapy between leukapheresis and LD chemotherapy was permitted to control disease burden. LD chemotherapy could be omitted if the white blood cell count was <1000 cells/µL. The major efficacy outcome measures were objective response rate per Lugano criteria  as assessed by an independent review committee and duration of response.
Of the 160 patients enrolled, 106 patients received tisagenlecleucel, including 92 patients who received product manufactured in the U.S. and were followed for at least 3 months or discontinued earlier. Eleven out of 160 patients enrolled did not receive tisagenlecleucel due to manufacturing failure. Thirty-eight other patients did not receive tisagenlecleucel, primarily due to death (n=16), physician decision (n=16), and adverse events (n=3).
Of the 92 patients receiving KYMRIAH, 90% received physician’s choice of bridging chemotherapy in the interval between start of screening and KYMRIAH infusion, among whom the median number of bridging chemotherapy regimens was 1 (range: 1 to 5) with 83% of patients receiving ≤2 regimens. A retrospectively identified subgroup of 68 patients was evaluable for the major efficacy outcome measures. Patients included in this subgroup either had no bridging chemotherapy, or had imaging that showed measurable disease after completion of bridging chemotherapy, prior to KYMRIAH infusion. Of the 24 patients not included, 8 had no evidence of disease at baseline prior to KYMRIAH infusion, 15 did not have baseline imaging following bridging chemotherapy, and 1 was excluded because of initial misclassification of a neuroendocrine tumor as DLBCL.
Among the efficacy evaluable population of 68 patients, the baseline characteristics were: median age 56 years (range: 22 to 74 years); 71% male; 90% white, 4% Asian, and 3% black or African American; 78% had primary DLBCL not otherwise specified (NOS) and 22% had DLBCL following transformation from follicular lymphoma, of whom 17% were identified as high grade; and 44% had undergone prior autologous HSCT. The median number of prior therapies was 3 (range: 1 to 6), 56% had refractory disease and 44% relapsed after their last therapy. Ninety percent of patients received LD chemotherapy (66% of patients received fludarabine and 24% received bendamustine) and 10% did not receive any LD chemotherapy. The median time from leukapheresis and cryopreservation to KYMRIAH infusion was 113 days (range: 47 to 196 days). The median dose was 3.5 × 108 CAR-positive viable T cells (range: 1.0 to 5.2 × 108 cells). Seventy-three percent of patients received KYMRIAH in the inpatient setting.
Efficacy was established on the basis of complete response (CR) rate and duration of response (DOR), as determined by an independent review committee (tables below). The median time to first response to KYMRIAH (CR or partial response [PR]) was 0.9 months (range: 0.7 to 3.3 months).
Response Rates in r/r DLBCL in the JULIET Study
Overall Response Rate (ORR) (CR+PR), n (%)(95% CI)
34 (50%)(37.6%, 62.4%)
CR Rate, n (%)(95% CI)
22 (32%)(21.5%, 44.8%)
PR Rate, n (%)(95% CI)
12 (18%)(9.5%, 28.8%)
The median DOR was not reached. Response durations were longer in patients who achieved CR, as compared to patients with a best response of PR (table below). Of the 22 patients who experienced a CR, 9 achieved this status by 1 month, 12 more by Month 3, and the last by Month 6 after KYMRIAH infusion.
Duration of Responsea (Months) in r/r DLBCL in the JULIET Study
|Overall DOR for Responders (Months)||N=34|
|(95% CI)||(5.1, NE)|
|Rangec||(0.03+ to 11.3+)|
|Median Follow-Up (95% CI)b||9.4 (7.9, 10.8)|
|DOR if BOR is CR||N=22|
|(95% CI)||(10.0, NE)|
|Rangec||(1.5+ to 11.3+)|
|DOR if BOR is PR||N=12|
|(95% CI)||(1.0, NE)|
|Rangec||(0.03+ to 11.3+)|
CR, complete response; DOR, duration of response; NE, not estimable; PR, partial response.
aAmong all responders. DOR measured from date of first objective response to date of progression or death from relapse.
bKaplan-Meier estimate in months.
cA + sign indicates a censored value.
Reference: 1. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
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.
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 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.
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.
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.