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.

Safety Profile

Adverse Reactions


Selected Adverse Reactions (≥10%) Following Treatment in the 4.8-Month Analysis From the USPI1*

 

Adverse ReactionAll Grades, (%)Grades 3 or Higher, (%)
  (N=68) (N=68)

Blood and lymphatic system disorders

Febrile Neutropenia

37 37

Cardiac disorders

Tachycardiaa

26 4

Gastrointestinal disorders

Nausea

26 3

Diarrhea

26 1

Vomiting

26 1

Constipation

18 0

Abdominal painb

16 3

General disorders and administration site conditions

Pyrexia

40 15

Fatiguec

25 0

Edemad

21 1

Chills

10 0

Paine

18 3

Immune system disorders

Cytokine release syndrome

79 49

Hypogammaglobulinemiaf

43 7

Infections and infestations

Infections–pathogen unspecified

41 16

Viral infectious disorders

26 18

Bacterial infectious disorders

19 13

Fungal infectious disorders

13 7

Investigations

International normalized ratio increased

13 0

Metabolism and nutrition disorders

Decreased appetite

37 15

Fluid overload

10 7

Musculoskeletal and connective tissue disorders

Myalgia

15 0

Arthralgia

12 1

Back pain

10 3

Nervous system disorders

Headacheg

37 3

Encephalopathyh

34 10

Psychiatric disorders

Deliriumi

21 4

Anxiety

13 3

Sleep disordersj

10 0

Renal and urinary disorders

Acute kidney injuryk

24 15

Respiratory, thoracic, and mediastinal disorders

Hypoxia

24 18

Coughl

21 0

Dyspneam

16 12

Pulmonary edema

16 10

Tachypnea

12 6

Pleural effusion

10 4

Nasal congestion

10 0

Skin and subcutaneous tissue disorders

Rashn

16 1

Vascular disorders

Hypotension

31 22

Hypertension

19 6

 

  • No new safety signals identified at median follow-up of 24 months (N=79)2

 

 NR, not reported.

*Table includes only nonlaboratory terms as reported in the Prescribing Information.

aTachycardia includes tachycardia and sinus tachycardia.
bAbdominal pain includes abdominal pain and abdominal pain upper.
cFatigue includes fatigue and malaise.
dEdema includes face edema, generalized edema, localized edema, and edema peripheral.
ePain includes pain and pain in the extremity.
fHypogammaglobulinemia includes hypogammaglobulinemia, immunoglobulins (Ig) decreased, blood IgG decreased, blood IgA decreased, and blood IgM decreased.
gHeadache includes headache and migraine.
hEncephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, and automatism.
iDelirium includes delirium, agitation, hallucination, hallucination visual, irritability, and restlessness.
jSleep disorders includes sleep disorders, insomnia, and nightmare.
kAcute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal tubular necrosis, and blood creatinine increased.
lCough includes cough and productive cough.
mDyspnea includes dyspnea, respiratory distress, and respiratory failure.
nRash includes rash, rash maculopapular, rash papular, and rash pruritic.

Safety Results From CHP 9593

  • The majority (89.3%) of patients with ‭non-CNS3 ALL in CHP 959 experienced at least 1 serious adverse event any time after CTL019 infusion‬‬‬‬
  • The most common (incidence ‭greater than or equal to 20%, all grades) serious adverse events regardless of study drug relationship were CRS (82.1%), febrile neutropenia (71.4%), hypotension (39.3%), encephalopathy (26.8%), and pyrexia (23.2%)
  • The most common (incidence greater than 30%, all grades) adverse events regardless of study drug relationship in the non-CNS3 ALL group were decreased white blood cell count (WBC; 94.6%), decreased hemoglobin (92.9%), decreased neutrophil count (91.1%), CRS (89.3%), decreased platelet count (87.5%), lymphopenia (82.1%), febrile neutropenia (78.6%), vomiting (78.6%), aspartate aminotransferase (AST) increased (75.0%), headache (75.0%), nausea (75.0%), alanine aminotransferase (ALT) increased (71.4%), decreased appetite (69.6%), hypogammaglobulinemia (66.1%), diarrhea (57.1%), cough (55.4%), hypotension (51.8%), pain (48.2%), tachycardia (46.4%), fatigue (44.6%), chills (39.3%), increased blood creatinine (35.7%), pyrexia (35.7%), activated partial thromboplastin time prolonged (33.9%), hyperphosphatemia (33.9%), and abdominal pain (32.1%)
  • The most frequently reported (in at least 30% of patients) grade 3/4 adverse events by preferred term, regardless of study drug relationship, were febrile neutropenia (78.6%), decreased neutrophil count (69.6%), lymphopenia (67.9%), decreased WBC count (62.5%), decreased platelet count (48.2%), CRS (46.4%), decreased appetite (35.7%), hypotension (32.1%), decreased hemoglobin (30.4%) and increased ALT (30.4%)‬‬‬‬

 

Warnings and Precautions

WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH® (tisagenlecleucel). 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

Most side effects, including serious adverse reactions, occurred primarily within the first 8 weeks following a single KYMRIAH infusion.4

Select each adverse reaction listed below to view more information.

  • In the global phase 2 pivotal trial, onset of CRS occurred a median of 3 days after the infusion (range: 1 to 51 days), with a median duration of 8 days. Only 2 patients had CRS onset after Day 10 (N=68)1,4
    • 77% of patients experienced some degree of CRS within 8 weeks of KYMRIAH infusion4
    • Grade 3 CRS occurred in 21% of patients in the global phase 2 pivotal trial within 8 weeks postinfusion; grade 4 CRS occurred in 25% of patients4
    • CRS can be managed effectively using an algorithm; please refer to the KYMRIAH Risk Evaluation and Mitigation Strategy (REMS) program materials for details1
  • Key manifestations of CRS may include fever, hypotension, hypoxia, and tachycardia1
    • CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy
  • Risk factors for severe CRS are high preinfusion tumor burden (>50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes1
    • In a retrospective analysis of a subset in the single-site phase 1/2 supportive CHP 959 trial, baseline disease burden was predictive of the severity of CRS5

CHP 959 (N=25)5

CHP 959 trial patient cohorts CHP 959 trial patient cohorts

CRi, complete remission with incomplete blood count recovery; NR, no response.

Based on baseline disease burden in bone marrow after lymphodepleting chemotherapy and before infusion of 25 pediatric trial patients. Median follow-up, 7 months (range: 1 to 24). Horizontal lines indicate medians.5

Severe CRS was defined as hypotension requiring the use of 2 or more vasopressors or respiratory failure requiring mechanical ventilation.5

  • The median time to the first neurologic event was 6 days from infusion, with a median duration of 6 days for patients with r/r B-cell ALL (N=68)1
  • Grade 3 neurologic events occurred in 13% of patients in the global phase 2 pivotal trial within 8 weeks postinfusion; there were no instances of grade 4 neurotoxicity4
  • Severe neurologic events occurred more frequently in patients with higher grade cytokine release syndrome4
  • The majority of neurologic events occurred within 8 weeks following KYMRIAH infusion4
  • Infectious risk in relapsed/refractory B-cell ALL is significantly elevated due to disease- and chemotherapy-induced neutropenia and prior infectious exposures6
    • Grade 3 infections occurred in 21% of patients in the global phase 2 pivotal trial within 8 weeks postinfusion; grade 4 infections occurred in 3% of patients4
    • Several severe infections occurred in patients prior to and after KYMRIAH infusion, and were associated with prolonged neutropenia: among 40 patients with grade 3 or 4 neutropenia unresolved by Day 28, 45% experienced grade 3 or 4 infection, which started at least 28 days postinfusion4
  • Grade 3 febrile neutropenia occurred in 32% of patients in the global phase 2 pivotal trial within 8 weeks postinfusion; grade 4 febrile neutropenia occurred in 3% of patients4
  • All responding patients had B-cell aplasia4
  • Grade 3 hypogammaglobulinemia occurred in 3% of patients in the global phase 2 pivotal trial within 8 weeks of infusion; there were no instances of grade 4 hypogammaglobulinemia7
  • After KYMRIAH, patients may receive immunoglobulin replacement for an indefinite amount of time1

The above listing does not include all potential side effects of KYMRIAH. Please be vigilant in monitoring all patients administered KYMRIAH for adverse reactions, and manage accordingly.

Cytokine Release Syndrome Treatment Algorithm

CRS is managed clinically according to the following algorithm.1

CRS SeverityManagement
Prodromal syndrome:
Low-grade fever, fatigue, anorexia
Observe in person; exclude infection; administer antibiotics per local guidelines if neutropenic; provide symptomatic support.
CRS requiring mild intervention (one or more of the following):
  • High fever
  • Hypoxia
  • Mild hypotension
Administer antipyretics, oxygen, intravenous fluids and/or low-dose vasopressors as needed.

CRS requiring moderate to aggressive intervention (one or more of the following):

  • Hemodynamic instability despite intravenous fluids and vasopressor support
  • Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen requirement including high-flow oxygen and/or need for mechanical ventilation
  • Rapid clinical deterioration
  • Administer high-dose or multiple vasopressors, oxygen, mechanical ventilation, and/or other supportive care as needed
  • Administer tocilizumab
    • Patient weight less than 30 kg: 12 mg/kg intravenously over 1 hour
    • Patient weight greater than or equal to 30 kg: 8 mg/kg intravenously over 1 hour (maximum dose 800 mg)

Repeat tocilizumab as needed at a minimum interval of 8 hours if there is no clinical improvement.
If no response to second dose of tocilizumab, consider a third dose of tocilizumab or pursue alternative measures for treatment of CRS.

Limit to a maximum total of 4 tocilizumab doses.

  • If no clinical improvement within 12 to 18 hours of the first tocilizumab dose, or worsening at any time, administer methylprednisolone 2 mg/kg as an initial dose, then 2 mg/kg per day until vasopressors and high-flow oxygen are no longer needed, then taper

 

References: 1. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 2. Grupp SA, Maude SL, Rives S, et al. Updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia. Presented at: 60th American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. 3. Data on file. Study CTL019B2101J. Novartis Pharmaceuticals Corp; Dec 2016. 4. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. 5. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517. 6. Data on file. Study CTL019B2202. Novartis Pharmaceuticals Corp; Sept 2017. 7. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia [Supplemental Appendix]. N Engl J Med. 2018;378(5):1-27. doi:10.1056/NEJMoa1709866.

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, 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 54 (79%) of the 68 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 33 (49%) of patients. The median time to onset of CRS in KYMRIAH trials 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 54 patients with r/r ALL who had 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 (eg, methylprednisolone).

Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, 1 patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Among patients with r/r ALL who had CRS, key manifestations included fever (96%), hypotension (67%), hypoxia (20%), and tachycardia (30%). 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 including pulmonary toxicity, cardiac toxicity, or hypotension, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden.

Ensure that 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 remain within proximity of the health care facility for at least 4 weeks following infusion and 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 severe CRS are high pre-infusion tumor burden (≥50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 49 (72%) of the 68 patients with r/r ALL following treatment with KYMRIAH including ≥ grade 3 in 21% of patients. Among patients who had a neurological toxicity, 88% occurred within 8 weeks after KYMRIAH infusion. Median time to the first event was 6 days (range: 1-359) from infusion, and the median duration was 6 days for patients with r/r ALL. 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 r/r ALL studies included headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%), sleep disorders (10%), dizziness (6%), tremor (9%), and peripheral neuropathy (4%). Other manifestations included seizures, mutism 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.

Serious Infections: Infections, including life-threatening or fatal infections, occurred in 95 (55%) of 174 patients after infusion with KYMRIAH in clinical trials. Fifty-eight (33%) patients experienced grade ≥3 infections, including fatal infections in 2 (3%) patients with r/r ALL after KYMRIAH infusion. 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 37% of patients with r/r ALL 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 ALL, ≥ grade 3 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 ≥ grade 3 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. Hypogammaglobulinemia was reported in 43% of patients with r/r ALL. 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 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, 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%) in patients with r/r ALL were cytokine release syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, edema, cough, and delirium.

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