For:
Pediatric and Young Adult r/r B-cell ALL
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…+
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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

 

A CONSISTENT SAFETY PROFILE THROUGH 24-MONTH FOLLOW-UP

Treatment with KYMRIAH® (tisagenlecleucel) involves coordination of care with a KYMRIAH Treatment Center. After it is determined that your patient is eligible for and prescribed KYMRIAH, you and the treatment center will both contribute to your patient’s care, so ongoing communication is key. Following KYMRIAH infusion, routine long-term monitoring is required to treat potential KYMRIAH-associated side effects.

Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following infusion with KYMRIAH.1,a With longer-term follow-up, no new adverse events were detected.2 Key manifestations of CRS included fever, hypotension, hypoxia, tachycardia, and may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy.1

Rates of CRS in ELIANA clinical trial

Median time to first event, 3 days from infusion (range, 1-22; 1 patient with onset after Day 10) Median time to resolution, 8 days (range, 1-36)1

Monitor patients 2 to 3 times during the first week and for at least 4 weeks following KYMRIAH infusion at the certified health care facility for signs and symptoms of CRS.1

  • Ensure that at least 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH1
  • Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time1
  • Instruct patients to remain within proximity of the certified health care facility for at least 4 weeks following infusion1
  • At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated1

In the ELIANA trial: to manage CRS, 10 (16%) patients received 2 doses of tocilizumab and 3 (5%) patients received 3 doses of tocilizumab.1

ALL, acute lymphoblastic leukemia; DLBCL, diffuse large B-cell lymphoma; USPI, United States Prescribing Information.

aMedian follow-up from time of infusion1.

Imagery supplied by Getty Images.


Neurological Events

After infusion with KYMRIAH, patients reported occurrence of neurological events (NEs). Onset of NEs can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. The majority of events occurred within 8 weeks of infusion. Most common NEs included: headache, encephalopathy, delirium, anxiety, sleep disorders, dizziness, tremor, peripheral neuropathy, seizures, mutism, aphasia.1

Rates of NEs in ELIANA clinical trial

Median time to first event, 6 days from infusion (range, 1-301).1

bMedian follow-up from time of infusion.1


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. 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


Adverse Reactions

Selected Adverse Reactions (≥10%) Following Treatment (24-month follow-up)1,c

 

Adverse Reaction All Grades, (%) Grades 3 or Higher, (%)
  (N=79)1 (N=79)1

Blood and lymphatic system disorders

Febrile neutropenia

34 34

Cardiac disorders

Tachycardiad

24 4

Gastrointestinal disorders

Vomiting

32 1

Diarrhea

29 1

Nausea

27 3

Abdominal paine

18 3

Constipation

18 0

General disorders and administration site conditions

Fever

42 13

Painf

25 3

Fatigueg

23 0

Edemah

23 8

Immune system disorders

Cytokine release syndrome

77 48

Hypogammaglobulinemiai

53 13

Infections and infestations

Infections–pathogen unspecified

57 27

Viral infectious disorders

37 22

Bacterial infectious disorders

29 16

Fungal infectious disorders

15 9

Metabolism and nutrition disorders

Decreased appetite

38 15

Hypocalcemia

20 6

Hyperferritinemiaj

10 3

Musculoskeletal and connective tissue disorders

Musculoskeletal paink 

32 4

Arthralgia

14 1

Nervous system disorders

Headachel

35 3

Encephalopathym

30 9

Psychiatric disorders

Deliriumn

19 4

Anxiety

17 3

Sleep disordero

11 0

Renal and urinary disorders

Acute kidney injuryp

22 14

Respiratory, thoracic, and mediastinal disorders

Coughq

27 0

Hypoxia

25 20

Dyspnear

19 14

Pulmonary edema

15 9

Nasal congestion

11 0

Oropharyngeal pain

10 0

Pleural effusion

10 4

Tachypnea

10 5

Skin and subcutaneous tissue disorders

Rashs

18 1

Vascular disorders

Hemorrhaget

32 10

Hypotension

29 20

Hypertension

19 5

 

cTable includes only nonlaboratory terms as reported in the Prescribing Information.

dTachycardia includes sinus tachycardia and tachycardia.
eAbdominal pain includes abdominal pain, abdominal pain upper.
fPain includes pain and pain in extremity.
gFatigue includes fatigue and malaise.
hEdema includes face edema, fluid overload, generalized edema, localized edema, edema peripheral.
iHypogammaglobulinemia includes hypogammaglobulinemia, immunoglobulins decreased, blood immunoglobulin G decreased, blood immunoglobulin A decreased, blood immunoglobulin M decreased, immunodeficiency, immunodeficiency common variable.
jHyperferritinemia includes serum ferritin increased.
kMusculoskeletal pain includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and non-cardiac chest pain.
lHeadache includes headache and migraine.
mEncephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, and automatism. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms.
nDelirium includes delirium, agitation, hallucination, hallucination visual, irritability, restlessness.
oSleep disorder includes sleep disorder, insomnia, and nightmare.
pAcute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, qenal tubular dysfunction, renal tubular necrosis, and blood creatinine increased.
qCough includes cough and productive cough.
rDyspnea includes acute respiratory failure, dyspnea, respiratory distress, and respiratory failure.
sRash includes dermatitis, rash, rash maculo-papular, rash papular, and rash pruritic.
tHemorrhage includes anal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, conjunctival hemorrhage, contusion, cystitis hemorrhagic, disseminated intravascular coagulation, epistaxis, gastrointestinal hemorrhage, gingival bleeding, hemarthrosis, hematemesis, hematuria, hemoptysis, heavy menstrual bleeding, melena, mouth hemorrhage, peritoneal hematoma, petechiae, pharyngeal hemorrhage, purpura, retinal hemorrhage, vaginal hemorrhage.


Select each adverse reaction listed below to view more information.

CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 61 (77%) of the 79 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 48% of patients. The median times to onset and resolution of CRS for patients with r/r ALL were 3 days (range: 1-22; 1 patient with onset after Day 10) and 8 days (range: 1-36), respectively.

Of the 61 patients with r/r ALL who had CRS, 31 (51%) received tocilizumab; 10 (16%) patients received 2 doses of tocilizumab, 3 (5%) patients received 3 doses of tocilizumab, and 17 (28%) patients received addition of corticosteroids (eg, methylprednisolone).

Two deaths occurred in patients with r/r ALL within 30 days of KYMRIAH infusion. One patient died with CRS and progressive leukemia, and 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 (93%), hypotension (69%), hypoxia (57%), and tachycardia (26%). 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.

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.

Ensure that a minimum of 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH. Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurological toxicities, including severe or life-threatening reactions, occurred in 56 (71%) of the 79 patients with r/r ALL following treatment with KYMRIAH including ≥ grade 3 in 22% of patients. Among patients who had a neurological toxicity, 84% occurred within 8 weeks after KYMRIAH infusion. Median time to the first event was 6 days from infusion (range: 1-301), and the median duration was 7 days. Resolution occurred within 3 weeks in 71% of patients. Encephalopathy lasting up to 70 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 r/r ALL studies included headache (35%), encephalopathy (30%), delirium (19%), anxiety (16%), sleep disorders (11%), dizziness (5%), tremor (8%), and peripheral neuropathy (4%). Other manifestations included seizures and aphasia.

Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of neurological toxicities. Rule out other causes of neurological symptoms. Monitor patients for signs or symptoms of neurological toxicities for at least 4 weeks after infusion and treat promptly. Neurological toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms of neurological toxicity occur at any time.

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.

The required components of the KYMRIAH REMS are:

  • Health care facilities that dispense and administer KYMRIAH must be enrolled in the program and comply with the REMS requirements
  • Certified health care facilities must have on-site, immediate access to tocilizumab and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hours after KYMRIAH infusion, if needed for treatment of CRS
  • Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer KYMRIAH are trained in the management of CRS and neurological toxicities

Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH (1-844-459-6742).

HLH/MAS, which can be life-threatening or fatal, has occurred following treatment with KYMRIAH. HLH was reported in 6% (5/79) of patients with r/r ALL (time to onset ranged from 3 to 18 days); all HLH events occurred during ongoing CRS and resolved. Treatment of HLH should be administered as per institutional standards.

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.

Infections, including life-threatening or fatal infections, occurred in 125 (64%) of 194 patients after KYMRIAH infusion. Seventy-seven patients (40%) experienced ≥ grade 3 infections, including fatal infections in 2 patients (3%) 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 34% 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. There is no evidence with manufacturing KYMRIAH for patients with a positive test for HIV or with active HBV or active hepatitis C virus (HCV). Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

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 granulocyte-macrophage colony-stimulating factor, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.

Hypogammaglobulinemia and agammaglobulinemia related to B-cell aplasia can occur in patients after KYMRIAH infusion. Hypogammaglobulinemia was reported in 53% 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 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.

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.

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 may yield false positive results in patients who have received KYMRIAH.

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.

The most common adverse reactions (>20%) in patients with r/r ALL were CRS, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, hemorrhage, musculoskeletal pain, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, tachycardia, edema, fatigue, and acute kidney injury.

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 Grade6 Symptomatic treatment Tocilizumab Corticosteroids

Grade 1

Mild symptoms requiring symptomatic treatment only (eg, low grade fever, fatigue, anorexia, etc)
Exclude other causes (eg, infection) and treat specific symptoms (eg, with antipyretics, antiemetics, analgesics, etc) In patients with persistent (>3 days) or refractory fever, consider managing as grade 2 CRS7. Not applicable.

Grade 2

Symptoms require and respond to moderate intervention. Oxygen requirement <40% or hypotension responsive to fluids or low dose of one vasopressor or grade 2 organ toxicity

Antipyretics, oxygen, intravenous fluids and/or low dose vasopressors as needed. Administer tocilizumabu intravenously over 1 hour:
  • 8 mg/kg (max. 800 mg) if body weight ≥30 kg
  • 12 mg/kg if body weight <30 kg
If no improvement after first dose, repeat every 8 hours (limit to a maximum of 3 dosages in 24 hours period; maximum total of 4 doses).

If no improvement within 24 hours of tocilizumab, administer a daily dose of 2 mg/kg/day methylprednisolone intravenously (or equivalent) until vasopressor and oxygen no longer needed, then taper.

If not improving, manage as appropriate grade below.

Grade 3

Symptoms require and respond to aggressive intervention. Oxygen requirement ≥40% or hypotension requiring high dose or multiple vasopressors or grade 3 organ toxicity or grade 4 transaminitis

High-flow oxygen. Intravenous fluids, and high-dose or multiple vasopressors. Treat other organ toxicities as per local guidelines

Per grade 2

If not improving, consider alternative therapy.v

Per grade 2

If not improving, manage as grade 4.

Grade 4

Life-threatening symptoms. Requirement for ventilator support or grade 4 organ toxicity (excluding transaminitis)

 

Mechanical ventilation. Intravenous fluids and high-dose vasopressor(s). Treat other organ toxicities as per local guidelines

Per grade 2

If not improving, consider alternative therapy.v

Administer methylprednisolone 1000 mg intravenously one to two times per day for 3 days

If not improving, consider methylprednisolone 1000 mg intravenously two to three times a day or alternate therapy.v

Continue corticosteroids until improvement to grade 1, and then taper as clinically appropriate.

uRefer to tocilizumab Prescribing Information for details.1

vAlternative therapy includes anti-cytokine and anti-T cell therapies as per institutional policy and published guidelines such as (but not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, intravenous immunoglobulin, and anti-thymocyte globulin.1

References: 1. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 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. Abstract 895. 3. Data on file. CTL019B2101J Final Analysis. Novartis Pharmaceuticals Corp; Oct 2018. 4. 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. 5. Data on file. Study CTL019B2202. Novartis Pharmaceuticals Corp; Sept 2017. 6. Lee DW et al. Blood. 2014;124(2):188-195. 7. Santomasso BD et al. J Clin Oncol. 2021;39(35):3978-3992. 

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 61 (77%) of the 79 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 48% of patients. The median times to onset and resolution of CRS for patients with r/r ALL were 3 days (range: 1-22; 1 patient with onset after Day 10) and 8 days (range: 1-36), respectively.

Of the 61 patients with r/r ALL who had CRS, 31 (51%) received tocilizumab; 10 (16%) patients received 2 doses of tocilizumab, 3 (5%) patients received 3 doses of tocilizumab, and 17 (28%) patients received addition of corticosteroids (eg, methylprednisolone).

Two deaths occurred in patients with r/r ALL within 30 days of KYMRIAH infusion. One patient died with CRS and progressive leukemia, and 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 (93%), hypotension (69%), hypoxia (57%), and tachycardia (26%). 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.

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.

Ensure that a minimum of 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH.  Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 56 (71%) of the 79 patients with r/r ALL following treatment with KYMRIAH including ≥ grade 3 in 22% of patients. Among patients who had a neurological toxicity, 84% occurred within 8 weeks after KYMRIAH infusion. Median time to the first event was 6 days from infusion (range: 1-301), and the median duration was 7 days. Resolution occurred within 3 weeks in 71% of patients. Encephalopathy lasting up to 70 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 r/r ALL studies included headache (35%), encephalopathy (30%), delirium (19%), anxiety (16%), sleep disorders (11%), dizziness (5%), tremor (8%), and peripheral neuropathy (4%). Other manifestations included seizures and aphasia.

Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of neurological toxicities. Rule out other causes of neurological symptoms. Monitor patients for signs or symptoms of neurological toxicities for at least 4 weeks after infusion and treat promptly. Neurological toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms of neurological toxicity occur at any time. 

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.

The required components of the KYMRIAH REMS are:

  • Health care facilities that dispense and administer KYMRIAH must be enrolled in the program and comply with the REMS requirements
  • Certified health care facilities must have on-site, immediate access to tocilizumab and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hours after KYMRIAH infusion, if needed for treatment of CRS
  • Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer KYMRIAH are trained in the management of CRS and neurological toxicities

Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH (1-844-459-6742).

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS, which can be life-threatening or fatal, has occurred following treatment with KYMRIAH. HLH was reported in 6% (5/79) of patients with r/r ALL (time to onset ranged from 3 to 18 days); all HLH events occurred during ongoing CRS and resolved. Treatment of HLH should be administered as per institutional standards.

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 patients after KYMRIAH infusion. Seventy-seven patients (40%) experienced ≥ grade 3 infections, including fatal infections in 2 patients (3%) 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 34% 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. There is no evidence with manufacturing KYMRIAH for patients with a positive test for HIV or with active HBV or active hepatitis C virus (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 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 granulocyte-macrophage colony-stimulating factor, 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 53% 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 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 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 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%) in patients with r/r ALL were CRS, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, hemorrhage, musculoskeletal pain, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, tachycardia, edema, fatigue, and acute kidney injury.

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