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

 

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; 11 (13%) patients received corticosteroids in addition to toculizumab.1

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

aMedian follow-up from time of infusion.

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,b

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

Bleeding episodesd

32 10

Cardiac disorders

Arrhythmiae

22 4

Gastrointestinal disorders

Vomiting

32 1

Diarrhea

29 1

Nausea

27 3

Abdominal painf

18 3

Constipation

18 0

General disorders and administration site conditions

Fever

42 13

Paing

25 3

Fatigueh

23 0

Edemai

19 1

Immune system disorders

Cytokine release syndrome

77 48

Hypogammaglobulinemiaj

53 13

Infections and infestations

Infections–pathogen unspecified

57 27

Viral infectious disorders

38 22

Bacterial infectious disorders

27 16

Fungal infectious disorders

15 9

Investigations

Serum ferritin increased

10 3

Metabolism and nutrition disorders

Decreased appetite

38 15

Hypocalcemia

20 6

Musculoskeletal and connective tissue disorders

Back pain

13 4

Myalgia

13 0

Arthralgia

10 1

Nervous system disorders

Headachek

35 3

Encephalopathyl

30 9

Psychiatric disorders

Deliriumm

19 4

Anxiety

16 3

Sleep disordern

11 0

Renal and urinary disorders

Acute kidney injuryo

22 14

Respiratory, thoracic, and mediastinal disorders

Coughp

27 0

Hypoxia

25 20

Dyspneaq

18 13

Pulmonary edema

15 9

Nasal congestion

11 0

Oropharyngeal pain

10 0

Pleural effusion

10 4

Tachypnea

10 5

Skin and subcutaneous tissue disorders

Rashr

18 1

Vascular disorders

Hypotension

29 20

Hypertension

19 5

 

cTable includes only nonlaboratory terms as reported in the prescribing information.

dBleeding episodes include anal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, conjunctival hemorrhage, contusion, cystitis hemorrhagic, disseminated intravascular coagulation, epistaxis, gastrointestinal hemorrhage, gingival bleeding, hemarthrosis, hematemesis, hematuria, hemoptysis, melena, menorrhagia, mouth hemorrhage, peritoneal hematoma, petechiae, pharyngeal hemorrhage, purpura, retinal hemorrhage, and vaginal hemorrhage.
eArrhythmia includes tachycardia.
fAbdominal pain includes abdominal pain and abdominal pain upper.
gPain includes pain and pain in extremity.
hFatigue includes fatigue and malaise.
iEdema includes face edema, generalized edema, localized edema, and edema peripheral.
jHypogammaglobulinemia includes hypogammaglobulinemia, immunoglobulins decreased, blood immunoglobulin G decreased, blood immunoglobulin A decreased, blood immunoglobulin M decreased, immunodeficiency, and immunodeficiency common variable.
kHeadache includes headache and migraine.
lEncephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, and automatism.
mDelirium includes delirium, agitation, hallucination, hallucination visual, irritability, and restlessness.
nSleep disorder includes sleep disorder, insomnia, and nightmare.
oAcute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal tubular necrosis, and blood creatinine increased.
pCough includes cough and productive cough.
qDyspnea includes dyspnea and respiratory distress, respiratory failure.
rRash includes dermatitis, rash, rash maculo-papular, rash papular, and rash pruritic.


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.

Ensure 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 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, 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, 83% 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 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 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 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.

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).

 

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 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 GM-CSF, 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 (NATs) 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 cytokine release syndrome, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, bleeding episodes, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, fatigue, acute kidney injury, and arrhythmia.

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 Severity Management
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; 2021. 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.

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.

Ensure 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 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 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, 83% 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 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 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 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 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 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 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 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 (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%) in patients with r/r ALL were cytokine release syndrome, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, bleeding episodes, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, fatigue, acute kidney injury, and arrhythmia.

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