IMPORTANT SAFETY INFORMATION (continued)
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 r/r ALL and 78 (74%) of the 106 patients with r/r DLBCL
receiving KYMRIAH, including ≥ grade 3 (Penn Grading
System) in 49% of patients with r/r ALL and in 23% of patients
with r/r DLBCL. 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 54 patients with r/r ALL who had CRS, 27 (50%)
received tocilizumab; 7 (13%) received 2 doses of tocilizumab,
3 (6%) received 3 doses of tocilizumab and 14 (26%) received
addition of corticosteroids (eg, methylprednisolone).
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.
Five deaths occurred within 30 days of KYMRIAH infusion.
One patient with r/r ALL 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. Of the 3 patients
with r/r DLBCL who died within 30 days of infusion, all
had history of CRS in the setting of stable to progressive
underlying disease, 1 of whom developed bowel necrosis.
Among patients with CRS, key manifestations included
fever (92% r/r ALL and r/r DLBCL), hypotension (67% r/r
ALL; 47% r/r DLBCL), hypoxia (20% r/r ALL; 35% r/r DLBCL),
and tachycardia (30% r/r ALL; 14% r/r DLBCL). 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, active graft vs host disease, or
worsening of leukemia burden.
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 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 in the r/r ALL population 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. Risk factors for developing
severe CRS in r/r DLBCL are unknown.
Neurological Toxicities: Neurological toxicities, including
severe or life-threatening reactions, occurred in 49 (72%) of
the 68 patients with r/r ALL and 62 (58%) of the 106 patients
with r/r DLBCL following treatment with KYMRIAH, including
≥ grade 3 in 21% of patients with r/r ALL and 18% of patients
with r/r DLBCL. Among 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 6 days
for patients with r/r ALL and 14 days for patients with
r/r DLBCL. Resolution occurred within 3 weeks in 79% of
patients with r/r ALL and 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 with
KYMRIAH included headache (37% r/r ALL; 21% r/r DLBCL),
encephalopathy (34% r/r ALL; 16% r/r DLBCL), delirium (21%
r/r ALL; 6% r/r DLBCL), anxiety (13% r/r ALL; 9% r/r DLBCL),
sleep disorders (10% r/r ALL; 9% r/r DLBCL), dizziness (6%
r/r ALL; 11% r/r DLBCL), tremor (9% r/r ALL; 7% r/r DLBCL),
and peripheral neuropathy (4% r/r ALL; 8% r/r DLBCL). 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 Evalua tion 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 with r/r
ALL or with r/r DLBCL after KYMRIAH infusion. Fifty-eight
patients (33%) experienced grade ≥3 infections, including fatal
infections in 2 patients (3%) with r/r ALL and 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.