ASH Clinical News ACN_4.5_FULL_ISSUE_DIGITAL | Page 32

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The most common MDE before or after MM diagnosis was anemia ( 17.9 % and 25.7 %, respectively ). The incidence of MDEs increased over time ( p < 0.001 ), particularly for hypercalcemia ( increased from < 0.2 % in 1991 to 13.2 % in 2006-2010 ) and bone fractures ( increased from 6.6 % to 19.2 %, respectively ).
There were significant differences in all complications at and following diagnosis according to patients ’ race ( p < 0.02 ), with a high incidence among African- Americans for all MDEs except bone fractures , which were highest among whites . These results suggest “ that better MM therapeutics and supportive care lead to less organ damage and possibly
more use of dialysis because of longer survival and a willingness to extend supportive care to more patients ,” the authors wrote .
Cost of care increased significantly by year of diagnosis , despite adjustment for inflation . Drug claims during the first six months after diagnosis increased sharply , from a median of $ 230 between 1991 and 1995 to $ 3,630 between
2006 and 2010 ( ranges not reported ; p < 0.001 ), and total claims increased from $ 5,110 to $ 27,800 , respectively ( p < 0.001 ).
“ There were significant differences in the cost of care by patient race ,” the researchers noted .
During the first six months after an MM diagnosis , median drug claims were highest among African-Americans ($ 1,300 ) and
chemotherapy , during KYMRIAH treatment , and until immune recovery following treatment with KYMRIAH .
Pregnant women who have received KYMRIAH may have hypogamma - globulinemia . Assess immuno globulin levels in newborns of mothers treated with KYMRIAH .
5.8 Secondary Malignancies Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their leukemia . Monitor life-long for secondary malignancies . In the event that a secondary malignancy occurs , contact Novartis Pharmaceuticals Corporation at 1-844-4KYMRIAH to obtain instructions on patient samples to collect for testing .
5.9 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 KYMRIAH 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 .
6 ADVERSE REACTIONS Most common adverse reactions ( incidence greater than 20 %) are hypogammaglobulinemia , infections-pathogen unspecified , pyrexia , decreased appetite , headache , encephalopathy , bleeding , hypotension , tachycardia , nausea , diarrhea , vomiting , viral infectious disorders , hypoxia , fatigue , acute kidney injury , and delirium .
The following serious adverse reactions are discussed in greater detail in another section of the label :
• Cytokine Release Syndrome [ see Warnings and Precautions ( 5.1 )]
• Neurological Toxicities [ see Warnings and Precautions ( 5.2 )]
• Infections and Febrile Neutropenia [ see Warnings and Precautions ( 5.5 )]
• Prolonged Cytopenias [ see Warnings and Precautions ( 5.6 )]
• Hypogammaglobulinemia [ see Warnings and Precautions ( 5.7 )]
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .
The safety data described in this section reflect exposure to KYMRIAH in the clinical trial ( Study 1 ) in which 68 patients with pediatric and young adult relapsed / refractory ( R / R ) B-cell ALL received CAR-positive viable T cells .
Based on a recommended dose which was weight-based , all patients received a single intravenous dose of KYMRIAH [ see Clinical Studies ( 14 )]. The most common adverse reactions were cytokine release syndrome ( 79 %), hypogammaglobulinemia ( 43 %), infections-pathogen unspecified ( 41 %), pyrexia ( 40 %), decreased appetite ( 37 %), headache ( 37 %), encephalopathy ( 34 %), hypotension ( 31 %), bleeding episodes ( 31 %), tachycardia ( 26 %), nausea ( 26 %), diarrhea ( 26 %), vomiting ( 26 %), viral infectious disorders ( 26 %), hypoxia ( 24 %), fatigue ( 22 %), acute kidney injury ( 22 %), and delirium ( 21 %).
Eleven deaths were reported for patients who received KYMRIAH , of which 2 deaths occurred within 30 days of infusion . Seven were disease-related , three were attributed to infections , and one to intra cerebral hemorrhage . Of the two deaths before Day 30 , one patient died with CRS and progressive leukemia and the second patient had resolving CRS with abdominal compartment syndrome , coagulopathy , and renal failure when an intracranial hemorrhage occurred .
The adverse reactions with greater or equal to 10 % incidence for any Grade are summarized in Table 2 .
Table 2 . Selected Adverse Reactions ( ≥ 10 %) Following Treatment with KYMRIAH ( N = 68 )
Adverse Reaction
All Grades Grades 3 or Higher (%) (%)
Cardiac disorders a Tachycardia 26 4
Gastrointestinal disorders Nausea 26 3 Diarrhea 26 1 Vomiting 26 1 Constipation 18 0 b Abdominal pain 16 3
General disorders and administration site conditions Pyrexia 40 15 Fatigue 22 0 Face edema 10 1 Edema peripheral 10 1 Chills 10 0
( continued )
Table 2 . Selected Adverse Reactions ( ≥ 10 %) Following Treatment with
KYMRIAH ( N = 68 )
Adverse Reaction
All Grades
(%)
Grades 3 or Higher
(%)
Immune system disorders Cytokine release syndrome
79
49
c Hypogammaglobulinemia
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
Pain in extremity
16
1
Myalgia
15
0
Arthralgia
12
1
Back pain
10
3
Nervous system disorders d
Headache
37
3
e Encephalopathy
34
10
Psychiatric disorders Delirium
21
4
Anxiety
13
3
Renal and urinary disorders Acute kidney injury
22
13
Respiratory , thoracic and mediastinal disorders
Hypoxia
24
18
Cough
19
0
Pulmonary edema
16
10
Tachypnea
12
6
Pleural effusion
10
4
Nasal congestion
10
0
Vascular disorders Hypotension
31
22
Hypertension
19
6
a Tachycardia includes tachycardia and sinus tachycardia .
b Abdominal pain includes abdominal pain , abdominal pain upper , gastrointestinal
pain , abdominal pain lower .
c
Hypogammaglobulinemia includes hypogammaglobulinemia , immunoglobulins
decreased , blood immunoglobulin G decreased , blood immunoglobulin A
decreased , blood immunoglobulin M decreased , hypogammaglobulinemia .
d Headache includes headache and migraine .
e Encephalopathy includes encephalopathy , cognitive disorder , confusional state ,
depressed level of consciousness , disturbance in attention , lethargy , mental status
changes , posterior reversible encephalopathy syndrome , somnolence , and
automatism .
f
Delirium includes delirium , agitation , hallucination , hallucination visual , irritability
, restlessness .
g Acute kidney injury includes acute kidney injury , anuria , azotemia , renal failure ,
renal tubular dysfunction , renal tubular necrosis .
Additional important adverse reactions that did not meet the threshold criteria
for inclusion in Table 2 were :
Blood and lymphatic system disorders : disseminated intravascular coagulation
( 9 %), histiocytosis lymphocytic hemophagocytosis ( 7 %), coagulopathy
( 6 %), Grade 3 and Grade 4 hypofibrinogenemia with Grade 3 and 4 CRS
( 16 %)
Cardiac Disorders : cardiac arrest ( 4 %), cardiac failure ( 7 %)
Gastrointestinal disorders : abdominal compartment syndrome ( 1 %)
General disorders and administration site conditions : multiple organ dysfunction
syndrome ( 3 %)
Immune system disorders : graft versus host disease ( 1 %)
Investigations : blood creatinine increased ( 7 %), activated partial thromboplastin
time prolonged ( 6 %)
Nervous System : intracranial hemorrhage ( 1 %), seizure ( 3 %)
Respiratory , thoracic , and mediastinal disorders : respiratory distress ( 6 %),
respiratory failure ( 6 %), acute respiratory distress syndrome ( 4 %)