ASH Clinical News ACN_4.5_FULL_ISSUE_DIGITAL - Page 32

Literature Scan
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 %)
Literature Scan 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 differ- ences 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 high- est among whites. These results suggest “that better MM thera- peutics 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 signifi- cantly by year of diagnosis, despite adjustment for inflation. Drug claims during the first six months B:7.75” increased sharply, after diagnosis from a T:7.5” median of $230 between 1991 and 1995 to $3,630 between S:7” chemotherapy, during KYMRIAH treatment, and until immune recovery fol- lowing 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 malignan- cies. 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 occupa- tions or activities, such as operating heavy or potentially dangerous machin- ery, during this initial period. 6 ADVERSE REACTIONS Most common adverse reactions (incidence greater than 20%) are hypogam- maglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, bleeding, hypotension, tachycardia, nausea, diar- rhea, 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 compart- ment syndrome, coagulopathy, and renal failure when an intracranial hemor- rhage occurred. The adverse reactions with greater or equal to 10% incidence for any Grade are summarized in Table 2. Table 2. 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