Download Update on the Side Effects of Tyrosine Kinase Inhibitors

Update on the Side Effects of
Tyrosine Kinase Inhibitors
Dr Jenny Byrne
Nottingham University Hospitals Trust
Imatinib is a Safe Drug....
IRIS Study: Most Frequently Reported AEs
Most Common
Adverse Events (by
5 Years)
•
•
All Grade AEs
Patients, %
Grade 3/4 AE’s
Patients %
Superficial Edema
60
2
Nausea
50
1
Muscle cramps
49
2
Musculoskeletal pain
47
5
Diarrhea
45
3
Rash/skin problems
40
3
Fatigue
39
2
Headache
37
<1
Abdominal pain
37
4
Joint pain
31
3
Only Serious Adverse Events (SAEs) were collected after 2005
Grade 3/4 adverse events decreased in incidence after years 1-2
IRIS 8 year update
IRIS SAEs in Year 8


No unique, previously unreported AEs attributed to imatinib
observed over the past 24 months
Since year 5 only 9 SAEs with suspected relationship to imatinib
have been reported (2%):





Congestive Heart Failure (n=3): all of the patients had pre-existing
cardiac disease prior to study entry
Second malignancy (n=3)*
Myositis (n=1); elevated CK (n=1); multiple sclerosis (n=1)
Pancreatitis (n=1); vomiting (n=1)
Dermatitis (n=1)
*With >400,000 patient years of estimated imatinib exposure, the analysis of
clinical safety data from clinical trials and spontaneous reports did not provide
evidence for an increased incidence of malignancies for patients treated with
imatinib compared to that of the general population
IRIS 8 year update
But many patients have low
level side effects...
Which can affect their quality of life…
ENRICH STUDY: Changes in Toxicity and QoL in
Patients Switched from Imatinib to Nilotinib
45 / 52 patients had a total of 182 low-grade (grade 1/2), imatinib-related,
nonhematologic AEs at baseline.
Of the 182 AEs, 130 were grade 1 and 52 were grade 2.
71.4%
ENRICH: Change in Severity of Most Frequently
Reported Imatinib-Related Nonhematologic AEs*
Cortes J, et al. Blood. 2012;120(21):[abstract 3782].
ENRICH: Change from Baseline in QoL
bCycle*
Cortes J, et al. Blood. 2012;120(21):[abstract 3782].
Nilotinib is Generally Better Tolerated…
But what about Long Term Toxicity...?
ENESTnd: 3-year adverse event data (any grade)
Symptomatic QT prolongation
Pancreatitis
Hepatotoxicity
Fluid retention
Effusions
Rash
Significant bleeding
Nilotinib 300 mg BID (n=279)
CNS haemorrhage
Imatinib 400 mg BID (n=280)
GI haemorrhage
Adverse event onset in
third year of therapy
Ischaemic heart disease
PAOD*
0
10
20
30
40
50
60
70
80
90
100
Patients (%)
*No patient discontinued the study as a result of PAOD. 6/7 patients (85%) with PAOD had pre-existing risk factors at baseline.
CNS: Central nervous system; GI: Gastrointestinal; PAOD: Peripheral arterial occlusive disease.
1.
Larson RA et al. Leukemia 2012 [Epub ahead of print].
ENESTnd:
3-year grade 3/4 laboratory abnormalities
AST increased
ALT increased
Bilirubin (total) increased
Lipase (blood) increased
Glucose increased
Nilotinib 300 mg BID (n=279)
Haemoglobin
Imatinib 400 mg BID (n=280)
Adverse event onset in
third year of therapy
Absolute neutrophils
(seg. + bands)
Platelet count
(direct)
0
10
20
30
40
50
60
70
80
90
100
Patients (%)
ALT: Alanine aminotransferase; AST: Aminotransferase; Seg.: segmented.
1.
Larson RA et al. Leukemia 2012 [Epub ahead of print].
ENESTnd: arterial Events by 4 Years
Patients, n (%)
IHD
(3 yrs in brackets)
PAOD (3 yrs in brackets)
Nilotinib
300 mg BID
n = 279
Nilotinib
400 mg BID
n = 277
Imatinib
400 mg QD
n = 280
11 (9)
4 (4)
14 (11)
5 (3)
3 (3)
0
 Between years 3 and 4, five new patients had an IHD event (2 in the nilotinib 300 mg BID
arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event (both
in the nilotinib 400 mg BID arm)
 1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly
reported drug-related SAE (arterial stenosis limb) leading to treatment discontinuation
Mechanism not clear - ? Related to high glucose levels
Worrying – need more data, especially as now approved 1st line
11
Data cutoff: 27Jul 2012.
Novartis Communication 25 Feb 2012:
Atherosclerotic Related Events
Imatinib 400 mg qd
N=280
Any
Grade 3/4
grade
n (%)
n (%)
Nilotinib 300 mg bid
N=279
Any grade Grade 3/4
n (%)
n (%)
Nilotinib 400 mg bid
N=277
Any grade Grade 3/4
n (%)
n (%)
Any AREs
4 (1.4)
17 (6.1)
23 (8.3)
Risk factors for ARE’s
4/4 (100%)
15/17 (88%)
0
0
0
0
10 (3.6)
8 (2.9)
0
0
4 (1.4)
3 (1.1)
5 (1.8 )
1 (0.4)
3 (1.1)
3 (1.1)
11 (3.9)
6 (2.2)
14 (5.1)
9 (3.2)
1 (0.4)
0
3 (1.1)
2 (0.7)
5 (1.8 )
4 (1.4)
AREs leading to
discontinuation
Peripheral Arterial
Occlusive Disease
(PAOD)
Ischemic Heart
disease
Ischemic
cerebrovascular
3 (1.1)
11 (3.9)
14 (5.1)
22/23 (96%)
‘Clinicians should vigorously manage cardiovascular risk factors and AREs
according to standard international guidelines regarding treatment of
hypertension, hyperlipidemia, and diabetes as well as smoking cessation’
Is Dasatinib any better...?
DASISION:
2-year adverse event data
Fluid retention
Superficial oedema
Any grade
Pleural effusion
Myalgia
Nausea
Diarrhoea
Dasatinib 100 mg QD (n=258)
Vomiting
Rash
Imatinib 400 mg QD (n=258)
Headache
Grade 3/4
Fatigue
Neutropenia
Thrombocytopenia
Anaemia
0
•
•
10
20
30
40
50
60
Patients (%)
70
80
90
100
Grade 3/4 biochemical abnormalities occurred in ≤3% of patients and with similar frequency in treatment arms except
hypophosphataemia (dasatinib: 7%; imatinib 25%)
Pulmonary arterial hypertension was diagnosed in 3 patients but did not lead to treatment discontinuation
1.
Kantarjian HM et al. Blood 2012; 119(5): 1123–1129.
Dasatinib and Pleural Effusions
• Occurs in approx. 20% of patients
but only 5% Grade 3-4
• Thought to be caused by more
potent inhibition of src
• Pleural fluid shows marked
lymphocytic infiltrate
• Associated with peripheral blood
lymphocytosis
• More common with higher / split
doses of dasatinib
• Median time from start of drug to
effusion is 5 weeks
• Most occur within 12 months
May resolve with steroid / diuretic combination and temporary stopping
of dasatinib
Others require drainage and permanent discontinuation
Pulmonary Arterial Hypertension
•
•
•
•
•
•
•
•
Circulation 2012, Montani et al
French study of 9 cases between 2008-2010
Estimated incidence 0.45% of patients exposed to dasatinib
Src inhibition thought to be implicated in pathogenesis
Late complication occurring 8-48 months after starting dasatinib
More common in females
Median age of patients 51 years
6/9 patients also had concomitant pleural effusions but PAH
persisted even after effusions resolved
• ? Reversible on stopping dasatinib
Evolution of clinical, functional, and hemodynamic
parameters after dasatinib discontinuation
Most patients
improved after
stopping dasatinib
but none returned
completely to
normal
How about the ‘new’ TKIs...?
Bosulif (bosutinib) and Iclusig
(ponatinib) both now licensed for 2nd
line in the USA and are coming...
Can we Predict their Side Effects..?
Target kinases for the 5 Tyrosine Kinase Inhibitors
Imatinib
(Phos. IC50)
PDGFR
72 nM
Nilotinib
(Phos. IC50)
BcrAbl
20 nM
Dasatinib
(Phos. IC50)
Src
0.1 nM
Bosutinib
(Phos. IC50)
Src
3 nM
Ponatinib
(Phos. IC50)
BcrABl1
0.37 nM
1. Manley PW, et al. Proc Am Assoc Cancer Res 2007;48:772.
2. Weisberg E, et al. Cancer Cell 2005;7:1129.
3. Remsing Rix LL, et al. Leukemia 2009;23:477.
4. O’Hare T. et al (2009) Cancer Cell. 16: 401-412
>
Kit
99 nM
>
PDGFR
75 nM
>
BcrAbl
1.8 nM
>
BcrAbl
85 nM
>
PDGFR
1.1 nM
>
BcrAbl
221 nM
>
Kit
209 nM
>
PDGFR
2.9 nM
>
PDGFR
>3000
>
Src
5.4 nM
>
Src
>1000 nM
>
Src
>1000 nM
>
Kit
18 nM
>
Kit
>10000 nM
>
Kit
12.5 nM
Bosutinib Study 200 (2nd Line):
Treatment-emergent Adverse Events
All Grades
(n = 288)
Grade 3–4
(n = 288)
Diarrhea
Nausea
Vomiting
Rash
Abdominal pain
Fatigue
Pyrexia
243 (84)
128 (44)
102 (35)
98 (34)
64 (22)
62 (22)
60 (21)
26 (9)
5 (2)
9 (3)
25 (9)
3 (1)
2 (1)
1 (<1)
Cough
45 (16)
0
Headache
42 (15)
0
Arthralgia
38 (13)
1 (<1)
Decreased appetite
36 (13)
2 (1)
Nasopharyngitis
34 (12)
0
Constipation
32 (11)
1 (<1)
Asthenia
31 (11)
5 (2)
Adverse Event, n (%)
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.
Bosutinib Study 200 (2nd Line):
Gastrointestinal Adverse Events
Parameter
Diarrhea
Nausea
Vomiting
243 (84)
128 (44)
102 (35)
Median time to onset, d
2
5
8
Median duration, d
27
10
3
Resolved, n (%)
206 (85)
117 (91)
98 (96)
Received concomitant medication, n (%)
165 (68)
52 (41)
35 (34)
Required dose reduction, n (%)
13 (5)
6 (5)
7 (7)
Required dose interruption, n (%)
35 (14)
10 (8)
15 (15)
6 (3)
2 (2)
4 (4)
Patients with event, n (%)
Discontinued treatment, n (%)
Start with low dose and build up gradually. Warn patients & give loperamide!
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.
Bosutinib Study 200 (2nd Line):
Other Grade 3–4 Laboratory Abnormalities
Laboratory Abnormality, n (%)
Grade 3–4 (n = 288)
Hypermagnesemia
35 (12)
Elevated ALT
30 (10)
Hypophosphatemia
23 (8)
Elevated lipase
23 (8)
Elevated uric acid
17 (6)
Elevated AST
14 (5)
Hypocalcemia
10 (3)
Hypomagnesemia
10 (3)
Hyperglycemia
9 (3)
Elevated INR
7 (2)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio.
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.
Study 200 (2nd Line): Grade 3–4
Hematologic Laboratory Abnormalities
Laboratory Abnormality, n (%)
Grade 3–4 (n = 288)
Thrombocytopenia
71 (25)
Neutropenia
48 (17)
Anemia
35 (12)
Generally less haematological toxicity than other 2nd line agents
– may be useful for patients who cannot tolerate other TKIs due
to low counts
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.
Bosutinib Study 200 (2nd Line):
Other Adverse Events of Interest
• Pleural effusion
– Observed in 10 (3%) patients (all grades)
– Grade 3–4 pleural effusion reported in 1 (<1%) patient
• Effects on QTcF interval
– On treatment, 25 (9%) patients had grade 1–2
prolongation and 1 (<1%) patient had grade 3–4
prolongation
– At treatment completion, 2 (2%) patients had grade 1–2
prolongation and none had grade 3–4 prolongation
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.
Ponatinib PACE Study:
Treatment Emergent AEs
CP-CML (N=270)
≥ 20% any grade Total
Any Grade
%
Non-hematologic
Rash*
43
Abdominal pain
40
Headache
40
Dry skin
40
Constipation
38
Fatigue
27
Pyrexia
23
Nausea
24
Arthralgia
26
Hypertension
23
Lipase increased
23
Pancreatitis
7
Amylase increased
7
Hematologic
Thrombocytopenia
44
Neutropenia
18
*Combines the terms erythematous, macular and14
papular rash
Anemia
14
Total Population (N=449)
Grade 3/4
%
Any Grade
%
Grade 3/4
%
4
9
3
2
2
1
1
1
3
7
11
6
1
38
38
35
35
34
27
27
26
25
21
19
6
7
4
9
2
2
2
2
2
1
2
7
12
5
2
34
16
8
42
24
20
34
21
14
Ponatinib Phase 2 PACE Study:
Treatment Emergent Serious AEs
SAEs in >6 Patients Total
Non-hematologic
Pancreatitis
Abdominal pain
Lipase increased
Diarrhea
Myocardial infarction
Cardiac failure
Atrial fibrillation
Hypertension
Coronary artery disease
Pneumonia
Pyrexia
Sepsis
Dehydration
Cellulitis
Hematologic
Anemia
Febrile neutropenia
Thrombocytopenia
Pancytopenia
Neutropenia
CP-CML (N=270)
n (%)
Total Population (N=449)
n (%)
17 (6)
10 (4)
5 (2)
3 (1)
8 (3)
5 (2)
8 (3)
6 (2)
6 (2)
7 (3)
7 (3)
2 (1)
2 (1)
2 (1)
24 (5)
18 (4)
7 (2)
7 (2)
14 (3)
13 (3)
12 (3)
8 (2)
6 (1)
22 (5)
15 (3)
8 (2)
6 (1)
6 (1)
5 (2)
1 (<1)
4 (1)
1 (<1)
2 (1)
13 (3)
13 (3)
13 (3)
6 (1)
6 (1)
• Serious adverse events of arterial thromboembolism, including arterial stenosis, were observed in patients with
15
cardiovascular risk factors
Iclusig Given FDA Approval but with Black
Box Warning (Dec 2012)
• Important for haematologists to be aware of these toxicities
• Ponatinib forms part of the new SPIRIT 3 trial for newly
diagnosed patients
Summary
•
•
•
•
•
•
No drug is side effect free!
Side effect profile depends on the degree of inhibition of the kinases
Side effects rarely recur on switching to different TKI
Long term toxicity may be emerging but more data needed
Choice of drug needs careful consideration for each patient
Refractory patients: main consideration must be to achieve disease
control
• Intolerant patients: ideally choose drug depending on other
comorbidities / risk factors (if funding allows)
– Diabetes / cardiovascular risk factors: ? avoid nilotinib / ponatinib
– Pulmonary issues: ? Avoid dasatinib
– Low blood counts: consider bosutinib
• May need to brush up on cardiology skills!