1. Update on the Side Effects of Tyrosine Kinase Inhibitors
Dr Jenny Byrne
Nottingham University Hospitals Trust

2. IRIS Study: Most Frequently Reported AEs
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
Musculoskeletal pain 47 5
Diarrhea 45 3
Rash/skin problems 40
Fatigue 39
Headache 37
<1
Abdominal pain 4
Joint pain 31
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

3. 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

4. But many patients have low level side effects...
Which can affect their quality of life…

5. 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%
ASH 2012

6. ENRICH: Change in Severity of Most Frequently Reported Imatinib-Related Nonhematologic AEs*
Cortes J, et al. Blood. 2012;120(21):[abstract 3782].

7. ENRICH: Change from Baseline in QoL bCycle*
Cortes J, et al. Blood. 2012;120(21):[abstract 3782].

8. Nilotinib is Generally Better Tolerated…

9. But what about Long Term Toxicity
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)
Imatinib 400 mg BID (n=280)
Adverse event onset in third year of therapy
CNS haemorrhage
Larson RA, Hochhaus A, Hughes TP et al. Nilotinib vs imatinib in patients with newly diagnosed philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: Enestnd 3-year follow-up. Leukemia 2012 [Epub ahead of print].
GI haemorrhage
Ischaemic heart disease
PAOD* 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.
Larson RA et al. Leukemia 2012 [Epub ahead of print].

10. 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)
Imatinib 400 mg BID (n=280)
Adverse event onset in third year of therapy
Haemoglobin
Larson RA, Hochhaus A, Hughes TP et al. Nilotinib vs imatinib in patients with newly diagnosed philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: Enestnd 3-year follow-up. Leukemia 2012 [Epub ahead of print].
Absolute neutrophils (seg. + bands)
Platelet count (direct) 10 20 30 40 50 60 70 80 90
100
Patients (%)
ALT: Alanine aminotransferase; AST: Aminotransferase; Seg.: segmented.
Larson RA et al. Leukemia 2012 [Epub ahead of print].

11. ENESTnd: arterial Events by 4 Years
Patients, n (%)
Nilotinib 300 mg BID
n = 279
Nilotinib 400 mg BID
n = 277
Imatinib 400 mg QD
n = 280
IHD (3 yrs in brackets)
11 (9)
14 (11)
3 (3)
PAOD (3 yrs in brackets)
4 (4)
5 (3)
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
Data cutoff: 27Jul 2012. 11 11 11

12. Novartis Communication 25 Feb 2012: Atherosclerotic Related Events
Imatinib 400 mg qd
N=280
Nilotinib 300 mg bid
N=279
Nilotinib 400 mg bid
N=277
Any grade
n (%)
Grade 3/4 n (%)
Any AREs        
4 (1.4)
3 (1.1)
17 (6.1)
11 (3.9)
23 (8.3)
14 (5.1)
Risk factors for ARE’s
4/4 (100%)
15/17 (88%)
22/23 (96%)
AREs leading to discontinuation
10 (3.6)
8 (2.9)
Peripheral Arterial Occlusive Disease (PAOD)         
5 (1.8 )
1 (0.4)
Ischemic Heart disease 
6 (2.2)
9 (3.2)
Ischemic cerebrovascular
2 (0.7)
‘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’

13. Is Dasatinib any better...?

14. DASISION: 2-year adverse event data
Fluid retention
Superficial oedema
Pleural effusion
Myalgia
Nausea
Any grade
Diarrhoea
Vomiting
Dasatinib 100 mg QD (n=258)
Rash
Imatinib 400 mg QD (n=258)
Headache
Fatigue
Kantarjian HM, Shah NP, Cortes JE et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119(5): 1123–1129.
Neutropenia
Grade 3/4
Thrombocytopenia
Anaemia 10 20 30 40 50 60 70 80 90
100
Patients (%)
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
Kantarjian HM et al. Blood 2012; 119(5): 1123–1129.

15. 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

16. Pulmonary Arterial Hypertension
Circulation 2012, Montani et al
French study of 9 cases between
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

17. Evolution of clinical, functional, and hemodynamic parameters after dasatinib discontinuation
Most patients improved after stopping dasatinib but none returned completely to normal

18. How about the ‘new’ TKIs...?
Bosulif (bosutinib) and Iclusig (ponatinib) both now licensed for 2nd line in the USA and are coming...

19. Can we Predict their Side Effects..?
Target kinases for the 5 Tyrosine Kinase Inhibitors
Imatinib
(Phos. IC50)
PDGFR
72 nM
>
Kit
99 nM
BcrAbl
221 nM
Src
>1000 nM
Nilotinib
20 nM
75 nM
209 nM
Dasatinib
0.1 nM
1.8 nM
2.9 nM
18 nM
Bosutinib
3 nM
85 nM
>3000
>10000 nM
Ponatinib
BcrABl1
0.37 nM
1.1 nM
5.4 nM
12.5 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:

20. Bosutinib Study 200 (2nd Line): Treatment-emergent Adverse Events
Adverse Event, n (%)
All Grades
(n = 288)
Grade 3–4
Diarrhea
243 (84)
26 (9)
Nausea
128 (44)
5 (2)
Vomiting
102 (35)
9 (3)
Rash
98 (34)
25 (9)
Abdominal pain
64 (22)
3 (1)
Fatigue
62 (22)
2 (1)
Pyrexia
60 (21)
1 (<1)
Cough
45 (16)
Headache
42 (15)
Arthralgia
38 (13)
Decreased appetite
36 (13)
Nasopharyngitis
34 (12)
Constipation
32 (11)
Asthenia
31 (11)
Treatment-emergent adverse events reported in 10% of patients are shown in the table.
No. (%) patients with pleural effusion: all grades, 10 (3); grade 3–4, 1 (<1)
No. (%) patients with pancreatitis: all grades, 2 (1); grade 3–4, 2 (1)
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136. 20

21. Bosutinib Study 200 (2nd Line): Gastrointestinal Adverse Events
Parameter
Diarrhea
Nausea
Vomiting
Patients with event, n (%)
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)
Discontinued treatment, n (%)
6 (3)
2 (2)
4 (4)
Start with low dose and build up gradually. Warn patients & give loperamide!
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136. 21

22. 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
Elevated uric acid
17 (6)
Elevated AST
14 (5)
Hypocalcemia
10 (3)
Hypomagnesemia
Hyperglycemia
9 (3)
Elevated INR
7 (2)
Non-hematologic laboratory abnormalities reported in 2% of patients are shown.
No. (%) patients discontinuing treatment due to above laboratory abnormalities
Elevated ALT: 6 (2)
Elevated AST: 6 (2)
Elevated lipase: 1 (<1)
Elevated transaminases: 2 (<1)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio.
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136. 22

23. 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)
No. (%) patients discontinuing treatment due to above hematologic laboratory abnormalities
Thrombocytopenia: 14 (5)
Neutropenia: 4 (1)
Anemia: 1 (<1)
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. 23

24. 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
No patients discontinued or interrupted the treatment due to QTcF prolongation (although there were 2 delays for atrial fibrillation and 1 delay for bradycardia).
Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136. 24

25. Ponatinib PACE Study: Treatment Emergent AEs
≥ 20% any grade Total
CP-CML (N=270)
Total Population (N=449)
Any Grade %
Grade 3/4
Non-hematologic
Rash* 43 4 38
Abdominal pain 40 9
Headache 3 35 2
Dry skin
Constipation 34
Fatigue 27 1
Pyrexia 23
Nausea 24 26
Arthralgia 25
Hypertension 7 21
Lipase increased 11 19 12
Pancreatitis 6 5
Amylase increased
Hematologic
Thrombocytopenia 44 42
Neutropenia 18 16
Anemia 14 8 20
*Combines the terms erythematous, macular and papular rash 14

26. Ponatinib Phase 2 PACE Study: Treatment Emergent Serious AEs
SAEs in >6 Patients Total
CP-CML (N=270)
n (%)
Total Population (N=449)
Non-hematologic
Pancreatitis
17 (6)
24 (5)
Abdominal pain
10 (4)
18 (4)
Lipase increased
5 (2)
7 (2)
Diarrhea
3 (1)
Myocardial infarction
8 (3)
14 (3)
Cardiac failure
13 (3)
Atrial fibrillation
12 (3)
Hypertension
6 (2)
8 (2)
Coronary artery disease
6 (1)
Pneumonia
7 (3)
22 (5)
Pyrexia
15 (3)
Sepsis
2 (1)
Dehydration
Cellulitis
Hematologic
Anemia
Febrile neutropenia
1 (<1)
Thrombocytopenia
4 (1)
Pancytopenia
Neutropenia
Serious adverse events of arterial thromboembolism, including arterial stenosis, were observed in patients with cardiovascular risk factors 15

27. 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

28. 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!