CML: side-effects and complications
of TKI therapy
Dragana Milojković
The Hammersmith Hospital, London, UK
Targeted therapy
Courtesy of J Melo
Off target effects: friendly fire
Inhibition of signalling pathway
? Clinical
Consequence
PDGF
Pleural effusion
Skin changes
c-kit
Low blood counts
Side-effects of imatinib therapy
GENERAL
Fatigue
EYES
Dryness
Peri-orbital oedema
LIVER
Transaminitis
MUSCULOSKELETAL
Arthalgia
Myalgia
CPK↑
SKIN
Dermatitis
Hypopigmentation
Stevens-Johnson
Alopecia
CARDIAC
CCF
Fluid retention
GI TRACT
Nausea/Vomiting
Diarrhoea
RENAL
Impairment
Imatinib and weight gain
•n=50 CML-CP
•weight analysed at 6 monthly intervals for 24 months
•patients were excluded if additional co-morbidities that could influence weight
loss or gain were present (eg thyroid disorder, diabetes)
Months after
start
N
Median gain, kg
(range)
% weight gain
(range)
p-value
No of patients with
weight gain
+6
48
3.4 (-6.0, 11.0)
4.8 (-5.3, 14.2)
<0.0001
37 (77%)
+12
45
4.1 (-3.1, 17.9)
5.3 (-4.2, 22.9)
<0.0001
38 (84%)
+18
43
4.7 (-3.4, 17.9)
6.3 (-4.8, 23.0)
<0.0001
36 (84%)
+24
35
5.2 (-8.4, 21.7)
6.2 (-12.0, 27.1)
<0.0001
30 (83%)
Months
BMI
0
+6
+12
+18
+24
Non-Obese
36 (80%)
29 (68%)
27 (68%)
22 (56%)
19 (58%)
Obese
9 (20%)
14 (32%)
13 (32%)
17 (44%)
14 (42%)
0.18
0.19
0.02
0.03
P-value comparison with time
0
Blood. 2012 Dec 13;120(25):5087-8
Imatinib - ? cardioprotective
• Lowers fasting blood glucose levels
• Decreases cholesterol and triglyceride levels
• Protects from diabetes mellitus-associated arteriosclerosis
• Attenuates in-stent re-stenosis
• Therapy for pulmonary arterial hypertension
Agostino et al J Oncol Pharm Pract 2011; 17: 197
Francechini et al Haematologica. 2008 Feb;93(2):317
Lassila et al Arterioscler Thromb Vasc Biol 2004; 24: 935
Hatano et al Int Heart J 2010; 51: 272
Nakamura et al Int J Cardiol 2011; 159: 100
Dasatinib
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP
At 2 years
Forest Plot Comparing Differences in AE Rates
for Dasatinib and Imatinib
Any grade
Grade 3/4
Fluid retention
Superficial edema
Pleural effusion
Myalgia
Nausea
Vomiting
Diarrhea
Fatigue
Headache
Rash
Neutropenia
Thrombocytopenia
Anemia
–40
l
l
l
l
l
l
l
l
l
l
l
l
l
–20
0
20
40
Rate Difference (dasatinib-imatinib) with 95% CI
Favors dasatinib Favors imatinib
17
Hochhaus A, et al. EHA 2011: Oral Presentation 1011.
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP
Rates of Grade 3/4 Cytopenias
24
Neutropenia
21
20
MMR
Thrombocytopenia
%
Dasatinib
Imatinib
11
Dark shading indicates
AE onset in the second
year of therapy
11
Anemia
8
%
 Grade 3/4 bleeding occurred in 1% of dasatinib-treated patients
and 1% of imatinib-treated patients
19
Hochhaus A, et al. EHA 2011: Oral Presentation 1011.
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP
At 2 years
Rates of Nonhematologic Adverse Events
of any Grade (≥10%)
25
Fluid retention
43
11
Superficial edema
36
14
Pleural effusion
0
22
Myalgia*
39
10
Nausea
23
Dasatinib
Imatinib
19
21
Diarrhea
5
Vomiting
10
11
Rash
Dark shading indicates
AE onset in the second
year of therapy
17
13
11
Headache
9
Fatigue
11
0
20
40
%
60
80
100
 Rates of grade 3/4 nonhematologic AEs of each type were 0–1% in both arms
*Includes myalgia, muscle inflammation, and musculoskeletal pain
18
Hochhaus A, et al. EHA 2011: Oral Presentation 1011.
DASISION: First-Line Dasatinib vs Imatinib in CML-CP – 12-month follow-up
DASISION: 12-month efficacy of dasatinib did not
appear to be impacted by pleural effusion
100
92
Pleural effusion
Rate by 12 months, %
82
83
80
No pleural effusion
All patients
60
54
45
46
40
20
0
n/N
24/26
192/233 216/259
CCyR
Porkka K, et al. ASH Annual Meeting 2010: Poster 2282.
14/26
105/233 119/259
MMR
Dasatinib induced pleural effusion
Patient
characteristics:
Age
HT/IHD
History:
Auto-immunity
Skin rash on - imatinib
- dasatinib
Dosing:
BD vs OD
Inhibition of PDGF/src
LC/NK cells
Inhibition of normal T cells
(TEC/BTK)
B J Haem 2008, 141, 734–747
Management of Pleural Effusion
on Dasatinib
1. Stop dasatinib
2. Stop dasatinib
3. Stop dasatinib
• Steroids, diuretics may also be helpful
Dasatinib induced skin toxicitypanniculitis
 Rare complication
 Skin tenderness, erythema, subcutaneous nodules
 -
Massive infiltration of
the hypodermis by
polymorphonuclear
leukocytes
 Reintroduction of dasatinib with oral prednisolone may be of
benefit
N Engl J Med 2006; 354:2623-2624
Platelet function abnormalities on TKIs
 Dasatinib: increased bleeding tendency despite normal platelet value
 Bleeding in 40% dasatinib treated patients (gr3/4 in 10%), GI and epistaxis
TKI
Abnormal Platelet Aggr
(AA)
(Epi)
%
%
Both
%
Abnormal
PFA
NORMAL
Aggregation
%
Imatinib
(n=20)
66
13
-
NO
33
Nilotinib
(n=9)
0
0
-
-
100
Dasatinib
(n=29)
70
85
59
YES
-
Bosutinib
(n=32)
7.5
7.5
-
-
85
Ponatinib
(n=5)
80
100
80
YES
-
Ponatinib>dasatinib>imatinib>bosutinib>nilotinib
Blood. 2009 Jul 9;114(2):261-3
Haematologica.2012: 97(9):1444
Dasatinib gastrointestinal toxicity:
colitis
 Rare complication
 Clinical presentation variable; can be similar to inflammatory
bowel disease
 Can be haemorrhagic
 ? Related to LGL expansion
 Dose related
Acta Haematol. 2010;123(4):205-6
Dasatinib and Pulmonary Arterial Hypertension
(PAH)
• BMS pharmacovigilance database (2006-2010)
• Incidence: 0.4%
• Echo pre starting dasatinib therapy in patients with IHD
• If PAH confirmed, dasatinib should be permanently discontinued
• French PH registry (2012)
- n=9
- majority incomplete recovery
- no patients reached a normal value of mean
pulmonary artery pressure (≤20 mm Hg)
- no predictive factor/ BMPR2 genetic status
• Treated with imatinib!
Montani et al, Circulation, 2012
Dasatinib: Pulmonary Arterial Hypertension
(PAH) and Pulmonary Hypertension (PH)
•
•
Incidence: 0.2% (PH 5%)
BMS pharmacovigilance database and HCP
reports (2006-2013)
– n=41
– 94% improvement/resolution PAH
(58% CR)
– 82% evaluable patients had
CV/pulmonary risk factor
– Multiple therapies (median 3) pre DAS
Montani D, et al. Circulation;2012:125(17):2128-2137.
Shah et al, Am J Haematology, Epub, 2015
Nilotinib
ENESTnd 24-month Update
ENESTnd: Nilotinib vs Imatinib in Ph+ CML-CP
Study Drug-Related Adverse Events and
Grade 3/4 Myelosuppression
Favors imatinib
Favors nilotinib (300 mg BID)
Fluid retention
Diarrhea
Headache
Muscle spasm
Any grade
Nausea
Pruritus
Rash
Vomiting
Anemia
Grade 3/4
Neutropenia
Thrombocytopenia
-0.5
-0.4 -0.3 -0.2 -0.1 0
0.1
0.2
0.3
0.4
0.5
Rate difference (imatinib - nilotinib) with 95% CI
Data cutoff: 20Aug2010
20 Larson RA, et al. J Clin Oncol. 2011;29(15s):421s [abstract 6511].
ENESTnd 24-Month Update
Grade 3/4 Myelosuppression
25
% of Patients
21
20
15
12
11
10
10
5
0
4
4
9
5
Anemia
Nilotinib 300 mg BID
Data cut-off: 20Aug2010.
12
Neutropenia
Nilotinib 400 mg BID
Thrombocytopenia
Imatinib 400 mg QD
Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207].
ENESTnd 24-Month Update
Selected Grade 3/4 Biochemical
Abnormalities
% of Patients
10
8
9
8
8
7
6
6
5
4
4
4
3
3
2
0
<1
0
Lipase ↑
Nilotinib 300 mg BID
Data cut-off: 20Aug2010.
ALT ↑
Total bilirubin ↑
Nilotinib 400 mg BID
Glucose ↑
Imatinib 400 mg QD
Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207].
ENESTnd Study: Cumulative Incidence of
Postbaseline Changes in Glycemic Status by 5 Years
Glycemic Status by 5 Years,
n (%)a
Nilotinib
300 mg BID
Nilotinib
400 mg BID
Imatinib
400 mg QD
n = 91
n = 93
n = 88
Prediabetes
34 (37.4)
46 (49.5)
35 (39.8)
Diabetes
17 (18.7)
17 (18.3)
2 (2.3)
n = 88
n = 91
n = 94
27 (30.7)
31 (34.1)
16 (17.0)
Normal glycemic status at
baselineb
Prediabetes at baselinec
Diabetes
 Among patients who were nondiabetic at baseline, more patients had
fasting plasma glucose or HbA1c levels within the diabetic range by 5 years
on nilotinib vs imatinib
Data cutoff: September 30, 2013
EHA 2103
Significant rise in cholesterol within
three months of nilotinib therapy
n=27
Over 12 months
(patient %)
LDL
48.1%  88.9%
Low
HDL
40.7%  7.4%
Plasma lipid profile of CP-CML patients prior to and during the first year of nilotinib therapy
Rea D et al. Haematologica 2014;99:1197-1203
ENESTnd Study: Cardiovascular Eventsa
by 5 Years
Nilotinib
300 mg BID
(n = 279)
Total, Y1-4,
Y5,
b
n (%)
n
nc
Nilotinib
400 mg BID
(n = 277)
Total, Y1-4,
Y5,
b
n (%)
n
nc
Imatinib
400 mg QD
(n = 280)
Total, Y1-4,
Y5,
b
n (%)
n
nc
Total patients with
CVEs
21
(7.5)
37
(13.4)
6
(2.1)
Ischemic heart
disease
18
4
24
14
11
(3.9)
11
0
Ischemic
cerebrovascular
events
4
(1.4)
3
Peripheral artery
disease
7
(2.5)
4
24
(8.7)
14
10
1
9
(3.2)
5
3
7
(2.5)
5
Y, year.
a All events, regardless of relationship to study drug.
b Data cutoff: July 27, 2012 (minimum follow-up of 48 cycles).
c Events reported between the 48-cycle and 60-month data cutoffs.
CVE, cardiovascular event.
4
2
5
(1.8)
3
2
4
1
(0.4)
1
0
2
0
0
0
Data cutoff: September 30, 2013
EHA 2103
Reported incidence of arteriothrombotic
effects on nilotinib
1st/2nd
Lovato et al 2013
Nilotinib
line
17/10
FU
Total
Incidence PAOD/
total vascular
events %
14.8 %
30
10 yr
Aichberger et al 2011
24
3 yr
Le Coutre et al 2011
179
12.5% (3/24)/
25%( 6/24)
6.15%
Hadzijusufovic et al,
2013
34
36 mo
36.1%
Lovato et al Eur J Haematol. 2013 Jun;90(6):531
Aichberger et al Am J Hematol 2011;86:533
Le Coutre et al J Natl Cancer Inst. 2011;103(17):1347
Bosutinib
Discontinuation From Treatment:
Safety Population
Bosutinib
(n = 248)
Imatinib
(n = 251)
71
80
29
20
Adverse event
19
5
Treatment failurea
3
10
Patient request
3
2
Lost to follow-up
2
0
Investigator request
1
1
Death
1
1
Protocol violation
0
1
Failed to return
1
0
Other
1
1
Parameter, %
Active patients
Discontinued patients
aTreatment
28
failure includes both disease progression and lack of efficacy.
(BELA: Bosutinib Efficacy and safety in newly diagnosed chronic myeloid LeukemiA)
Non-haematologic Laboratory Abnormalities:
Safety Population, Grade 3, Incidence 5%
Patients with event (%)
25
20.6%
20
15
13.5%
10
5
Bosutinib
10.1%
Imatinib
7.3%
4.8%
3.2%
2.8%
4.0%
0
Increased ALT
29
Increased AST
Increased lipase
Hypophosphatemia
(BELA: Bosutinib Efficacy and safety in newly diagnosed chronic myeloid LeukemiA)
Hematologic Laboratory Abnormalities:
Safety Population, Grade 3, Incidence 5%
Patients with event (%)
25
22.7%
20
15
12.5%13.1%
8.9%
10
Bosutinib
Imatinib
6.0% 6.4%
5
0
Anemia
30
Neutropenia
Thrombocytopenia
(BELA: Bosutinib Efficacy and safety in newly diagnosed chronic myeloid LeukemiA)
Treatment-emergent Adverse Events:
Safety Population, Incidence 10%
Bosutinib
(n = 248)
event,a
Adverse
%
All grades Grade 3/4
Any event
96
64
Diarrhea
68
10
Vomiting
32
3
Nausea
31
1
Rash
20
1
Pyrexia
16
1
Abdominal pain upper
12
0
Abdominal pain
12
1
Fatigue
11
1
Headache
10
1
Upper respiratory tract
10
0
infection
Bone pain
4
0
Muscle cramps
2
0
Periorbital edema
1
0
31
Imatinib
(n = 251)
All grades Grade 3/4
95
47
21
1
13
0
35
0
15
1
9
1
5
0
5
0
12
1
8
0
Overall
P valueb
NS
0.001
0.001
NS
NS
0.022
0.007
0.005
NS
NS
6
0
NS
10
20
14
1
0
0
0.004
0.001
0.001
(BELA: Bosutinib Efficacy and safety in newly diagnosed chronic myeloid LeukemiA)
Bosutinib-Incidence of Vascular TEAEs
BELA study
● No significant difference (P ≥ 0.122) in individual and overall incidence of
vascular TEAEs with bosutinib vs. imatinib
– most common: hypertension (6.0% vs 4.4%; P = 0.427)
Pooled analysis of patients treated with bosutinib (BELA/study 200 )
● 12.7% of BOS pts had vascular TEAEs (no significant difference)
● Cardiovascular TEAE
– low overall incidence
• angina pectoris 1.2%; coronary artery disease 1.2%
● Cerebrovascular TEAE
– no individual TEAE observed in >3 bosutinib-treated patients
● Peripheral vascular TEAE
– uncommon, except for hypertension (6.4%)
•
Newly occurring vascular TEAE rates decreased with longer BOS treatment
Cortes JE, et al. Long-Term Evaluation of Vascular Toxicity in Patients With Ph+ Leukemias Treated With Bosutinib. ASCO 2014, poster 7060.
32
Ponatinib
Skin changes on Ponatinib
Iclusig Given FDA Approval but
with Black Box Warning (Dec 2012)
• ?aspirin for all
• ?change to warfarin in patients already receiving aspirin
Ponatinib: Multivariate Analysis of Arterial
Thrombotic AEs-dose intensity
• Risk factors significantly
associated with arterial
thrombotic AEs:
Estimated Probability
0.3
0.2
0.1
fit & 95% CI
0.0
15
30
Dose Intensity (mg/day)
45
– Older age (p<0.0001)
– History of diabetes (p=0.0003)
– Higher dose intensity to time of
first event (p=0.0009)
– History of ischemia (p=0.0087)
– Longer time since diagnosis
(p=0.0228)
– Higher baseline neutrophils
(p=0.0276)
– Higher baseline platelets (p=0.0466)
• Each 15 mg/day reduction in dose intensity results in a predicted
reduction of ~40% in the risk of an arterial thrombotic event
• Accumulation of events with increased FU:
- 3 ½ yr FU phase 1 study: VOE in 17/43 (40%), 28% SAE
- Phase 2 PACE trial: CP-CML (n=270), 25% AE, 18% SAE
Data are similar for vascular occlusive events
ASH 2013 Abstract 650
ESH 2014
Malignancies occurring during therapy with
TKIs for CML and other haematological
malignancies
•Records of 1445 patients treated with TKIs were reviewed to
investigate frequency and characteristics of second
malignancies (excluding AML/ALL/MDS)- risk of second
cancers lower than expected
•Incidence and Mortality of Second Malignancies In 559
Patients with Chronic Myeloid Leukemia (CML) Treated with
Imatinib Frontline: Data From the GIMEMA CML Working
Party- no increase
Blood. 2011;118(16):4353-8
Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 2281
Early intervention = less intervention !
Toxicity
 Haematological
– Stop TKI
– G-CSF/Epo/? TPO
– Dose reduction
 Non-haematological
– Stop TKI
– Prednisolone: po/topical
– PPI
– Cetirizine
– Loperamide
– Dose reduction
– Statin/aspirin
Minimal cross-intolerance between TKIs
Summary
• Choice of TKI depends on the efficacy and tolerability of the
agent in the context of its known side-effect profile
• Tailored TKI therapy according to the patients co-morbidities
• Important to prevent irreversible complications of TKI therapy
• Active screening/management of CV risk factors
• Identification of risk factors and the management of ATE
complications with cardiovascular/ haemostasis and
thrombosis colleagues
Acknowledgements
Simone Claudiani
Simiona Deplano
Alistair Reid
Jamshid Khorashad
Letizia Foroni
Jane Apperley
Junia Melo
Haematology departmen
d.milojkovic@imperial.ac.uk