1. Managing Side Effects of TKIs
Ming YAO M.D.
Division of Hematology
Department of Internal Medicine
National Taiwan University Hospital

2. Goals of Managing Side Effects of TKIs in CML
Optimize patient’s adherence to TKI
Maximize safety and efficacy of TKIs
Case of a non-compliant CML patient
A 38-year-old man, took imatinib 400 mg per day from Jul, as initial treatment of CML, MMR achieved one year post Imatinib tx. He took imatinib irregularly since Jul-2009 due to GI upset. Loss of CCyR was noted then regained MMR after resuming imatinib.

3. General Concepts in Managing Side Effects of TKIs
Side effects vary from person to person.
Individuals may tolerate one drug much better than another.
Side effects generally increase as dose increases.
Management of side effects essential to encourage compliance or adherence.

4. General Principles in Managing Side Effects of TKIs
Generally, grade 3/4 AEs are addressed via dose interruption followed by resumption of treatment at a reduced dose after resolution of toxicity;
Dose reduction and temporary discontinuation of TKIs have been used effectively to treat events of neutropenia and thrombocytopenia in the clinical trial setting. 
The time frame of recovery of individual patients guides dosing decisions.
Common mild or moderate AEs are addressed via specific treatments or supportive care.

5. Common Adverse Reactions Reported in
Newly Diagnosed CML Clinical Trials of
Imatinib 400 mg Once Daily ( >10% of Patients)
Probably Hematlogic AEs Related
ALL GRADES (%)
GRADES 3/4 (%)
(N   551)
Fatigue 39
1.8
Headache 37
0.5
Dizziness 19
0.9
Cough 20
0.2
Nasopharyngitis 31
URI 21
Pyrexia 18
Sore throat
Influenza 14
Sinusitis 11
Hemorrhage 29
GI hemorrhage 2
CNS hemorrhage
<1

6. Imatinib
Management of Select Side Effects Associated with Imatinib Treatment of CML-CP
Hematologic
● Grade 3/4 neutropenia (ANC<1,000/uL):
Dose interruption until ANC > 1,500/Ul
Growth factors can be used in combination with imatinib
for patients with resistant neutropenia.
● Grade 3/4 thrombocytopenia (PLT<50K/uL):
Keep Imatinib with PLT transfusion or
Dose interruption until PLT > 75K/uL

7. Imatinib-induced Thrombocytopenia
46-year-old man, CML, ever treated w INF, PCyR
Start imatinib 400mg /d in late CP
3 months post imatinib, Gr 4 thrombocytopenia but achieved CCyR and MMR
He received regular PLT conc. transfusion and kept on imatinib 400mg /d
Resolution of thrombocytopenia at one year post imatinib
He remained MMR and continued imatinib for 10 years

8. Common Adverse Reactions Reported in
Newly Diagnosed CML Clinical Trials of
Imatinib 400 mg Once Daily ( >10% of Patients)
ALL GRADES (%)
GRADES 3/4 (%)
(N=551)
Fluid retention 62
2.5
Superficial edema 60
1.5
Other fluid retention  7
1.3
Weight increased 16 2
Nonhematologic—Specific interventions (Grade 2 or 3 severity)
● Edema: Diuretics, supportive care
● Fluid retention (pleural effusion, pericardial effusion, edema, and ascites):
Weighed and monitored closely; salt restriction
Diuretics, supportive care, dose reduction, interruption, or discontinuation. Consider echocardiogram to check left ventricular ejection fraction.

9. Periorbital Edema

10. Common Adverse Reactions Reported in
Newly Diagnosed CML Clinical Trials of
Imatinib 400 mg Once Daily ( >10% of Patients)
ALL GRADES (%)
GRADES 3/4 (%)
(N=551)
Nausea 50
1.3
Diarrhea 45
3.3
Abdominal pain 37
4.2
Vomiting 23 2
Dyspepsia 19
Constipation 11
0.7
● GI upset:
Take medication with a meal and large glass of water
split dosing, eg 200mg bid
taking the imatinib prior to going to bed.
antiemetic
● Diarrhea: Supportive care

11. Common Adverse Reactions Reported in
Newly Diagnosed CML Clinical Trials of
Imatinib 400 mg Once Daily ( >10% of Patients)
ALL GRADES (%)
GRADES 3/4 (%)
(N=551)
Muscle cramps 49
2.2
Musculoskeletal pain 47
5.4
Joint pain 31
2.5
Myalgia 24
1.5
Bone pain 11
1.6
● Muscle cramps and musculoskeletal pain :
increased fluid intake
calcium and potassium supplements
tonic water (quinine content)
NSAID

12. Common Adverse Reactions Reported in
Newly Diagnosed CML Clinical Trials of
Imatinib 400 mg Once Daily ( >10% of Patients)
ALL GRADES (%)
GRADES 3/4 (%)
(N=551)
Skin rashes 40
2.9
Insomnia 15
Depression
0.5
● Rash:
Most cases of skin toxicity are mild to moderate in severity
and appear soon after treatment begins.
Topical or systemic steroids
Dose reduction, interruption, or discontinuation for severe
case (rare)

13. Imatinib
If any of the grade 2 or 3 toxicities are not responsive to symptomatic measures, treat as grade 4.
Nonhematologic—Grade 4
Hold drug until grade 1 or better, then consider resuming dose at 25%–33% dose reduction (not less than 300mg). Consider change to dasatinib, nilotinib, or clinical trial.
Nonhematologic — Liver
● Grade 2: Hold drug until grade <1. Resume at 25%–33% dose reduction (not less than 300 mg). Evaluate for
other hepatotoxic drugs that may be contributing to toxicity, including acetaminophen.
Consider change to DASA, NILO, or clinical trial.
● Grade 3/4: Consider change to DASA, NILO, or clinical trial.

14. Imatinib intolerance
68-year-old woman CML-CP began imatinib (IM)400 mg/d
Quickly developed gr. 1 periorbital edema, loose stools, and a slight elevation in bilirubin; reassurance !
CCyR in 3M post IM
After 6 Ms of therapy, she had a gr. 3 skin rash covering 30%-60% of her body. IM was suspended, treated with topical and oral steroids until the rash completely resolved
Resume IM at 300 mg/d, rashes recurred, stop IM again
After several attempts to restart IM, which rapidly resulted in a recurrent rash, the patient was considered to be intolerant to IM.
Shift to to nilotinib, 400 mg twice daily. Six years after diagnosis, she is maintaining an MMR and is tolerating the nilotinib well.

15. Dasatinib Common Side Effects (All Patients, All Grades)
Fluid retention (edema) 37%
Diarrhea 31%
Headache 24%
Nausea 22%
Pleural effusion 22%
Rash 22%
Fatigue 21%
Hemorrhage 21%
Dyspnea 20%
Musculoskeletal pain 14%
Bleeding and thrombocytopenia (platelet dysfunction in vitro), platelets can drop very quickly, hemorrhage possible, monitor carefully.
Fluid retention can be severe, including pleural or pericardial effusion. If develop dyspnea (shortness of breath), do chest x-ray. May occur months into therapy.
Side effects less severe at 140 mg once a day dose vs. 70 mg twice a day.
Possible prolongation of QTc interval

16. Dasatinib-induced pleural effusions
Dasatinib-induced pleural effusions are potentially serious and require prompt diagnosis and treatment.
For patients with grade 2-3 pleural effusion, dasatinib therapy should be discontinued; a short course of diuretics or use of an oral steroid, such as prednisone 20 mg/day three times daily, should be administered.
Patients should be educated to report symptoms of chest pain, dyspnea, and dry cough as soon as they occur.
A lower dasatinib dose should be used when treatment is resumed.
Comorbid conditions (autoimmune disease, hypertension, cardiovascular disease) may play a role in the development of pleural effusions. Patients with these conditions, therefore, may need closer monitoring.

17. Dasatinib-induced pleural effusions &Thrombocytopenia
42-year-old man, CML AP
CHR but only PCyR after IM 600mg/d for one year
Shift to dasatinib (DA)140 mg/d
Gr 4 thrombocytopenia w Gr 3 pleural effusion
Hold DA then he was back to Gr 1 AEs
Resume DA at 100 mg/d, CCyR achieved (6M post DA)
Gr 4 AEs again, PLT transfusion w diuretics
Loss of CCyR (18M post DA)
Allogeneic HSCT w unrelated donor
Remained CMR 7 years post-allo-HSCT

18. Nilotinib Common Side Effects (All Patients, All Grades)
Rash 33%
Pruritis (itching) 29%
Nausea 31%
Headache 31%
Fatigue 28%
Diarrhea 22%
Constipation 21%
Vomiting 21%
Arthralgias 18%
Cough 17%
Special considerations in using nilotinib are related to QT interval prolongation.
Patients with hypokalemia, hypomagnesemia, or long QT syndrome should be avoided or employed with caution.
Nilotinib should not be used with strong CYP3A4 inhibitors.
ECG should be conducted before starting nilotinib, 7 days after initiation of therapy, with any dose changes, and regularly during treatment.

19. Nilotinib: Hepatotoxicity
Use with caution in patients with known hepatic impairment.
Liver enzyme and bilirubin elevations are often transient, resolve with short treatment break.
Elevated lipase and amylase may occur.
Pancreatitis has also occurred.
● Elevated serum levels of lipase, amylase, bilirubin, and/or hepatic transaminases (grade >3 ) serum levels return to grade < 1. Resume nilotinib at 400 mg once daily.

20. Nilotinib induced Hyperbilirubinemia
42-year-old man, CML CP
Nilotinib 300 mg bid as 1st line treatment
CCyR with CMR achieved 3M post NI
Gr 3 Hyperbilirubinemia & Gr 2 ALT elevation
Adjust NI to 400 mg/d
Gr 2 Hyperbilirubinemia without malaise, so hold NI
resumed NI at 400 mg/d when AE returned to Gr 1
Resolution of Hyperbilirubinemia 6M after resuming NI
Now on NI 400 mg/d, CML remains CMR

21. Summary
All 3 TKI’s well-tolerated compared to traditional chemotherapy and interferon.
With aggressive adverse effects management, most patients have good quality of life.
Adverse effects generally decrease over time.
Management of side effects is essential to encourage compliance or adherence.