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, 2009 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) (N 551)
Fatigue 39 1.8
Headache 37 0.5
Dizziness 19 0.9
Cough 20 0.2
Nasopharyngitis 31 0
URI 21 0.2
Pyrexia 18 0.9
Sore throat 18 0.2
Influenza 14 0.2
Sinusitis 11 0.2
Hemorrhage 29 1.8
GI hemorrhage 2 0.5
CNS hemorrhage <1 0

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.  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
IMATINIB-INDUCED THROMBOCYTOPENIA

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) (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) (N=551)
Nausea 50 1.3
Diarrhea 45 3.3
Abdominal pain 37 4.2
Vomiting 23 2
Dyspepsia 19 0
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) (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) (N=551)
Skin rashes 40 2.9
Insomnia 15 0
Depression 15 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. 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.
IMATINIB

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%
 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
Rash 22%
Fatigue 21%
Hemorrhage 21%
Dyspnea 20%
Musculoskeletal pain 14%

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.