Managing Gleevec Side EffectsManaging Gleevec Side EffectsPresented by: The Life Raft GroupPresented by: The Life Raft Group

February 8, 2006February 8, 2006

Special thanks to Jonathan Trent, M.D., Ph.D., Special thanks to Jonathan Trent, M.D., Ph.D., Department of Sarcoma, MD Anderson Cancer Department of Sarcoma, MD Anderson Cancer Center, for his helpful comments. Center, for his helpful comments. (Dr. Trents’ personal observations are noted in blue)

Gleevec Side Effects

Despite publicity to the contrary, Gleevec can have significant side effects

But side effects do tend to get better over time• Could be related to the theory of Gleevec drug levels

falling over time (levels can decrease 40% over 12 months)

Being able to manage Gleevec side effects is a key step that allows patients to take their Gleevec as prescribed

Patient/Doctor Communications

It is important for patients to report side effects and discuss their management with their doctor

The material presented here is for information purposes only• It is not a substitute for talking to your doctor

Common Side Effects

Fatigue Anemia Nausea or vomiting Diarrhea Edema/fluid retention Cramps

Rash/skin problems Joint pain Eyes

• Itchy, watery eyes• Bleeding (less often)

Sensitive to sunlight

Less Common Side Effects

Bleeding Elevated liver function tests (detected on a blood test) Kidney problems Serious edema (fluid retention) Hematological (blood counts) including

neutropenia (low neutrophil counts) Hypothyroidism (low thyroid function)

Dose-related side effects

Edema Fatigue Anemia Rash

• -however female gender may be a higher risk factor Bleeding Nausea Diarrhea Hematological effects (effects on blood counts) These are worse in patients started at 800mg compared to

patients started at 400mg. Starting at 400mg for 4 weeks then increasing to 800 mg may help patients tolerate the higher dose. It does in my experience and is supported by a study at ASCO (Dileo et al, ASCO 2005)

Fatigue/anemia-the number 1 complaint

KIT signaling is important to the formation of blood cells, including red blood cells• Suppression of normal blood cell formation is estimated to be

minor, in the range of 10% to 20% Sutent may suppress blood counts more as it also inhibits

FLT-3, another important growth factor for blood cells Anemia can be caused by:

• Bleeding (which can be undetected)• Iron deficiency and B12 deficiency- both common in patients who

have had stomach surgery. These can all be tested for by a doctor.

Some report fatigue a few hours after taking Gleevec

Growth Factors affecting HematopoiesisAMGEN®

Fatigue/anemia solutions

Some patients benefit from Procrit/Aranesp (EPO) shots• These growth factors can stimulate red blood cell production• Some patients require a higher dose• EPO increases hemoglobin levels in most anemic GIST patients

who have not progressed under imatinib treatment, but not in refractory GIST patients*

We have anecdotal reports of benefit from iron supplementation (in some patients?)• Patients should talk to their doctor before taking iron on their own• There are IV formulations if patients are nauseated. I use IV iron all

the time. Increased rest helps some patients B12 may need to be given as an injection like EPO since

pills may not be absorbed if some of the stomach is missing.

*ASCO 2004-abstract 9046

Nausea

Likely caused by local irritant properties of the drug Take Gleevec with a meal and a large glass of water Spread out Gleevec during the meal, i.e., eat a little, take

a Gleevec, eat a little more, take another Gleevec, etc. In severe/continuing cases, your doctor might split your

dose. This has reduced nausea and other side effects in some patients

Anti-nausea medications may help (Compazine or Zofran) Patients with a history of esophagitis or hiatal hernia

should take Gleevec at least 2 hours before bedtime Patient-reported solutions

• “Medicinal chocolate”• “Sweet potato”

Diarrhea solutions

May be related to inhibition of KIT in ICC or due to local irritant effect of the drug

Usually manageable with antidiarrheal meds, i.e., Imodium

Other “Patient solutions” (talk to your doctor first)• Denatured tincture of opium (DTO) …10-12 drops in

water every four hours• ½ pint of flavored or plain yogurt at bedtime• Abnormal intestinal flora? Improved with Amoxicillin.• Bioflorin Giuliani capsules during antibiotic treatment

Rash/skin problems

More common in females and at higher doses Varies from mild to severe Varies in cause and treatment:

• Shingles (treated with antiviral, steroids makes it worsen)• True Gleevec drug rash (most common)• Heat sensitivity• Fungal infection (ringworm, steroids may make it worsen)• Cellulitis (requires an antibiotic)

May require referral to a dermatologist Rashes are the most common side effect requiring

permanent discontinuation of Gleevec

Rash/skin problems-2

Most cases are mild and self-limiting• Treatable with antihistamines or topical steroids

Moderate cases • Oral steroids (prednisone) (depending on cause)

Severe cases (depending on cause)

• Immediate discontinuation of Gleevec and systemic steroids

• Restart Gleevec with prednisone and taper off the prednisone over several weeks

Mild rash/itching

Patient reported remedies• Neutrogena anti itch lotion• Florisone• Zyrtec• Sarna cream• Gold Bond medicated anti-itch cream

For neuropathy (nerve pain)• Neurontin (provides pain relief, but does not prevent

nerve damage)

Edema/fluid retention

Dose-related Periorbital (around the eyes) edema is common

• Typically worse in the morning• Some patients report limiting salt intake may help• Topical phenylephrin 0.25% may help• Antihistamine like claritin or zyrtec

Lower-extremity edema is also seen• Lasix with potassium supplements is a common treatment

Generalized/severe fluid retention is rare• Potentially life threating!• Pulmonary, pleural or pericardial effusion, ascites, anasarca, and

cerebral edema.

Edema/fluid retention-2

Risk factors• Female• Over 65• History of cardiac or renal problems

In older patients with a history of cardiac or renal impairment, starting Gleevec at a lower dose may be advisable

Patients should be monitored for rapid weight gain Severe fluid retention is usually treated by:

• Stopping Gleevec• Control edema with diuretics• Restart Gleevec, possibly at a lower dose while maintaining or

increasing diuretic (may need to start at a very low dose, ie 50 mg a day, and increase to 400 mg over 6-8 weeks. I’ve done this with several patients)

Cramps/bone and joint pain

Cramps in hands, feet, calves and thighs Calcium and magnesium levels may drop over

time while taking Gleevec Supplementation with calcium and magnesium

may improve symptoms. Vitamin D helps absorb calcium.

Quinine or quinine water may also be helpful Patient reported remedies

• Soma (carisoprodol) and quinine sulfate• Gatorade/powerade

Eyes

Bleeding in the eyes may occur several times a year or more• Usually looks worse than it is• Usually affects only one eye at a time• Usually clears up in a few days without any specific

treatment Itchy, teary eyes I treat with artificial tears 2 drops

each eye 4 times a day

Sensitivity to sunlight

KIT signaling is important in melanocytes Melanocytes produce the pigment in the skin Gleevec may make skin more susceptible to

sunburn by inhibition of KIT signaling in melanocytes

Limit sun exposure, but no not completely avoid the sun• Sunlight is the best source of Vitamin D!

Bleeding

An uncommon, but potentially serious side effect Observed in GIST patients in the pre-Gleevec era May bleed into the GI tract

• Liver tumors may also bleed Not observed in the adjuvant Gleevec trials

• Related more to GIST than to Gleevec?AND/OR

• Related to Gleevec’s effects on some tumors? Dose related, some patients (on higher doses)

with bleeding may benefit from a dose reduction One theory is that tumors that are rapidly

shrinking (from Gleevec) may rip blood vessels

Elevated liver enzymes

Rare side effect-may have several different causes

One CML patient died from liver failure• Patient was taking a fairly high dose of Tylenol for a

month prior to starting Gleevec (but dose was below the maximum dose)

• Patient was also taking Diflucan (which can cause liver problems)

Some LRG patients report that taking pomegranate juice resulted in a reduction of liver enzymes

Elevated liver enzymes- autoimmune hepatitis

At least three LRG patients (and others in the literature) developed drug-induced autoimmune hepatitis while taking Gleevec• This was not always diagnosed promptly• Responds to steroid therapy (prednisone) and imuran

(an immunosuppressive agent)• Blood tests for ANA antibody may help detect this, but

this was only mildly elevated in some patients– Liver biopsies might also be recommended

• Might it be reasonable to try a course of prednisone without the biopsy?

• ALT (and to a lesser extent AST) may be most affected enzymes

Kidney problems

Reduced kidney function has been reported (rare) These cases have usually been related to

prolonged use of Gleevec• A dose reduction may be needed

Do multiple CT scans with contrast contribute to this problem? • Possibly, particularly in patients who are not drinking

adequate fluids and are dehydrated

Neutropenia

Lowered count of neutrophils (below 1.0) A rare side effect of Gleevec Tends to decrease over time May require dose interruption and/or growth factor

support • Growth factor support can be used to prevent dose

reduction or interruption. The growth factor support is not always permanent.

Hypothyroidism

Sutent may result in hypothyroidism• Very rare with Gleevec

Patients taking these drugs should have thyroid function monitored especially if taking Sutent

Can be corrected with thyroid hormone supplementation

Gleevec or GIST?

Although Gleevec causes side-effects, so does a growing tumor

Telling the difference between the effects of the tumor and the side-effects of Gleevec is not always easy