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Safety

Managing Side Effects

FDA-cited adverse-event profiles and management guidance for GIST tyrosine-kinase inhibitors.

4 treatments 72 associations
For clinician use. This page summarizes published adverse-event profiles to inform clinical discussion. Individual patient risk profiles, comorbidities, and drug interactions may modify the likelihood and severity of these effects. It does not direct management — review against current product labeling and guidelines.

Avapritinib 300mg daily

Abdominal Pain
Grade 1–3 Very Common (>30%)

Stomach and belly pain or cramping. FDA label Table 12: abdominal pain/cramping 57.2% all grades, 13.8% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: abdominal pain grouped 31%, 6% Grade ≥3 (N=204). May relate to GI irritation from oral TKI or tumor-related symptoms.

Clinical management: Differentiate drug-related pain from disease progression or surgical complication. Rule out GI perforation (Section 5.6) if acute severe pain. Mild: dietary adjustment, antacids. Moderate: evaluate with imaging if new pattern. H2 blocker or PPI if dyspeptic component. Grade 3+: hold TKI per Section 2.13, surgical evaluation.
⚠️ When to escalate: Sudden sharp belly pain that is very bad, belly pain with fever, belly pain with throwing up and you cannot keep fluids down, blood in your stool with belly pain.
Cognitive Effects / Memory Impairment
Grade 1–3 Very Common (>30%)

Difficulties with memory, concentration, word-finding, and executive function. FDA label Section 5.2: cognitive effects in 41% of GIST patients (N=204), 5% Grade ≥3. Table 5: grouped cognitive impairment 48%. Memory impairment 21%, cognitive disorder 12%. Related to avapritinib CNS penetration.

Clinical management: FDA-identified risk — counsel patients and caregivers before starting. Baseline cognitive assessment recommended. Grade 1: continue with monitoring. Grade 2: dose reduce to 200mg per Section 2.3. Grade 3: hold until ≤ Grade 1, then restart at reduced dose or discontinue. Neuropsychological testing if functional impact. Screen for depression which can mimic.
⚠️ When to escalate: Big memory problems that get in the way of your daily life, feeling confused, trouble with tasks you used to do easily, changes in your behavior that your family notices — tell your care team soon.
Decreased Appetite
Grade 1–3 Very Common (>30%)

Reduced desire to eat, with or without weight loss. FDA label Table 12: anorexia 31.1% all grades, 6.6% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: decreased appetite 38%, 2.9% Grade ≥3 (N=204). Can impact nutritional status over long treatment duration.

Clinical management: Monitor weight at each visit. Nutrition referral if >5% weight loss. Appetite stimulants (megestrol, dronabinol) for persistent Grade 2+. Rule out contributing factors: nausea, taste changes, depression. Calorie-dense supplements. Dose reduction per Section 2.13 if severe.
⚠️ When to escalate: Losing weight without trying (more than 5 pounds in a month), not able to eat enough to keep your weight up, feeling very weak from not eating.
Diarrhea
Grade 1–3 Very Common (>30%)

Frequent loose or watery stools. FDA label Table 12: diarrhea 56.2% all grades, 8.1% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: 37%, 4.9% Grade ≥3 (N=204). Usually mild and manageable.

Clinical management: Mild (Grade 1-2): loperamide PRN, dietary modification. Grade 3+: hold TKI until resolution per Section 2.13, then resume at same or reduced dose. Rule out infectious causes (C. difficile) if severe or febrile. Monitor electrolytes and hydration.
⚠️ When to escalate: More than 6 loose stools a day, blood in your stool, fever with diarrhea, signs you are dried out (dark pee, dizzy), diarrhea not getting better in 48 hours.
Fatigue
Grade 1–3 Very Common (>30%)

Persistent tiredness not fully relieved by rest. FDA label Table 12: fatigue/lethargy/malaise/asthenia 69.3% all grades, 11.7% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 5: 61%, 9% Grade ≥3. May involve anemia, thyroid dysfunction, or sleep disruption.

Clinical management: Screen for contributing factors at each visit: check CBC (anemia), TSH (thyroid), iron studies. Exercise oncology referral — physical activity is the strongest evidence-based intervention. Adjust medication timing if fatigue is time-dependent (some patients do better taking TKI at bedtime).
⚠️ When to escalate: Tiredness so bad you cannot take care of yourself, sudden new tiredness that gets much worse (may mean low blood counts or thyroid problems).
Increased Lacrimation (Watery Eyes)
Grade 1–2 Very Common (>30%)

Excessive tearing of the eyes. FDA Ayvakit Table 5: increased lacrimation 33% all grades, 0% Grade ≥3 in GIST (N=204). Also reported with imatinib. Usually mild and not vision-threatening. Related to TKI effects on lacrimal gland signaling.

Clinical management: Reassure patient — cosmetic nuisance, not dangerous. Ophthalmology referral only if visual symptoms, eye pain, or suspected infection. Artificial tears PRN. No dose modification typically required.
Nausea / Vomiting
Grade 1–3 Very Common (>30%)

Feeling sick to stomach with or without vomiting. FDA label Table 12: nausea 58.1% and vomiting 37.4% in metastatic GIST at 400mg (N=818). Ayvakit Table 5: nausea 64%, vomiting 38% (N=204). Usually mild to moderate with TKIs. Often manageable and improves over time.

Clinical management: Prescribe anti-emetic PRN (ondansetron 4-8mg). Recommend taking imatinib with food and a large glass of water to reduce GI irritation. Dose splitting (200mg BID instead of 400mg once) may reduce nausea. Dose reduction if persistent Grade 2+ despite anti-emetics per Section 2.13.
⚠️ When to escalate: Throwing up so much you cannot keep your medicine down, not able to eat or drink for more than 24 hours, signs you are dried out (dark pee, dizzy, dry mouth).
Periorbital Edema
Grade 1–3 Very Common (>30%)

Swelling around the eyes, often most noticeable in the morning. Caused by PDGFR inhibition in periocular tissues. FDA label Table 12: 76.7% all grades in metastatic GIST at 400mg (N=818). Severe fluid retention reported in 9-13.1% of GIST patients per Section 5.1.

Clinical management: Monitor severity at each visit. Grade 1-2: reassurance and observation. Grade 3+: dose reduction per Section 2.13, short-course diuretics (furosemide 20-40mg). Rule out nephrotic syndrome if generalized edema develops. Ophthalmology referral if visual symptoms.
⚠️ When to escalate: Sudden bad swelling of your face or throat, changes in your eyesight or eye pain, trouble breathing with face swelling.
Anemia
Grade 1–3 Common (10–30%)

Low red blood cell count causing fatigue, shortness of breath, and pale appearance. FDA label Table 12: anemia 32.0% all grades, 4.9% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 6: hemoglobin decreased Grade 3 in 7%, Grade 4 in 2.5%. May relate to GI blood loss or bone marrow suppression.

Clinical management: Monitor hemoglobin at each visit. Check iron studies, B12, folate, reticulocyte count. Mild (Hgb 10-12): observe. Moderate (Hgb 8-10): dose reduction per Section 2.13, iron supplementation if deficient. Severe (Hgb <8): hold TKI, transfusion if symptomatic, evaluate for GI bleeding source.
⚠️ When to escalate: Very tired and it stops you from doing daily things, hard to breathe when resting or with very little effort, chest pain, dizzy or feel like fainting, heart beating very fast.
Constipation
Grade 1–3 Common (10–30%)

Infrequent or difficult bowel movements. FDA label Table 12: constipation 14.8% all grades, 5.1% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: constipation 23%, 1.5% Grade ≥3 (N=204). May be worsened by anti-emetics (ondansetron) or decreased activity.

Clinical management: First-line: increased fluid intake, dietary fiber, stool softener (docusate). Second-line: osmotic laxative (polyethylene glycol). Avoid stimulant laxatives long-term. Rule out bowel obstruction if acute onset with abdominal distension. Consider ondansetron contribution.
⚠️ When to escalate: No bowel movement for 3 or more days, bad belly pain or bloating with constipation, throwing up with constipation.
Dyspnea (Shortness of Breath)
Grade 1–4 Common (10–30%)

Difficulty breathing or feeling short of breath. FDA label Table 12: dyspnea 13.6% all grades, 6.8% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: dyspnea 17%, 2.5% Grade ≥3 (N=204). May indicate pleural effusion (Section 5.1), anemia, or disease progression.

Clinical management: Evaluate urgently — differentiate fluid retention (pleural effusion per Section 5.1) from pulmonary embolism, pneumonia, or disease progression. Check SpO2, CBC (anemia), chest imaging. If pleural effusion: dose reduction/interruption per Section 2.13, thoracentesis if large. Echocardiogram to rule out cardiac cause.
⚠️ When to escalate: Suddenly hard to breathe, short of breath when resting or lying down, chest pain with breathing, coughing up blood, lips or fingers turning blue — get emergency help right away.
Headache
Grade 1–3 Common (10–30%)

Head pain, ranging from mild tension-type to severe. FDA label Table 12: headache 22.0% all grades, 5.7% Grade 3/4/5 in metastatic GIST (N=818). With avapritinib: new or severe headaches require urgent evaluation to rule out intracranial hemorrhage per Section 5.1.

Clinical management: Mild: acetaminophen PRN. Avoid NSAIDs if platelets low. With avapritinib: any new severe or unusual headache warrants urgent CT head to rule out ICH per FDA warning Section 5.1. Monitor for associated neurological symptoms. Persistent headache: evaluate for fluid retention, hypertension.
⚠️ When to escalate: Sudden bad headache that is not like your usual headaches (especially on avapritinib — this needs urgent checking), headache with vision changes, confusion, or weakness, headache that acetaminophen does not help.
Skin Rash / Dermatitis
Grade 1–3 Common (10–30%)

Skin irritation ranging from mild redness to significant eruptions. FDA label Table 12: rash/desquamation 38.1% all grades, 7.6% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 5: rash 23%, 2.1% Grade ≥3. Usually maculopapular on trunk and arms, appearing in first 1-2 months.

Clinical management: Grade 1: topical emollients, observation. Grade 2: topical corticosteroids (triamcinolone 0.1%), oral antihistamines for pruritus. Grade 3: hold TKI per Section 2.13, systemic steroids if needed, dermatology referral. Severe bullous or exfoliative rash: permanently discontinue.
⚠️ When to escalate: Blisters or peeling skin, rash over large parts of your body, rash with fever or mouth sores, open wounds on your skin.
Thrombocytopenia
Grade 1–4 Common (10–30%)

Low platelet count, increasing bleeding risk. FDA: more common with avapritinib — Ayvakit Table 6: platelet count decreased Grade 3 in 10%, Grade 4 in 7%. Contributes to hemorrhage risk. Requires careful monitoring, especially with avapritinib.

Clinical management: Monitor platelets at baseline, weekly for 4 weeks, then monthly. Grade 3 (25,000-50,000): hold until ≥75,000, resume at same dose per Section 2.3. Grade 4 (<25,000): hold until ≥75,000, resume at reduced dose. Avoid concurrent anticoagulants with avapritinib. Platelet transfusion for active bleeding.
⚠️ When to escalate: Bleeding that is not normal or lasts a long time, blood in your pee or stool, heavy nosebleeds, big bruises showing up without getting hurt, tiny red dots on your skin, bad headache (with avapritinib — may mean bleeding in your brain).
Hepatotoxicity
Grade 1–4 Uncommon (1–10%)

Liver inflammation detected by elevated liver enzymes (ALT/AST) and/or bilirubin. FDA label Section 5.4: Grade 3/4 ALT elevations in 6.8% of Phase 2 GIST patients. Ayvakit Table 6: ALT increased Grade 3 in 2%, Grade 4 in 0.5%. Usually reversible with dose modification.

Clinical management: Baseline LFTs before starting. Monitor monthly for first 3 months, then at each visit. Grade 2 (ALT/AST 3-5× ULN): hold until ≤ Grade 1, resume at same dose. Grade 3 (5-20× ULN): hold until ≤ Grade 1, resume at reduced dose per Section 2.13. Grade 4: permanently discontinue. Rule out viral hepatitis.
⚠️ When to escalate: Skin or eyes turning yellow (jaundice), dark-colored pee, very tired with pain on the right side of your belly, bleeding or bruising that is not normal.
Tumor Hemorrhage
Grade 2–4 Uncommon (1–10%)

Bleeding from the tumor site, particularly relevant for GI-located tumors. FDA label Section 5.5: Grade 3/4 hemorrhage in 12.9% in Phase 3 GIST trial. Table 12: hemorrhage (other) 12.3% all grades, 6.7% Grade 3/4/5. Can occur early as tumor responds (necrosis). GI tumor sites may be the source.

Clinical management: Counsel patients about GI bleeding risk, especially in first 1-2 months. Baseline hemoglobin. Low threshold for endoscopy if GI bleeding signs. Hold TKI for significant hemorrhage per Section 2.13, resume after stabilization. Surgery consultation for uncontrolled bleeding.
⚠️ When to escalate: Black or tarry stools, throwing up blood or stuff that looks like coffee grounds, sudden belly pain, feeling lightheaded or dizzy, fast heartbeat — get medical help right away.
Intracranial Hemorrhage
Grade 3–5 Rare (<1%)

Bleeding inside the skull. FDA label Section 5.1: intracranial hemorrhage in 1.1% of GIST patients (0.7% Grade ≥3). Risk may be increased with concurrent anticoagulation. Avapritinib must be permanently discontinued if ICH occurs per Section 2.3.

Clinical management: FDA warning — discuss risk before starting. Avoid concurrent anticoagulants and antiplatelet agents if possible. Baseline brain MRI if history of CNS lesions. Immediate discontinuation if suspected. Urgent CT head for new severe headache. Monitor platelets closely. Do NOT restart after confirmed ICH per Section 2.3.
⚠️ When to escalate: Sudden bad headache unlike any you have had before, sudden confusion or trouble speaking, sudden weakness or numbness on one side, sudden vision changes, passing out — CALL 911 RIGHT AWAY.

Imatinib 400mg daily

Abdominal Pain
Grade 1–3 Very Common (>30%)

Stomach and belly pain or cramping. FDA label Table 12: abdominal pain/cramping 57.2% all grades, 13.8% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: abdominal pain grouped 31%, 6% Grade ≥3 (N=204). May relate to GI irritation from oral TKI or tumor-related symptoms.

Clinical management: Differentiate drug-related pain from disease progression or surgical complication. Rule out GI perforation (Section 5.6) if acute severe pain. Mild: dietary adjustment, antacids. Moderate: evaluate with imaging if new pattern. H2 blocker or PPI if dyspeptic component. Grade 3+: hold TKI per Section 2.13, surgical evaluation.
⚠️ When to escalate: Sudden sharp belly pain that is very bad, belly pain with fever, belly pain with throwing up and you cannot keep fluids down, blood in your stool with belly pain.
Anemia
Grade 1–3 Very Common (>30%)

Low red blood cell count causing fatigue, shortness of breath, and pale appearance. FDA label Table 12: anemia 32.0% all grades, 4.9% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 6: hemoglobin decreased Grade 3 in 7%, Grade 4 in 2.5%. May relate to GI blood loss or bone marrow suppression.

Clinical management: Monitor hemoglobin at each visit. Check iron studies, B12, folate, reticulocyte count. Mild (Hgb 10-12): observe. Moderate (Hgb 8-10): dose reduction per Section 2.13, iron supplementation if deficient. Severe (Hgb <8): hold TKI, transfusion if symptomatic, evaluate for GI bleeding source.
⚠️ When to escalate: Very tired and it stops you from doing daily things, hard to breathe when resting or with very little effort, chest pain, dizzy or feel like fainting, heart beating very fast.
Decreased Appetite
Grade 1–3 Very Common (>30%)

Reduced desire to eat, with or without weight loss. FDA label Table 12: anorexia 31.1% all grades, 6.6% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: decreased appetite 38%, 2.9% Grade ≥3 (N=204). Can impact nutritional status over long treatment duration.

Clinical management: Monitor weight at each visit. Nutrition referral if >5% weight loss. Appetite stimulants (megestrol, dronabinol) for persistent Grade 2+. Rule out contributing factors: nausea, taste changes, depression. Calorie-dense supplements. Dose reduction per Section 2.13 if severe.
⚠️ When to escalate: Losing weight without trying (more than 5 pounds in a month), not able to eat enough to keep your weight up, feeling very weak from not eating.
Diarrhea
Grade 1–3 Very Common (>30%)

Frequent loose or watery stools. FDA label Table 12: diarrhea 56.2% all grades, 8.1% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: 37%, 4.9% Grade ≥3 (N=204). Usually mild and manageable.

Clinical management: Mild (Grade 1-2): loperamide PRN, dietary modification. Grade 3+: hold TKI until resolution per Section 2.13, then resume at same or reduced dose. Rule out infectious causes (C. difficile) if severe or febrile. Monitor electrolytes and hydration.
⚠️ When to escalate: More than 6 loose stools a day, blood in your stool, fever with diarrhea, signs you are dried out (dark pee, dizzy), diarrhea not getting better in 48 hours.
Fatigue
Grade 1–3 Very Common (>30%)

Persistent tiredness not fully relieved by rest. FDA label Table 12: fatigue/lethargy/malaise/asthenia 69.3% all grades, 11.7% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 5: 61%, 9% Grade ≥3. May involve anemia, thyroid dysfunction, or sleep disruption.

Clinical management: Screen for contributing factors at each visit: check CBC (anemia), TSH (thyroid), iron studies. Exercise oncology referral — physical activity is the strongest evidence-based intervention. Adjust medication timing if fatigue is time-dependent (some patients do better taking TKI at bedtime).
⚠️ When to escalate: Tiredness so bad you cannot take care of yourself, sudden new tiredness that gets much worse (may mean low blood counts or thyroid problems).
Fluid Retention / Weight Gain
Grade 1–3 Very Common (>30%)

Generalized fluid accumulation causing weight gain, swollen legs, or abdominal bloating. FDA label Section 5.1: severe fluid retention in 9-13.1% of GIST patients. Table 12: edema 76.7% all grades, weight gain 12.0% at 400mg. Can include pleural effusion or ascites in severe cases.

Clinical management: Baseline weight and monitor at each visit. Mild edema: dietary sodium restriction, compression stockings. Moderate: add diuretic (furosemide). Severe (pleural effusion, ascites): dose reduction or interruption per Section 2.13. Echocardiogram if new-onset — rule out cardiac etiology.
⚠️ When to escalate: Gaining more than 3 pounds in one week, hard to breathe, belly getting bigger, chest feels tight, cannot lie flat — these may mean fluid around your lungs.
Muscle Cramps
Grade 1–3 Very Common (>30%)

Involuntary painful muscle contractions, most commonly in hands, feet, calves, and thighs. FDA label Table 12: myalgia 32.2% all grades in metastatic GIST (N=818). Table 14: muscle spasms 16.3% in adjuvant GIST (N=337). Often worse at night. Related to TKI effects on muscle cell signaling.

Clinical management: First-line: calcium and magnesium supplementation. Quinine is contraindicated per FDA safety warning. Dose reduction if Grade 3 cramps limiting function per Section 2.13. Rule out electrolyte abnormalities (Ca²⁺, Mg²⁺, K⁺).
⚠️ When to escalate: Cramps so bad you cannot walk or do daily tasks, muscle weakness that does not go away, cramps with dark-colored urine.
Nausea / Vomiting
Grade 1–3 Very Common (>30%)

Feeling sick to stomach with or without vomiting. FDA label Table 12: nausea 58.1% and vomiting 37.4% in metastatic GIST at 400mg (N=818). Ayvakit Table 5: nausea 64%, vomiting 38% (N=204). Usually mild to moderate with TKIs. Often manageable and improves over time.

Clinical management: Prescribe anti-emetic PRN (ondansetron 4-8mg). Recommend taking imatinib with food and a large glass of water to reduce GI irritation. Dose splitting (200mg BID instead of 400mg once) may reduce nausea. Dose reduction if persistent Grade 2+ despite anti-emetics per Section 2.13.
⚠️ When to escalate: Throwing up so much you cannot keep your medicine down, not able to eat or drink for more than 24 hours, signs you are dried out (dark pee, dizzy, dry mouth).
Periorbital Edema
Grade 1–3 Very Common (>30%)

Swelling around the eyes, often most noticeable in the morning. Caused by PDGFR inhibition in periocular tissues. FDA label Table 12: 76.7% all grades in metastatic GIST at 400mg (N=818). Severe fluid retention reported in 9-13.1% of GIST patients per Section 5.1.

Clinical management: Monitor severity at each visit. Grade 1-2: reassurance and observation. Grade 3+: dose reduction per Section 2.13, short-course diuretics (furosemide 20-40mg). Rule out nephrotic syndrome if generalized edema develops. Ophthalmology referral if visual symptoms.
⚠️ When to escalate: Sudden bad swelling of your face or throat, changes in your eyesight or eye pain, trouble breathing with face swelling.
Skin Rash / Dermatitis
Grade 1–3 Very Common (>30%)

Skin irritation ranging from mild redness to significant eruptions. FDA label Table 12: rash/desquamation 38.1% all grades, 7.6% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 5: rash 23%, 2.1% Grade ≥3. Usually maculopapular on trunk and arms, appearing in first 1-2 months.

Clinical management: Grade 1: topical emollients, observation. Grade 2: topical corticosteroids (triamcinolone 0.1%), oral antihistamines for pruritus. Grade 3: hold TKI per Section 2.13, systemic steroids if needed, dermatology referral. Severe bullous or exfoliative rash: permanently discontinue.
⚠️ When to escalate: Blisters or peeling skin, rash over large parts of your body, rash with fever or mouth sores, open wounds on your skin.
Arthralgia / Bone Pain
Grade 1–3 Common (10–30%)

Joint and bone pain, particularly in the limbs and back. FDA label Table 12: arthralgia 13.6%, myalgia 32.2% in metastatic GIST (N=818). May relate to fluid shifts in joint spaces or periosteal effects. Can be persistent over long treatment duration.

Clinical management: First-line: acetaminophen or NSAIDs (if no GI concerns and platelets adequate). Physical therapy referral for persistent symptoms. Rule out disease progression if new-onset bone pain after prolonged treatment. Consider dose reduction for Grade 3 per Section 2.13.
⚠️ When to escalate: New bone pain after months on treatment (needs pictures to check for disease changes), pain that keeps you from sleeping or doing daily things, joint swelling or redness.
Constipation
Grade 1–3 Common (10–30%)

Infrequent or difficult bowel movements. FDA label Table 12: constipation 14.8% all grades, 5.1% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: constipation 23%, 1.5% Grade ≥3 (N=204). May be worsened by anti-emetics (ondansetron) or decreased activity.

Clinical management: First-line: increased fluid intake, dietary fiber, stool softener (docusate). Second-line: osmotic laxative (polyethylene glycol). Avoid stimulant laxatives long-term. Rule out bowel obstruction if acute onset with abdominal distension. Consider ondansetron contribution.
⚠️ When to escalate: No bowel movement for 3 or more days, bad belly pain or bloating with constipation, throwing up with constipation.
Dyspnea (Shortness of Breath)
Grade 1–4 Common (10–30%)

Difficulty breathing or feeling short of breath. FDA label Table 12: dyspnea 13.6% all grades, 6.8% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: dyspnea 17%, 2.5% Grade ≥3 (N=204). May indicate pleural effusion (Section 5.1), anemia, or disease progression.

Clinical management: Evaluate urgently — differentiate fluid retention (pleural effusion per Section 5.1) from pulmonary embolism, pneumonia, or disease progression. Check SpO2, CBC (anemia), chest imaging. If pleural effusion: dose reduction/interruption per Section 2.13, thoracentesis if large. Echocardiogram to rule out cardiac cause.
⚠️ When to escalate: Suddenly hard to breathe, short of breath when resting or lying down, chest pain with breathing, coughing up blood, lips or fingers turning blue — get emergency help right away.
Headache
Grade 1–3 Common (10–30%)

Head pain, ranging from mild tension-type to severe. FDA label Table 12: headache 22.0% all grades, 5.7% Grade 3/4/5 in metastatic GIST (N=818). With avapritinib: new or severe headaches require urgent evaluation to rule out intracranial hemorrhage per Section 5.1.

Clinical management: Mild: acetaminophen PRN. Avoid NSAIDs if platelets low. With avapritinib: any new severe or unusual headache warrants urgent CT head to rule out ICH per FDA warning Section 5.1. Monitor for associated neurological symptoms. Persistent headache: evaluate for fluid retention, hypertension.
⚠️ When to escalate: Sudden bad headache that is not like your usual headaches (especially on avapritinib — this needs urgent checking), headache with vision changes, confusion, or weakness, headache that acetaminophen does not help.
Neutropenia
Grade 2–4 Common (10–30%)

Low white blood cell count (neutrophils), increasing infection risk. FDA label Table 12: neutropenia 11.5%, leukopenia 17.0% in metastatic GIST at 400mg (N=818). Ayvakit Table 6: neutrophil count decreased Grade 3 in 7%, Grade 4 in 3.4%. Usually early in treatment (first 1-3 months).

Clinical management: Monitor CBC weekly for the first month, then at each visit. Grade 3 (ANC 500-1000): hold TKI until ANC ≥1500, resume at same dose per Section 2.13. Grade 4 (ANC <500): hold until ANC ≥1500, resume at reduced dose. G-CSF is rarely needed with TKIs.
⚠️ When to escalate: A temperature of 100.4°F (38°C) or higher — this is an EMERGENCY, go to the hospital right away. Also: shaking chills, sore throat, cough, burning when you pee while your blood counts are low.
Skin Depigmentation
Grade 1–2 Common (10–30%)

Lightening of skin color, particularly noticeable in patients with darker skin tones. Caused by imatinib inhibition of KIT signaling in melanocytes. Avapritinib: hair color changes in 21% per Table 5 (N=204). Typically reversible after discontinuation.

Clinical management: Counsel patients proactively before starting treatment — cosmetic, not dangerous. No treatment required. Document extent and reassure. Skin color typically returns 3-6 months after discontinuation. Sun protection advised for affected areas.
Tumor Hemorrhage
Grade 2–4 Common (10–30%)

Bleeding from the tumor site, particularly relevant for GI-located tumors. FDA label Section 5.5: Grade 3/4 hemorrhage in 12.9% in Phase 3 GIST trial. Table 12: hemorrhage (other) 12.3% all grades, 6.7% Grade 3/4/5. Can occur early as tumor responds (necrosis). GI tumor sites may be the source.

Clinical management: Counsel patients about GI bleeding risk, especially in first 1-2 months. Baseline hemoglobin. Low threshold for endoscopy if GI bleeding signs. Hold TKI for significant hemorrhage per Section 2.13, resume after stabilization. Surgery consultation for uncontrolled bleeding.
⚠️ When to escalate: Black or tarry stools, throwing up blood or stuff that looks like coffee grounds, sudden belly pain, feeling lightheaded or dizzy, fast heartbeat — get medical help right away.
Hepatotoxicity
Grade 1–4 Uncommon (1–10%)

Liver inflammation detected by elevated liver enzymes (ALT/AST) and/or bilirubin. FDA label Section 5.4: Grade 3/4 ALT elevations in 6.8% of Phase 2 GIST patients. Ayvakit Table 6: ALT increased Grade 3 in 2%, Grade 4 in 0.5%. Usually reversible with dose modification.

Clinical management: Baseline LFTs before starting. Monitor monthly for first 3 months, then at each visit. Grade 2 (ALT/AST 3-5× ULN): hold until ≤ Grade 1, resume at same dose. Grade 3 (5-20× ULN): hold until ≤ Grade 1, resume at reduced dose per Section 2.13. Grade 4: permanently discontinue. Rule out viral hepatitis.
⚠️ When to escalate: Skin or eyes turning yellow (jaundice), dark-colored pee, very tired with pain on the right side of your belly, bleeding or bruising that is not normal.

Imatinib 400mg daily (Extended/Indefinite)

Abdominal Pain
Grade 1–3 Very Common (>30%)

Stomach and belly pain or cramping. FDA label Table 12: abdominal pain/cramping 57.2% all grades, 13.8% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: abdominal pain grouped 31%, 6% Grade ≥3 (N=204). May relate to GI irritation from oral TKI or tumor-related symptoms.

Clinical management: Differentiate drug-related pain from disease progression or surgical complication. Rule out GI perforation (Section 5.6) if acute severe pain. Mild: dietary adjustment, antacids. Moderate: evaluate with imaging if new pattern. H2 blocker or PPI if dyspeptic component. Grade 3+: hold TKI per Section 2.13, surgical evaluation.
⚠️ When to escalate: Sudden sharp belly pain that is very bad, belly pain with fever, belly pain with throwing up and you cannot keep fluids down, blood in your stool with belly pain.
Anemia
Grade 1–3 Very Common (>30%)

Low red blood cell count causing fatigue, shortness of breath, and pale appearance. FDA label Table 12: anemia 32.0% all grades, 4.9% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 6: hemoglobin decreased Grade 3 in 7%, Grade 4 in 2.5%. May relate to GI blood loss or bone marrow suppression.

Clinical management: Monitor hemoglobin at each visit. Check iron studies, B12, folate, reticulocyte count. Mild (Hgb 10-12): observe. Moderate (Hgb 8-10): dose reduction per Section 2.13, iron supplementation if deficient. Severe (Hgb <8): hold TKI, transfusion if symptomatic, evaluate for GI bleeding source.
⚠️ When to escalate: Very tired and it stops you from doing daily things, hard to breathe when resting or with very little effort, chest pain, dizzy or feel like fainting, heart beating very fast.
Decreased Appetite
Grade 1–3 Very Common (>30%)

Reduced desire to eat, with or without weight loss. FDA label Table 12: anorexia 31.1% all grades, 6.6% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: decreased appetite 38%, 2.9% Grade ≥3 (N=204). Can impact nutritional status over long treatment duration.

Clinical management: Monitor weight at each visit. Nutrition referral if >5% weight loss. Appetite stimulants (megestrol, dronabinol) for persistent Grade 2+. Rule out contributing factors: nausea, taste changes, depression. Calorie-dense supplements. Dose reduction per Section 2.13 if severe.
⚠️ When to escalate: Losing weight without trying (more than 5 pounds in a month), not able to eat enough to keep your weight up, feeling very weak from not eating.
Diarrhea
Grade 1–3 Very Common (>30%)

Frequent loose or watery stools. FDA label Table 12: diarrhea 56.2% all grades, 8.1% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: 37%, 4.9% Grade ≥3 (N=204). Usually mild and manageable.

Clinical management: Mild (Grade 1-2): loperamide PRN, dietary modification. Grade 3+: hold TKI until resolution per Section 2.13, then resume at same or reduced dose. Rule out infectious causes (C. difficile) if severe or febrile. Monitor electrolytes and hydration.
⚠️ When to escalate: More than 6 loose stools a day, blood in your stool, fever with diarrhea, signs you are dried out (dark pee, dizzy), diarrhea not getting better in 48 hours.
Fatigue
Grade 1–3 Very Common (>30%)

Persistent tiredness not fully relieved by rest. FDA label Table 12: fatigue/lethargy/malaise/asthenia 69.3% all grades, 11.7% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 5: 61%, 9% Grade ≥3. May involve anemia, thyroid dysfunction, or sleep disruption.

Clinical management: Screen for contributing factors at each visit: check CBC (anemia), TSH (thyroid), iron studies. Exercise oncology referral — physical activity is the strongest evidence-based intervention. Adjust medication timing if fatigue is time-dependent (some patients do better taking TKI at bedtime).
⚠️ When to escalate: Tiredness so bad you cannot take care of yourself, sudden new tiredness that gets much worse (may mean low blood counts or thyroid problems).
Fluid Retention / Weight Gain
Grade 1–3 Very Common (>30%)

Generalized fluid accumulation causing weight gain, swollen legs, or abdominal bloating. FDA label Section 5.1: severe fluid retention in 9-13.1% of GIST patients. Table 12: edema 76.7% all grades, weight gain 12.0% at 400mg. Can include pleural effusion or ascites in severe cases.

Clinical management: Baseline weight and monitor at each visit. Mild edema: dietary sodium restriction, compression stockings. Moderate: add diuretic (furosemide). Severe (pleural effusion, ascites): dose reduction or interruption per Section 2.13. Echocardiogram if new-onset — rule out cardiac etiology.
⚠️ When to escalate: Gaining more than 3 pounds in one week, hard to breathe, belly getting bigger, chest feels tight, cannot lie flat — these may mean fluid around your lungs.
Nausea / Vomiting
Grade 1–3 Very Common (>30%)

Feeling sick to stomach with or without vomiting. FDA label Table 12: nausea 58.1% and vomiting 37.4% in metastatic GIST at 400mg (N=818). Ayvakit Table 5: nausea 64%, vomiting 38% (N=204). Usually mild to moderate with TKIs. Often manageable and improves over time.

Clinical management: Prescribe anti-emetic PRN (ondansetron 4-8mg). Recommend taking imatinib with food and a large glass of water to reduce GI irritation. Dose splitting (200mg BID instead of 400mg once) may reduce nausea. Dose reduction if persistent Grade 2+ despite anti-emetics per Section 2.13.
⚠️ When to escalate: Throwing up so much you cannot keep your medicine down, not able to eat or drink for more than 24 hours, signs you are dried out (dark pee, dizzy, dry mouth).
Periorbital Edema
Grade 1–3 Very Common (>30%)

Swelling around the eyes, often most noticeable in the morning. Caused by PDGFR inhibition in periocular tissues. FDA label Table 12: 76.7% all grades in metastatic GIST at 400mg (N=818). Severe fluid retention reported in 9-13.1% of GIST patients per Section 5.1.

Clinical management: Monitor severity at each visit. Grade 1-2: reassurance and observation. Grade 3+: dose reduction per Section 2.13, short-course diuretics (furosemide 20-40mg). Rule out nephrotic syndrome if generalized edema develops. Ophthalmology referral if visual symptoms.
⚠️ When to escalate: Sudden bad swelling of your face or throat, changes in your eyesight or eye pain, trouble breathing with face swelling.
Arthralgia / Bone Pain
Grade 1–3 Common (10–30%)

Joint and bone pain, particularly in the limbs and back. FDA label Table 12: arthralgia 13.6%, myalgia 32.2% in metastatic GIST (N=818). May relate to fluid shifts in joint spaces or periosteal effects. Can be persistent over long treatment duration.

Clinical management: First-line: acetaminophen or NSAIDs (if no GI concerns and platelets adequate). Physical therapy referral for persistent symptoms. Rule out disease progression if new-onset bone pain after prolonged treatment. Consider dose reduction for Grade 3 per Section 2.13.
⚠️ When to escalate: New bone pain after months on treatment (needs pictures to check for disease changes), pain that keeps you from sleeping or doing daily things, joint swelling or redness.
Constipation
Grade 1–3 Common (10–30%)

Infrequent or difficult bowel movements. FDA label Table 12: constipation 14.8% all grades, 5.1% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: constipation 23%, 1.5% Grade ≥3 (N=204). May be worsened by anti-emetics (ondansetron) or decreased activity.

Clinical management: First-line: increased fluid intake, dietary fiber, stool softener (docusate). Second-line: osmotic laxative (polyethylene glycol). Avoid stimulant laxatives long-term. Rule out bowel obstruction if acute onset with abdominal distension. Consider ondansetron contribution.
⚠️ When to escalate: No bowel movement for 3 or more days, bad belly pain or bloating with constipation, throwing up with constipation.
Dyspnea (Shortness of Breath)
Grade 1–4 Common (10–30%)

Difficulty breathing or feeling short of breath. FDA label Table 12: dyspnea 13.6% all grades, 6.8% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: dyspnea 17%, 2.5% Grade ≥3 (N=204). May indicate pleural effusion (Section 5.1), anemia, or disease progression.

Clinical management: Evaluate urgently — differentiate fluid retention (pleural effusion per Section 5.1) from pulmonary embolism, pneumonia, or disease progression. Check SpO2, CBC (anemia), chest imaging. If pleural effusion: dose reduction/interruption per Section 2.13, thoracentesis if large. Echocardiogram to rule out cardiac cause.
⚠️ When to escalate: Suddenly hard to breathe, short of breath when resting or lying down, chest pain with breathing, coughing up blood, lips or fingers turning blue — get emergency help right away.
Headache
Grade 1–3 Common (10–30%)

Head pain, ranging from mild tension-type to severe. FDA label Table 12: headache 22.0% all grades, 5.7% Grade 3/4/5 in metastatic GIST (N=818). With avapritinib: new or severe headaches require urgent evaluation to rule out intracranial hemorrhage per Section 5.1.

Clinical management: Mild: acetaminophen PRN. Avoid NSAIDs if platelets low. With avapritinib: any new severe or unusual headache warrants urgent CT head to rule out ICH per FDA warning Section 5.1. Monitor for associated neurological symptoms. Persistent headache: evaluate for fluid retention, hypertension.
⚠️ When to escalate: Sudden bad headache that is not like your usual headaches (especially on avapritinib — this needs urgent checking), headache with vision changes, confusion, or weakness, headache that acetaminophen does not help.
Hepatotoxicity
Grade 1–4 Common (10–30%)

Liver inflammation detected by elevated liver enzymes (ALT/AST) and/or bilirubin. FDA label Section 5.4: Grade 3/4 ALT elevations in 6.8% of Phase 2 GIST patients. Ayvakit Table 6: ALT increased Grade 3 in 2%, Grade 4 in 0.5%. Usually reversible with dose modification.

Clinical management: Baseline LFTs before starting. Monitor monthly for first 3 months, then at each visit. Grade 2 (ALT/AST 3-5× ULN): hold until ≤ Grade 1, resume at same dose. Grade 3 (5-20× ULN): hold until ≤ Grade 1, resume at reduced dose per Section 2.13. Grade 4: permanently discontinue. Rule out viral hepatitis.
⚠️ When to escalate: Skin or eyes turning yellow (jaundice), dark-colored pee, very tired with pain on the right side of your belly, bleeding or bruising that is not normal.
Muscle Cramps
Grade 1–3 Common (10–30%)

Involuntary painful muscle contractions, most commonly in hands, feet, calves, and thighs. FDA label Table 12: myalgia 32.2% all grades in metastatic GIST (N=818). Table 14: muscle spasms 16.3% in adjuvant GIST (N=337). Often worse at night. Related to TKI effects on muscle cell signaling.

Clinical management: First-line: calcium and magnesium supplementation. Quinine is contraindicated per FDA safety warning. Dose reduction if Grade 3 cramps limiting function per Section 2.13. Rule out electrolyte abnormalities (Ca²⁺, Mg²⁺, K⁺).
⚠️ When to escalate: Cramps so bad you cannot walk or do daily tasks, muscle weakness that does not go away, cramps with dark-colored urine.
Neutropenia
Grade 2–4 Common (10–30%)

Low white blood cell count (neutrophils), increasing infection risk. FDA label Table 12: neutropenia 11.5%, leukopenia 17.0% in metastatic GIST at 400mg (N=818). Ayvakit Table 6: neutrophil count decreased Grade 3 in 7%, Grade 4 in 3.4%. Usually early in treatment (first 1-3 months).

Clinical management: Monitor CBC weekly for the first month, then at each visit. Grade 3 (ANC 500-1000): hold TKI until ANC ≥1500, resume at same dose per Section 2.13. Grade 4 (ANC <500): hold until ANC ≥1500, resume at reduced dose. G-CSF is rarely needed with TKIs.
⚠️ When to escalate: A temperature of 100.4°F (38°C) or higher — this is an EMERGENCY, go to the hospital right away. Also: shaking chills, sore throat, cough, burning when you pee while your blood counts are low.
Skin Depigmentation
Grade 1–2 Common (10–30%)

Lightening of skin color, particularly noticeable in patients with darker skin tones. Caused by imatinib inhibition of KIT signaling in melanocytes. Avapritinib: hair color changes in 21% per Table 5 (N=204). Typically reversible after discontinuation.

Clinical management: Counsel patients proactively before starting treatment — cosmetic, not dangerous. No treatment required. Document extent and reassure. Skin color typically returns 3-6 months after discontinuation. Sun protection advised for affected areas.
Skin Rash / Dermatitis
Grade 1–3 Common (10–30%)

Skin irritation ranging from mild redness to significant eruptions. FDA label Table 12: rash/desquamation 38.1% all grades, 7.6% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 5: rash 23%, 2.1% Grade ≥3. Usually maculopapular on trunk and arms, appearing in first 1-2 months.

Clinical management: Grade 1: topical emollients, observation. Grade 2: topical corticosteroids (triamcinolone 0.1%), oral antihistamines for pruritus. Grade 3: hold TKI per Section 2.13, systemic steroids if needed, dermatology referral. Severe bullous or exfoliative rash: permanently discontinue.
⚠️ When to escalate: Blisters or peeling skin, rash over large parts of your body, rash with fever or mouth sores, open wounds on your skin.
Tumor Hemorrhage
Grade 2–4 Uncommon (1–10%)

Bleeding from the tumor site, particularly relevant for GI-located tumors. FDA label Section 5.5: Grade 3/4 hemorrhage in 12.9% in Phase 3 GIST trial. Table 12: hemorrhage (other) 12.3% all grades, 6.7% Grade 3/4/5. Can occur early as tumor responds (necrosis). GI tumor sites may be the source.

Clinical management: Counsel patients about GI bleeding risk, especially in first 1-2 months. Baseline hemoglobin. Low threshold for endoscopy if GI bleeding signs. Hold TKI for significant hemorrhage per Section 2.13, resume after stabilization. Surgery consultation for uncontrolled bleeding.
⚠️ When to escalate: Black or tarry stools, throwing up blood or stuff that looks like coffee grounds, sudden belly pain, feeling lightheaded or dizzy, fast heartbeat — get medical help right away.

Imatinib 800mg daily

Abdominal Pain
Grade 1–3 Very Common (>30%)

Stomach and belly pain or cramping. FDA label Table 12: abdominal pain/cramping 57.2% all grades, 13.8% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: abdominal pain grouped 31%, 6% Grade ≥3 (N=204). May relate to GI irritation from oral TKI or tumor-related symptoms.

Clinical management: Differentiate drug-related pain from disease progression or surgical complication. Rule out GI perforation (Section 5.6) if acute severe pain. Mild: dietary adjustment, antacids. Moderate: evaluate with imaging if new pattern. H2 blocker or PPI if dyspeptic component. Grade 3+: hold TKI per Section 2.13, surgical evaluation.
⚠️ When to escalate: Sudden sharp belly pain that is very bad, belly pain with fever, belly pain with throwing up and you cannot keep fluids down, blood in your stool with belly pain.
Anemia
Grade 1–3 Very Common (>30%)

Low red blood cell count causing fatigue, shortness of breath, and pale appearance. FDA label Table 12: anemia 32.0% all grades, 4.9% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 6: hemoglobin decreased Grade 3 in 7%, Grade 4 in 2.5%. May relate to GI blood loss or bone marrow suppression.

Clinical management: Monitor hemoglobin at each visit. Check iron studies, B12, folate, reticulocyte count. Mild (Hgb 10-12): observe. Moderate (Hgb 8-10): dose reduction per Section 2.13, iron supplementation if deficient. Severe (Hgb <8): hold TKI, transfusion if symptomatic, evaluate for GI bleeding source.
⚠️ When to escalate: Very tired and it stops you from doing daily things, hard to breathe when resting or with very little effort, chest pain, dizzy or feel like fainting, heart beating very fast.
Decreased Appetite
Grade 1–3 Very Common (>30%)

Reduced desire to eat, with or without weight loss. FDA label Table 12: anorexia 31.1% all grades, 6.6% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: decreased appetite 38%, 2.9% Grade ≥3 (N=204). Can impact nutritional status over long treatment duration.

Clinical management: Monitor weight at each visit. Nutrition referral if >5% weight loss. Appetite stimulants (megestrol, dronabinol) for persistent Grade 2+. Rule out contributing factors: nausea, taste changes, depression. Calorie-dense supplements. Dose reduction per Section 2.13 if severe.
⚠️ When to escalate: Losing weight without trying (more than 5 pounds in a month), not able to eat enough to keep your weight up, feeling very weak from not eating.
Diarrhea
Grade 1–3 Very Common (>30%)

Frequent loose or watery stools. FDA label Table 12: diarrhea 56.2% all grades, 8.1% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: 37%, 4.9% Grade ≥3 (N=204). Usually mild and manageable.

Clinical management: Mild (Grade 1-2): loperamide PRN, dietary modification. Grade 3+: hold TKI until resolution per Section 2.13, then resume at same or reduced dose. Rule out infectious causes (C. difficile) if severe or febrile. Monitor electrolytes and hydration.
⚠️ When to escalate: More than 6 loose stools a day, blood in your stool, fever with diarrhea, signs you are dried out (dark pee, dizzy), diarrhea not getting better in 48 hours.
Fatigue
Grade 1–3 Very Common (>30%)

Persistent tiredness not fully relieved by rest. FDA label Table 12: fatigue/lethargy/malaise/asthenia 69.3% all grades, 11.7% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 5: 61%, 9% Grade ≥3. May involve anemia, thyroid dysfunction, or sleep disruption.

Clinical management: Screen for contributing factors at each visit: check CBC (anemia), TSH (thyroid), iron studies. Exercise oncology referral — physical activity is the strongest evidence-based intervention. Adjust medication timing if fatigue is time-dependent (some patients do better taking TKI at bedtime).
⚠️ When to escalate: Tiredness so bad you cannot take care of yourself, sudden new tiredness that gets much worse (may mean low blood counts or thyroid problems).
Fluid Retention / Weight Gain
Grade 1–3 Very Common (>30%)

Generalized fluid accumulation causing weight gain, swollen legs, or abdominal bloating. FDA label Section 5.1: severe fluid retention in 9-13.1% of GIST patients. Table 12: edema 76.7% all grades, weight gain 12.0% at 400mg. Can include pleural effusion or ascites in severe cases.

Clinical management: Baseline weight and monitor at each visit. Mild edema: dietary sodium restriction, compression stockings. Moderate: add diuretic (furosemide). Severe (pleural effusion, ascites): dose reduction or interruption per Section 2.13. Echocardiogram if new-onset — rule out cardiac etiology.
⚠️ When to escalate: Gaining more than 3 pounds in one week, hard to breathe, belly getting bigger, chest feels tight, cannot lie flat — these may mean fluid around your lungs.
Muscle Cramps
Grade 1–3 Very Common (>30%)

Involuntary painful muscle contractions, most commonly in hands, feet, calves, and thighs. FDA label Table 12: myalgia 32.2% all grades in metastatic GIST (N=818). Table 14: muscle spasms 16.3% in adjuvant GIST (N=337). Often worse at night. Related to TKI effects on muscle cell signaling.

Clinical management: First-line: calcium and magnesium supplementation. Quinine is contraindicated per FDA safety warning. Dose reduction if Grade 3 cramps limiting function per Section 2.13. Rule out electrolyte abnormalities (Ca²⁺, Mg²⁺, K⁺).
⚠️ When to escalate: Cramps so bad you cannot walk or do daily tasks, muscle weakness that does not go away, cramps with dark-colored urine.
Nausea / Vomiting
Grade 1–3 Very Common (>30%)

Feeling sick to stomach with or without vomiting. FDA label Table 12: nausea 58.1% and vomiting 37.4% in metastatic GIST at 400mg (N=818). Ayvakit Table 5: nausea 64%, vomiting 38% (N=204). Usually mild to moderate with TKIs. Often manageable and improves over time.

Clinical management: Prescribe anti-emetic PRN (ondansetron 4-8mg). Recommend taking imatinib with food and a large glass of water to reduce GI irritation. Dose splitting (200mg BID instead of 400mg once) may reduce nausea. Dose reduction if persistent Grade 2+ despite anti-emetics per Section 2.13.
⚠️ When to escalate: Throwing up so much you cannot keep your medicine down, not able to eat or drink for more than 24 hours, signs you are dried out (dark pee, dizzy, dry mouth).
Periorbital Edema
Grade 1–3 Very Common (>30%)

Swelling around the eyes, often most noticeable in the morning. Caused by PDGFR inhibition in periocular tissues. FDA label Table 12: 76.7% all grades in metastatic GIST at 400mg (N=818). Severe fluid retention reported in 9-13.1% of GIST patients per Section 5.1.

Clinical management: Monitor severity at each visit. Grade 1-2: reassurance and observation. Grade 3+: dose reduction per Section 2.13, short-course diuretics (furosemide 20-40mg). Rule out nephrotic syndrome if generalized edema develops. Ophthalmology referral if visual symptoms.
⚠️ When to escalate: Sudden bad swelling of your face or throat, changes in your eyesight or eye pain, trouble breathing with face swelling.
Skin Rash / Dermatitis
Grade 1–3 Very Common (>30%)

Skin irritation ranging from mild redness to significant eruptions. FDA label Table 12: rash/desquamation 38.1% all grades, 7.6% Grade 3/4/5 in metastatic GIST (N=818). Ayvakit Table 5: rash 23%, 2.1% Grade ≥3. Usually maculopapular on trunk and arms, appearing in first 1-2 months.

Clinical management: Grade 1: topical emollients, observation. Grade 2: topical corticosteroids (triamcinolone 0.1%), oral antihistamines for pruritus. Grade 3: hold TKI per Section 2.13, systemic steroids if needed, dermatology referral. Severe bullous or exfoliative rash: permanently discontinue.
⚠️ When to escalate: Blisters or peeling skin, rash over large parts of your body, rash with fever or mouth sores, open wounds on your skin.
Arthralgia / Bone Pain
Grade 1–3 Common (10–30%)

Joint and bone pain, particularly in the limbs and back. FDA label Table 12: arthralgia 13.6%, myalgia 32.2% in metastatic GIST (N=818). May relate to fluid shifts in joint spaces or periosteal effects. Can be persistent over long treatment duration.

Clinical management: First-line: acetaminophen or NSAIDs (if no GI concerns and platelets adequate). Physical therapy referral for persistent symptoms. Rule out disease progression if new-onset bone pain after prolonged treatment. Consider dose reduction for Grade 3 per Section 2.13.
⚠️ When to escalate: New bone pain after months on treatment (needs pictures to check for disease changes), pain that keeps you from sleeping or doing daily things, joint swelling or redness.
Constipation
Grade 1–3 Common (10–30%)

Infrequent or difficult bowel movements. FDA label Table 12: constipation 14.8% all grades, 5.1% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: constipation 23%, 1.5% Grade ≥3 (N=204). May be worsened by anti-emetics (ondansetron) or decreased activity.

Clinical management: First-line: increased fluid intake, dietary fiber, stool softener (docusate). Second-line: osmotic laxative (polyethylene glycol). Avoid stimulant laxatives long-term. Rule out bowel obstruction if acute onset with abdominal distension. Consider ondansetron contribution.
⚠️ When to escalate: No bowel movement for 3 or more days, bad belly pain or bloating with constipation, throwing up with constipation.
Dyspnea (Shortness of Breath)
Grade 1–4 Common (10–30%)

Difficulty breathing or feeling short of breath. FDA label Table 12: dyspnea 13.6% all grades, 6.8% Grade 3/4/5 in metastatic GIST at 400mg (N=818). Ayvakit Table 5: dyspnea 17%, 2.5% Grade ≥3 (N=204). May indicate pleural effusion (Section 5.1), anemia, or disease progression.

Clinical management: Evaluate urgently — differentiate fluid retention (pleural effusion per Section 5.1) from pulmonary embolism, pneumonia, or disease progression. Check SpO2, CBC (anemia), chest imaging. If pleural effusion: dose reduction/interruption per Section 2.13, thoracentesis if large. Echocardiogram to rule out cardiac cause.
⚠️ When to escalate: Suddenly hard to breathe, short of breath when resting or lying down, chest pain with breathing, coughing up blood, lips or fingers turning blue — get emergency help right away.
Headache
Grade 1–3 Common (10–30%)

Head pain, ranging from mild tension-type to severe. FDA label Table 12: headache 22.0% all grades, 5.7% Grade 3/4/5 in metastatic GIST (N=818). With avapritinib: new or severe headaches require urgent evaluation to rule out intracranial hemorrhage per Section 5.1.

Clinical management: Mild: acetaminophen PRN. Avoid NSAIDs if platelets low. With avapritinib: any new severe or unusual headache warrants urgent CT head to rule out ICH per FDA warning Section 5.1. Monitor for associated neurological symptoms. Persistent headache: evaluate for fluid retention, hypertension.
⚠️ When to escalate: Sudden bad headache that is not like your usual headaches (especially on avapritinib — this needs urgent checking), headache with vision changes, confusion, or weakness, headache that acetaminophen does not help.
Hepatotoxicity
Grade 1–4 Common (10–30%)

Liver inflammation detected by elevated liver enzymes (ALT/AST) and/or bilirubin. FDA label Section 5.4: Grade 3/4 ALT elevations in 6.8% of Phase 2 GIST patients. Ayvakit Table 6: ALT increased Grade 3 in 2%, Grade 4 in 0.5%. Usually reversible with dose modification.

Clinical management: Baseline LFTs before starting. Monitor monthly for first 3 months, then at each visit. Grade 2 (ALT/AST 3-5× ULN): hold until ≤ Grade 1, resume at same dose. Grade 3 (5-20× ULN): hold until ≤ Grade 1, resume at reduced dose per Section 2.13. Grade 4: permanently discontinue. Rule out viral hepatitis.
⚠️ When to escalate: Skin or eyes turning yellow (jaundice), dark-colored pee, very tired with pain on the right side of your belly, bleeding or bruising that is not normal.
Neutropenia
Grade 2–4 Common (10–30%)

Low white blood cell count (neutrophils), increasing infection risk. FDA label Table 12: neutropenia 11.5%, leukopenia 17.0% in metastatic GIST at 400mg (N=818). Ayvakit Table 6: neutrophil count decreased Grade 3 in 7%, Grade 4 in 3.4%. Usually early in treatment (first 1-3 months).

Clinical management: Monitor CBC weekly for the first month, then at each visit. Grade 3 (ANC 500-1000): hold TKI until ANC ≥1500, resume at same dose per Section 2.13. Grade 4 (ANC <500): hold until ANC ≥1500, resume at reduced dose. G-CSF is rarely needed with TKIs.
⚠️ When to escalate: A temperature of 100.4°F (38°C) or higher — this is an EMERGENCY, go to the hospital right away. Also: shaking chills, sore throat, cough, burning when you pee while your blood counts are low.
Skin Depigmentation
Grade 1–2 Common (10–30%)

Lightening of skin color, particularly noticeable in patients with darker skin tones. Caused by imatinib inhibition of KIT signaling in melanocytes. Avapritinib: hair color changes in 21% per Table 5 (N=204). Typically reversible after discontinuation.

Clinical management: Counsel patients proactively before starting treatment — cosmetic, not dangerous. No treatment required. Document extent and reassure. Skin color typically returns 3-6 months after discontinuation. Sun protection advised for affected areas.
Tumor Hemorrhage
Grade 2–4 Common (10–30%)

Bleeding from the tumor site, particularly relevant for GI-located tumors. FDA label Section 5.5: Grade 3/4 hemorrhage in 12.9% in Phase 3 GIST trial. Table 12: hemorrhage (other) 12.3% all grades, 6.7% Grade 3/4/5. Can occur early as tumor responds (necrosis). GI tumor sites may be the source.

Clinical management: Counsel patients about GI bleeding risk, especially in first 1-2 months. Baseline hemoglobin. Low threshold for endoscopy if GI bleeding signs. Hold TKI for significant hemorrhage per Section 2.13, resume after stabilization. Surgery consultation for uncontrolled bleeding.
⚠️ When to escalate: Black or tarry stools, throwing up blood or stuff that looks like coffee grounds, sudden belly pain, feeling lightheaded or dizzy, fast heartbeat — get medical help right away.
Thrombocytopenia
Grade 1–4 Uncommon (1–10%)

Low platelet count, increasing bleeding risk. FDA: more common with avapritinib — Ayvakit Table 6: platelet count decreased Grade 3 in 10%, Grade 4 in 7%. Contributes to hemorrhage risk. Requires careful monitoring, especially with avapritinib.

Clinical management: Monitor platelets at baseline, weekly for 4 weeks, then monthly. Grade 3 (25,000-50,000): hold until ≥75,000, resume at same dose per Section 2.3. Grade 4 (<25,000): hold until ≥75,000, resume at reduced dose. Avoid concurrent anticoagulants with avapritinib. Platelet transfusion for active bleeding.
⚠️ When to escalate: Bleeding that is not normal or lasts a long time, blood in your pee or stool, heavy nosebleeds, big bruises showing up without getting hurt, tiny red dots on your skin, bad headache (with avapritinib — may mean bleeding in your brain).