Q15: What are the principles for the use of tyrosine kinase inhibitors (TKI) in special populations?
A: The following principles are mainly quoted from the instructions of each drug, Wuhan Union Hospital, Department of Hematology, Wei-Ming Li
A) Application of imatinib in special populations
(1) Dosage for pediatric patients
When the patient is a child over 3 years old, the recommended daily dose is 260 mg/m2 (maximum dose is 400 mg/m2) in the chronic phase and 340 mg/m2 (maximum dose is 600 mg/m2) in the accelerated or acute phase according to the data of foreign clinical studies. several hundred milligrams.
There is no experience with the treatment of children under three years of age.
(2) Dosage in elderly patients There is no special dose adjustment for elderly patients.
(3) Dosage for patients with renal failure
The renal clearance of imatinib is negligible and no reduction in systemic clearance is predicted in patients with renal impairment. Since clinical trials have never been conducted in patients with renal impairment, no dose adjustments can be recommended. Particular caution is needed in the dosing of drugs in patients with severe renal impairment.
4) Dosage in patients with hepatic failure
Administration of imatinib mesylate in patients with hepatic impairment may result in elevated plasma concentrations. Since there is no clinical data on the use of Imatinib Mesylate in patients with hepatic impairment, no dose adjustment can be recommended. This product should be used with caution in patients with hepatic impairment and should be used with discretion in patients with severe hepatic failure after careful weighing of the risk-benefit ratio.
(B) Application of nilotinib in special populations
1) Dosing in children and adolescents
No clinical studies have been conducted in children or adolescents, so the drug is not recommended for use in patients under the age of 18 years.
2) Dosage in elderly patients Patients older than 65 years of age do not require special dose adjustments.
(3) Dosage in patients with renal impairment
Clinical studies have not been conducted in patients with renal impairment. Only a small portion of this product and its metabolites are excreted by the kidneys, so the overall clearance is not predicted to decrease in patients with renal impairment. Therefore, no dose adjustment is required for patients with renal impairment.
4) Dosing in patients with hepatic impairment
Treatment with this product is not recommended for patients with liver impairment whose transaminases (ALT) exceed 2.5 times normal or whose bilirubin (TBIL) is elevated more than 1.5 times normal.
If nilotinib capsules must be used, a dose reduction should be considered in patients with concomitant hepatic impairment. For patients with mild or moderate hepatic impairment, the starting dosing regimen is 300 mg twice daily, with gradual increase to 400 mg twice daily while observing patient tolerability.
For patients with severe hepatic impairment, the initial dosing regimen is 200 mg twice daily, gradually increase the dose to 300 mg twice daily, and increase the dose to 400 mg twice daily as tolerated.
C) Application of Dasatinib in Special Populations
(1) Dosing in pediatric patients Due to the lack of clinical safety and efficacy data, this product is not recommended for the treatment of pediatric and adolescent patients under 18 years of age.
In elderly patients, no clinically significant age-related pharmacokinetic differences have been observed. Therefore, no specific dose adjustment is required for elderly patients.
(3) Dosing in patients with impaired renal function
Clinical trials of this product have not been conducted in patients with reduced renal function (trials excluded patients with serum creatinine concentrations (Scr) >1.5 times the upper limit of normal). Because renal clearance of dasatinib and its metabolites is <4%, systemic clearance is not expected to be reduced in patients with renal insufficiency. < span="">
4) Dosing in patients with hepatic impairment
Patients with mild, moderate, or severe hepatic impairment may receive the recommended starting dose. Nevertheless, this product should be used with caution in patients with hepatic impairment.
Q16: What are the non-hematological adverse effects of tyrosine kinase inhibitors (TKI)?
A: The mechanism of action of the three TKI is similar and therefore some of the non-hematological adverse reactions are also similar.
If a severe non-hematologic adverse reaction occurs during TKI administration, treatment should be stopped immediately and aggressively managed until the adverse reaction resolves. Subsequent treatment can be started at an appropriately reduced dose, with the degree of dose reduction chosen based on the severity of the initial adverse reaction.
It is important to inform patients that they should not be alarmed or overly concerned when an adverse reaction occurs. Most of the adverse reactions caused by TKI are mild to moderate and are not life-threatening, and can usually be controlled until they disappear after treatment. Only a small number of more serious cases require permanent discontinuation or replacement of the drug. Therefore, it is important to carry out relevant examinations as prescribed by the doctor to detect adverse reactions in a timely manner. When an adverse reaction occurs, be sure to consult your primary care physician and take timely measures to deal with it, do not arbitrarily reduce or stop the drug to avoid affecting the efficacy!
Adverse drug reactions (ADRs) are classified into the following five classes according to their incidence.
Very common: 10% < ADR
Common: 1 % < ADR ≤ 10%.
Uncommon: 0.1% < ADR ≤ 1%.
Rare: 0.01% < ADR ≤ 0.1%.
Very rare: ADR ≤0.01%.
The following is a list of common adverse reactions with reference to the drug instructions for patients to understand. But remember, always use the drug under the guidance of a doctor and do not handle it at your own discretion.
(A) The more common non-hematological adverse reactions to Imatinib
Very common adverse reactions include: peripheral swelling (including facial edema, lower limb swelling, etc.), fatigue, headache, nausea, vomiting, diarrhea, dyspepsia, abdominal pain, rash, muscle cramps (commonly known as cramps), musculoskeletal pain, and weight gain.
Common adverse reactions include: malaise, fever, chills, chills, rigors, loss of appetite, insomnia, dizziness, taste disturbance, abnormal sensation, hypoesthesia, eyelid swelling, conjunctivitis, increased tearing, blurred vision, subconjunctival hemorrhage, dry eyes, flushing, hemorrhage, rhinorrhea, dyspnea, cough, bloating, flatulence, constipation, gastroesophageal reflux, oral ulcers, dry mouth, gastritis, elevated liver enzymes, facial swelling, periorbital puffiness, pruritus, erythema, dry skin, alopecia, hair thinning, night sweating, photoallergic reaction, joint swelling, weight loss.
(B) More common non-hematological adverse reactions to nilotinib
Very common adverse reactions include: loss of appetite, headache, nausea, constipation, diarrhea, vomiting, rash, pruritus, alopecia, dry skin, myalgia, fatigue, hypophosphatemia (including decreased blood phosphorus), hyperbilirubinemia (including elevated blood bilirubin), elevated alanine aminotransferase, elevated aspartate aminotransferase, and elevated lipase.
Common adverse reactions include: abdominal pain, dyspepsia, loss of appetite, erythema, arthralgia, muscle cramps, bone pain, extremity pain, weakness, peripheral edema, folliculitis, upper respiratory tract infections (including pharyngitis, nasopharyngitis, rhinitis), skin papillomas, electrolyte imbalances (including low magnesium, high potassium, low potassium, low sodium, low calcium, high calcium, high phosphorus), diabetes, hyperglycemia, hypercholesterolemia, hyperlipidemia dizziness, peripheral neuropathy, hypoesthesia, sensory abnormalities, ocular hemorrhage, periocular edema, ocular pruritus, conjunctivitis, dry eyes (including dry eye disease), angina pectoris, cardiac arrhythmias (including ventricular block, flutter, precontraction, tachycardia, atrial fibrillation, bradycardia), palpitations, prolonged QT interval, hypertension, flushing, dyspnea, exertional dyspnea, epistaxis, cough , vocal difficulties, pancreatitis, abdominal discomfort, bloating, dyspepsia, taste disturbances, flatulence, nocturnal sweating, eczema, rubella, erythema, hyperhidrosis, contusions, acne, dermatitis (including allergic, exfoliative and acne-like), dry skin, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, low back pain, urinary frequency, chest pain (including non-cardiac chest pain), pain, fever, chest discomfort decreased hemoglobin, elevated blood amylase, elevated blood alkaline phosphatase, elevated gamma-glutamyl transferase, elevated creatine phosphokinase, decreased body weight, weight gain.
(C) More common non-hematologic adverse reactions to dasatinib
Very common adverse reactions include fluid retention (including pleural effusion), dyspnea, cough, abdominal pain, vomiting, diarrhea, headache, nausea, rash, bleeding, fatigue, musculoskeletal pain, infections (including bacterial, viral, fungal, non-specific infections), superficial edema, and fever.
Common adverse reactions include sepsis (including fatal outcome), pneumonia (including bacterial, viral, and fungal pneumonia), upper respiratory tract infection/inflammation, herpesvirus infection, small bowel colitis infection, anorexia, appetite disorders, hyperuricemia, depression, insomnia, visual disturbances (including visual disturbances, blurred vision, and decreased visual acuity), dry eyes, tinnitus, congestive heart failure/cardiac insufficiencyb , pericardial effusion, arrhythmias (including tachycardia), palpitations, hypertension, flushing, pulmonary edema, pulmonary hypertension, pulmonary infiltrates, pneumonia, gastrointestinal bleeding, colitis (including neutropenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, bloating, constipation, oral soft tissue disease, hair loss, dermatitis (including eczema), pruritus, acne, skin dryness, urticaria, hyperhidrosis, arthralgia, myalgia, muscle inflammation, muscle weakness, musculoskeletal stiffness, weakness, pain, chest pain, generalized edema, cold, weight loss, weight gain.
Q17: What are the principles of management of non-hematological adverse reactions due to TKI administration?
A: For some common non-hematological adverse reactions, they are summarized as follows.
1) Management of fluid retention (i.e., swelling).
All three TKI have about 50% of patients with fluid retention, including facial and lower extremity swelling, which is generally mild to moderate, and some severe patients may develop multiple plasma cavities (e.g., pleural effusion is common with dasatinib).
2) Dose adjustment in case of severe hepatic toxicities.
If bilirubin (TBIL) > 3 times the upper limit of the normal range or transaminase (ALT) > 5 times the upper limit of the normal range, it is advisable to stop taking TKI drugs and add liver protective or cholestatic drugs until the above indicators fall below 1.5 or 2.5 times the upper limit of the normal range, respectively.
Subsequent TKI therapy can be continued in reduced doses. The adult daily dose of imatinib was reduced from 400 mg to 300 mg or from 600 mg to 400 mg; nilotinib was reduced from 800 mg/day to 600 mg/day and dasatinib was reduced from 100 mg/day to 70 mg/day.
3) Management of musculoskeletal pain.
The cause of skeletal pain may be related to the clearance of leukemia cells from the bone marrow. It usually appears during the initial month of treatment and usually resolves on its own. Symptoms usually involve the femur, tibia, hip and knee joints.
For more severe musculoskeletal or joint pain, pain medications, including non-steroidal anti-inflammatory drugs (NSAIDs, such as aspirin, ibuprofen, Xylazine, etc.), may be used, as indicated in the following table.
No previous history of gastrointestinal (GI) bleeding
or platelets >100×109/L
NSAID
Previous history of gastrointestinal (GI) bleeding
NSAID + proton pump inhibitor, NSAID + H2 histamine receptor blocker, cyclooxygenase inhibitor
Platelets <100×109/L
or NSAID drugs are contraindicated
Paracetamol (use with caution) Mild narcotic analgesics
(* There has been controversy as to whether paracetamol should be used in patients treated with imatinib. There have been cases of patients in the accelerated phase of CML who died of liver failure after taking paracetamol for fever while on imatinib treatment. (It has not been possible to determine whether the patient’s death was related to paracetamol drug use.) Note: NSAIDs are irritating to the stomach, so if patients have a history of gastrointestinal bleeding or lower than normal platelets they need to be treated with additional gastric protection drugs proton pump inhibitors or H2 histamine receptor blockers. In addition, in my personal experience, some patients require the addition of hormones (e.g., prednisone) for relief.
4) Management of painful muscle spasms (commonly known as cramps).
This symptom is a common symptom of adverse reactions in CML patients treated with TKI (especially imatinib) and is mostly seen in the hands, feet, calf gastrocnemius and thighs. Painful cramps may involve persistent muscle contractions and do not change in frequency, pattern, or severity of occurrence over time.
Although TKI treatment does not affect calcium and magnesium ion levels, taking calcium and magnesium supplements can relieve the symptoms of painful spasms. Quinidine also has a symptom-relieving effect.
5) Management of nausea and vomiting.
Nausea and vomiting symptoms are very common in Imatinib treatment. The severity of nausea and vomiting varies from mild to moderate. Because nausea symptoms are dose-related, the daily dose of imatinib use can be separated and taken with two meals. If nausea persists, consider using anti-nausea medications such as prochlorperazine, ortansetron, etc. for relief.
6) Management of rash.
Allergic rash is a very common adverse reaction to TKI therapy, mostly seen on the forearms and trunk, and less frequently on the face. The rash is often erythematous or maculopapular-like in nature with more severe pruritus, although the majority of rashes are mild and self-limiting. Mild rashes can be controlled with steroids (e.g., prednisone) or antihistamines (e.g., paracetamol, reserpine).
This article is published with permission from Dr. Weiming Lai.