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Dasatinib treatment is associated with severe (NCI CTCAE Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. These events occur earlier and more frequently in patients with advanced-phase CML or Ph+ ALL than in those with chronic-phase CML.
Complete blood counts (CBCs) should be performed every 2 weeks during the first 12 weeks, then every 3 months thereafter, or as clinically indicated.
CBCs should be performed weekly during the first 2 months, then monthly thereafter, or as clinically indicated.
CBCs should be performed before the start of each chemotherapy block and as clinically indicated. During consolidation chemotherapy blocks, CBCs should be performed every 2 days until recovery.
Myelosuppression is usually reversible and is generally managed by temporary discontinuation of dasatinib and/or dose reduction.
Dasatinib can cause severe and fatal bleeding. In all clinical studies of CML or Ph+ ALL, less than 1% of patients receiving dasatinib experienced Grade ≥3 central nervous system (CNS) bleeding (including death). The incidence of Grade 3/4 bleeding in adult patients was 5.8%, which typically required treatment interruption and blood transfusion. The incidence of Grade 5 bleeding was 0.4%.
The most common site of bleeding is the gastrointestinal tract. Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopenia in humans, dasatinib induces platelet dysfunction in vitro.
Concomitant use of drugs that inhibit platelet function or anticoagulants may increase the risk of bleeding.
Dasatinib may cause fluid retention. In the 5-year follow-up of the randomized study in adults with newly diagnosed chronic-phase CML:
5% of patients reported Grade 3 or 4 fluid retention, including 3% with Grade 3 or 4 pleural effusion.
In adult patients with newly diagnosed or imatinib-resistant/intolerant chronic-phase CML treated with the recommended dose of dasatinib:
6% experienced Grade 3 or 4 fluid retention.
In adult patients with advanced-phase CML or Ph+ ALL treated with the recommended dose of dasatinib:
8% reported Grade 3 or 4 fluid retention, including 7% with Grade 3 or 4 pleural effusion.
In pediatric patients with chronic-phase CML:
10.3% of patients reported Grade 1 or 2 fluid retention.
Patients presenting with symptoms of pleural effusion or other fluid retention (e.g., new or worsening dyspnea at rest or with activity, pleuritic chest pain, or dry cough) should be promptly evaluated with chest X-ray or additional diagnostic imaging.
Fluid retention events are usually managed with supportive care measures, which may include diuretics or short courses of corticosteroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Consider dose reduction or treatment interruption.
Dasatinib can cause cardiac dysfunction. In the 5-year follow-up of the randomized trial in adults with newly diagnosed chronic-phase CML, the following cardiac adverse reactions occurred:
Cardiac ischemic events (dasatinib: 3.9% vs. imatinib: 1.6%);
Cardiac-related fluid retention (dasatinib: 8.5% vs. imatinib: 3.9%);
Conduction system abnormalities, most commonly arrhythmias and palpitations (dasatinib: 7.0% vs. imatinib: 5.0%).
Two cases (0.8%) of peripheral arterial occlusive disease occurred in the imatinib group, and two cases (0.8%) of transient ischemic attack occurred in the dasatinib group.
Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
Dasatinib may increase the risk of pulmonary arterial hypertension (PAH) in adult and pediatric patients. This risk can occur at any time after initiating treatment, including more than 1 year after treatment start.
Manifestations include dyspnea, fatigue, hypoxemia, and fluid retention. PAH may be reversible upon discontinuation of dasatinib.
Before initiating dasatinib treatment and during treatment, evaluate patients for signs and symptoms of underlying cardiopulmonary disease. If PAH is confirmed, permanently discontinue dasatinib.
Dasatinib may increase the risk of QTc interval prolongation in patients, including those with:
Hypokalemia or hypomagnesemia;
Congenital long QT syndrome;
Concomitant use of antiarrhythmic drugs or other drugs that prolong the QT interval;
A history of cumulative high-dose anthracycline therapy.
Correct hypokalemia or hypomagnesemia before and during dasatinib administration.
Cases of severe mucocutaneous reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients receiving dasatinib.
Permanently discontinue dasatinib in patients who experience severe mucocutaneous reactions during treatment, if no other etiology can be identified.
Tumor lysis syndrome (TLS) has been reported in patients with imatinib-resistant disease, primarily in those with advanced-phase disease.
Due to the potential risk of TLS, maintain adequate hydration, correct uric acid levels, and monitor electrolyte levels before initiating dasatinib treatment. Patients with advanced disease and/or high tumor burden may be at increased risk and require more frequent monitoring.
Based on limited human data, dasatinib may cause fetal harm when administered to pregnant women. Adverse pharmacologic effects, such as fetal edema, fetal leukopenia, and fetal thrombocytopenia, have been reported following maternal exposure to dasatinib.
Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during dasatinib treatment and for 30 days after the last dose.
In pediatric trials of chronic-phase CML with at least 2 years of dasatinib treatment:
5 patients (5.2%) reported adverse reactions related to skeletal growth and development, including 1 case of Grade 3 severity (growth retardation).
These 5 cases included delayed epiphyseal fusion, decreased bone mineral density, growth retardation, and gynecomastia. Among these 5 cases, 1 case of decreased bone mineral density and 1 case of gynecomastia resolved during treatment.
Monitor pediatric patients for skeletal growth and development.
Dasatinib may cause hepatotoxicity, manifested by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase.
Monitor transaminases at baseline and monthly during treatment, or as clinically indicated. Reduce the dose, interrupt, or permanently discontinue dasatinib based on the severity of hepatotoxicity.
When dasatinib is administered in combination with chemotherapy, hepatotoxicity (in the form of elevated transaminases and hyperbilirubinemia) has been observed. Monitor liver function when dasatinib is used in combination with chemotherapy.
FDA，2024.07
