On November 9, 2017, dasatinib (Sprycel) was granted regular approval for treatment of pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase.1,2
Supporting Efficacy Data
Approval was based on findings among 97 pediatric patients with chronic-phase CML from a phase I dose-ranging trial and a phase II single-arm trial.2 In total, 51 patients from the phase II trial were newly diagnosed with chronic-phase CML, and 46 patients, including 17 from the phase I trial and 29 from the phase II trial, were resistant to or intolerant of previous treatment with imatinib. Most patients received oral dasatinib at 60 mg/m2 once daily, with treatment continued until disease progression or unacceptable toxicity.
Dasatinib carries warnings/precautions for myelosuppression and bleeding events, fluid retention, cardiac dysfunction, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, tumor-lysis syndrome, embryofetal toxicity, and effects on growth and development in pediatric patients.
The median duration of therapy was 51.1 months (range = 1.9–99.6 months). After 24 months of treatment, complete cytogenetic response had occurred in 96.1% of newly diagnosed patients and 82.6% of patients resistant to or intolerant of imatinib. At a median follow-up of 4.5 years in newly diagnosed patients and 5.2 years in imatinib-resistant or -intolerant patients, the median duration of complete cytogenetic response, major cytogenetic response, and major molecular response could not be estimated, with no disease progression observed in greater than half of responders at data cutoff.
How It Works
Dasatinib inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ kinases. Modeling studies indicate that dasatinib binds to multiple conformations of the ABL kinase. In studies in vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate–sensitive and –resistant disease and inhibited the growth of CML and acute lymphoblastic leukemia cell lines overexpressing BCR-ABL. Dasatinib was observed to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression.
How It Is Used
The recommended starting dosage for pediatric patients is once daily based on weight, as follows: 10 to < 20 kg = 40 mg; 20 to < 30 kg = 60 mg; 30 to < 45 kg = 75 mg; and ≥ 45 kg = 100 mg. Tablet dosing is not recommended for patients weighing < 10 kg. The dose should be recalculated every 3 months based on changes in body weight or more often if necessary. In patients not achieving hematologic or cytogenetic response at the starting dosage, the dose should be increased as follows: from 40 to 60 mg; from 60 to 70 mg; from 70 to 90 mg; and from 100 to 120 mg, respectively.
Concomitant use of dasatinib with strong CYP3A4 inhibitors (eg, grapefruit juice, clarithromycin, telithromycin [Ketek], nefazodone, itraconazole, ketoconazole, atazanavir) should be avoided. If concomitant use cannot be avoided, a dasatinib dose decrease should be considered (eg, from 140 to 40 mg, 100 to 20 mg, and 70 to 20 mg; treatment should be stopped in patients taking 60 or 40 mg daily until the inhibitor is discontinued, with a 1-week washout period after discontinuation before resuming dasatinib. Concomitant use of dasatinib with strong CYP3A4 inducers (eg, rifampin, carbamazepine, enzalutamide [Xtandi], phenytoin, St. John’s wort) should be avoided; if concomitant use cannot be avoided, a dasatinib dose increase should be considered; if the dose is increased, patients should be monitored closely for toxicity. Concomitant use of dasatinib with antacids, H2 antagonists, and proton pump inhibitors should be avoided.
Detailed dose adjustments for cytopenias are provided in the labeling. For severe nonhematologic adverse reactions, treatment should be withheld until resolution and then resumed at a reduced dose.
In clinical studies, dasatinib treatment in adults and pediatric patients was continued until disease progression or intolerability. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response has not been established.
Among the 97 patients treated in the two studies, the most common adverse events of any grade were headache (28%), diarrhea (21%), nausea (20%), skin rash (19%), pain in extremity (19%), abdominal pain (16%), and vomiting (13%). Grade 3 or 4 adverse events consisted of headache (3%), pain in extremity (1%), and arthralgia (1%). Drug-related serious adverse events occurred in 14%. Adverse events led to discontinuation of treatment in 1%. Myelosuppression has been commonly reported in all patient populations studied. Grade 3 or 4 elevations of transaminases or bilirubin and grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia have been reported in patients with all phases of CML.
Dasatinib has warnings/precautions for myelosuppression and bleeding events, including severe thrombocytopenia, neutropenia, and anemia; fluid retention (sometimes severe, including pleural effusions); cardiac dysfunction; pulmonary arterial hypertension; QT prolongation; severe dermatologic reactions; tumor-lysis syndrome; embryofetal toxicity; and effects on growth and development in pediatric patients, including epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia. Complete blood cell counts should be monitored regularly. Adequate hydration should be maintained and uric acid levels corrected prior to initiating treatment. Bone growth and development shuold be monitored in pediatric patients. ■
1. U.S. Food and Drug Administration: FDA approves dasatinib for pediatric patients with CML. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm584725.htm. Accessed November 29, 2017.
2. Sprycel (dasatinib) tablets prescribing information, Bristol-Myers Squibb Company, November 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021986s020lbl.pdf. Accessed November 29, 2017.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).