The FDA has expanded the indication for dasatinib tablets to include the treatment of pediatric patients 1 year of age and older with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in combination with chemotherapy.
Dasatinib is the only second-generation tyrosine kinase inhibitor approved for this patient population. The approval, which was granted following priority review by the FDA, is based on data from the phase II study, CA180-372 (NCT01460160).
Dasatinib is associated with the following warnings and precautions: myelosuppression, bleeding-related events, fluid retention, cardiovascular events, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, tumor lysis syndrome, embryo-fetal toxicity, and effects on growth and development in pediatric patients.
The efficacy of dasatinib tablets in combination with chemotherapy was evaluated in a single cohort of the phase II, multicenter, single-arm CA180-372 study, which included 78 pediatric patients with newly diagnosed B-cell precursor Ph+ ALL. At 3 years, the study demonstrated an event-free survival (EFS) binary rate of 64.1 percent (95% confidence interval [CI]: 52.4 to 74.7). Event-free survival is defined as the time from the start of dasatinib to lack of complete response at the end of the third high-risk block, relapse, secondary malignancy, or death from any cause.
Of the 81 patients evaluated for safety, fatal adverse reactions occurred in three patients (4%), and eight (10%) experienced adverse reactions leading to treatment discontinuation, including fungal sepsis, hepatotoxicity of graft versus host disease, thrombocytopenia, CMV infection, pneumonia, nausea, enteritis, and drug hypersensitivity. The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral, and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletal pain.
"As treatments have advanced in recent years, we've seen improvements in outcomes for pediatric patients with Ph+ ALL overall, but there remains a need for additional options," said Stephen Hunger, MD, lead study author, Chief of the Division of Oncology and Director of the Center for Childhood Cancer Research at Children's Hospital of Philadelphia. "The phase II CA180-372 trial was particularly informative because it was designed to limit the use of cranial irradiation and stem cell transplant. In the study, dasatinib plus chemotherapy demonstrated a 3-year event-free survival benefit. These results show that dasatinib is an effective medication for physicians to consider for children and adolescents with Ph+ ALL."
In the CA180-372 trial, the 78 patients evaluated for efficacy in cohort 1 received dasatinib at a daily dose of 60 mg/m2 for up to 24 months, in combination with chemotherapy. The backbone chemotherapy regimen was the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol. Efficacy was established based on 3-year EFS, defined as the time from the start of dasatinib to lack of complete response at the end of the third high-risk block, relapse, secondary malignancy, or death from any cause. The trial was designed such that patients with central nervous system 3 disease receive cranial irradiation. Patients were assigned to receive stem cell transplant (SCT) based on minimal residual disease if they were considered high-risk.
The recommended starting dosage for dasatinib in pediatric patients with Ph+ ALL is based on body weight. The recommended dose should be administered orally once daily, and the dose should be recalculated every 3 months based on changes in body weight, or more often if necessary. For pediatric patients with Ph+ ALL, dasatinib therapy should begin on or before day 15 of induction chemotherapy, when diagnosis is confirmed, and continue for 2 years.