Fouad Namouni, MD
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion to dasatinib (Sprycel) in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), according to Bristol-Myers Squibb, the manufacturer of the TKI.1
This recommendation includes dasatinib in tablet form and powder for oral suspension formulation, the latter of which was approved by the European Commission in July 2018.
“We are pleased with today’s CHMP recommendation for Sprycel
in pediatric patients with Ph-positive ALL, and look forward to the possibility of expanding Sprycel’s pediatric indications in the [European Union] to include young patients with this particularly high-risk leukemia,” said Fouad Namouni, MD, head, oncology development, Bristol-Myers Squibb.
The positive opinion is based on findings from the ongoing, multicenter, historically controlled, phase II CA180-372 trial (NCT01460160), which is evaluating the addition of dasatinib
to a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone in pediatric patients with newly diagnosed Ph-positive ALL.
In results of the study, which were presented at the 2017 ASH Annual Meeting, the 3-year event-free survival rate for the dasatinib combination was 65.5% (95% CI, 57.7%-73.7%), while the 3-year overall survival (OS) rate was 91.5% (95% CI, 84.2%-95.5%).2
In the trial, 106 patients aged <18 years old were treated with continuous daily dasatinib starting at day 15 of induction chemotherapy. A complete remission was achieved by all treated patients. At day 78, which was the end of first block of treatment, patients with minimal residual disease (MRD) ≥0.05% were eligible for hematopoietic stem cell transplantation (HSCT) in first remission. This was also true for patients with MRD 0.005% to 0.05% who were still MRD-positive following an additional 3 high-risk chemotherapy blocks. Of the 106 treated patients, 19 met these criteria, with 14.2% (n = 15) being treated with HSCT. The other 91 patients were treated with dasatinib plus chemotherapy for 2 years.
Regarding safety, grade 3/4 adverse events (AEs) with the combination included febrile neutropenia (75.5%), sepsis (23.6%), bacteremia (24.5%), elevated ALT (21.7%), elevated AST (10.4%), pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%).
AE-related discontinuations of treatment occurred in 2 patients, 1 of which was linked to allergy and 1 that was due to thrombocytopenia. During the protocol therapy, 7 patient deaths occurred. Two deaths were transplant-related and 5 were in patients receiving chemotherapy (sepsis, 3; pneumonia, 1; unknown cause, 1).
In August 2018, the FDA accepted a supplemental biologics license application for dasatinib for use in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed Ph-positive ALL, also based on the CA180-372 data. The FDA is scheduled to make its decision on the application by December 29, 2018.
The FDA initially approved dasatinib in 2006 for the treatment of adults with Ph-positive chronic myeloid leukemia (CML) in chronic phase (CP) who are resistant or intolerant to prior therapy including imatinib (Gleevec). Dasatinib is also FDA approved for adults with Ph-positive ALL who are resistant or intolerant to prior therapy, and for adults with newly diagnosed Ph-positive CP-CML.
In November 2017, the FDA expanded the approval of dasatinib to include pediatric patients with Ph-positive CML-CP; the European Commission granted the same indication in July 2018.
- Bristol-Myers Squibb Receives Positive CHMP Opinion Recommending Sprycel (dasatinib) for Pediatric Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Bristol-Myers Squibb. Published December 17, 2018. https://bit.ly/2rI46RQ?rel=0" . Accessed December 17, 2018.
- Sprycel (dasatinib) Added to Standard Chemotherapy Demonstrates Three-Year Survival Benefit in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Posted December 9, 2017. Accessed August 30, 2018. https://bit.ly/2MEcNta?rel=0" .