Dasatinib Approved in EU for Pediatric Ph+ ALL

Fouad Namouni, MD

The European Commission has approved 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.

The approval, which includes dasatinib in both tablet form and powder for oral suspension formulation, is based on findings from the 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%).

“We are proud that the approval by the European Commission brings children with Ph+ acute lymphoblastic leukemia a new treatment option, including a powder formulation developed as part of our commitment to addressing the unique needs of children with cancer,” Fouad Namouni, MD, head, oncology development, Bristol-Myers Squibb, said in a statement.

In CA180-372, 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 January 2019, the FDA approved dasatinib tablets in combination with chemotherapy for the treatment of pediatric patients ≥1 year of age with newly diagnosed Ph+ acute lymphoblastic leukemia. 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.

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 February 11, 2019. https://bit.ly/2MEcNta?rel=0.