Dasatinib Benefits Children and Adolescents With Relapsed or Refractory Leukaemia: Presented at EHA

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Title: Dasatinib Benefits Children and Adolescents With Relapsed or Refractory Leukaemia: Presented at EHA
URL: http://www.pslgroup.com/dg/223B72.htm
Doctor's Guide
June 17, 2008

By Emma Hitt, PhD

COPENHAGEN, Denmark -- June 17, 2008 -- Dasatinib appears to provide benefits to children and adolescents with relapsed or refractory leukaemia, according to new findings presented at the 13th Congress of the European Hematology Association (EHA).

"This topic is extremely important because currently 70% to 80% of all drugs used to treat refractory leukaemia in children are used off label," noted the lead author C. Michel Zwaan, MD, PhD, Department of Paediatric Oncology, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam, Netherlands.

Dasatinib, a second-generation tyrosine kinase inhibitor, has been approved for adults with all phases of chronic myeloid leukaemia (CML) or Philadelphia (Ph)-chromosome-positive acute lymphoblastic leukaemia (ALL) resistant or intolerant to imatinib.

The current open-label, phase 1/2, dose-finding trial is the first to evaluate dasatinib in children or adolescents with various leukaemia subtypes. The study, presented on June 15, was conducted in 12 centres in the Innovative Therapies for Children With Cancer (ITCC) Consortium.

Findings presented included the first 41 patients treated in the study. Patients were 1 to 21 years old with a median age of 11 years. Patients had CML that was resistant or intolerant to imatinib, relapsed or refractory ALL that was Ph-positive or Ph-negative, or acute myeloid leukaemia (AML) in second or a subsequent relapse. Of 41 patients, 24 had received a prior stem cell transplant. Most patients had received at least 1 year of imatinib treatment.

The starting dose of dasatinib was 60 mg/m² once daily. In nonresponders, dose escalation was permitted as long as the patient could tolerate it.

Analysis of pharmacokinetics indicated that dasatinib was readily absorbed after administration, with a maximum concentration occurring within 1 hour. Plasma levels were dependent on the dose given.

Dasatinib was generally well tolerated. Treatment-related adverse events that occurred in at least 10% of patients were nausea (34% grade 1/2; 2% grade 3/4). Any grade of vomiting was reported in 14%; headache in 14%; diarrhoea in 15% (all grade 1/2); and rash in 12% (all grade 1/2). One case of pleural effusion was observed in a patient receiving dasatinib 100 mg/m².

Among the 8 patients with chronic-phase Ph-positive CML, a major haematological response was observed in 75% of patients, a complete cytogenetic response in 75% patients, and a partial cytogenetic response in 13%. Responses in other Ph-chromosome-positive leukaemias (n = 12) included 25% with a major haematological response and 50% with a complete cytogenetic response.

According to Dr. Zwaan, no impressive results have been obtained in patients with Ph-chromosome-negative leukaemias to date.

"This agent appears to be an effective treatment option for children and adolescents with Philadelphia-chromosome-positive leukaemias," Dr. Zwaan said. "Dasatinib is being further explored in Philadelphia-chromosome-negative c-Kit-mutated AML. The activity of dasatinib needs to be compared to that of imatinib, especially in Ph-chromosome-positive ALL, but also in CML," he said in an interview.

According to Dr. Zwaan, some children with CML have been on study for more than 2 years. "In ALL, duration of response is shorter, but dasatinib, after producing remission, has allowed some children to undergo a second stem-cell transplantation."

[Presentation title: Dasatinib in Children and Adolescents With Relapsed or Refractory Leukaemia: Preliminary Results of the CAL80018 Phase I/II Study From the ITCC Consortium. Abstract 923]

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