Dasatinib Shows Promise for Pediatric CML, ALL Patients

A phase I study of dasatinib in children and adolescents with chronic myeloid leukemia (CML) and other malignancies determined dosing for further studies and suggested the drug is well tolerated and effective in these patients.

“Long-term data from children treated with imatinib demonstrate growth impairment and a negative impact on bone remodeling,” wrote researchers led by C. Michel Zwaan, MD, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands. “It is not known whether these are class effects.” Dasatinib is another tyrosine kinase inhibitor that has shown good results with CML in adult patients; the current phase I trial was a dose-escalation study in 58 children with either imatinib-pretreated CML (17 patients), Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) or CML in the accelerated phase (17 patients), or treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML; 24 patients).

The recommended dose for phase II studies was established at 60 mg/m² for chronic phase CML patients and 80 mg/m² for the other groups of patients. Dr. Zwaan said in an email that in terms of adverse events, the drug was “perhaps even better tolerated in the short term” compared with adults. The most common adverse events were nausea (31% of patients, though only 2% with grade 3 or 4), headache (22% and 3%), and diarrhea (21% and no higher grade events).

Of the chronic phase CML patients, 82% achieved a complete cytogenetic response (CCyR) and 47% achieved a major molecular response; Dr. Zwaan said the agent seems “certainly as effective” as dasatinib in adults. No patient with Ph-negative ALL or AML responded to the therapy; 65% of advanced phase CML or Ph-positive ALL patients achieved CCyR, 35% achieved a confirmed complete hematologic response.

In spite of the early efficacy seen with dasatinib in these pediatric patients, there are issues with the idea of giving TKIs in children. The question is “whether they can be used for a very long time during childhood and throughout adult life,” Dr. Zwaan said. “The second important question is whether there is a subgroup that is cured with these drugs; in other words, if we can ever stop the drug.” Several studies have looked into and continue to examine whether imatinib and other TKIs can be stopped in CML patients; the drugs can be extremely effective, but they are expensive and continuing them indefinitely can be problematic.

“For those that cannot stop the main question is which drug-imatinib, nilotinib, dasatinib-has the best long-term safety profile,” Dr. Zwaan said. Several phase II and III trials of dasatinib in pediatric patients are now underway.