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Dasatinib may be effective option for pediatric leukemia
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ORLANDO, Fla. — For pediatric and adolescent patients with both Philadelphia (Ph)+ and Ph– leukemias, dasatinib may be an effective and tolerable treatment option, according to preliminary dose-finding study data presented at the 48th Annual Meeting of the American Society of Hematology.
Dasatinib (Sprycel, Bristol-Myers Squibb) has demonstrated efficacy in imatinib-resistant or -intolerant Ph+ disease and is approved in the United States and Europe for adult chronic myeloid leukemia and Ph+ acute lymphocytic leukemia.
Few effective treatment options for pediatric patients with relapsed or refractory leukemias are available, said Christian M. Zwaan, MD, pediatric oncologist at the Sophia Children’s Hospital in Rotterdam, The Netherlands.
Even though pediatric study of pharmacologic agents generally starts at 80% of the adult recommended dose, children can often tolerate higher doses than adults because they are healthier and lack the cardiac and renal problems which often limit adult dosing, according to Zwaan.
The intent of Zwaan’s study is to determine a recommended dasatinib dose by disease stratum in children and adolescents with relapsed or refractory leukemia.
Patients and dosing
The study included 22 children (aged 1 to 20) with imatinib-resistant or -intolerant CML, post-imatinib relapsed Ph+ ALL or Ph– ALL or acute myelogenous leukemia in more than two relapses. Eleven patients had prior imatinib therapy; 16 of the patients had received prior chemotherapy; and nine had prior stem cell transplants.
Patients were stratified into four groups according to disease severity, with the first stratum including patients with chronic phase (n=2) and the fourth stratum including those with more than two relapses or refractory disease after more than two prior induction regimens (n=11).
The median daily dose, with dose escalations proceeding at the time of this report, is 77 mg/m2, and the median duration of therapy is 0.72 months. Initial doses were 80 mg/m2 per day in six patients and 60 mg/m2 per day in the rest.
Among the 11 patients in the first three strata, six had hematologic and/or cytogenetic responses, four of them with complete hematologic and cytogenetic responses. Three patients in the second stratum achieved clearance of cerebrospinal fluid blasts. Two of eleven in the fourth stratum, one with Ph– AML and one with Ph– ALL, achieved a significant decrease in white blood cells.
Response duration ranges from 21 to 217 or more days. Time to response ranges from 21 to 63 days, with time to best response between seven and 98 or more days.
Zwaan noted that two patients have been responding for longer than seven months, and others have relapsed after as little as two weeks. “While there were some complete remissions, all patients are expected to relapse because this is monotherapy,” Zwaan said in an interview.
“What we want to do is to give dasatinib up-front on top of chemotherapy to try to improve overall survival before the patients relapse,” he said.
Some activity, Zwann said, was observed for dasatinib in Ph– leukemias. “So we think the indication may be broader than just Ph+ disease.”
Dasatinib was generally well-tolerated and had a favorable safety profile. Nonhematologic toxicities were mostly mild to moderate in severity. One patient had a pleural effusion that responded to diuretics, steroids and drug interruption. Cytopenias were infrequent, occurring in only one patient who had been heavily pretreated (including stem cell transplant).
“In this preliminary analysis, dasatinib showed efficacy in pediatric patients with Ph+ and Ph– leukemias,” Zwaan said.
The next studies will be conducted with dasatinib in conjunction with chemotherapy. – by Walter Alexander
For more information:
- Chromik J, Pfeifer H, Wunderle L, et al. Sustained molecular responses to dasatanib (SPRYCEL) in patients with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) or lymphoid blast phase (LyBP) chronic myeloid leukemia after imatinib (IM) failure: a single-center experience. Abstract 285. Presented at: 48th Annual Meeting of the American Society of Hematology. Dec. 9-12, 2006; Orlando, Fla.