MADRID — Dasatinib (Sprycel, Bristol-Myers Squibb) has shown efficacy and safety in children similar to those already demonstrated in adults with chronic myeloid leukemia in the chronic phase (CML-CP) and has an added advantage of being available as a liquid (from powder) formulation in addition to oral tablets.
“These data suggest that dasatinib may be considered a new standard of care for pediatric patients with CML-CP and includes a liquid formulation,” said first author, C. Michel Zwaan, MD, PhD, from Erasmus MC–Sophia Children’s Hospital Department of Pediatric Oncology/Hematology, Rotterdam, the Netherlands.
At present, imatinib (Gleevec, Novartis) is the only approved BCR-ABL–targeted tyrosine kinase inhibitor for pediatric patients with CML-CP. Thus, there are no approved alternative therapies for the 25% to 30% of patients who do not respond to or are intolerant of the drug.
“There is an unmet need for safe and effective treatment options and alternative formulations,” Dr Zwaan said.
Dasatinib represents an effective alternative for adults, and now the data show it can offer an alternative in children also.
Previously, data from a phase 1 studyphase 1 study, published in the Journal of Clinical Oncology by Dr Zwaan and colleagues, showed that dasatinib demonstrated safety and efficacy in pediatric patients that compared favorably with the treatment effects seen in adults.
Now, the same team has presented results from a phase 2 study, the largest ongoing prospective trial of pediatric patients with CML-CP, here at the European Hematology Association (EHA) 2017 Congress. This study enrolled 145 patients younger than age 18 years, and at the meeting Dr Zwaan reported on 130 patients who were treated, including 54% who were adolescents aged 12 to 18 years.
The patients were grouped into one of three cohorts. One group consisted of patients who were imatinib resistant or intolerant and received dasatinib tablets, 60 mg/m2 once per day (n = 29); of these patients, 25 were resistant, 2 were intolerant, and 2 were undetermined.
Another group was composed of patients with newly diagnosed CML-CP, who were treated with dasatinib 60 mg/m2 once per day (n = 51) or the liquid (powder) formulation of 72 mg/m2 once per day (n = 33).
All patients were treated for at least 1 year.
In the third cohort was imatinib-resistant or -intolerant patients with CML in the accelerated or blastic phase, but this was closed early because of poor response.
The results showed the study met its primary objectives, with a cumulative major cytogenetic response (MCyR) of 30% or more as early as 3 months in the imatinib- resistant/intolerant group, and a cumulative rate of complete cytogenic response (CCyR) of 55% or more as early as 6 months among the newly diagnosed group.
Patients in the resistant/intolerant group had a median time of 3.9 months to a CCyR, while patients in the tablet and liquid formulation newly diagnosed groups had median times of 5.7 months and 5.6 months, respectively.
A median duration of response was not reached for any of the groups.
All patients had a minimum follow-up of 2 years, and the imatinib-resistant/intolerant group had an estimated progression-free survival rate by 48 months of 78%; the rate was 93% in the newly diagnosed group.
A median progression-free survival was not reached, as only 7 patients in each cohort progressed.
Among patients who did have disease progression, the reasons for progression included the loss of MCyR among 3 patients in the resistant/intolerant group and 4 patients in the newly diagnosed group; loss of complete hematologic response in 2 patients in each group; and the development of CML-blastic phase in 2 patients in the resistant/intolerant group and 1 patient in the newly diagnosed group.
There was one death in the resistant/intolerant group, but the death occurred 1 year after cessation of dasatinib and was not believed to be associated with the use of the drug, the researchers said.
There were no cases of dasatinib-related pleural/pericardial effusion, pulmonary edema or hypertension, or pulmonary arterial hypertension, and the adverse events associated with dasatinib occurring in 10% of more of patients were otherwise consistent with those reported in adults, including nausea/vomiting, myalgia/arthralgia, and fatigue.
One patient developed hypersensitivity that was related to dasatinib and led to discontinuation of the drug.
In terms of pediatric bone growth and development, which is highly relevant in a pediatric/adolescent population, Dr Zwaan commented, there were no cases of epiphyses delayed fusion or osteopenia, one case of gynecomastia, and one case of growth retardation; neither of the latter was grade 3 or 4.
The findings on bone growth are particularly notable in relation to long-term data showing growth impairment among children treated with imatinib and potentially negative effects on bone remodeling, Dr Zwann commented.
“We did not see major growth problems in children with dasatinib in terms of CTC grading, [however] we still need to analyze data on Z-scores,” he said.
Dr Zwaan noted that the newly diagnosed patients had the option to switch from the liquid formulation to the oral tablet formulation after a year, which about two thirds of patients, primarily older adolescents, chose to do.
The findings offer important evidence of dasatinib being potentially as beneficial for children as for adults with chronic CML, Dr Zwaan concluded.
“This is the largest ongoing, prospective trial of pediatric patients with chronic-phase CML, and we found that dasatinib was safe and effective as a first- or second-line therapy in children,” Dr Zwaan said.
“We observed early and durable responses with dasatinib which met prespecified study objectives for both cohorts,” he added.
Approached for comment, Monica Bocchia, MD, director of the Department of Hematology at the University of Siena, Italy, who co-moderated the session, agreed that there is an unmet need in patients with CML-CP that dasatinib could fill.
“The findings are important, as in achieving a deep response, dasatinib could reduce the need of bone marrow transplantation in children,” she told Medscape Medical News.
She said that treating children with chronic-phase CML is a bigger clinical challenge than treating the same disease in adults.
“CML is rare in children, but they respond worse to imatinib than adults and for them bone marrow transplant remains the treatment of choice,” Dr Bocchia said.
The study received support from Bristol-Myers Squibb. Dr Zwaan is a consultant for Bristol-Myers Squibb. Dr Bocchia has received honoraria from Janssen, Novartis, and Bristol-Myers Squibb.
European Hematology Association (EHA) 2017 Congress. Abstract S422. Presented June 24, 2017.
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