Photo by Bill Branson
Child with cancer
CHICAGO—The largest ongoing and prospective trial of pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP), according to the best knowledge of the investigators, has found dasatinib to be safe and effective as first- or second-line therapy for these children.
Patients refractory to or intolerant of imatinib had a major cytogenetic response (MCyR) by 3 months and responses at 12 and 24 months exceeded 90%.
Newly diagnosed patients had a complete cytogenetic response (CCyR) by 6 months.
“We believe our data suggests that dasatinib could be considered as a new standard of care (SOC) for children with CML in chronic phase,” said study author Lia Gore, MD, of the University of Colorado School of Medicine/Children’s Hospital Colorado in Aurora.
She presented the findings of the study at the ASCO 2017 Annual Meeting (abstract 10511).
Study design
CA 180-226 is a phase 2, open-label, nonrandomized, prospective study conducted in 18 countries. Patients younger than 18 years with newly diagnosed CML-CP, or imatinib-resistant/intolerant (R/I) CML-CP, or CML in accelerated phase, or Ph+ acute lymphoblastic leukemia (ALL) were enrolled on the study between March 2009 and September 2014.
Dr Gore’s presentation focused on the CML-CP patients in the study, both the newly diagnosed and the imatinib-R/I patients.
The imatinib-R/I patients received dasatinib 60 mg/m2 tablets once daily, and the newly diagnosed patients received the same tablet dosage daily or a powdered formulation for oral suspension (PFOS) of dasatinib at 72 mg/m2 daily.
Dr Gore noted the different dosage in the oral suspension formulation is based on bioavailability studies performed in adults, which was determined to be equivalent to the 60 mg/m2 tablet formulation.
Once accrual was reached in the tablet cohort, newly diagnosed patients were accrued to the PFOS cohort. The patients on PFOS could switch to tablets after a year or more on the oral suspension.
Patients remained on treatment until disease progression, unacceptable toxicity occurred, or the patient/physician preference.
All patients had a minimum follow-up of 2 years. The longest follow-up was more than 90 months.
Primary objectives of the study were MCyR greater than 30% for imatinib-R/I patients and complete CCyR greater than 55% for newly diagnosed patients.
Secondary objectives included time to and duration of response, major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety.
Baseline patient characteristics
One hundred thirteen patients were treated across the 3 cohorts—29 in the imatinib-R/I receiving tablets, 51 newly diagnosed patients receiving tablets, and 33 newly diagnosed patients in the PFOS arm. A total of 84 patients had newly diagnosed disease.
Of the 29 imatinib-R/I patients, 25 were resistant, 2 intolerant, and 2 undetermined. And 6 of the 25 resistant patients had defined imatinib-resistance mutations.
Median age was 13.8 years in the imatinib-R/I cohort, 12.9 years in the newly diagnosed on tablets, and 11.7 years in the PFOS group. Other baseline characteristics were similar among the cohorts.
“Importantly, there were 3 patients less than 2 years of age, and a substantial proportion of patients were actually less than 12 years of age,” Dr Gore pointed out.
Dasatinib exposure
The median duration of therapy was 50 months and 42 months in the R/I and newly diagnosed cohorts, respectively.
Forty-eight percent of the imatinib-R/I patients and 73% of the newly diagnosed patients are still on treatment. A relatively small number of patients discontinued therapy.
The median duration of therapy was shorter in the PFOS cohort because they were enrolled only after accrual to the tablet cohort. However, they were also followed up for more than 2 years.
Of the 33 patients on PFOS, 22 eventually switched to tablet formulation.
Results
The primary endpoint for imatinib-R/I patients—MCyR greater than 30%—was reached by 3 months, and MCyR at 12 and 24 months exceeded 90%. The median time to response was 3.1 months (range, 2.8 – 4.1), and median duration of response was not yet reached (range, 54.9 – not estimable).
For newly diagnosed patients, the preset defined rate of interest of 55% for CCyR was reached as early as 6 months, and exceeded 90% by 12 and 24 months.
Dr Gore pointed out that intolerant patients also reached CCyR relatively quickly, although it was not a specified endpoint.
Data indicate that responses occurred relatively quickly and continued to increase over time of follow-up.
MMR also continued to increase over time and showed no difference between formulation and response rate.
Median PFS has not been reached, as only 7 patients in each cohort had disease progression.
One imatinib-R/I patient died 1 year after stopping treatment. The patient, who had a GI bleed unrelated to dasatinib, had discontinued therapy for progressive disease with loss of MCyR.
Safety
Overall safety was very similar to the dasatinib exposure and experience in adults, Dr Gore said, and there were no differences in events between PFOS and tablets.
One patient in the PFOS cohort had a dasatinib-related grade 3 hypersensitivity reaction, which resolved after discontinuation of dasatinib.
“What’s important here,” she said, “is that there were almost no adverse events of severity in either cohort, only 1 in the imatinib refractory and intolerant and 1 in the newly diagnosed cohorts.”
“Most importantly for those of us with a lot of experience in this field,” she added, “there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, pulmonary hypertension, or any vascular occlusive events in patients noted on this trial.”
“Additionally, for pediatricians, we care a lot about what happens to growth in these patients and prospectively we collected a lot of data related to growth parameters in bone growth and development."
Of the dasatinib-related adverse events occurring in 10% or more of patients, there were only 5 growth and development events noted out of the 113 patients treated and all were grade 1 or 2 events, Dr Gore pointed out.
In the R/I cohort, one patient had osteopenia and gynecomastia. At the time of data analysis, this event had resolved even though the patient continued on dasatinib.
“We believe our data suggests that dasatinib could be considered as a new standard of care for children with CML in chronic phase,” she said.
“It includes the advantage of a liquid formulation as well as the advantages of once daily dosing and administration without regard to fed or fasting state,” she added, “which for all of us who treat children know could be quite important.”
The study was funded by Bristol-Myers Squibb.
