Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Abstract

IMPORTANCEA randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).OBJECTIVE To determine whether dasatinib given at a daily dosage of 80 mg/m 2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m 2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. DESIGN, SETTING, AND PARTICIPANTSThis open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. INTERVENTIONS Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. MAIN OUTCOMES AND MEASURESThe primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. RESULTS Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR,) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups.CONCLUSIONS AND RELEVANCE Intensive chemotherapy including dasatinib at a dosage of 80 mg/m 2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m 2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation.

Pediatric acute lymphoblastic leukemia

“…126 Newer generations of tyrosine kinase inhibitors are available, and a randomized study showed that pediatric patients who received chemotherapy with 80 mg/m 2 /day of dasatinib, a dual ABL/SRC inhibitor with more potent activity against BCR-ABL1 and better CNS penetration than imatinib, had better EFS, OS, and CNS disease control when compared to patients who received imatinib (300 mg/m 2 /day). 127 Ponatinib has potent activity in both wild-type and mutant BCR-ABL1 ALL, including cells harboring the gatekeeper ABL1 T315I mutation. Combination chemotherapy with ponatinib and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine resulted in excellent 2-year EFS in adults with newly diagnosed Ph-positive ALL.…”

Successful outcome of disseminated candida tropicalis osteomyelitis on remission induction for childhood Philadelphia chromosome–positive acute lymphoblastic leukemia

“…In the successful management of Ph-positive ALL, dasatinib the second-generation Abl-tyrosine kinase inhibitor is crucial. According to our randomized clinical trial, dasatinib at a dosage of 80 mg/m 2 per day yielded superior results in the treatment of Ph-positive ALL (9). Anti-infection combined with surgical incision and drainage, and dasatinib administration, which together led to the successful treatment of osteomyelitis while maintaining a remission state of Ph-positive ALL.…”

Treatment of childhood cancer in China: Current status and future direction

“…A randomized study comparing two different tyrosine kinase inhibitor (imatinib versus dasatinib) was also completed. 11 Other than prospective studies, the Group also conducted retrospective studies on some rare conditions. 12 Other than the two national groups, some hospitals also initiated regional multicenter studies.…”