Prior to the development of tyrosine kinase inhibitors (TKIs), Philadelphia chromosome (Ph) –positive (Ph+) acute lymphoblastic leukemia (ALL) was traditionally associated with an overall survival (OS) of less than 25 percent.1 However, adding imatinib, the first generation TKI targeting the tyrosine kinase domain of Bcr-Abl, to traditional treatment regimens has drastically improved cure rates, even calling into question the need for hematopoietic stem cell transplantation (HSCT) in some children and young adults. Nevertheless, drug resistance and relapse remain a difficult challenge. Later-generation TKIs designed to overcome drug resistance mutations within the ABL1 kinase domain hope to address this problem.1 Dasatinib is a second-generation TKI and a combination ABL/SRC kinase inhibitor. Unlike imatinib, dasatinib has excellent central nervous system (CNS) penetration owing to its ability to cross the blood-brain barrier. While some studies have suggested that dasatinib may be superior to imatinib for the treatment of Ph+ pediatric ALL, randomized controlled studies directly comparing the efficacy of dasatinib to imatinib have been infeasible in pediatrics because of a paucity of patients.
The Chinese Children’s Cancer Group ALL-2015 (CCCG-ALL-2015) study is a multi-institutional clinical trial that enrolled patients with ALL aged zero to 18 years. It contains two open-label randomized studies, including a randomized comparison of chemotherapy plus imatinib versus chemotherapy plus dasatinib in patients that were positive for the t(9;22) Ph by cytogenetics, fluorescence in situ hybridization, or polymerase chain reaction. Patients were treated on the intermediate-risk arm according to a modified St. Jude Total XV/XVI backbone. All participants received upfront therapy with dexamethasone for four days, followed by a four-drug induction with prednisone, vincristine, daunorubicin, and asparaginase. Imatinib (300 mg/m2 per day) or dasatinib (80 mg/m2 per day) was added once the translocation was confirmed and was continued for the duration of therapy. Postinduction patients received consolidation therapy with high-dose methotrexate, mercaptopurine, and triple intrathecal chemotherapy followed by continuation treatment with repeated cycles of cytotoxic agents. No patient received prophylactic cranial radiation. Patients who had positive minimal residual disease (MRD; > 1%) at end induction were allocated to receive HSCT.
CCCG-ALL-2015 enrolled a total of 5,525 participants between January 1, 2015, and September 18, 2018. Of these, 225 patients were confirmed to be Ph+ (4.1%). Thirty-five participants declined randomization and one patient died prior to treatment. Thus, 189 patients were enrolled for randomization, with 92 randomized to receive dasatinib and 97 to receive imatinib during induction. Of these, 91 participants went on to receive dasatinib and 92 to receive imatinib during consolidation. Finally, during continuation, 84 patients continued to receive dasatinib, and 82 received imatinib. Based on end-of-induction MRD status, 184 patients were intermediate-risk, and five were high-risk (HR). Four of these HR patients went on to HSCT, and only one survived to four years postdiagnosis. The trial stopped early based on an interim analysis that demonstrated superior outcomes on the dasatinib arm.
In the authors’ intention-to-treat analysis, with a median follow-up time of 26.4 months, the four-year event-free survival (EFS) was significantly better in the dasatinib group (71.0%) than in the imatinib group (48.9%). The OS was also significantly better in the dasatinib group (88.4%) versus the imatinib group (69.2%). The four-year cumulative risk of relapse was also lower in the dasatinib group than in the imatinib group, as was the risk of isolated CNS relapse. However, the cumulative risk of any CNS relapse and the cumulative risk of death in remission were similar in both groups. Treatment with imatinib, age 10 years or older, a white blood cell count of 100 x 103 cells/μL or greater at diagnosis, and a T-cell phenotype were all associated with an inferior EFS in the multivariate analysis. Similarly, in the as-treated analysis, the authors found that the dasatinib group had a higher EFS, cumulative risk of any relapse, and isolated CNS relapse when protocol removal was included as adverse events. The occurrence of common toxicities did not differ significantly between the groups.
Importantly, this phase III trial found significant improvement in EFS and OS using a higher dose of dasatinib (80 mg/m2 per day) than prior phase II studies evaluating dasatinib in pediatric BCR-ABL1+ ALL — Children’s Oncology Group (COG) studies AALL0622 and AALL1122. These trials found no difference in survival with 60 mg/m2 per day of dasatinib as compared with historical controls treated with imatinib on similar backbones — COG AALL0031 and EsPhALL 2004, respectively.2,3 The investigators’ ability to complete a randomized trial in pediatric BCR-ABL1 ALL is remarkable. Of note, the current study has a relatively short follow-up time, and treatment backbones on this trial differed from those used by EsPhALL and the COG.2,3 It is important to ensure that the benefit of dasatinib is maintained with time. Additionally, the dose of imatinib used in this study is lower (300 mg/m2) than the dose used on prior COG trials and the dose being evaluated on an open joint EsPhALL/COG trial (340 mg/m2; NCT03007147). It is unclear if a higher dose of imatinib would have been more effective. Impressive results from the current study suggest that indeed, treatment with higher doses of dasatinib may confer improved survival and decreased relapse rates when compared to the first-generation imatinib. Additional studies comparing TKIs, establishing the best chemotherapy backbone, and incorporating immunotherapy are warranted.
Dr. McClory and Dr. Teachey indicated no relevant conflicts of interest.