Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: Results of Children’s Oncology Group Trial AALL0622

Abstract

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

Delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib

“…This study was approved by the Institutional Review Board of Cincinnati Children's Hospital Medical Center. Patients were treated according to Children's Oncology Group protocols AALL0031, AALL0232, AALL0622, AALL1122, AALL0434, AALL1131 (2 g/m 2 dosing for patients with Down syndrome, 5 g/m 2 dosing for all others), AALL0631 (4 g/m 2 dosing), or AALL0932 (1 g/m 2 dosing, LR‐M arm). Dose reductions or omissions due to toxicity were made for subsequent HDMTX courses per protocol criteria or physician discretion in certain cases.…”

Dasatinib and low‐intensity chemotherapy for Philadelphia chromosome‐positive acute lymphoblastic leukemia in a child with Down syndrome

“…Dasatinib has been employed as first‐line therapy for adult Ph+ ALL to induce deep remission. However, the recent study in children did not show an advantage for dasatinib over imatinib …”

“…Clinical studies on TKIs for pediatric Ph+ ALL suggested that hematopoietic stem cell transplantation in first CR could be avoided in a subset of children with Ph+ ALL, especially in MRD‐negative patients . However, the higher WBC count at diagnosis conferred a higher risk of late relapse in patients with chemotherapy only, and IKZF1 deletions were also associated with a higher risk of relapse, especially in standard risk patients …”

Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib

“…Treatments and responses are summarized in Figure 1. He achieved molecular remission with induction chemotherapy per the CALGB 10403 protocol [15], followed by consolidation per the AALL0622 protocol [16]. The TKI dasatinib was added to induction therapy, but was subsequently discontinued due to elevated transaminases, which also prompted vincristine and daunorubicin dose reductions.…”