Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study

Abstract

This study was designed to test the hypothesis that high-dose asparaginase consolidation therapy improves survival in pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma. Five hundred and fifty-two patients (357 patients with T cell acute lymphoblastic leukemia (ALL) and 195 patients with advanced stage lymphoblastic lymphoma) were enrolled in POG study 8704 (T-3). Treatment included rotating combinations of high-dose myelosuppressive chemotherapy agents proven to be effective in T cell ALL in other POG group-wide or local institutional protocols (including vincristine, doxorubicin, cyclophosphamide, prednisone, asparaginase, teniposide, cytarabine and mercaptopurine). After achieving a complete remission (CR), patients were randomized to receive or not receive high-dose intensive asparaginase consolidation (25 000 IU/m²) given weekly for 20 weeks by intramuscular injection. Intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine) was given to prevent CNS disease, and CNS irradiation was used only for patients with leukemia and an initial WBC of >50 000/μor patients with active CNS disease at diagnosis. CR was achieved in 96% of patients. The high-dose asparaginase regimen was significantly superior to the control regimen for both the leukemia and lymphoma subgroups. Four-year continuous complete remission rate (CCR) for the leukemia patients was 68% (s.e. 4%) with asparaginase as compared to 55% (s.e. 4%) without. For the lymphoma patients, 4-year CCR was 78% (s.e. 5%) with asparaginase and 64% (s.e. 6%) in the controls. The overall one-sided logrank test had a P value <0.001 favoring asparaginase, while corresponding values were P = 0.002 for ALL and P = 0.048 lymphoblastic lymphoma. Toxicities were tolerable, but there were 18 failures due to secondary malignancies (16 with non-lymphocytic leukemia or myelodysplasia). Neither WBC at diagnosis (leukemia patients) nor lymphoma stage were major prognostic factors. We conclude that when added to a backbone of effective rotating agents, repeated doses of asparaginase during early treatment improve the outcome for patients with T cell leukemia and advanced stage lymphoblastic lymphoma.