Results of CCG-5941: Intensified Multiagent Chemotherapy and Non-Cross Resistant Maintenance Therapy for Advanced Lymphoblastic Lymphoma in Children and Adolescents.

The treatment of advanced (Stage III/IV) pediatric lymphoblastic lymphoma (LL) has recently utilized treatment strategies similar to childhood acute lymphoblastic leukemia (ALL) with prolonged maintenance chemotherapy for up to two years (Burkhardt et al JCO, 2006) compared to older treatment strategies of less intense lymphoma type therapy (Anderson et al NEJM, 1983). The CCG previously piloted a “NY regimen” for “lymphomatous” ALL with a new intensive induction/intensive conditioning and alternating non-cross resistant combination maintenance therapy (Steinherz et al JCO, 1986). We modified the NY regimen for lymphomatous ALL in children with advanced (Stage III/IV) lymphoblastic lymphoma with ≤25% BM lymphoblasts. Between July 1994 and June 1997, 85 eligible LL patients with advanced disease (Stage III/IV) were enrolled in a pilot study CCG-5941 to estimate toxicity, feasibility and efficacy of a short (12 month) aggressive multiagent chemotherapy regimen. Patients were staged according to the St. Jude staging system. Induction (3wks) consisted of VCR, Pred, Daunomycin, Cyclophosphamide, L-ASP and IT MTX/ARA-C. Consolidation (3wks) consisted of VCR, ARA-C, VP-16, HD MTX and IT MTX. There were six maintenance courses each consisting of 4 pulses: A (Cylcophosphamide, 6TG), B (VCR, Pred, Dauno), C (VCR, HD MTX, L-ASP) and D (ARA-C, VP-16). CNS positive pts received 1800 cGy-cranial and 600 cGy spinal at completion of chemotherapy (approximately 1 yr). Central pathology review (84%) and immunophenotyping were preformed with CD3, CD5, CD45RO, TDT, CD 79 and CD20. Neupogen (G-CSF) was given after each cycle to maintain dose intensity. Median age 10 yrs (1–18 yrs), 64% male, median f/u 7.2 yrs, 91% T-cell, 7% B-cell, 2% mixed lineage, 27% LDH ≥2nL, 12 % M2 BM, 5% CNS positive. Among the 85 patients there were four deaths unrelated to disease progression (4.7%), three due to infectious complications and one due to venoclusive disease of the liver. Two second malignant neoplasms (AML) have occurred. Hematopoietic (grade III/IV) toxicity occurred in approximately 80% of patients, resulting in delays in chemotherapy. The 5yr event free survival (EFS) is 78±4.5% and 3 yr overall survival (OS) is 85±3.9%. Analysis of EFS by age, sex, induction responses, marrow status at diagnosis (M2 vs M1), presence of CNS disease, LDH ≥2nL and presence of mediastinal mass was not significant. The prognosis in patients with progressive/relapsed disease was dismal with a 2 yr OS of 33±14%. These pilot results suggest that this experimental approach in children and adolescents with advanced LL is safe and feasible and results in similar long term efficacy as compared to more prolonged maintenance ALL type chemotherapy regimens.