Long-term follow-up of short intensive multiagent chemotherapy without high-dose methotrexate ('Orange') in children with advanced non-lymphoblastic non-Hodgkin's lymphoma: a Children's Cancer Group Report

Despite prolonged therapy (18 months), children with advanced non-lymphoblastic, non-Hodgkin's lymphoma (NHL) treated on previous Children's Cancer Group (CCG) trials achieved less than a 60% 5-year event-free survival (EFS). In this study we piloted a shorter but more intensive protocol ('Orange') to determine the feasibility, safety, and efficacy of this alternative treatment approach. Thirty-nine children received a CHOP-based induction, etoposide/ifosfamide consolidation, DECAL (dexamethasone, etoposide, cisplatin, cytosine arabinoside (Ara-C) and L-asparaginase) intensification, and either one or two similar but less intense maintenance courses. Patients were stratified to standard-risk (5 months) vs high-risk (7 months) treatment. High risk was defined as either bone marrow disease, CNS disease, mediastinal mass greater than or equal to one-third thoracic diameter at T5 and/or LDH greater than or equal to2 times institutional upper limits of normal. All other patients were considered to be standard risk. Results were compared with the previous CCG NHL study (CCG-503). Sixteen and 23 patients were considered standard- vs high-risk, respectively. The 5-year EFS and overall survival (OS) were 77 +/- 7% and 80 +/- 7%, respectively. The 5-year EFS and OS were significantly better in the standard- VS igh-risk subgroups (100% vs 61 +/- 11 %) (P < 0.003) and (100% vs 65 +/- 11 %) (P < 0.01), respectively. Lactate dehydrogenase (LDH) greater than or equal to2 x normal (NL) was associated with significantly poorer outcomes (LDH greater than or equal to2 x NL vs <2 x NL) (5-year EFS: 55 +/- 12% vs 100%) (P < 0.0004). This CCG hybrid regimen, 'Orange', of short and more intensive therapy resulted in a significant improvement in outcomes compared with the previous CCG trial of more prolonged but less intense therapy. This regimen that deletes high-dose methotrexate, if confirmed in a larger trial, could be considered as an alternative treatment approach in children without high tumor burdens (LDH <2 x NL) and Murphy stage III disease.