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

Abstract

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 CHOPbased 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 у one-third thoracic diameter at T5 and/or LDH у2 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 high-risk subgroups (100% vs 61 ± 11%) (P Ͻ 0.003) and (100% vs 65 ± 11%) (P Ͻ 0.01), respectively. Lactate dehydrogenase (LDH) у2 × normal (NL) was associated with significantly poorer outcomes (LDH у2 × NL vs Ͻ2 × NL) (5-year EFS: 55 ± 12% vs 100%) (P Ͻ 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 Ͻ2 × NL) and Murphy stage III disease. Leukemia (2002) 16, 594-600.

Risk factors and treatment of childhood and adolescent Burkitt lymphoma/leukaemia

“…The subsequent CCG-5911 study investigated two pilot studies, the LMB 86 and a hybrid CCG regimen referred to as 'Orange', which consisted of a CHOP -like regimen followed by an ifosfamide and etoposide regimen, and then a DECAL (dexamethasone, etoposide, cisplatin, high-dose cytarabine and L-asparaginase) regimen. The 2-year EFS was 77% in the pilot CCG hybrid 'Orange' group with an associated decrease in toxicity compared to the LMB 86 approach (Fig 10) (Cairo et al, 2002).…”

“…The 5-year overall survival was estimated to be 77 ± 7%. From Cairo et al (2002). Nature Publishing Group.…”

Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents

“…[1][2][3][4][5][6][7][8] About 90% of histologic subtypes of childhood de novo high-risk (BM with or without CNS) B-NHL are of the aggressive subtype, including mature B-cell acute lymphoblastic leukemia (B-ALL), Burkitt lymphoma (BL) and Burkitt-like (BLL) histology and to a lesser extent, an intermediate subtype, diffuse large B-cell lymphoma (DLBCL). [9][10][11] Despite an improvement in overall survival (S) with multiagent intensive chemotherapy, there is a significant incidence of serious morbidity, including grade III/IV mucositis (40%-70%), systemic infection (60%-80%), myelosuppression (80%-100%), prolonged hospitalization (median 10-14 days during each induction cycle), and a toxic death rate of 1%-2% in remission with potential long-term cardiac and gonadal toxicities and secondary malignancies.…”

“…[9][10][11] Despite an improvement in overall survival (S) with multiagent intensive chemotherapy, there is a significant incidence of serious morbidity, including grade III/IV mucositis (40%-70%), systemic infection (60%-80%), myelosuppression (80%-100%), prolonged hospitalization (median 10-14 days during each induction cycle), and a toxic death rate of 1%-2% in remission with potential long-term cardiac and gonadal toxicities and secondary malignancies. 4,5,7,8 Reduction therapy with cyclophosphamide, Oncovin (vincristine) and prednisone (COP), induction therapy with cyclophosphamide, Oncovin (vincristine), prednisone, Adriamycin (doxorubicin), and methotrexate (COPADM), and intensification with cytarabine (high dose and continuous infusion) plus etoposide (CYVE 12 ) (Lymphoma Malignancy B [LMB] 86 and 89 group C therapy) was originally introduced by Patte et al and the Société Française d'Oncologie Pédiatrique (SFOP) for advanced (BM with or without CNS) childhood B-NHL and subsequently investigated by Cairo et al in the Children's Cancer Group (CCG) and by Atra et al for the United Kingdom Children's Cancer Study Group (UKCCSG). 4,13,14 However, in view of the high morbidity of this therapy, the exact intensity that is required for optimal results is still unclear.…”

Prospective analysis of minimal bone marrow infiltration in pediatric Burkitt's lymphomas by long-distance polymerase chain reaction for t(8;14)(q24;q32)

“…6,10,11 Based on this observation, we assessed whether MDD positivity at diagnosis were associated to high levels of LDH. As shown in Table 1, 11/12 BM-positive patients had LDH above 1000 U/l, whereas only 8/21 patients with negative BM had an LDH value higher than 1000 U/l (P ¼ 0.0036 according to the two-tailed Fisher exact test).…”