Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study

Abstract

Primary Mediastinal large B-cell Lymphoma (PMLBL) is a rare entity predominantly affecting adolescents and young adults. Recently, an international phase 2 trial in pediatric patients using dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) failed to reproduce excellent survival reported in some adult studies. The optimal therapy regimen needs to be determined in this disease. French prospective LMB2001 trial included all patients < 18 years with mature B-cell lymphoma treated in French centers. For patients with PMLBL, treatment included 4 to 8 courses of Lymphomes Malins B (LMB)-based chemotherapy without radiotherapy. From 2008, rituximab was added before each chemotherapy course. From 09/2001 to 03/2012, 42 patients with PMLBL were registered. The median age was 15 years (range 8-18). 21 patients were treated by chemotherapy plus rituximab. The median follow-up was 7.1 years (Interquartile range, 5.8-11.1). Five-year event-free (EFS) and overall survival (OS) were 88.1% (95%Confidence Interval (CI), 75.0%-94.8%) and 95.2% (95%CI, 84.0%-98.7%) for the whole population. The 5-year EFS was 81.0% (95%CI, 60.0%-92.3%) and 95.2% (95%CI, 77.3%-99.2%) (HR=0.24 (95%CI 0.03-2.2)) and 5-year OS was 90.5% (95%CI, 71.1%-97.3%) and 100% for patients treated without and with rituximab, respectively. Only 1/21 patients treated with rituximab and LMB-based chemotherapy had local early treatment failure but achieved prolonged complete remission with second-line chemotherapy and radiotherapy. Intensive LMB-based chemotherapy with rituximab achieved excellent survival in children/adolescents with PMLBL. Further international prospective studies are required to confirm these results in this population.

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

“…The Inter-B-NHL ritux 2010 study reported grade ≥3 infections in 4% of the courses and 17% of the patients compared with 58.6% infections grade ≥3 in other LMB-based chemotherapy trials. The LMB2001 trial included 42 children with primary mediastinal B-cell lymphoma (PMBCL) treated with LMB with or without rituximab, and recorded one case of candidemia (4.8%) in the rituximab arm, but no toxic death [ 30 ]. Strikingly, a study on 88 children with diffuse large B cell lymphoma (DLBCL) that included patients with human immunodeficiency virus (HIV) infection did not observe an increased incidence of infection-related deaths in patients who received rituximab plus chemotherapy compared with those who were treated with chemotherapy alone [ 31 ].…”

Pediatric Aggressive Mature B-Cell Lymphomas, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

“…The French LMB2001 prospective study evaluated intensive LMB-based chemotherapy (based on the FAB/ LMB96 protocol) in pediatric patients with PMBL (42 of 773 patients with newly diagnosed B-cell NHL had PMBL). 28 All patients received prephase COP followed by 4 to 8 courses (induction, consolidation, and maintenance) of chemotherapy, and rituximab was added to chemotherapy after 2008. In 2010, the protocol was modified to recommend 6 courses of LMB-modified chemotherapy (B/C) with rituximab for all patients (2 induction courses of R-COPADM followed by 2 consolidation courses of R-CYVE [rituximab, cytarabine, and etoposide] and 2 courses of maintenance therapy [vincristine, cytarabine, doxorubicin, prednisone, and rituximab]).…”

“…These results are in contrast to the EFS and OS rates for dose-adjusted EPOCH-R reported in the aforementioned analyses, 31,32 and the survival rates reported in this phase II study are also inferior to those reported in the LMB2001 prospective study (discussed previously). 28 In the absence of data from randomized trials, optimal first-line treatment of patients with PMBL has not been established. Enrollment in a clinical trial is preferred for all patients.…”

“…Based on the available data (as discussed previously), the following regimens are included as options for first-line therapy: dose-adjusted EPOCH-R (6 cycles) 31,32 or R-CHOP (6 cycles) 30 6 RT or LMB-modified B/C chemotherapy with rituximab (see PBCL-12, page 1271). 28 There are not enough data on the use of RT in pediatric patients and RT was not part of the protocol for pediatric patients with PMBL. Definitive diagnosis may not be feasible before starting initial treatment.…”

“…31 In retrospective and prospective series of pediatric patients with PMBL, although PET/CT was used for response assessment after a few cycles of chemotherapy and at EOT, no treatment decisions were based on the results of PET/CT scans. 28,31,33 residual mass was recommended. 28 A PET-adapted treatment approach was also used to identify adult patients for whom RT can be safely omitted, and only those with a PET-positive scan at EOT received RT.…”