Page 175 - Haematologica Vol. 107 - September 2022

ARTICLE - Rituximab with LMB-chemotherapy regimen in PMLBL M.E. Dourthe et al.
most commonly presents in female adolescents and young adults with signs and symptoms of bulky mediasti- nal disease. It is biologically related to nodular sclerosis Hodgkin lymphoma on pathology and gene expression profiling although some phenotype markers (MUM1, MAL),4 as well as lactate dehydrogenase (LDH) levels and 18flu- orodeoxyglucose-positron emission tomography/ com- puted tomography (18F-FDG PET/CT) findings help discriminate mediastinal Hodgkin lymphoma from PMLBL.5 In adults with PMLBL, although there is a lack of consen- sus about the optimal therapeutic strategy for newly di- agnosed patients, highly curative strategies, including rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) and dose-adjusted etoposide, dox- orubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) are mainly rec- ommended.6 However, significant cumulative doses of chemotherapy are achieved with both chemotherapy regimens and a substantial rate of patients still need radi- ation therapy (RT), especially with R-CHOP.
In children and adolescents, the first prospective inter- national phase II study of DA-EPOCH-R regimen7 failed to reproduce the outstanding survival reported with this regimen in some adults studies. Treatment strategies orig- inally designed for Burkitt lymphoma are successfully used for children with diffuse large B-cell lymphoma (DLBCL)8,9 but patients with PMLBL presented more aggressive dis- ease and specific approaches were needed.10,11 Herein, we reported the experience of the prospective French LMB 2001 study with 42 PMLBL patients treated with intensive LMB-based chemotherapy between 09/2001 and 03/2012, with the addition of rituximab from 2008.
Methods
Diagnosis, classification and staging
The French LMB 2001 prospective study included patients less or equal to 18 years old, with mature B-cell lym- phoma including PMLBL. Patients with known pre-existing immunodeficiency were not included. For the purpose of this analysis, pathology was planned to be reviewed by national experts for diagnosis as PMLBL. The LMB2001 study has been approved by the SFCE Scientific Commit- tee and National Ethics Committee. Parents/legal guard- ians provided written informed consent for the inclusion of their children in the studies in accordance with the Declaration of Helsinki. Minimal work-up included clinical examination, chest x-ray, abdominal ultrasound or CT, two bone marrow (BM) aspirates and biopsies, cerebrospinal fluid (CSF) cytology, and standard blood analysis including LDH level (≤ or >2N the upper limit of the institution’s nor- mal range). PET/CT was recommended but staging was not based on its result only. Other imaging was performed
as clinically indicated. Staging was based according to the St Jude’s/Murphy’s and Ann Arbor classifications.
Study therapy
LMB2001 was a FAB (French-American-British)/LMB 96- based protocol. Treatment was based on St Jude’s/Murphy’s stage. Therapeutic groups were defined as in previous LMB studies.9 All patients received a pre- phase of low-dose cyclophosphamide, vincristine, and prednisone (COP). Group B patients (stage III and non-CNS stage IV with marrow involvement <25%) received therapy similar to Group B on FAB/LMB96 with four cycles of chemotherapy. For all Group C patients, Group C1 patients (stage IV disease with marrow involvement ≥25% without CNS-positive disease) received high-dose methotrexate (HD MTX) (8 g/m2) as previously given over 4 hours, whereas Group C3 patients (central nervous system [CNS]-positive) received HD MTX (8 g/m2) over 24 hours.12 Consecutive courses were given as soon as blood counts recovered and the patient's condition allowed, except for the maintenance courses, which were given at 28-day in- tervals.
From 2008, it was recommended to add rituximab (R) as an intravenous (IV) infusion (375 mg/m2) on day 1 of each chemotherapy course. Additionally, based on an unpub- lished prognostic analysis, patients with bulky mediastinal mass (>10 cm) and/or high LDH serum level (> 2N on the Institution upper limit value), and/or lombo-aortic nodes were assigned to Group C1 regimen. Lastly, in 2010, the LMB-modified B/C chemotherapy with rituximab (total 6 doses) was recommended for all patients, consisting of two courses of RCOPADM Group B (cyclophosphamide, vincris- tine, prednisone, adriamycin, HD MTX 3 g/m2) followed by two courses of RCYVE Group C (with high-dose cytarabine, and etoposide) and two courses of maintenance therapy with rituximab. Patients received two double intrathecal (DIT) only at day 2 of each COPADM course (Table 1). Remission assessment was performed after the first con- solidation course for Group B and after the second con- solidation course for Group C and B/C. In patients with a residual mass by radiographic evaluation, an excision or biopsy for pathology review was recommended. However, as residual mass is frequent in PMLBL, if the therapy re- sponse was adequate and a biopsy was not performed, the patients were to remain on assigned treatment, and remission re-evaluated at the end of therapy. For Group B patients, if viable tumor cells were identified, the therapy was switched to the more intensive Group C1 regimen. Pa- tients with biopsy-proven viable tumor cells after the sec- ond consolidation course ((R)CYVE2) were considered to have primary refractory disease and evaluated as an event. No-treatment decisions were based on 18F-FDG PET/CT results only, and 18F-FDG PET/CT were not re- viewed for the purpose of this analysis. Patients with per-
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