Dose-Dense CHOP Plus Rituximab (R-CHOP14) Seems To Overcome, in Large B Cell Lymphoma, the Negative Prognostic Significance of B Cell Origin.
Authors: Rigacci Luigi , Nassi Luca , di Lollo Simonetta , Puccini Benedetta , Doria Morena , Mappa Silvia , Capaccioli Gloria , Alterini Renato , Carrai Valentina , Bosi Alberto 
Published: October 2019

Abstract
Diffuse large B cell lymphoma (DLBCL) is one of the most common types of lymphoproliferative disorder. Approximately half of all patients will be cured of their disease by primary therapy the remainder die of the disease. Clinical outcome in patients with DLBCL is poorly predictable. Gene-expression profiling in DLCBL has brought an insight into the biological heterogeneity of the disease. Two major subgroups were identified: germinal centre B (GCB) cell, activated B cells (ABC) or non-germinal centre (non-GCB). The GCB group has a significantly better survival than the ABC group. Immunohistochemistry has been evaluated as a surrogate for this molecular classification. The aim of this study was to define retrospectively the B-cell origin of 21 patients treated with R-CHOP14 and to evaluate if the intensified immuno-chemotherapy could improve their clinical outcome. We performed immunohistochemical stains on formalin-fixed paraffin-embedded tissues from diagnostic biopsies with the following antibodies: CD10, bcl-6, bcl-2, MUM1 and Mib1. Based on the algorithm published by Hans et al. we subdivided the patients in GCB origin and ABC origin. We evaluated also the prognostic value of single protein expression. Fourteen patients were male and 9 female, 9 were stage I–II and 12 stage III–IV, 12 presented symptoms at diagnosis and 13 showed bulky disease. Six patients had more than one extranodal sites involved and 13 showed abnormal LDH value, the IPI was intermediate-high risk in 7 and high risk in 3 patients. Half patients presented beta2 microglobulin and ESR elevated. According to immunohistochemistry analysis 9 patients derived from germinal centre and 12 from non-germinal centre, 14 patients presented a positive CD10, 9 a positivity for bcl6, 7 a positive bcl2 and 9 a positive MUM1. Fourteen patients (67%) obtained a complete remission (CR), 4 a partial response (PR) and 3 were non responders (NR). All patients with PR and 2 out 3 NR derived from germinal centre. Four out 14 CR patients experienced relapse, three (75%) derived from non-germinal centre. Six patients died, three derived from GCB and three from non-GCB. After a median period of observation of 500 days (range 98–1870 days) the overall survival (OS) was 71% and the failure free survival (FFS) was 49%. The statistical analysis was performed comparing the B cell origin and clinical characteristics, moreover was also evaluated the expression of bcl2 either in GCB or in non-GCB lymphomas. In univariate and multivariate analysis the overall survival was not affected by clinical characteristics nor B cell origin. In univariate analysis FFS was significantly higher in low and low-intermediate IPI risk patienta (p 0.01) and in multivariate analysis IPI and B cell origin were the only two factors that influenced the FFS. In conclusion even if few patients were evaluated we can point out that the intensification could enhance the efficacy of R-CHOP regimen improving the overall survival also in patients with ABC lymphoma. In contrast it seems that R-CHOP14 does not improve the FFS of patients with ABC origin. Further analysis with larger sample sizes of DLBCL patients are needed to verify this preliminary observations.