Contiguous follicular lymphoma and follicular lymphoma in situ harboring N-glycosylated sites

International audienceFollicular lymphoma in situ (FLIS) is composed of a clonal B-cell population harboring the typical t(14;18) hallmark of follicular lymphoma (FL), forming unconventional BCL2 Bright CD10 + cell foci in an otherwise normal reactive lymph node (LN). The diagnosis of FLIS is made on the fortuitous discovery of unconventional BCL2 Bright CD10 + cell foci. 1 Several studies recently demonstrated that FLIS are already advanced precursors in follicular lymphomagene-sis, but not necessarily committed to malignant transformation. 2,3 However, the relationship between FLIS and FL still remains unclear, as only a minority (<5%) of FLIS patients eventually develop FL. This is in line with the usually indolent progression of the disease, and the genomic instability observed in FLIS cells, which can engage FL precursor cells either in an evolutionary malignant process, or to an evolutionary dead end. 4 We report the case of a 35-year old male patient who presented with a cervical adenopathy. Histological examination of the excised LN displayed an altered architecture suggestive of FL, consisting of high number of monomorphic large follicles, uniformly spread in the cortical and medullary areas. Most follicles contained a predominant population of small cleaved cells with scant macrophages and mitoses. The mantle zone was reduced or absent. However, in a minor cortical area, a few follicles showed features mimicking residual classical germ cells (GC), including a smaller size, higher cell polymorphism, and a preserved mantle zone (Figure 1A). The BCL2 immunostaining (clone 100) was negative in follicles displaying a typical FL pattern. In contrast, follicles located in the pseudo-residual area were BCL2bright, i.e. more strongly stained than the surrounding mantle zone and reactive T cells (Figure 1B). Most follicles were only slightly positive for Ki67 (Online Supplementary Figure S1A). Both BCL2 – and BCL2 + follicles were CD10 positive (Online Supplementary Figure S1B) and contained a BCL2/JH break-point evidenced by fluorescence in situ hybridization (FISH) (Figure 1C). Taken together these results suggested the diagnosis of simultaneous occurrence of BCL2 – FL (grade I/II) and of BCL2 + FLIS in the same LN. We decided to further analyze those two lesions independently, and performed macrodissection in order to proceed with individual molecular analyses when required. Sanger sequenc-ing revealed that both FLIS and FL shared the same BCL2/JH sequence at the t(14;18)+ breakpoint, and thus originated from the same clone (Figure 1D). We tested two other anti-BCL2 antibodies (E17, SP66) directed against other epitopes, but the staining remained BCL2-in the FL area of the LN, similar to the anti-BCL2 antibody (clone 100) staining (Figure 1E and F). We thus sequenced exons 1 to 3 of the BCL2 gene (B-cell CLL/lym-phoma 2, NG_009361.1). Punctual mutations, resulting in amino acid substitutions, were found in the FL component (Online Supplementary Table S1), and were indeed located in the targeted aa41 to aa54 epitope of clone 100 (mutation

Antithymocyte Globulin in Reduced-Intensity Conditioning Regimen Allows a High Disease-Free Survival Exempt of Long-Term Chronic Graft-versus-Host Disease

AbstractNonmyeloablative (NMA) regimens allow the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients considered unfit for standard myeloablative conditioning (MAC) regimens using high-dose alkylating agents with or without total body irradiation (TBI). Reduced-intensity conditioning (RIC) regimens, based on fludarabine (Flu), busulfan (Bu), and rabbit antithymocyte globulin (r-ATG), represent an intermediate alternative between NMA and MAC regimens. This platform was subsequently optimized by the introduction of i.v. Bu and the use of 5 mg/kg r-ATG, based on the hypothesis that these modifications would improve the safety of RIC allo-HSCT. Here we report a study conducted at our institution on 206 patients, median age 59 years, who underwent allo-HSCT after conditioning with Flu, 2 days of i.v. Bu, and 5 mg/kg r-ATG (FBx-ATG) between 2005 and 2012. The prevalence of grade III-IV acute graft-versus-host disease (GVHD) was 9%, and that of extensive chronic GVHD was 22%. Four-year nonrelapse mortality (NRM), relapse, and overall survival (OS) rates were 22%, 36%, and 54%, respectively. NRM tended to be influenced by comorbidities (hematopoietic cell transplantation–specific comorbidity index [HCT-CI] <3 versus HCT-CI ≥3: 18% versus 27%; P = .075), but not by age (<60 years, 20% versus ≥60 years, 25%; P = .142). Disease risk significantly influenced relapse (2 years: low, 8%, intermediate, 28%, high, 34%; very high, 63%; P = .017). Both disease risk (hazard ratio [95% confidence interval]: intermediate, 2.1 [0.8 to 5.2], P = .127; high, 3.4 [1.3 to 9.1], P = .013; very high, 4.0 [1.1 to 14], P = .029) and HCT-CI (hazard ratio [95% confidence interval]: HCT-CI ≥3, 1.7 (1.1 to 2.8), P = .018) influenced OS, but age and donor type did not. The FBx-ATG RIC regimen reported here is associated with low mortality and high long-term disease-free survival without persistent GVHD in both young and old patients. It represents a valuable platform for developing further post-transplantation strategies aimed at reducing the incidence of relapse, particularly in the setting of high-risk disease

Surveillance du réarrangement BcI2-IgH par PCR chez les patients atteints de lymphome folliculaire et traités par autogreffe en première ligne de traitement dans l'essai GELF-94 du GELA

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Retreatment with rituximab in 178 patients with relapsed and refractory B-cell lymphomas: A single institution case control study

The role of rituximab retreatment in relapsed B-cell lymphoma is not well known. We undertook a single center retrospective cohort study to investigate the efficacy of retreatment with rituximab with or without chemotherapy in patients with relapsed and refractory B-cell lymphomas. We only included patients treated first-line and in first progression; 178 patients were included in the study, of whom 29 had diffuse large B-cell lymphoma (DLBCL) and 28 had follicular lymphoma (FL). The overall response rate for the first treatment was 81 and for the second treatment was 66. The median progression-free survival (PFS) for all patients from diagnosis was 13.2 months and from relapse was 12.5 months (not statistically different). For DLBCL the median PFS from diagnosis was 9.6 months and from relapse was 8.4 months, and for FL the median PFS from diagnosis was 26.4 months and from relapse was 19.2 months (not statistically different). The 5-year overall survival was 57. In a historical comparison with rituximab-naive patients, rituximab-retreated patients had a shorter time to initial relapse than control patients, but there was no difference between the two groups for PFS from relapse. In conclusion, retreatment with rituximab, with or without chemotherapy, yields a high overall response rate in patients with relapsed and refractory B-cell lymphomas. Relapse occurring after rituximab-containing therapy appears to be more aggressive than that occurring after chemotherapy alone. The outcome of retreatment, in terms of progression-free survival, is similar to that of primary treatment

Retreatment with rituximab in 178 patients with relapsed and refractory B-cell lymphomas: a single institution case control study

The role of rituximab retreatment in relapsed B-cell lymphoma is not well known. We undertook a single center retrospective cohort study to investigate the efficacy of retreatment with rituximab with or without chemotherapy in patients with relapsed and refractory B-cell lymphomas. We only included patients treated first-line and in first progression; 178 patients were included in the study, of whom 29% had diffuse large B-cell lymphoma (DLBCL) and 28% had follicular lymphoma (FL). The overall response rate for the first treatment was 81% and for the second treatment was 66%. The median progression-free survival (PFS) for all patients from diagnosis was 13.2 months and from relapse was 12.5 months (not statistically different). For DLBCL the median PFS from diagnosis was 9.6 months and from relapse was 8.4 months, and for FL the median PFS from diagnosis was 26.4 months and from relapse was 19.2 months (not statistically different). The 5-year overall survival was 57%. In a historical comparison with rituximab-naive patients, rituximab-retreated patients had a shorter time to initial relapse than control patients, but there was no difference between the two groups for PFS from relapse. In conclusion, retreatment with rituximab, with or without chemotherapy, yields a high overall response rate in patients with relapsed and refractory B-cell lymphomas. Relapse occurring after rituximab-containing therapy appears to be more aggressive than that occurring after chemotherapy alone. The outcome of retreatment, in terms of progression-free survival, is similar to that of primary treatment

Plasma TNF-α and IL-10 Level-Based Prognostic Model Predicts Outcome of Patients with Diffuse Large B-Cell Lymphoma in Different Risk Groups Defined by the International Prognostic Index

Tumor necrosis factor (TNF)-α and interleukin (IL)-10 are key cytokines involved in lymphoma development. Their pretreatment plasma levels were reported to influence the clinical course of non-Hodgkin's lymphoma. In this study the impact of combined elevation of TNF-α and IL-10 on disease features and outcome of patients with diffuse large B-cell lymphoma (DLBCL) were investigated. Plasma TNF-α and IL-10 levels were determined at the time of diagnosis in a group of 106 DLBCL patients uniformly treated with anthracycline-based regimens. Three risk groups depending on the pretreatment levels of the cytokines were identified: low-, intermediate-, and high-risk groups. In univariate analysis, the cytokine intermediate- and high-risk groups were associated with lower probability of achieving a complete remission (odds ratio [OR] = 0.2, 95% confidence interval [CI] 0.06-0.6, p = 0.006 and OR = 0.05, 95% CI 0.01-0.2, p < 0.0001, respectively) and shorter progression-free survival (PFS) (OR = 4.4, 95% CI 1.9-10.2, p < 0.001 and OR = 9.7, 95% CI 4.1-23.0, p < 0.0001, respectively) and overall survival (OS) (OR = 4.2, 95% CI 1.7-10.1, p = 0.002 and OR = 11.2, 95% CI 4.4-28.4, p < 0.0001, respectively) in comparison with the cytokine low-risk group. In multivariate analysis, the cytokine intermediate- and high-risk groups also correlated with shorter PFS (relative risk [RR] = 4.5, 95% CI 1.9-10.9, p = 0.001 and RR = 5.8, 95% CI 2.2-15.3, p < 0.0001, respectively) and OS (RR = 4.6, 95% CI 1.8-12.0, p = 0.001 and RR = 7.5, 95% CI 2.7-20.9, p < 0.0001, respectively) regardless of the International Prognostic Index (IPI) scoring system. The TNF-α and IL-10 level-based index may work as an additional model to the IPI for predicting the survival of DLBCL patients. This model may help to identify patients in a given IPI risk group for whom more accurate and risk-adapted treatment could be advise