Nodular Lymphocyte Predominant Hodgkin Lymphoma Research Articles

Pathology and classification of aggressive mature B-cell lymphomas.

Pathology and classification of aggressive mature B-cell lymphomas.

Excellent outcome in Hodgkin lymphoma with ABVD and CMT: A single‐centre retrospective analysis

Background: ABVD alone or in combination with radiotherapy(CMT) is the mainstay of therapy for Hodgkin lymphoma (HL). We retrospectively evaluated outcome of HL patients followed up at Haemato Oncology Care Centre, Vadodara, India, between 2007 to 2016. Methods: Sixty-three patients were analysed for this study, males 65% (n = 41), females 35% (n = 22). The median age was 28 years (range, 8 y to 75 y). Classical Hodgkin lymphoma 93% (n = 59) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) 7% (n = 04). Stage I 1.6% (n = 1), Stage II 25.4%(n = 16), Stage III 58.6%(n = 37), Stage IV 14.3%(n = 09). B symptoms present in 58.6% (n = 37), Bulky disease in 12% (n = 8). ABVD 6 cycles given to Stage IIB, III, IV, and 4 cycles given to (II A). All patients with Bulky disease 9.6% (n = 6) received radiation therapy post completion of ABVD.Two patients with bulky disease (3%) refused to take radiation therapy. Interim PET post 2 cycles of ABVD done in all patients. Bone marrow examination at the end of treatment done only in patients with Stage IV disease. One patient of NLPHL Stage I did not receive any treatment, follow up every 3 months done. One patient had bilateral pulmonary thrombo embolism at diagnosis, received enoxaparin 1 mg/kg SC, BID till completion of chemotherapy. Kaplan–Meier survival estimates were used to evaluate progression-free survival (PFS) and overall survival (OS). Results: The median follow-up was 49 months (range, 2-107 months). PET CR1 achieved after II cycles of ABVD in 96% (n = 60) and progression of disease in 3.2% (n = 2). Four patients (6%) relapsed within 18 months, of 4 relapsed, 50% (n = 2) patients received salvage chemotherapy (DHAP n = 1,GCD n = 1), both achieved PET CR2. Only 1 patient of CR 2 undergone BEAM auto PBSCT. Five-year PFS and OS were 71.4% and 90.4%, respectively. For early stage (IIA), PFS and OS were 73.1% and 94.1%, respectively, whereas for advance stage (IIB, III, IV), PFS and OS were 69.7% and 86.8%, respectively. Adversed events observed during therapy were pulmonary fibrosis in 6.5% (n = 4), constipation in 3% (n = 2), convulsion in 3% (n = 2), neutropenia grade III, IV % 6.5% (n = 4), peripheral neuropathy 6.5%(n = 4), mucositis with esophagitis 1.6% (n = 1), invasive aspergillosis pneumonia 1.6% (n = 1), fungal nail infection 1.6% (n = 1), herpes zoster 1.6% (n = 1). Posttreatment sequelae observed in total 4.8% patients (n = 3), coronary artery disease n = 1 (3 y post CMT), bilateral idiopathic lower limb edema n = 1 (1 y post ABVD), hepatic epithelial hemanagioendothelioma n = 1 (1 y post auto PBSCT), one patient died of disease progression (post CR2). Lost to follow-up total were 17% (n = 11), with complete remission status 3% (n = 2), with relapse status 4% (n = 3), with progression of disease 3% (n = 2), with disease status not known 6% (n = 4). Conclusions: Patients with HL on ABVD or CMT who achieved PET CR, irrespective of stage and unfavourable risk factor, have an excellent prognosis. Low cost and limited manageable regimen-related toxicity make it feasible to achieve higher cure rate in even economically challenged patients of Hodgkin lymphoma at our centre. Keywords: ABVD; Hodgkin lymphoma (HL)

Predominance of CD4+ T Cells in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma and Identification of a Subset of Patients With Peripheral B-Cell Lymphopenia.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a morphologic variant of large B-cell lymphoma whose flow cytometry findings are not well characterized. Nineteen cases with flow cytometric immunophenotyping were identified from the case records of four institutions between 2001 and 2016. In most cases, neoplastic B cells were not detected by flow cytometry. Overall, cases showed a predominance of CD4+ T cells, which in some cases was marked. Significant coexpression of CD57 was seen on CD4+ T cells where this marker was analyzed, which correlated with PD-1 expression. Two cases also showed a profound systemic B-cell lymphopenia, which was associated in one case with hypogammaglobulinemia. Overall, our work challenges previous findings that cases of THRLBCL are rich in CD8+ T cells and highlights parallels between THRLBCL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Also, an association of THRLBCL with systemic B-cell lymphopenia has not been previously reported but may represent an underrecognized manifestation.

HLA dependent immune escape mechanisms in B-cell lymphomas: Implications for immune checkpoint inhibitor therapy?

ABSTRACTAntigen presentation by tumor cells in the context of Human Leukocyte Antigen (HLA) is generally considered to be a prerequisite for effective immune checkpoint inhibitor therapy. We evaluated cell surface HLA class I, HLA class II and cytoplasmic HLA-DM staining by immunohistochemistry (IHC) in 389 classical Hodgkin lymphomas (cHL), 22 nodular lymphocyte predominant Hodgkin lymphomas (NLPHL), 137 diffuse large B-cell lymphomas (DLBCL), 39 primary central nervous system lymphomas (PCNSL) and 19 testicular lymphomas. We describe a novel mechanism of immune escape in which loss of HLA-DM expression results in aberrant membranous invariant chain peptide (CLIP) expression in HLA class II cell surface positive lymphoma cells, preventing presentation of antigenic peptides. In HLA class II positive cases, HLA-DM expression was lost in 49% of cHL, 0% of NLPHL, 14% of DLBCL, 3% of PCNSL and 0% of testicular lymphomas. Considering HLA class I, HLA class II and HLA-DM together, 88% of cHL, 10% of NLPHL, 62% of DLBCL, 77% of PCNSL and 87% of testicular lymphoma cases had abnormal HLA expression patterns. In conclusion, an HLA expression pattern incompatible with normal antigen presentation is common in cHL, DLBCL, PCNSL and testicular lymphoma. Retention of CLIP in HLA class II caused by loss of HLA-DM is a novel immune escape mechanism, especially prevalent in cHL. Aberrant HLA expression should be taken into account when evaluating efficacy of checkpoint inhibitors in B-cell lymphomas.

Nodular lymphocyte predominant Hodgkin lymphoma in Sweden between 2000 and 2014: an analysis of the Swedish Lymphoma Registry.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent CD20+ lymphoma. Its scarcity has made clinical trials difficult and there is no consensus on first-line treatment. We conducted a population-based study of all patients diagnosed with NLPHL in Sweden between 2000 and 2014 (N=158; 41 women and 117 men), focusing on clinical features, therapy and overall survival. The median female and male age was 59 and 44years, respectively (P=0·002). In early-stage disease, there was little mortality and no survival differences between therapies. In patients with advanced-stage disease, mortality was relatively high in patients who did not receive first-line rituximab but absent in those who did (10-year survival, 55% vs. 100%; P=0·033); there were no imbalances of prognostic factors between those two groups. In advanced stages, first-line rituximab use increased markedly between 2000-2004 and 2005-2014 (7% vs. 67%; P<0·00005), as did 10-year survival, 53% vs. 72% (multivariate P=0·027). Although all patients were diagnosed in the 2000s, this is the longest-followed (and largest) population-based cohort. We report a hitherto unreported 15-year median age difference between sexes, increasing rituximab use and improved survival.

The pathobiology and treatment of Hodgkin lymphoma. Where do we go from Gianni Bonadonna's lesson?

This article reviews the evolution of the diagnosis and treatment of Hodgkin lymphoma (HL) since its discovery in 1832. The morphological, phenotypic and molecular characteristics of both nodular lymphocyte-predominant HL and classical HL are revised in the light of recent molecular information and possible impact on the identification of risk groups as well as the use of targeted therapies. The seminal contribution of Gianni Bonadonna to developing new treatment strategies for both advanced and early-stage HL is highlighted.

Advanced stage nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents: clinical characteristics and treatment outcome - a report from the SFCE & CCLG groups.

Advanced stage nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) is extremely rare in children and as a consequence, optimal treatment for this group of patients has not been established. Here we retrospectively evaluated the treatments and treatment outcomes of 41 of our patients from the UK and France with advanced stage nLPHL. Most patients received chemotherapy, some with the addition of the anti CD20 antibody rituximab or radiotherapy. Chemotherapy regimens were diverse and followed either classical Hodgkin lymphoma or B non-Hodgkin lymphoma protocols. All 41 patients achieved a complete remission with first line treatment and 40 patients are alive and well in remission. Eight patients subsequently relapsed and 1 patient died of secondary cancer (9 progression-free survival events). The median time to progression for those who progressed was 21months (5·9-73·8). The median time since last diagnosis is 87·3months (8·44-179·20). Thirty-six (90%), 30 (75%) and 27 (68%) patients have been in remission for more than 12, 24 and 36months, respectively. Overall, the use of rituximab combined with multi-agent chemotherapy as first line treatment seems to be a reasonable therapeutic option.

Features of Imaging of Different Types of Hodgkin’s Lymphoma Using Combined Positron Emission and Computed Tomography

Background &amp; Aims. At present, PET-CT has an important clinical significance in Hodgkin's lymphoma (HL) and is used both for initial tumor staging and restaging and for the evaluation of treatment efficacy. Published data indicate the possible lack of radiotracer accumulation in the tumor tissue in HL before primary treatment. A low metabolic activity of the tumor tissue prior to treatment makes it difficult to assess the treatment dynamics during the anti-tumor therapy. The aim of this work is to determine the incidence of the low metabolic activity of tumor tissue in HL. Methods. Findings of 131 18F-fluorodeoxyglucose (FDG) whole body PET-CT scans of patients with histologically verified HL (over the period from 2011 to 2015) were studied retrospectively. Patterns of FDG accumulation in different histological types of HL, as well as the levels of metabolic activity in patients with tumor-related toxicity symptoms (B-symptoms) were studied. Results. The low metabolic activity was detected in 4 % of patients with de novo HL. The highest levels of metabolic activity were detected in nodular sclerosis and the lowest ones in nodular lymphocyte-predominant HL. Higher levels of radiotracer metabolic activity were observed in patients with general symptoms. Conclusion. In general, a high metabolic activity of the neoplasm is typical for HL. Primary staging before the treatment should be performed for a more accurate evaluation of dynamics of HL treatment outcomes, because in a number of cases a baseline low FDG accumulation in the neoplasm may imitate the absence of a viable tumor tissue in the affected lymph nodes at assessment of treatment results.

Characterization and Purification of Neoplastic Cells of Nodular Lymphocyte Predominant Hodgkin Lymphoma from Lymph Nodes by Flow Cytometry and Flow Cytometric Cell Sorting

We report the flow cytometric (FC) identification and characterization of lymphocyte predominant (LP) cells from tissues involved by nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). First, we immunophenotyped the NLPHL cell line (DEV) confirming a germinal center immunophenotype, lack of expression of CD32 and CD58, and expression of CD54. Nineteen of 26 lymph nodes involved by NLPHL demonstrated a population with an LP immunophenotype (73%), which included expression of germinal center markers (CD75/Bcl-6-positive, CD32-weak/negative without CD10), a B-cell immunophenotype (CD19/CD20/CD40+), IgD and/or IgM expression (67%), and lack of programmed death-ligand 1/ligand 2. The LP cells demonstrated an adhesion macromolecule expression pattern distinct from Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (CHL) (uniform CD50 and variable CD58 for NLPHL; minimal CD50, bright CD58 expression for CHL). A two-tube consensus assay identified LP cells in all seven NLPHL cases examined and only one non-NLPHL case (94 cases evaluated). Finally, FC cell sorting studies confirm that FC-defined populations have an LP cytomorphology. Taken together, these findings demonstrate a two-tube consensus assay can be used to immunophenotype NLHPL with high specificity and sensitivity and rapidly purify LP cells for genetic studies. This study also confirms aneuploidy in LP cells, provides antigens that may be helpful in distinguishing NLPHL from CHL, and suggests that Tcells interact less avidly with LP cells than with Hodgkin and Reed-Sternberg cells.

Characterization of the Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by a low percentage of neoplastic lymphocyte predominant (LP) cells in a background of lymphocytes. The goal of this study is to characterize the microenvironment in NLPHL. Ten NLPHL cases and seven reactive lymph nodes (RLN) were analyzed by flow cytometry for the main immune cells and multiple specific subpopulations. To discriminate between cells in or outside the tumor cell area, we used CD26. We observed significantly lower levels of CD20+ B-cells and CD56+ NK cells and higher levels of CD4+ T-cells in NLPHL in comparison to RLN. In the subpopulations, we observed increased numbers of PD-1+CD4+ T follicular helper cells (TFH), CD69+CD4+ and CD69+CD8+ T-cells and CCR7-CD45RA-CD4+ effector memory T-cells, while FoxP3+CD4+ T regulatory cells (Tregs) and CCR7-CD45RA+ terminally differentiated CD4+ T-cells were decreased in NLPHL compared to RLN. CD69+ cells were increased in the tumor cell area in CD4+ and CD8+ T-cells, while FoxP3+CD25+CD4+ Tregs and CD25+CD8+ T-cells were significantly increased outside the tumor area. Thus, we show a markedly altered microenvironment in NLPHL, with lower numbers of NK cells and Tregs. PD-1+CD4+ and CD69+ T-cells were located inside, and Tregs and CD25+CD8+ cells outside the tumor cell area.

Relapsed Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): High Efficacy of High Dose Chemotherapy and Autologous Stem Cell Transplantation (HDC auto-SCT). A Study of the Lymphoma Working Party (LWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Background: NLPHL is a relatively uncommon subtype of Hodgkin lymphoma (HL) accounting for about 5-6% of all HL cases. It has unique clinico-pathological, morphologic and immunohistochemical features with CD20-positive "lymphocyte predominant cells". Although long-term survival is better than in classical HL, frequent relapses are common and progression/transformation to aggressive non-Hodgkin lymphoma (NHL) may occur. Whilst HDC auto-SCT is considered as standard of care for relapsed/refractory classical HL, data on HDC auto-SCT in relapsed/refractory NLPHL is sparse. Here, we report a registry study of HDC auto-SCT for NLPHL using the EBMT database, representing the largest sample analyzed to date.Design: Eligible were patients with NLPHL18 years or older who underwent a first auto-SCT between 2003 and 2013, and were registered with the EBMT. Patients with NLPHL transformed to DLBCL were not eligible. The primary objective was 5-year progression-free survival (PFS). Baseline patient, disease and transplant data were collected from EBMT MED-A standard forms. Centers with potentially eligible patients were contacted to provide additional treatment and follow-up details with a copy of written diagnostic report for central review. Statistical analysis was descriptive and employed log rank comparisons for univariate assessment of the impact of baseline characteristics on survival endpoints.Results: We identified 92 patients who met the inclusion criteria with full data including a written diagnostic pathology report available. Of these, 36 patients were excluded after histopathology report review (17 classical HL, 2 NHL, 17 no sufficient information). The final sample comprised 56 patients. There was a predominance of male patients with a male:female ratio of 88%:12%. Median age was 36 (interquartile range (IQR) 29-50) years. Most patients (65%) had advanced stage (III-IV) at diagnosis and one third had B-symptoms. Prior to HDC auto-SCT, 71% patients had 2, 20% had 3, and the remainder had more than 3 lines of treatment (median: 2 lines). Rituximab was used in 62% of patients. The median time from diagnosis to HDC auto-SCT was 21 (IQR 14-51) months. Disease status prior to HDC auto-SCT was complete remission (CR) in 54% and partial remission (PR) in 43%. Most commonly used HDC was BEAM (84% patients), with additional rituximab in 13%. With a median follow-up of survivors of 5 (IQR 3.6-6.6) years, 5-year PFS and overall survival were 67% (95%CI 55-82) and 86% (95%CI 77%-96%), respectively. The 5-year incidence of relapse was 32% (95%CI 20-46). There were no transplant-related deaths. Univariate comparisons considering age, time from diagnosis to transplant, number of pre-treatment lines and rituximab use during induction, salvage and/or HDT failed to identify significant predictors of PFS or OS endpoints.Conclusions: This study, the largest reported thus far on HDC auto-SCT in NLPHL, shows that two thirds of patients remain free of disease 5 years after HDC auto-SCT. In contrast with the usual characteristics of patients with NLPHL, those included in this series had high-risk disease with B-symptoms and advanced stage at diagnosis, and half the patients had HDC auto-SCT less than 2 years after diagnosis. This study demonstrates that patients with NLPHL and adverse features can benefit from HDC auto SCT at relapse. [Display omitted] DisclosuresMontoto:Roche: Honoraria; Gilead: Research Funding. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Moraleda:Pfizer: Research Funding. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Meissner:Amgen: Other: Travel Support; Takeda: Other: Travel Support; Celgene: Other: Travel Support; Teva: Other: Travel Support. Dreger:Novartis: Speakers Bureau; Gilead: Consultancy; Gilead: Speakers Bureau; Novartis: Consultancy; Janssen: Consultancy; Roche: Consultancy.

Relapsed Nodular Lymphocyte-Predominant Hodgkin Lymphoma: An Analysis from the German Hodgkin Study Group (GHSG)

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare entity accounting for approximately 5% of all Hodgkin lymphoma (HL) cases. Pathological and clinical features differ from classical HL (cHL). Pathologically, the malignant lymphocyte predominant (LP) cells stain consistently positive for CD20 and are negative for CD30. Clinically, NLPHL often has an indolent course. However, patients tend to develop late and multiple relapses. Since data on the treatment of relapsed NLPHL are scarce, we used the database of the German Hodgkin Study Group (GHSG) to obtain information on characteristics, treatment and outcome of NLPHL patients with disease recurrence after initial response to first-line treatment. A total of 99 patients who had their first-line treatment within 12 GHSG studies between 1993 and 2008 and subsequently relapsed with NLPHL histology were identified and considered for the present analysis. Patients with primary disease progression or transformation into aggressive B-cell non-Hodgkin lymphoma (NHL) at relapse were not included. At initial NLPHL diagnosis, the median age of the 99 eligible patients was 40 years; 66% of patients had early favorable, 14% had early unfavorable and 20% had advanced stages. First-line treatment consisted of radiotherapy (RT) alone in 22%, combined-modality treatment (CMT) in 68%, single agent anti-CD20 antibody treatment with rituximab in 7% and chemotherapy alone in 3% of patients. At a median observation of 10.8 years from initial diagnosis, relapse occurred after a median of 6.2 years. At relapse, 32% of patients received RT alone or conventional chemotherapy followed by RT, 28% received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) and 26% had anti-CD20 antibody treatment either alone or in combination with conventional chemotherapy. In 13% of cases, patients either received no salvage treatment or the kind of salvage treatment was unknown. At a median observation of 3.8 years after disease recurrence, 11% of patients had developed a second relapse and 4% a third relapse. Five-year progression-free survival (PFS) estimates after occurrence of the first relapse were 78.6% (95%-CI: 61.6%-95.6%), 90.0% (95%-CI: 76.5%-100%) and 72.4% (95%-CI: 53.6%-91.2%) after salvage treatment with RT alone or conventional chemotherapy followed by RT, high-dose chemotherapy followed by ASCT and anti-CD20 antibody treatment optionally combined with conventional chemotherapy, respectively. Thus, there were no significant differences between the applied approaches. Only 10 patients (10%) died during observation; 5 deaths were NLPHL-related, 3 patients died due to second malignancies, and 1 patient each died from respiratory failure and infection. Hence, 90% of NLPHL patients who developed disease recurrence after initial response to first-line treatment were alive at the end of follow-up. Given these excellent survival data, it appears necessary to define patients who are sufficiently treated with non-toxic approaches associated with a potentially low risk for the development of late effects. A pragmatic approach based on the present data may consist in the division of relapsed NLPHL patients into 2 groups. Patients with a longer remission after first-line treatment who present with limited tumor mass at relapse may be treated with anti-CD20 antibodies alone or in combination with conventional chemotherapy, RT alone or conventional chemotherapy followed by RT. In contrast, patients with early disease recurrence and more extensive disease at relapse including extranodal involvement may require more aggressive treatment consisting of high-dose chemotherapy followed by ASCT. Disclosuresvon Tresckow:Novartis: Consultancy, Other: travel grants, Research Funding; Takeda: Consultancy, Other: travel grants; Millenium: Consultancy. Engert:Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding.

Gray Zone Lymphoma (GZL) with Features Intermediate Between Diffuse Large B-Cell Lymphoma (DLBCL) and Classical Hodgkin Lymphoma (cHL): Pathologic Classification and Clinical Outcomes from a Multicenter Consensus Study

BACKGROUND: GZL (B-cell lymphoma, unclassifiable, with features intermediate between DLBCL andcHL) was first described in 2005 and included in the 2008 WHO classification. The majority of cases present withmediastinal disease and share features withcHL and primarymediastinal large B-cell lymphoma (PMBCL). Non-mediastinal lymphomas with similar features have also been reported. Due to the relative rarity and the diagnostic complexity of this disease, data on GZL are limited and further description of this entity is desired.METHODS: Clinical data from cases originally diagnosed as GZL were collected from 15 academic centers across the United States and Canada (Evens et al. Am J Hematol, 2015). In an attempt to further characterize the diagnostic features and clinical correlations, 73 cases (including 62 cases from the aforementioned series and 11 subsequently collected cases) were obtained and submitted for central pathology review using criteria of the 2016 revisedWHO classification. All diagnostic samples were evaluated with a panel comprising CD20, CD79a, PAX5, OCT2, BCL6, MUM1, CD30, CD15, CD3 and EBV by in situ hybridization (EBER). Beyond the tumor cellimmunoprofile, diagnostic criteria included: tumor cell density and morphology, necrosis, and the microenvironment. Five cases were rejected for insufficient material/technical issues. Collectively, 68 cases were evaluated by 5 experthematopathologists and consensus diagnosis was reached at multi-headed scope review. Additionally, clinical data were obtained to analyze patient (pt) characteristics and disease outcomes.RESULTS: Of 68 cases given an original diagnosis of GZL from academic institutions, only 26 cases (38%) were confirmed as GZL on consensus review. Pt characteristics of these 26 GZL cases included: 15M/11F; median age 37 years (range 19-72); 42% B symptoms; 61% anemia; 35% increased LDH; and 33% with hypoalbuminemia. 11/26 (42%) biopsies were mediastinal in origin, and in an additional 4 cases, a mediastinal mass was present clinically; 11 (42%) had only peripheral lymphadenopathy/disease (ie, non-mediastinal). 60% of pts had stage I/II disease with 16% having stage IV. GZL cases were characterized by high tumor cell density and paucity of a mixed inflammatory background (both contrary as seen in cHL). The immunohistochemical profiles of the 26 consensus GZL cases are noted in the Table. Notably, only 1 GZL case was EBV positive. 42/68 (62%) of the original cases were reclassified as follows: nodular sclerosis (NS)cHL, n=27 [n=10 of which werecHL, NS grade 2 (cHL-NS2)] and one lymphocyte-richcHL (LRCHL), n=1; DLBCL NOS, n=4; PMBCL, n=2; nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), n=3; EBV positive LBCL, n=3; and B-cell lymphoproliferative disorder, n=1. Most cases ofcHL diagnosed as GZL had strong CD20 expression. Further, cHL-NS2 was often misdiagnosed as GZL usually due to confluent growth of lacunar cells. Clinically, therapy received and outcomes were available for 25 of 26 of the aforementioned consensus GZL cases; the overall response rate (ORR) for these consensus confirmed GZL cases was 64% (complete remission (CR) 48%) with 28% ofpts experiencing primary refractory disease to frontline therapy. Relapse rates by primary chemotherapy regimen for thesepts were: ABVD 5/6 (83%); CHOP 7/17 (41%); and EPOCH 1/2 (50%). Among consensus GZLpts with relapsed disease, 71% underwent autologous SCT. With a median follow-up of 40 months, the 3-year PFS was 44% with 3-year OS of 90% for the consensus GZL pts. Among all other cases that were reclassified to a non-GZL diagnostic entity, the ORR was 75% (CR 67%) with 3-year PFS and OS rates of 52% and 80%, respectively. This included a relapse rate of 86% amongpts with cHL-NS2.CONCLUSIONS: Accurate diagnosis of GZL remains challenging. Relative rarity of the cases and overlap withcHL, especially thecHL-NS variant with lymphocytic depletion and confluent lacunar cells (also known as cHL-NS2), contribute to this difficulty. Diagnosis should be based on integration of architectural, cytological andimmunophenotypic features. In addition, relapse rates are high with standard chemotherapy regimens, especially ABVD-based therapy. Enhanced biologic understanding and improved therapeutic strategies are needed for GZL. [Display omitted] DisclosuresEvens:Takeda: Other: Advisory board. Abramson:Abbvie: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Consultancy. Fenske:Celgene: Honoraria; Millennium/Takeda: Research Funding; Pharmacyclics: Honoraria; Seatle Genetics: Honoraria. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board. Blum:Pharmacyclics: Research Funding.

Repetitive Low-Dose Radiation Therapies As an Alternative Option for Indolent Non-Hodgkin Lymphoma

Introduction:Low-dose radiation therapy (LD-RT) is a therapeutic option in indolent non Hodgkin B-cell lymphomas (iNHL), usually in the palliative setting. If most iNHL are highly sensitive to radiation therapy, with good local control obtained with a dose of 4 Gy in 2 fractions, little is known about the efficacy and outcome of repetitive courses of LD-RT. We report here the results of a study cohort of repetitive LD-RT in iNHL.Methods: We retrospectively reviewed the records of all iNHL patients treated by two or more courses of LD-RT at Gustave Roussy, between January 1990 and December 2015. Patients received LD-RT as palliative treatment for low-bulky disease, patient's comfort or painful adenopathy. Clinical data, histological types, outcome and treatment lines were collected. Overall survival was the time between lymphoma diagnosis and death from any cause. Last LD-RT follow-up period was the time between the last LD-RT session and latest news.Results: Thirty-five pts were analyzed. Among them, 24 pts (69%) had Follicular Lymphoma (FL), 6 pts (17%) Marginal Zone Lymphoma (MZL), 3 pts (9%) had B-cell primitive Cutaneous Lymphoma Follicular Type (CL-FL) and 2 pts (6%) Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL). At lymphoma diagnosis, median age was 57 years [range 20-80]. Ann Arbor stage was I-II in 18 pts (51%), and III-IV in 17 pts (49%). Patients received a median of 4 therapeutics lines (range 2-11), and 2 LD-RT courses (range 2-6). Median overall survival was 146 months [29-298 months]. Four patients had died: 2 of disease progression and 2 others from concomitant illness (1 cardiac disease and 1 hepatocellular carcinoma). No patient had experienced transformation to diffuse large B cell lymphoma after RT-LD treatments. In the vast majority of cases (31/35; 89%), the LD-RT were successively performed to lymphoma relapse outside irradiation fields. Exclusive repetitive courses of LD-RT without chemotherapy were received by 8/35 (23%) of patients; while 24/35 (69%) patients received repetitive LD-RT alternately with immunotherapies or chemotherapies; and 3/35 (9%) others repetitive LD-RT alternately with standard dose RT.After the second course of LD-RT, 12/35 (34%) patients were managed in watch and wait approach, 6/35 (17%) received another LD-RT and 17/35 (49%) patients had experienced a progressive disease and were treated with immunotherapy or chemotherapy or standard dose radiotherapy.The LD-RT was the last treatment modality in 18/35 (51%) patients with histological types distributed in FL (n=10), MZL (n=5) and CT-FL (n=3). With a median last LD-RT follow up of 32 months [7-177 months], 23/35 (66%) patients remained in complete remission, 9/35 patients (26%) had experienced progressive disease and 3/35 (9%) patients had obtained stable disease.Conclusion: As palliative treatment modality, the repetitive low dose radiation therapy 4 Gy in two fractions could provide alternative option treatment in iNHL. This study support further investigations of this simple, well tolerated and not costly therapy in iNHL, especially in the context of new immunotherapeutic agent's area. DisclosuresMichot:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ribrag:ArgenX: Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Nodular Lymphocyte Predominant Hodgkin Lymphoma. Experience in a Single Institution in Argentina

Background: Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) is a rare subtype of Hodgkin Lymphoma (HL) that represents approximately 5% of HL and discloses a distinct clinical-pathological features with an overall good prognosis. Treatment strategies have been based on protocols for HL. Selected patients can be treated with surgery alone.Objective: Our aim was to describe the clinical characteristics, management and outcome of patients with NLPH.Methods: Between March 2000 and June 2016, 16 patients (14 M/2 F), median age: 9.8 (range 4.9-14.5) years, were consecutively diagnosed in our institution. Initial chemotherapy schedules were ABVD (Doxorubicin, Bleomycin, Vinblastine and Dacarbazine), COPP/ABVD or AV-PC (Adriamycin/Vincristine/Prednisone/Cyclophosphamide) were administered to 14 patients. When response was partial or null, additional chemotherapy was administered, IF-RT, Anti CD20 and/or HDC/Autologous SCT. A watch-and-wait strategy after lymph node complete surgery was used in two cases when this strategy became trustworthy.Results: Fourteen patients (87.5%) showed nodal compromise being cervical localization the most frequent localization. Thirteen patients (81.2%) presented localized disease (stage IA: 8, stage IB: 1, stage IIA:4) and 3 (18.7%) advanced disease (stage IIIA:1, stage IVA:1, IVB:1). Two patients had B symptoms. Two IA stage cases (12.5%) had complete node resection. Five patients (31.2%) received 4 cycles of ABVD. One patient (6.2%) received COPP/ABVD. Five patients (31,2%) received 3 cycles of AV-PC. One patient (6.2%) received 6 cycles of AV-PC plus 4 doses of Rituximab. One patient (6.2%) presented progressive disease after 3 cycles of ABVD, additional chemotherapy was administered and HDC/Autologous SCT. Three (18%) patients received IF-RT plus chemotherapy. One patient is still on treatment. Response to treatment was: CR in 12 pts (75%), Partial-response: 2 pts (12.5%), NR: 1 pts (6.2%). Median follow up: 58.4 (range 2-89) months. All patients remain in CR. Conclusion: Although the management of NLPHL was not uniform in our retrospective analysis, the results were promising. Watch and wait strategy plays an important role to avoid adverse effects associated with therapy. Tailored therapy according to staging and disease response, seemed to be a good strategy in our setting. DisclosuresNo relevant conflicts of interest to declare.

Atypical variants of nodular lymphocyte–predominant Hodgkin lymphoma show low microvessel density and vessels of distention type

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) presents different histopathologic growth patterns, including atypical forms showing overlapping histopathologic and clinical features with T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL). Because growth patterns are associated with vessel distribution, the aim of the present study was to compare angiogenesis in different NLPHL patterns with THRLBCL as well as other lymphomas. Atypical variants of NLPHL and THRLBCL (n=10 per group) both showed a low microvessel density (MVD; 1.16-1.31/μm2) with a diffuse vessel distribution. In contrast, in typical NLPHL (n=10), follicular areas with low MVD were retained, whereas an increase in vessels in the interfollicular areas was observed (MVD 1.35/μm2). THRLBCL and typical NLPHL could additionally be distinguished by differences in their molecular angiogenesis signature. Furthermore, the number of intravascular T cells was significantly reduced in THRLBCL (0.0028 T cells/mm2 vessel area) when compared with typical NLPHL (0.0059 T cells/mm2 vessel area), potentially reflecting the different composition of the microenvironment in these 2 lymphoma entities. The results of our study reveal a similar vascular pattern and angiogenesis behavior in atypical NLPHL variants and THRLBCL in contrast to the retained follicular pattern in typical NLPHL.

Cyclin D1 expression and polysomy in lymphocyte-predominant cells of nodular lymphocyte-predominant Hodgkin lymphoma.

Cyclin D1 protein expression in lymphocytes is classically associated with mantle cell lymphoma. Although increasingly recognized in other lymphoproliferative disorders, cyclin D1 expression and CCND1 gene abnormalities have not been well studied in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Using a double stain for CD20/cyclin D1, we quantified cyclin D1 expression in 10 cases of NLPHL and correlated those findings with SOX11 expression, CCND1 gene abnormalities, and clinical data. For comparison, we examined 5 cases of T cell-/histiocyte-rich large B-cell lymphoma (THRLBCL). All cases of NLPHL stained for cyclin D1 showed at least rare positivity in lymphocyte-predominant (LP) cells. In 4 cases, at least 20% of LP cells were positive for CD20/cyclin D1. Neither SOX11 expression nor CCND1 gene rearrangement was found in any of the cases, but fluorescence in situ hybridization showed a proportion of the large cells with 3 to 4 copies of nonfused IGH and CCND1 signals or 3 intact CCND1 break-apart signals. Further study with CCND1/CEP11 showed polysomy in 6 of 9 cases with cyclin D1 expression and 5 of 16 NLPHL not examined for cyclin D1. Two of 5 cases of THRLBCL showed rare positive staining for CD20/cyclin D1; 1 case showed polysomy with CCND1/CEP11. Results show that cyclin D1 may be expressed in LP cells without SOX11 expression or CCND1 translocation. Polysomy with increased copies of CCND1 may account for cyclin D1 expression in some cases. Cyclin D1 expression is not useful for distinguishing NLPHL from THRLBCL and has no apparent clinical significance in NLPHL.

Peripheral T-cell lymphomas of follicular helper T-cell type frequently display an aberrant CD3−/dimCD4+ population by flow cytometry: an important clue to the diagnosis of a Hodgkin lymphoma mimic

AbstractNodal follicular helper T-cell-derived lymphoproliferations (specifically the less common peripheral T-cell lymphomas of follicular type) exhibit a spectrum of histologic features that may mimic reactive hyperplasia or Hodgkin lymphoma. Even though angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma of follicular type share a common biologic origin from follicular helper T-cells and their morphology has been well characterized, flow cytometry of peripheral T-cell lymphomas of follicular type has not been widely discussed as a tool for identifying this reactive hyperplasia/Hodgkin lymphoma mimic. We identified 10 peripheral T-cell lymphomas of follicular type with available flow cytometry data from five different institutions, including two cases with peripheral blood evaluation. For comparison, we examined flow cytometry data for 8 classical Hodgkin lymphomas (including 1 lymphocyte-rich classical Hodgkin lymphoma), 15 nodular lymphocyte predominant Hodgkin lymphomas, 15 angioimmunoblastic T-cell lymphomas, and 26 reactive nodes. Lymph node histology and flow cytometry data were reviewed, specifically for the presence of a CD3−/dimCD4+ aberrant T-cell population (described in angioimmunoblastic T-cell lymphomas), besides other T-cell aberrancies. Nine of 10 (90%) peripheral T-cell lymphomas of follicular type showed a CD3−/dimCD4+ T-cell population constituting 29.3% (range 7.9–62%) of all lymphocytes. Five of 10 (50%) had nodular lymphocyte predominant Hodgkin lymphoma or lymphocyte-rich classical Hodgkin lymphoma-like morphology with scattered Hodgkin-like cells that expressed CD20, CD30, CD15, and MUM1. Three cases had a nodular growth pattern and three others exhibited a perifollicular growth pattern without Hodgkin-like cells. Epstein–Barr virus was positive in 1 of 10 cases (10%). PCR analysis showed clonal T-cell receptor gamma gene rearrangement in all 10 peripheral T-cell lymphomas of follicular type. By flow cytometry, 11 of 15 (73.3%) angioimmunoblastic T-cell lymphomas showed the CD3−/dimCD4+ population (mean: 19.5%, range: 3–71.8%). Using a threshold of 3% for CD3−/dimCD4+ T cells, all 15 nodular lymphocyte predominant Hodgkin lymphoma controls and 8 classical Hodgkin lymphomas were negative (Mann–Whitney P=0.01, F-PTCL vs Hodgkin lymphomas), as were 25 of 26 reactive lymph nodes. The high frequency of CD3−/dimCD4+ aberrant T cells is similar in angioimmunoblastic T-cell lymphomas and peripheral T-cell lymphomas of follicular type, and is a useful feature in distinguishing peripheral T-cell lymphomas of follicular type from morphologic mimics such as reactive hyperplasia or Hodgkin lymphoma.

A strong host response and lack of MYC expression are characteristic for diffuse large B cell lymphoma transformed from nodular lymphocyte predominant Hodgkin lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.

Management of Early-stage Hodgkin Lymphoma: A Practice Guideline

In the past, treatment for patients with early-stage Hodgkin lymphoma consisted mainly of radiotherapy. Now, chemotherapy alone and chemoradiotherapy are treatment options. These guidelines aim to provide recommendations on the optimal management of early-stage Hodgkin lymphoma. We conducted a systematic review searching MEDLINE, EMBASE, the Cochrane Library and other literature sources from 2003 to 2015, and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Two authors independently reviewed and selected studies, and appraised the evidence quality. The document underwent internal and external review by content, methodology experts, a patient representative and clinicians in Ontario. We have issued recommendations for patients with classical Hodgkin lymphoma and with nodular lymphocyte predominant Hodgkin lymphoma; with favourable and unfavourable prognosis; and for the use of positron emission tomography to direct treatment. We have provided our interpretation of the evidence and considerations for implementation. Examples of recommendations are: ‘Patients with early-stage classical Hodgkin lymphoma should not be treated with radiotherapy alone’; ‘chemotherapy plus radiotherapy or chemotherapy alone are recommended treatment options for patients with early-stage non-bulky Hodgkin lymphoma’; ‘The Working Group does not recommend the use of a negative interim positron emission tomography scan alone to identify patients with early-stage Hodgkin lymphoma for whom radiotherapy can be omitted without a reduction in progression-free survival’. Through the use of GRADE, recommendations were geared towards patient important outcomes and their strength reflected the available evidence and its interpretation from the patients’ point of view.