Lymphocyte Predominant Hodgkin Lymphoma Research Articles

How immunologic and genetic biomarkers impact Hodgkin lymphoma classification, diagnosis, and management: a huge potential that yet needs to be exploited.

"Ne è passata di acqua sotto i ponti." It has been a long time since the diagnosis of Hodgkin lymphoma (HL) was exclusively based on the detection of typical Reed-Sternberg cells and the recognition of the characteristic morpho-histological background, as well as on the pathologist's skill. The discovery of immunologic, molecular genetic and virologic biomarkers has provided an objective contribution to the diagnosis and a scientific basis for a modern classification of HL. Recent updates have clarified the nature of the so-called nodular lymphocyte predominant HL and its link to the T-cell/histiocyte-rich large B-cell lymphomas as well as its relationship with the lymphocyte-rich subset of classical HL (CHL). Molecular virology studies assessed a role for the Epstein-Barr virus in the pathogenesis of a fraction of CHL of the general population, and virtually in all cases of CHL occurring in people infected by HIV. Finally, immunologic and genetic findings corroborated the existence of grey zone lymphomas at the edges of CHL. Overall, these advances provided additional and useful information to address the treatment of patients affected by HL.

Observation after Surgery for Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) frequently presents with limited stage IA disease and has a relatively indolent course. Although definitive radiation therapy (RT) is the standard treatment in this setting, national guidelines suggest that observation may be appropriate for stage IA patients with a completely excised solitary lymph node. As this is a rare histology (∼5% of Hodgkin lymphoma cases), there are few prospective studies characterizing present-day clinical management. We hypothesized that RT is being omitted frequently, particularly in younger patients to limit long-term toxicity and risk of secondary malignancy. We used the National Cancer Data Base (NCDB) to interrogate patterns of care for stage IA NLPHL. In particular, we sought to evaluate how often RT is omitted and if there are factors that can predict for patients that receive surgery followed by observation. The NCDB was queried for patients with stage IA NLPHL who received surgery followed by observation or RT. Multiple logistic regression was used to identify factors that were significantly associated with receipt of surgery followed by observation. Variables examined included facility type, age, sex, race, insurance status, distance to treatment facility, Charlson-Deyo comorbidity scores, median household income and year of diagnosis. 441 patients treated from 2004 – 2013 were identified with a median follow-up of 50.4 months. Median age was 40 years old (range, 4-86 years). 40% (175/441) did not receive RT after surgery with a median age of 35 (range, 4-86 years). 68% (54/80) of pediatric patients (<21 years) did not receive RT after surgery. Observation after surgery in age groups 21-40, 41-60, and >60 years was 37% (53/144), 27% (40/149) and 41% (28/68), respectively. Median time from diagnosis to receipt of RT was 2.3 months. Under multiple logistic regression, receipt of RT was significantly associated with increasing age (ρ = 0.011, odds ratio 1.030, 95% CI: 1.007 – 1.053) and lower income (median household income < $38,000/year) (ρ = 0.012, odds ratio 2.454, 95% CI 1.222- 4.927). Patients with Medicare (ρ = 0.007, odds ratio: 0.155, 95% CI 0.040 – 0.598) and a higher Charlson-Deyo comorbidity index of 1 (ρ = 0.049, odds ratio: 0.510, 95% CI 0.261 – 0.998) were more likely to be observed following surgery. Facility type, sex, race, distance to treatment facility and year of diagnosis were not significantly associated with receipt of RT or observation. In this analysis, a large percentage of stage IA NLPHL patients (including more than 2/3 of pediatric patients) were observed following surgery. Increasing age was significantly associated with receipt of RT after surgery. Our results suggest that omission of RT (“watch and wait”) is occurring frequently in contemporary clinical practice, especially for younger patients, and may be a reasonable consideration in select patients with stage IA NLPHL.

Monoamine oxidase A is highly expressed in classical Hodgkin lymphoma.

Monoamine oxidase A (MAOA) is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines and produces H2 O2 . It facilitates the progression of gliomas and prostate cancer, but its expression and functional relevance have not been studied in lymphoma. Here, we evaluated MAOA in 427 cases of Hodgkin and non-Hodgkin lymphoma and in a spectrum of reactive lymphoid tissues by immunohistochemistry on formalin-fixed, paraffin-embedded specimens. MAOA was expressed by Hodgkin Reed-Sternberg (HRS) cells in the majority of classical Hodgkin lymphomas (cHLs) (181/241; 75%), with 34.8% showing strong expression. Weak MAOA was also noted in a minority of primary mediastinal large B-cell lymphomas (8/47; 17%) and in a mediastinal gray-zone lymphoma. In contrast, no MAOA was found in non-neoplastic lymphoid tissues, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL; 0/8) or any other non-Hodgkin lymphomas studied (0/123). MAOA was more common in Epstein-Barr virus (EBV)-negative compared to EBV-positive cHL (p < 0.0001) and was especially prevalent in the EBV-negative nodular sclerosing subtype. Similar to primary human lymphoma specimens, most cHL-derived cell lines displayed MAOA activity, whereas non-Hodgkin-lymphoma-derived cell lines did not. The MAOA inhibitor clorgyline reduced the growth of L1236 cells and U-HO1 cells, and shRNA knockdown of MAOA reduced the growth of L1236 cells. Conversely, ectopic overexpression of MAOA increased the growth of MAOA-negative HDLM2 cells. Combined treatment with clorgyline and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was more effective in reducing cell growth than either regimen alone. In summary, MAOA is highly expressed in cHL and may reflect the distinct biology of this lymphoma. Further studies on the potential utility of MAOA as a diagnostic marker and therapeutic target are warranted. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Nodular lymphocyte predominant Hodgkin's lymphoma in daily practice: A multicenter experience.

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare subtype of Hodgkin's lymphoma. In this study, we aimed to investigate the clinical features and therapeutic outcomes of patients with NLPHL who were diagnosed at different institutes in Turkey. We retrospectively reviewed the records of the patients diagnosed with NLPHL. Adult patients who were diagnosed after 2005 with histological confirmation were selected for the study. Forty-three patients were included in the study. Median age of patients was 37.5years (18-70) at the time of diagnosis. About 60.5% patients were diagnosed as stage I and II NLPHL, and remaining 39.5% had stage III and IV disease. Median follow-up was 46months. During follow-up, none of the patients died. Seven patients relapsed or progressed after initial therapy at a median of 12months. Five of 7 relapsed/refractory patients (71.4%) were salvaged with chemotherapy only (DHAP, ICE), and the remaining 2 (28.6%) were salvaged with chemoimmunotherapy. All of relapsed/refractory patients were able to achieve complete remission after salvage therapy. Lactate dehydrogenase levels were significantly higher in patients with progressive disease compared with nonprogressive disease. Our study showed an excellent outcome with all patients alive at last contact with a median follow up of 46months despite a wide range of different therapeutic approaches. All relapsed and refractory patients were successfully salvaged despite a low frequency of patients received immunotherapy in conjunction with chemotherapy. Our results suggest that immunotherapy may be reserved for further relapses.

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.

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.

Long-Term Response and Possible Cure of Patients With B-Cell Malignancies With Dose-Escalated Rituximab.

Rituximab (R), a chimeric monoclonal antibody targeting CD20 antigen on B-cells, has become a standard of care in the treatment of B-cell malignancies, most often in conjunction with cytotoxic chemotherapy. Activity has been demonstrated in many subtypes of B-cell lymphoma, including diffuse large cell lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), lymphocyte-predominant Hodgkin lymphoma, and Waldenström macroglobulinemia (WM). Additionally, dose escalation of R as a single agent has demonstrated improved activity in previously treated/poor prognosis CLL. We present 4 cases of B-cell malignancy (2 CLL variants/MCL, 1 FL, 1 WM) who received dose-escalated R as a single agent and achieved complete response (3 patients) and stable disease/partial response (1 patient) of 6.5+ to 15+ years duration. They have been off treatment for 6.5+ to 15+ years. Toxicity was minimal, with initial infusion reactions similar to those observed with standard dose infusions. There were no serious treatment-related adverse events or infections. Dose escalated R as a single agent may possibly be curative for some patients with B-cell malignancies, unlike the standard empiric dose of 375 mg/m2, and deserves further study.

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.

Intermediate-Risk Lymphocyte-Predominant Hodgkin Lymphoma: AHOD0031: A Report from the Children's Oncology Group

Background: Children's Oncology Group (COG) AHOD0031 demonstrated that early response assessment in pediatric intermediate-risk Hodgkin lymphoma (HL) permits reduction or augmentation in therapy with maintenance of excellent event-free (EFS) and overall survival (OS). While the majority of patients on this trial had classical HL (cHL), patients with lymphocyte-predominant HL (LPHL) were included. Pediatric patients with LPHL typically present with localized disease and such low risk patients have excellent outcomes with surgical resection alone or minimal chemotherapy. However, management of patients with intermediate-risk LPHL is less clear due to their small number in most clinical trials. We report the outcomes of these patients on AHOD0031 and present directions for future therapeutic strategies.Methods: Eligible patients had clinical stage I-IIA with bulk, I-IIAE, I-II B, IIIA-IVA with or without bulk. Patients initially received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC), followed by a response evaluation of rapid early (RER) versus slow early responder (SER) status. All SER patients were randomized to an additional two cycles of ABVE-PC +/- 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA). All SER patients received 21 Gy involved field radiotherapy (IFRT) following completion of chemotherapy. RER patients received 2 additional cycles of ABVE-PC. RER with complete responder (CR) status (RER/CR) patients were randomized to involved field radiotherapy (IFRT) or no further therapy. RER/non-CR patients were non-randomly assigned to IFRT.Results: Ninety-seven (5.7%) of the 1712 eligible patients on AHOD0031 had LPHL, with the remainder cHL. Compared to patients with cHL, patients with LPHL were younger (p=0.0001), more often male (p<0.0001), and less likely to have B symptoms (p=0.0006), bulk (p<0.0001) or stage IV disease (p<0.0001). Five-year event-free survival (EFS) was marginally superior in patients with LPHL (91.2%) compared with cHL (83.2%) (p = 0.08) (Figure 1), without difference in overall survival (OS) (p = 0.21). LPHL patients treated with chemotherapy alone (N = 33) had a 5-year EFS of 93.4% and OS of 100%. Stage and presence of bulk disease, RER or SER status and use of IFRT did not impact EFS or OS in LPHL patients. The proportion of patients who were RER was higher in LPHL compared with cHL (93.7% vs. 81.0%). Furthermore, LPHL patients were more likely to achieve a CR compared to cHL patients (68% vs. 45%; p=0.00003). There was only one reported subsequent malignant neoplasm among the LPHL patients, a non-Hodgkin lymphoma one year after treatment in a patient who received IFRT.Discussion: Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes as demonstrated in this analysis. The majority of patients treated with the ABVE-PC backbone achieve RER/CR status and can be successfully treated without radiation therapy. Future therapeutic strategies should focus on further reduction in cytotoxic therapy for these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Management of Classical Hodgkin's Lymphoma: Single Center Experience from Tawam Hospital, United Arab Emirates

Classical Hodgkin's lymphoma (cHL) is an uncommon lymphoproliferative disorder. In general Hodgkin's lymphoma is a disease of the younger population affecting mostly patient of 15 to 30 years of age. There is second peak of incidence noticed among older population of 70 years of age or more.Histologically, Hodgkin's lymphoma is broadly classified into nodular lymphocyte predominant or classical Hodgkin's lymphoma which is further sub classified into 4 subtypes: lymphocyte-rich, lymphocyte-depleted, mixed cellularity and nodular sclerosis. The commonest subtype is the nodular sclerosis which accounts for 70% of the cases of classical HL, this is followed by the mixed cellularity subtype which account for 20 to 25% of the cases. cHL is characterized by the presence of the Reed Sternberg cells (HRS cells) within a background of non-malignant inflammatory cells. Most patient with advanced stage Hodgkin's lymphoma in general are managed with either the 6 to 8 cycles of ABVD combination chemotherapy or 6 cycles of escalated BEACOPP.In this retrospective study, we reviewed the cHL patient's demographics, management and their outcome in our center. The data base in this institution was searched over 5 year's period (January 2011 to December 2015). 29 patients were identified to be included in the study however one patient was lost to follow up so the outcome of his disease could not be traced. Data was collected regarding age, sex, stage, International prognostic index (IPI), treatment and outcome.The median age was 50 years (range 21 to 62 years). Out of the total number, 57% were males (N 16) and 43% were females (N 12). In terms of the histological subtypes of our cohort, the commonest was the nodular sclerosis subtype which occurred in 75% (N 21) followed by mixed cellularity 25 % (N 7)Most of the patients were diagnosed with early stage disease (stage 1-2) 71 % (N 20) while the rest had advanced stage disease. In terms of the international prognostic scoring stratification, the majority are of good risk group with IPI score 1 at 43% (N 12), IPI score 2 at 25% (N 7), while IPI score 3 is 14% (N 4), IPI score 4 is 11% ( N 3) and IPI score 5 is only in 7% ( N 2) of the patients.The majority of patients were managed with ABVD combination chemotherapy with excellent outcome as 85 % of our evaluated patients achieved complete response at the end of their treatment course. Only 15 % of the patients had residual disease at the end of their treatment. One patient received BEACOPP combination chemotherapy, his IPI scorewas 3 and he had persistent disease at the end of his treatment. Although the number of the patients included is small, our study confirmed that ABVD protocol is an excellent regimen for the treatment of classical Hodgkin's lymphoma. This is shown in a significant number of our patient achieving complete response after receiving 6 to 8 cycles of ABVD. DisclosuresOsman:BMS: Honoraria. Lal:BMS: Honoraria. Hussain:BMS: Honoraria. Alam:BMS: Consultancy, Honoraria; Biologix: Honoraria.

Outcome of Hodgkin Lymphoma after Progression Following Autologous Stem Cell Transplantation

Background Clinical trials have demonstrated a high level of effectiveness for brentuximab vedotin (BV) for patients with relapsed or refractory classical Hodgkin lymphoma (HL); however, how patients fare in routine clinical practice if their HL recurs after autologous stem cell transplant (ASCT) is less clear. Our primary objective was to characterize overall survival (OS) and progression-free survival (PFS) among a cohort of real-world patients treated with BV after ASCT. The secondary objective was to characterize the outcome of treatment after failure of ASCT or ASCT and BV.Methods We screened the population-based British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database to identify patients with classical HL (excluding lymphocyte predominant HL) who were aged >16 years at initial diagnosis, staged and treated in BC, had primary treatment with ABVD or equivalent chemotherapy, underwent ASCT as part of first treatment for refractory or relapsed disease and relapsed again after ASCT. We excluded patients who have been treated at any time with a checkpoint inhibitor. We determined Kaplan-Meier estimates of overall (OS) and progression free survival (PFS) from the date of the progression that occurred after ASCT and, for those treated with the agent, after subsequent BV. Therapies given in sequence without a pause between therapies were considered part of the same line of therapy.Results Between 1986 and 2015 93 patients experienced recurrence of HL after ASCT. Their median age at initial diagnosis was 30 years and 51% were male. After failure of ASCT 23 (25%) received radiation monotherapy and 61 received chemotherapy (66%), either as a single agent or in various combinations and of these 9 (10%) also received radiation; 6 (6%) received a second transplant (5 allogeneic and 1 repeat ASCT); and 5 refused or were too frail for treatment other than with corticosteroids. The median PFS and OS from the time of relapse after ASCT for these 93 patients were 7.1 (range 0.2-352) and 16.2 months (range 0.2-352), respectively. Of those 93, 17 patients received BV alone or BV+bendamustine at some point following ASCT. The median age of BV-treated patients was 33 years at the time of their original diagnosis and 29% were male. Among those 17 patients, 9 received single agent BV and 8, BV+bendamustine as part of a clinical trial. The median time from ASCT to the start of BV was 27.5 months. Counting ASCT as 2nd line treatment, 10 individuals received BV as 3rd line, 6 as 4th line and 1 as 5th line therapy. For all 17 patients the subsequent median PFS and OS from the time of BV initiation were 5.1 (range 1.5-34.6) and 18.8 months (range 2.4-40.5), respectively. 12 of these patients relapsed again and their subsequent median PFS and OS were 0.6 (range 0.5-29) and 3 (range 0.5-30) months, respectively. All 9 patients who received single agent BV relapsed again at a median of 2 months (range 1.2-9.7); 5 of the 8 patients treated with BV+bendamustine remain in remission 6 to 36 months later.Conclusions These data highlight the poor prognosis for patients with relapsed or refractory cHL, particularly for those whose lymphoma recurs after brentuximab vedotin as well as the highly individualized management of patients whose lymphoma has recurred after ASCT. Future therapies that prevent or significantly delay relapse will help in alleviate the substantial clinical burden due to relapsed and refractory Hodgkin lymphoma. DisclosuresConnors:Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding.

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.

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.

Treatment of low-risk pediatric lymphocyte-predominant Hodgkin lymphoma

Treatment of low-risk pediatric lymphocyte-predominant Hodgkin lymphoma

Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children's Oncology Group.

Children's Oncology Group study AHOD03P1 was designed to determine whether excellent outcomes can be maintained for patients with low-risk, pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) with a strategy of resection alone or minimal chemotherapy. Patients with stage IA LPHL in a single node that was completely resected were observed without further therapy; recurrences were treated with three cycles of doxorubicin/vincristine/prednisone/cyclophosphamide (AV-PC). Patients with unresected stage IA or stage IIA LPHL were treated with three cycles of AV-PC. Patients with less than a complete response (CR) to AV-PC received 21-Gy involved-field radiation therapy (IFRT). A total of 183 eligible patients were enrolled; 178 were evaluable. Of these, 52 patients underwent complete resection of a single node. There were 13 relapses at a median of 11.5 months; 5-year event-free survival (EFS) was 77% (range, 62% to 87%). A total of 135 patients received AV-PC; 126 were treated at diagnosis and nine at relapse after surgery alone. Eleven patients receiving AV-PC had less than CR and received IFRT. Fourteen first events occurred among 135 patients (12 relapses and two second malignancies). Two relapses occurred in patients who had received IFRT. Five-year EFS was 88.8% (95% CI, 81.8% to 93.2%). Five-year EFS for the entire cohort was 85.5% (95% CI, 79.2% to 90.1%); overall survival was 100%. Some 75% of highly selected pediatric patients with LPHL may be spared chemotherapy after surgical resection alone. Pediatric LPHL has excellent EFS with chemotherapy that is less intensive than standard regimens; > 90% of patients can avoid radiation therapy. The salvage rate for the few relapses is high, with 100% survival overall.

An Immunohistochemical Survey of SNARE Proteins Shows Distinct Patterns of Expression in Hematolymphoid Neoplasia.

Five proteins from the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) complex family were studied in normal hematopoietic cells in bone marrow; normal lymphocytes at different stages of maturation and differentiation in bone marrow, thymus, tonsil, and lymph node; malignant lymphomas; and leukemias. Sixty-eight reactive and 380 hematopoietic and lymphoid neoplasms were immunohistochemically stained for syntaxin 7 (STX7), vesicle-associated membrane proteins (VAMP2, VAMP7, VAMP8), and synaptosomal-associated protein 23 (SNAP23). STX7 has potential for being a useful marker for distinguishing between normal B precursors (hematogones) vs B lymphoblasts, as well as between the "popcorn" cells of nodular lymphocyte-predominant Hodgkin lymphoma vs the Reed-Sternberg cells of classic Hodgkin lymphoma or the B cells of T-cell, histiocyte-rich B-cell lymphoma. VAMP2 is uniquely expressed by both reactive and malignant plasma cells, in contrast to B-cell non-Hodgkin lymphoma. There is differential expression of SNARE proteins in normal and neoplastic lymphoid tissue depending on lymphocyte maturation stage. Differential SNARE protein expression in the lymphoid system may have potential use in diagnosis and may offer clues to lymphoma biology. VAMP2 is a promising new plasma cell marker.

Large B-cell transformation in nodular lymphocyte-predominant Hodgkin lymphoma: 40-year experience from a single institution

AbstractA number of reports have shown a propensity of nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) to transform into diffuse large B-cell lymphoma (DLBCL). Long-term data on the incidence and outcomes of transformed NLPHL are lacking. A comprehensive analysis of the actively maintained Mayo Clinic Lymphoma Database was performed. Between 1970 and 2011, 222 consecutive adult patients with new untreated NLPHL were identified. Median age at diagnosis was 40 years, and 146 (66%) were males. The median follow-up was 16 years. Seventeen patients (7.6%) developed a transformation to DLBCL. The median time to transformation was 35 months (range, 6-268 months). Based on the observed 17 transformations during 2304 patient-years of follow-up, the rate of transformation was 0.74 per 100 patient-years. In a multivariate analysis, use of any prior chemotherapy (P = .04) and splenic involvement (P = .03) were significantly associated with increased risk of transformation. The 5-year overall survival (OS) in those with transformed disease was 76.4%, and transformation did not adversely affect OS when compared with patients who did not experience transformation. In this large single-institution cohort with long-term follow-up, the risk of transformation was lower than that observed in other low-grade lymphomas.

Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas

Activation of the programmed death 1 (PD1)/PD1 ligand (PDL1) pathway is important for tumor cells to escape from immune control. The clinical efficacy of therapeutic modulation of the PD1-PDL1 pathway has been recently shown in classical Hodgkin lymphoma (cHL), but little is known about the frequency and diagnostic and prognostic importance of PDL1 expression in lymphomas. The available anti-PDL1 antibody clones E1L3N and SP142 were compared, and a large cohort of Hodgkin lymphomas (n=280) and B-cell lymphomas (n=619) was examined for PDL1 using E1L3N. The results were correlated with the expression of other phenotypic markers, interphase fluorescence in situ hybridization data of the 9p24.1 region (PDL1 locus), and the clinical outcome. PDL1 was expressed on more than 5% of tumor cells in 70% of cHL, 54% of nodular lymphocyte-predominant Hodgkin lymphoma, and 35% of primary mediastinal B-cell lymphomas; in the latter, PDL1 expression correlated with PDL1 gains (ρ=0.573). PDL1 was expressed in 31% of primary diffuse large B-cell lymphomas (DLBCLs), whereas most other entities did not express PDL1. In cHL, expression of PDL1 correlated with increased numbers of granzyme+ T cells (ρ=0.251) and CD68+ macrophages (ρ=0.221) but with decreased numbers of FoxP3+ T cells (ρ=0.145). In activated B-cell-like DLBCL, PDL1 positively correlated with PD1+ T cells, whereas an inverse correlation with FoxP3+ T cells was seen in the germinal center B-cell-like DLBCL. PDL1 expression can be diagnostically valuable in some gray zones around DLBCL and cHL; it identifies an "immune escape" cluster of cHL and activated B-cell-like DLBCL with increased granzyme+ and PD1+ T cells and macrophages and decreased regulatory T cells.