Nodular Lymphocyte-predominant Hodgkin Lymphoma Patients Research Articles

Histopathological and clinical features of nodular lymphocyte-predominant Hodgkin lymphoma and their impact on prognosis: first report from Iran

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL). It shows different histoarchitectural patterns which are reported to be of prognostic significance. This study aimed to investigate the clinicopathological features of NLPHL cases in Shiraz, Iran, and their possible impact on prognosis. Between March 2014 and November 2019, all records for lymphoma were extracted from the electronic files of hospitals affiliated with Shiraz University of Medical Sciences. The slides of all NLPHL cases were extracted and reviewed. Other necessary data was retrieved from hospital records and through direct contact with patients. Among1168 lymphoma cases, 382 were HLs and 19.1% (73) of them were of the NLPHL type. The median age of NLPHL patients was 34 years. Of the patients, 51.5% showed variant patterns, and 11% of them had BM involvement. The variant morphology was significantly associated with BM involvement (p = 0.02). Patients with higher stage tumors had lower OS and PFS rates. Stage, BM involvement, and infra-diaphragmatic involvement were significantly associated with outcomes. The rate of NLPHL and variant morphology seems to be high in our center in Iran. The variant morphology was associated with a higher BM involvement rate but not with OS or PFS. Higher stage, BM, and subdiaphragmatic disease involvement were associated with worse outcomes.

Maintenance Rituximab in Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) in the First Line Setting or at Relapse

Introduction: Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) is a CD20 positive subtype of Hodgkin lymphoma and can frequently present an indolent behavior. Indeed, NLPHL patients relapse more commonly than patients with classic Hodgkin Lymphoma, but relapses can usually be responsive to lower intensity therapy such as rituximab. The choice of frontline and relapse therapies depends on different factors, including staging and burden of disease, thus therapy can range from observation, to radiotherapy (XRT) alone, to systemic therapy such as R-CHOP, R-ABVD or single agent Rituximab (R) or to combined modality (systemic therapy and XRT). However, it is unclear whether maintenance rituximab (MR) would be of clinical benefit if administered after induction therapy. Methods: We retrospectively reviewed the characteristics and outcomes of 17 consecutive patients treated at our center between 12/1972 and 7/2019, with proven diagnosis of NLPHL and who received MR after having achieved complete response (CR) or partial response (PR) after any line of therapy. MR consisted of rituximab 375 mg/m2 once every 2 or 3 months for 2 years or rituximab 375 mg/m2 weekly 4 times every 6 months for 2 years, for a total maximum of 12 doses over 2 years. Progression free survival (PFS) time was calculated from start date of MR to progression date, transformation date or death date, whichever happened first. Patient with no progression, transformation or death were censored at the last follow-up date. Results: At time of initial diagnosis, median age was 37 (range, 15-50 years), 13 patients (76.5%) were male, and 4 patients (24%) had Ann Arbor stage III-IV disease. At completion of the line of induction therapy followed by MR, 75.0% of patients presented CR and 25% presented PR. However 18.7% of patients were restaged with computer tomography (CT) and 81.3% with Positron emission tomography-computed tomography (PET/CT), making the treatment response evaluation uneven. Nine patients received MR after frontline therapy, including R-CHOP in 5 patients (55.6%), rituximab monotherapy in 2 patients (22.2%), R-CVP in 1 patient (11.1%) and rituximab induction with XRT in 1 patient (11.1%). The median number of rituximab maintenance doses was 8 (range 3-12) and the median duration of MR was over 25 months (range 10-32 months). Among these patients, only one (11.1%), treated with frontline R-CHOP, progressed 97.6 months after initiation of MR. No salvage treatment was needed at time of progression, and this patient was still alive at last follow-up, 7 months after progression. No transformation and no death occurred in this patient cohort. Seven patients received MR after second line therapy, including induction R and MR (R+MR) in 5 patients (71.4%), R-CHOP in 1 patient (14.3%) and R with lenalidomide in 1 patient (14.3%). The median number of rituximab maintenance doses was 10 (range 6-12) and the median duration of MR was over 18 months (range 14-20 months). Among these patients who received MR after second line, 1 patient (14.3%) presented with transformation into diffuse large B-cell lymphoma, 7 years after start of MR. This patient received R-EPOCH chemotherapy and frontline autologous stem cell transplant (ASCT) and died of ASCT related infection 1 month after ASCT. One patient received third line R+MR with 12 doses of MR and was in complete remission at last follow-up, 93 months after start of 3rd line therapy. Globally, after a median follow-up from start of any line of MR of 54 months (range: 15-119 months), 1 patient (5.9%) progressed and did not require salvage therapy and 1 patient (5.9%) presented a transformation and died of ASCT-related infection; 5-year PFS and 5-year OS were100% (median PFS and OS were not reached). Conclusions: Patients with NLPHL receiving MR, either after frontline or subsequent lines of therapy, rarely experience relapse and have a very favorable prognosis. However, larger randomized prospective trials are essential to confirm the eventual clinical benefit of maintenance rituximab. Figure Disclosures Pinnix: Merck: Research Funding. Lee:Seattle Genetics, Inc.: Research Funding.

The time to relapse correlates with the histopathological growth pattern in nodular lymphocyte predominant Hodgkin lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first-line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.

PB2000 OUTCOME OF PEDIATRIC NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA, IS ABVD THE BEST REGIMEN? 10 YEARS SINGLE CENTER EXPERIENCE, REPORT FROM CHILDREN CANCER HOSPITAL, EGYPT.

Background:Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype of Hodgkin lymphoma (HL) in children and accounts for 5–10% of all pediatric HL.Aims:The aim of the study to analyze the clinical characteristics and treatment outcome of Pediatric NLPHL.Methods:Retrospective study including all newly diagnosed patients less than 18 years old with NLPHL and treated in children cancer hospital Egypt CCHE between 2007 and 2017.Results:Among 43 pediatric NLPHL patients, 29 had early stage (18 with stage I, 11 with stage II). Fourteen patients had advanced stage (7 with stage III & 7 with stage IV). Eleven patients had a mediastinal disease, 8 patients had splenic involvement, 2 patient had bulky disease and 10 patient had B symptoms at diagnosis.28 Patients with Early‐stage disease treatment; surgery and observation 6 patients, Chemotherapy 6 patients and Combined modality 17 patients. Relapse was seen in 7(25%) patients, 1 observation arm, 3 from chemotherapy arm (ABVD) and 3 from the combined arm (ABVD+IFRTH). 14 advanced stage patients received treatment; Chemotherapy (ABVD) 6 patients, Combined (ABVD+IFRTH) 8 patients, Relapse in 7 (50%) patients (all stage 4 disease), 6 from chemotherapy arm and 1 from the combined arm. 2 patients died (stage IV) from progressive disease and sepsis. B symptoms, mediastinal and splenic involvement had a significant impact on DFS on univariate analysis while combined treatment modality (Chemotherapy and Radiotherapy) had an impact on the outcome of both univariate and multivariate analysis.5 Years DFS, OS for whole group was 64% and 94% respectively, while 5y DFS for early stage 83% and advanced stage 45% (p‐value = .01) and 5 Years OS for early stage was 100% and advanced stage 87 % (p‐value = .08).Summary/Conclusion:Early stage NLPHL had a better outcome but unexpected higher relapse in chemotherapy treatment arm raising a question about the role of radiotherapy while advanced stage disease had poor outcome rising a question of what should be the best chemotherapy regimen for pediatric NLPHL patients.

Favorable outcomes with de-escalated radiation therapy for limited-stage nodular lymphocyte-predominant Hodgkin lymphoma

AbstractRadiation fields for limited-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) have shrunk over time; involved-site radiation therapy (ISRT) has replaced extended-field radiation therapy (EFRT) and involved-field radiation therapy (IFRT), but this has not been validated. The role of systemic therapy is unclear. We reviewed 71 stage I/II NLPHL patients and assessed progression-free survival (PFS), overall survival (OS), locoregional disease-free survival, and distant disease-free survival (DDFS). Median patient age was 39 years, and 61% had stage II disease. Thirty-six (51%) received radiation therapy (RT) only, 6 (8%) received systemic therapy only, and 29 (41%) received both. More patients receiving combined therapy had B symptoms (P = .035) and stage II disease (P = .001). In the RT-only group, 9 (25%) received EFRT, 13 (36%) received IFRT, and 14 (39%) received ISRT; in the combined-modality group, 3 (10%) received EFRT, 7 (24%) received IFRT, and 19 (66%) received ISRT. After a median follow-up of 6.2 years, 15 patients relapsed (13 distant, 2 locoregional). Five-year PFS and OS rates were 86% and 96% and did not differ by treatment. In the RT-only group, follow-up was shorter in the ISRT cohort (2.6 years vs 17.9 years [EFRT] and 8.5 years [IFRT], P < .01), but 5-year PFS did not differ by field size (P = .20). Locoregional control rates were 100% for the RT-only and combined groups, and corresponding 5-year DDFS rates were 93% and 95% (P = .95). Eight patients (11%) experienced a second malignancy (1 within RT field). Six patients died (1 from lymphoma). Use of limited ISRT fields does not appear to increase the risk of locoregional relapse, even when RT is given as single-modality therapy.

A Clinical and Pathological Comparison of Different Immunomorphological Subvariants of Nodular Lymphocyte-Predominant Hodgkin’s Lymphoma at Initial Diagnosis

Background. Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare Hodgkin's lymphoma subtype with a variable growth pattern and immune tissue architecture of tumor. Clustering of patients into subgroups based on immunohistochemical (IHC) tumor subvariants is essential for prognosis assessment and development of new differentiated treatment approaches. Aim. To study clinical course of NLPHL in patients with different IHC-subvariants of the disease and identify a poor prognosis subgroup. Materials &amp; Methods. From 2010 to 2017 the Department of Anatomic Pathology at the National Medical Hematology Research Center undertook morphological and IHC-analysis of lymph node and bone marrow core biopsies of 60 NLPHL patients: 47 men and 13 women (male/female ratio of 3.6:1) aged 17-68 years (median 37 years). IHC-analysis with expanded panel of antibodies was performed in all cases of determining IHC-subvariants in accordance with WHO-2017 classification. Results. The clinical and immunomorphological comparative study of NLPHL with variant immune tissue architecture allowed to divide the patient population into three subgroups with differently manifested areas similar to T-cell/ histiocyte-rich large B-cell lymphoma (THRLBCL) in lymph node sections or other site biopsies. These subgroups are characterized by different clinical course of the disease. The subgroup with ≥ 50 % THRLBCL-like areas was marked by the prevalence of clinical stage IV and significantly larger amount of extranodal lesions. Conclusion. In NLPHL the most unfavorable clinical course is typical of the patients whose biopsies contain ≥ 50 % THRLBCL-like areas. Semi-quantification of THRLBCL-like areas allowed to define a spectrum of NLPHL IHC-subvariants correlating with the clinical course of the disease. The true transformation into diffuse large B-cell lymphoma is a rare event, it occurred in 2 (3 %) out of 60 patients.

Outcome of Lymphocyte Predominant Hodgkin Lymphoma: A Single Institutional Analysis

Background: Nearly 5% of patients diagnosed with Hodgkin lymphoma have the nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), also known as Hodgkin paragranuloma or lymphocytic and histiocytic predominant Hodgkin disease. Given the rarity of this variant of Hodgkin lymphoma, there is no consensus on the standard of care/regimen in this subgroup of patients. Therapeutic approach has spanned from radiotherapy alone, combined chemo-radiotherapy to chemotherapy alone or observation and recently the use of Rituximab anti CD20 monoclonal antibody as these cells expresses CD20 marker. We opt to evaluate the outcome of patients with newly diagnosed NLPHL in our institution. We also reviewed outcome of NLPHL patients treated with various chemotherapy such as ABVD, CVP or RCHOP ± Radiation.Methods: We retrospectively reviewed medical records of over 300 patients [mean age 45 (13-76)] with Hodgkin Lymphoma at Beaumont Hospital, an academic community center from January 2007 - January 2017. Given the rarity of the disease, a total of 13 patients were found to have pathologically confirmed diagnosis of NLPHL. Data regarding age, sex, stage of disease, treatment and outcome was analyzed.Results: Total 13 patients with NLPHL with age range from 13 to 80 years were studied. Demographic distribution of studied patients were 8(62%) white, 4 (31%) African Americans and 1 (7.6%) Asian. Out of these, 8 (62%) were males and 5 (38%) females. A total of 9 (69%) patients have stage III disease on diagnosis while 4 (31%) patients had stage II disease on diagnosis. Out of 9 patients with stage III disease, 6 (67%) received chemotherapy alone (ABVD or CVP) whereas 3 (33%) received combined chemotherapy and radiotherapy. One patient in the chemotherapy alone arm, recurred within 24 months of treatment and received local therapy with radiation. Among those with stage II disease on diagnosis, 3 patients received radiation therapy alone while one patient was observed and did not receive any treatment. Overall, out of 13 patients studied, 12 (92%) are still alive and continues to follow with our clinic with no recorded relapse to date. One patient developed astrocytoma grade III and died of intracranial hemorrhage.CONCLUSION: Although the standard therapeutic management for patients with NLPHL remains controversial. Our data showed that regardless of the regimen selected (chemotherapy alone or combined chemo-Radiotherapy), patients with Lymphocyte predominant Hodgkin Lymphoma treated with ABVD ± Radiation have excellent outcome. Although our study represents a single institutional analysis, it concurs with recent studies that clinical outcome in patients with NLPHL is favorable with chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

The Tumor Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma Is a Unique Immunobiological Entity Distinct from Classical Hodgkin Lymphoma

There is proven pre-clinical and clinical efficacy of mono or combinatorial immune strategies to boost host anti-lymphoma immunity, with classical Hodgkin Lymphoma (cHL) seen as the ‘poster child’. Approaches include blockade of immune-checkpoints on exhausted tumor-specific T-cells (via mAb blockade of PD-1, TIM3, LAG3, TIGIT or their ligands), activation of T-cells via mAbs agonistic to CD137, and finally modulation of FOXP3, CTLA-4 and/or LAG3 regulatory T-cells (Tregs) or immunosuppressive tumor-associated macrophages (TAMs). In contrast, studies characterizing the circulating and intra-tumoral microenvironment (TME) of the distinct but rare CD20+ Hodgkin Lymphoma entity (5-8% of HL), Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL), are minimal. Furthermore, to our knowledge no functional profiling studies comparing the host immunity of NLPHL with cHL has been performed.We compared host immunity in 29 NLPHL patients, 30 cHL patients and 10 healthy individuals, with a focus on pertinent and clinically actionable immune parameters. Paraffin-embedded tissue and paired (pre- and post-therapy) peripheral blood mononuclear cells samples were interrogated by digital multiplex hybridization (Nanostring Cancer Immune Profiling Panel) and flow cytometry.Although cytotoxic T-cell gene counts (CD8a, CD8b) were similar, compared to cHL there were higher levels of the immune effector activation marker CD137 (gene counts 439 vs. 287; P<0.01). Consistent with this, CD4 and the Treg markers LAG3, FOXP3 and CTLA-4 were lower in NLPHL (2-4 fold lower, all P<0.05), with no difference in T-helper cell activation markers CD40L and CD30L seen between tumors. TAMs and dendritic cell markers MARCO, CD36, CD68, CD163, COLEC12 and CD11b were all lower in NLPHL than cHL (all P<0.05). In line with the known ‘rossette’ formed around LP cells by PD-1+ T-lymphocytes, we observed strikingly elevated PD-1 and the other T-cell checkpoints TIM3 and TIGIT in NLPHL (all 2-3 fold, P<0.001). However, in line with the known gene amplification of PD-L1 on HRS cells and its presence on TAMs, gene counts of this checkpoint ligand were 2-fold higher in cHL (P<0.001).Flow cytometry profiling of immune subsets in peripheral blood showed findings consistent with findings in the TME. Specifically, there was elevation of multiple exhaustion markers within CD4, CD8, and NK immune effector cells, with a striking proportion of highly anergic dual-LAG3/PD-1 positive CD8+ T-cells. Also there was elevation of immune-suppressive monocyte/macrophages in cHL relative to NLPHL.Relative to healthy lymph nodes, there was prominent up-regulation of a range of T-cell associated exhaustion markers in both NLPHL and cHL, indicating dysregulated priming of effector immune responses and host immune homeostasis. Comparison between NLPHL and cHL illustrated that NLPHL had a myriad of features that marked its intratumoral TME as a unique immunobiological entity typified by elevated immune checkpoint markers and T-cells with a highly anergic phenotype.Put together, these findings indicate that distinct immune evasion mechanisms are operative within the TME of NLPHL, including markedly higher levels of multiple immune-checkpoints relative to cHL. In contrast, Treg subsets and immune-suppressive monocyte/macrophages were relatively lower than that seen in cHL. T-cells frequently had dual immune-checkpoint expression. The findings from this study provides a compelling pre-clinical rationale for targeting PD-1 or combinatory checkpoint inhibition in NLPHL and sets the basis for future ‘chemo-free’ rituximab + checkpoint inhibitor clinical trials. DisclosuresTobin:Amgen: Other: Educational Travel; Celgene: Research Funding. Birch:Medadvance: Equity Ownership. Keane:Takeda: Other: Educational Meeting; BMS: Research Funding; Roche: Other: Education Support, Speakers Bureau; Celgene: Consultancy, Research Funding; Merck: Consultancy. Gandhi:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Bone Marrow Involvement in Patients With Nodular Lymphocyte Predominant Hodgkin Lymphoma.

The spectrum of bone marrow lesions in patients with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) has not been evaluated systematically. In this study, we analyzed a cohort of 262 NLPHL patients who underwent staging bone marrow evaluation or targeted bone biopsy as a part of their initial diagnostic workup, among which lymphoma was detected in 24 (9.2%) patients. Eleven patients had bone marrow findings of NLPHL (few large B cells in a background of small B cell and T cell), and 13 patients had either T-cell/histiocyte-rich large B-cell lymphoma (large B cells in a background of T cells and histiocytes) or typical diffuse large B-cell lymphoma (sheets of large B cells). Bone marrow involvement was more common in patients with variant NLPHL histologic patterns in the lymph node as compared with those who had classic patterns (12/18 vs. 4/16; P=0.02). An additional 27 NLPHL patients had bone marrow specimens involved by lymphoid aggregates composed of small T cells and B cells without large B cells; this subgroup had a longer event-free survival than patients with lymphoma in the bone marrow (145 vs. 35 mo). Disease recurrence or progression was more frequent in patients with bone marrow involvement by either NLPHL or LBCL, compared with patients who had lymphoid aggregates (13/21 vs. 8/26; P=0.04). In conclusion, staging bone marrow sampling detects lymphoma in a sizeable subset of NLPHL patients, particularly those with variant histologic patterns. Lymphoid aggregates lacking large B cells in staging bone marrow specimens from NLPHL patients can be regarded as clinically benign without impact on stage, outcome, or risk stratification.

Nodular lymphocyte-predominant Hodgkin lymphoma: a unique disease deserving unique management.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity with an incidence of 0.1 to 0.2/100 000/y. Compared with the more common subtypes of classical Hodgkin lymphoma, NLPHL is characterized by distinct pathological and clinical features. Histologically, the disease-defining lymphocyte predominant cells consistently express CD20 but lack CD30. Clinically, NLPHL mostly has a rather indolent course, and patients usually are diagnosed in early stages. The prognosis of early-stage NLPHL is excellent, with progression-free survival and overall survival rates exceeding 90% after involved-field radiotherapy (IF-RT) alone (stage IA) or combined modality treatment consisting of a brief chemotherapy with 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by IF-RT (early stages other than stage IA). In contrast, patients with advanced disease at diagnosis tend to relapse either with NLPHL histology or with histological transformation into aggressive B-cell non-Hodgkin lymphoma despite more aggressive first-line treatment with 6 to 8 cycles of multiagent chemotherapy. However, even NLPHL patients with multiple relapses successfully respond to salvage therapy in many cases. Salvage therapies range from single-agent anti-CD20 antibody treatment to high-dose chemotherapy followed by autologous stem cell transplantation. Treatment at disease recurrence should be chosen on the basis of various factors, including histology at relapse, time to relapse, extent of disease at relapse, and prior treatment. Because death among NLPHL patients is more often caused by therapy-related late effects than lymphoma-related complications, optimizing the risk-benefit ratio of treatment by decreasing toxicity whenever possible is the major goal of clinical research in this disease.

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.

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.

High-dose chemotherapy and autologous stem cell transplantation for relapsed or refractory nodular lymphocyte predominant Hodgkin lymphoma.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a distinct subtype of Hodgkin lymphoma. We report our results of relapsed/refractory NLPHL patients who received high-dose chemotherapy and autogenic stem cell transplantation (HDC auto-SCT). Seventeen NLPHL patients received HDC auto-SCT (1996–2014): male 14 and female 3, with median age at diagnosis of 22 years, at HDC auto-SCT 28 years (15–58 years). At the time of relapse/progression, 13 (76 %) had NLPHL and 4 (24 %) had transformed diffuse large B cell lymphoma. The reason for HDC auto-SCT was refractory NLPHL in 12 patients and relapsed in 5 patients. Salvage chemotherapy was etoposide, methylprednisolone, cisplatinum, and Ara-C (ESHAP); eight patients also received rituximab with ESHAP. HDC was carmustine, etoposide, cytarabine, and melphalan (BEAM). Post-auto-SCT, complete remission was achieved in 14 (82 %), partial remission in 1 (6 %), and progressive disease in 2 (12 %) patients. The median follow-up is 63 months from auto-SCT (6–124 months). Of the nine patients who received only ESHAP, four had post-auto-SCT events versus no event in all eight patients who received rituximab+ESHAP. Kaplan–Meier estimates of 5-year event-free survival for the whole group is 76 %: rituximab+salvage (100 %) versus salvage alone (56 %), P=0.041. Overall survival is 94 %: 100 versus 89 %, respectively, P=not significant (NS). Even in refractory NLPHL patients, long-term disease-free survival is possible after HDC auto-SCT. Post-auto-SCT relapse or progression can still be managed with chemo/chemo+immunotherapy/ radiation. These encouraging results of rituximab in salvage setting should be explored further in a clinical trial setting for this patient population.

Characteristics and Outcomes of Patients With Nodular Lymphocyte-Predominant Hodgkin Lymphoma Versus Those With Classical Hodgkin Lymphoma: A Population-Based Analysis

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is rare, comprising approximately 5% of all Hodgkin lymphoma (HL) cases. Patients with NLPHL tend to have better prognoses than those with classical HL (CHL). Our goal was to assess differences in survival between NLPHL and CHL patients, controlling for differences in patient and disease characteristics. Using data from the population-based Surveillance, Epidemiology and End Results (SEER) cancer registry program, we identified patients diagnosed with pathologically confirmed HL between 1988 and 2010. We identified 1,162 patients with NLPHL and 29,083 patients with CHL. With a median follow-up of 7 years, 5- and 10-year overall survival (OS) rates were 91% and 83% for NLPHL, respectively, and 81% and 74% for CHL, respectively. After adjusting for all available characteristics, NLPHL (vs CHL) was associated with higher OS (hazard ratio [HR]: 0.62, P<.01) and disease-specific survival (DSS; HR: 0.48, P<.01). The male predominance of NLPHL, compared to CHL, as well as the more favorable prognostic features in NLPHL patients are most pronounced in NLPHL patients <20 years old. Among all NLPHL patients, younger patients were less likely to receive radiation, and radiation use has declined by 40% for all patients from 1988 to 2010. Receipt of radiation was associated with better OS (HR: 0.64, P=.03) and DSS (HR: 0.45, P=.01) in NLPHL patients after controlling for available baseline characteristics. Other factors associated with OS and DSS in NLPHL patients are younger age and early stage. Our results in a large population dataset demonstrated that NLPHL patients have improved prognosis compared to CHL patients, even after accounting for stage and baseline characteristics. Use of radiation is declining among NLPHL patients despite an association in this series between radiation and better DSS and OS. Unique treatment strategies for NLPHL are warranted in both early and advanced stage disease.

The clinical and pathological characteristics of 14 patients' nodular lymphocyte predominant Hodgkin's lymphoma

目的探讨结节性淋巴细胞为主型霍奇金淋巴瘤（NLPHL）患者的临床病理特征及疗效。方法收集14例NLPHL患者的临床资料，对其临床病理特征及近、远期疗效进行相关性分析。结果14例患者均为初治者，男、女各7例，中位发病年龄38（13～54）岁，中位随访时间为55.5（23～189）个月。发病率占同期霍奇金淋巴瘤（HL）的6.3%（14/223）。免疫组织化学检查结果示14例患者CD20均呈（+）/弱（+），CD30均（−），仅1例患者呈CD15弱（+）。14例患者中13例因自觉浅表淋巴结肿大就诊，所有患者惰性起病，病情进展缓慢。7例患者采用单纯化疗，7例患者采用放、化疗联合治疗。14例患者均有效，其中完全缓解（CR）+未证实的CR（CRu）12例。5年无疾病生存率为85.7%，5年总生存率为100.0%。单纯化疗与放、化疗联合治疗相比，不同的化疗方案相比，其近、远期疗效差异均无统计学意义（P值均>0.05）。结论NLPHL患者瘤细胞呈CD20（+）/弱（+），CD30（−），极少数患者呈CD15弱（+）。NLPHL在HL患者中所占比例低，以中青年患者多见，起病缓慢，与经典型HL患者相比疗效较好。

Treatment of Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): An Analysis from the German Hodgkin Study Group (GHSG)

Introduction: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity accounting for about 5% of all HL cases. As compared with classical HL (cHL), NLPHL is characterized by the absence of CD30 and the consistent expression of CD20 on the malignant lymphocyte predominant (LP) cells. Given a more indolent clinical course, especially early-stage NLPHL is often treated less aggressive than classical HL (cHL). In stage IA patients, radiotherapy (RT) alone is applied at most institutions. However, this clinical practice is not based on data from prospective clinical trials with sufficient follow-up. To shed more light on the optimal treatment of stage IA NLPHL, we performed an analysis including patients with long-term follow-up treated within German Hodgkin Study Group (GHSG) clinical trials.Patients: A total of 256 stage IA NLPHL patients treated within 7 prospective GHSG studies between 1988 and 2009 were included in the analysis. Treatment consisted of combined-modality treatment (CMT) (n=72), extended-field RT (EF-RT) (n=49), involved-field RT (IF-RT) (n=108) or four weekly doses of the anti-CD20 antibody rituximab (n=27).Results: The median age at NLPHL diagnosis was 38.5 years (range: 17-75); 194/256 (75.8%) patients were male and 62/256 (24.2%) patients were female. Median follow-up for the whole patient group was 91 months (98 months for CMT, 118 months for EF-RT, 87 months for IF-RT, 49 months for rituximab). All patients responded to treatment irrespective of the treatment modality applied. At 8 years, progression-free survival (PFS) and overall survival (OS) rates were 88.5% and 94.5% for CMT, 84.3% and 95.7% for EF-RT and 91.9% and 99.0% for IF-RT; 4-year PFS and OS rates for patients treated with rituximab were 81.0% and 100%. Seventeen patients developed a second malignancy in the course of follow-up (8 after CMT, 3 after EF-RT, 4 after IF-RT, 2 after rituxmab). Nine of these second malignancies were solid tumors (4 after CMT, 2 after EF-RT, 1 after IF-RT, 2 after rituximab) and 8 were hematologic malignancies (4 after CMT, 1 after EF-RT, 3 after IF-RT, none after rituximab). A total 12 deaths occurred. The most common cause of death was cardiac failure (n=3). Only one patient died from NLPHL.Conclusion: Based on this large analysis with long-term follow-up, IF-RT should be the standard of care for stage IA NLPHL. Treatment with single agent rituximab is associated with an increased event rate when compared with IF-RT and should therefore not be routinely used in stage IA NLPHL patients. However, given the shorter follow-up in comparison with CMT, EF-RT and IF-RT, final conclusions regarding rituximab especially in terms of treatment-related late sequelae cannot yet be drawn. Addition of chemotherapy does not improve the excellent outcome achieved with RT alone. DisclosuresOff Label Use: Rituximab in NLPHL.

Histopathological features and their prognostic impact in nodular lymphocyte-predominant Hodgkin lymphoma--a matched pair analysis from the German Hodgkin Study Group (GHSG).

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity. We performed a matched-pair analysis to evaluate the prognostic impact of several histopathological features in this distinct Hodgkin lymphoma subtype. Lymph node samples of NLPHL patients were tested for CD15, IgD, phosphorylated STAT6, ICOS and Epstein-Barr virus status of the malignant lymphocyte-predominant cells as well as epithelioid cell clusters and activated T cells in the microenvironment. None of these features was associated with a particular clinical outcome. However, patients presenting with epithelioid cell clusters showed a non-significant trend towards a lower relapse rate, justifying further evaluation of this marker.

Advanced-stage nodular lymphocyte predominant Hodgkin lymphoma compared with classical Hodgkin lymphoma: a matched pair outcome analysis

AbstractDue to disease rarity, there is limited information regarding the optimal therapy and outcome for patients with advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Forty-two patients with NLPHL by the Revised European-American Lymphoma/World Health Organization classification with advanced-stage disease were identified and paired 1:2 with a matched control with classical Hodgkin lymphoma (CHL) matched by age, gender, stage, decade of diagnosis, and treatment received. The median follow-up was 11.3 years (range, 1.9 to 35.5 years) for NLPHL patients and 10.7 years (range, 1.6 to 26.3 years) for CHL patients. The majority received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)–like chemotherapy. Although the 10-year overall survival (OS) (P = .579) and HL freedom from treatment failure (HL-FFTF) were similar between NLPHL and CHL patients (75% vs 73%; P = .610), the time to progression (TTP), which also includes the development of secondary aggressive lymphoma, was inferior in NLPHL (10-year, 63% vs 73%; P = .040). Splenic involvement was associated with an inferior 10-year TTP in patients treated with ABVD (48% vs 71%; P = .049) and an increased cumulative incidence of secondary aggressive lymphoma (P = .014) providing a rationale for further evaluation of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with rituximab in NLPHL.

Long-Term Outcomes in Patients with Early Stage Nodular Lymphocyte-Predominant Hodgkin’s Lymphoma Treated with Radiotherapy

PurposeRadiation therapy (RT) is commonly used as definitive treatment for early-stage nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL). We evaluated the cause-specific survival (CSS), overall survival (OS), and second malignancy (SM) rates in patients with early-stage NLPHL treated with RT.Methods and MaterialsPatients with stage I-II NLPHL between 1988 and 2009 who underwent RT were selected from the Surveillance, Epidemiology and End Results database. Univariate analysis (UVA) for CSS and Os was performed using the Kaplan-Meier method and included age, gender, involved site, year of diagnosis, presence of B-symptoms, and extranodal involvement (ENI). Multivariable analysis (MVA) was performed using Cox Proportional Hazards modeling and included the above clinical variables. SM were classified as RT-related or non-RT-related. Freedom from SM and freedom from RT-related SM were determined using the Kaplan-Meier method.ResultsThe study cohort included 469 patients. Median age was 37 years. The most common involved sites were the head and neck (36%), axilla/arm (26%), and multiple lymph node regions (18%). Sixty-eight percent had stage I disease, 70% were male, 4% had ENI, and 7% had B-symptoms. Median follow-up was 6 years. Ten-year CSS and Os were 98% and 88%, respectively. On UVA, none of the covariates was associated with CSS. Increasing age (p<0.01) and female gender (p<0.01) were associated with worse Os. On MVA, older age (p<0.01), female gender (p=0.04), multiple regions of involvement (p=0.03), stage I disease (p=0.02), and presence of B-symptoms (p=0.02) were associated with worse Os. Ten-year freedom from SM and freedom from RT-related SM were 89% and 99%, respectively.ConclusionsThis is the largest series to evaluate the outcomes of stage I-II NLPHL patients treated with RT and found that this patient population has an excellent long-term prognosis and a low rate of RT-related second malignancies.

Does Functional Imaging Distinguish Nodular Lymphocyte-Predominant Hodgkin Lymphoma From T-Cell/Histiocyte-Rich Large B-Cell Lymphoma?

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is often associated with concurrent or subsequent development of T-cell/histiocyte-rich large B-cell lymphoma (THR-LBCL). Distinguishing the two is important because their therapies are different. Functional imaging with PET/CT is used to stage both Hodgkin and non-Hodgkin lymphomas. Aggressive lymphomas are usually more PET avid than the indolent subtypes. Therefore, it is possible that PET/CT may help distinguish NLPHL from THR-LBCL. Herein, we retrospectively describe the clinical and PET/CT findings of 12 patients with NLPHL or THR-LBCL seen from 2004-2010. Six patients each were identified and the average SUVmax was 6.9 (range, 5.7-7.3) in NLPHL and 16.6 (range, 4-29) in THR-LBCL (p= 0.055). Bone and extranodal involvement was found in one patient with NLPHL compared to four patients with THR-LBCL. This patient failed to respond to ABVD and was subsequently found to have THR-LBCL. We suggest that patients with NLPHL and THR-LBCL have different clinical and PET/CT characteristics. NLPHL patients had lower SUVmax on PET/CT compared to those with THR-LBCL. The presence of bone or extranodal involvement is more common in patients with THR-LBCL. Patients with NLPHL and an uncharacteristically higher SUVmax on PET/CT, or those with bone or extranodal involvement, should alert the clinician to consider the presence of THR-LBCL.