Mediastinal Gray Zone Lymphoma Research Articles

Clinical Characteristics and Prognosis of 56 Lymphoma Patients with Mediastinal Masses

To analyze the incidence, clinical characteristics, treatment efficacy and prognosis of lymphoma patients with mediastinal masses. The clinical data of 56 lymphoma patients with mediastinal masses treated in our hospital from February 2007 to January 2018 were collected, and the clinical characteristics, typing, staging, treatment efficacy as well as prognosis analyzed retrospectively. Among the 56 patients, male and female were 25 (45%) cases and 31(55%) cases, respectively. The median age was 31 (17-72) years old, out of them 48 (86%) patients aged below 40 years old. According to pathological classification, 9 (16.1%) cases were diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS), 26(46.4%) cases were primary mediastinal large B cell lymphoma (PMBCL), 17 (30.4%) cases were classical Hodgkin's lymphoma (cHL), and 4 (7.1%) cases were primary mediastinal grey zone lymphoma (MGZL). All the patients were treated with chemotherapy or immuno-chemotherapy.The median follow-up time was 54.5(11-149) months. In cHL group, 10 cases received involved field radiotherapy (IFRT), 10 (58.8%) cases achieved complete remission (CR), 2 (11.8%) cases achieved partial remisson (PR), and 5 (29.4%) patients experienced progressive disease (PD) , 6 patients with relapsed/refractory disease received autologous hematopoietic stem cell transplantation (auto-HSCT), the 1, 2, and 5 year overall survival (OS) rates of cHL group were 94.1%, 88.2%, and 67.2%, respectively. In MGZL group, 3 cases combined with IFRT, 1 case with auto-HSCT, 2 (50%) cases achieved CR, 2 (50%) cases experienced PD, the 1, 2, 5 year OS rates of MGZL group were 66.7%, 66.7%, and 33.3%, respectively. In PMBCL group, 8 cases combined with IFRT, 7 cases with auto-HSCT, 22 (84.0%) cases achieved CR, 2 (8.0%) cases achieved PR, 1 (4.0%) case was stable disease (SD) and 1 (4.0%) case experienced PD, the 1, 2 year OS rates of PMBCL group were both 100%, and 5 year OS rate was 95.7%. In DLBCL-NOS group, 3 cases combined with IFRT, 2 cases with auto-HSCT, 4 (44.5%) cases achieved CR, 2 (22.2%) cases achieved PR, 1 (11.1%) case was stable disease (SD) and 2 (22.2%) cases experienced PD, the 1 year OS rate of DLBCL-NOS cohort was 100%, 2, and 5 year OS rates were both 77.8%. There was a significant difference of OS rate among these 4 group (P＜0.05). In intra-group comparison, OS rate in PMBCL group were significantly longer than both MGZL group (P＜0.01) and cHL group(P＜0.05), and showed no significant difference from DLBCL-NOS group (P＞0.05). Mediastinal masses are characterized by unique clinical features due to their unique anatomical location. Several B cell originated lymphomas including cHL,MGZL,PMBCL and DLBCL-NOS, manifested primary or secondary mediastina involvement, tend to occur in young adults and have similar clinical features. However, their therapeutic response was significantly different. The prognosis of PMBCL is prior to MGZL and cHL.

Gene Expression Profiling of Mediastinal Gray Zone Lymphoma and Its Relationship to Primary Mediastinal B-cell Lymphoma and Classical Hodgkin Lymphoma

Mediastinal gray zone lymphoma (MGZL) has immunopathologic features between classical Hodgkin lymphoma (cHL) and primary mediastinal thymic B-cell lymphoma (PMBL), leading to uncertainty regarding its biological relationship to these entities. We performed gene expression profiling from patients with MGZL (20), cHL (18), and PMBL (17) and show MGZL clusters between cHL and PMBL. Expression signatures reveal germinal B-cell and IFN regulatory factor 4 (IRF4) signatures were relatively low in MGZL and cHL compared with PMBL, indicating downregulation of the B-cell program in MGZL, a hallmark of cHL. T-cell and macrophage signatures were higher in MGZL and cHL compared with PMBL, consistent with infiltrating immune cells, which are found in cHL. The NFκB signature was higher in MGZL than PMBL, and like cHL, MGZL and PMBL express NFκB inducing kinase (NIK), indicating noncanonical signaling. These findings indicate that while MGZL has distinctive clustering, it is biologically closer to cHL.

Trends and Outcomes of Gray Zone Lymphoma in the United States: A Population-Based Registry Study

Introduction Gray zone lymphoma (GZL) denotes a group of unclassifiable lymphomas, having features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma. First described in 2005 and recognized in the WHO classification in 2008 as mediastinal GZL. Recently, a non-mediastinal GZL (NMGZL) was also characterized. Given its rarity and new recognition, information on its incidence and survival is scarce. Methods The SEER (Surveillance, Epidemiology, and End Results) registry was used to identify patients with histologically confirmed GZL between 2005-2016. Incidence rates (IR) were age-adjusted according to the 2000 US Standard Population. Annual percentage change (APC) and overall survival (OS) were assessed using the weighted least square and Kaplan-Meier methods, respectively. Factors with p-values Results A total of 564 cases were identified corresponding to an IR of 0.53 per million person-years. The IR of GZL increased over time, from 0.14 in 2005 to 1.27 in 2016, with an APC of 27.7% (95% confidence intervals [CI]: 23.1-32.4), p Conclusions This represents the largest population-based study for GZL. IRs increased over time, notably in the elderly; which may be explained by a better understanding of the disease and the recent characterization of NMGZL, occurring mostly in the elderly. Older age, advanced stage, and presence of SS may predict worse outcomes. Survivors of GZL may have increased future risk of thyroid tumors, possibly attributed to neck radiation.

Pruritic cutaneous lesions mimicking dermatitis artefacta in the course of mediastinal gray-zone lymphoma.

Pruritic cutaneous lesions mimicking dermatitis artefacta in the course of mediastinal gray-zone lymphoma.

Phase 2 Study of Alemtuzumab Added to Dose-Adjusted EPOCH-R in Relapsed and Refractory Aggressive B-Cell Lymphomas

Introduction: Relapsed and refractory aggressive B-cell lymphomas can be cured with hematopoietic stem cell transplant (HSCT), but effective salvage regimens are required. Anthracyclines are the most effective agents in lymphoma and dose-adjusted doxorubicin, etoposide, vincristine, cyclophosphamide, prednisone with rituximab (DA-EPOCH-R) was originally developed in relapsed/refractory lymphomas. Gene-expression profiling of diffuse large B-cell lymphoma (DLBCL) identified stromal signatures associated with inferior survival and targeting the tumor microenvironment may block important survival signals. Alemtuzumab is a humanized monoclonal antibody targeting CD52, present on both B and T-cells. We hypothesized that targeting CD52 could overcome treatment resistance. We report the safety and activity of alemtuzumab added to DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas, including Hodgkin lymphoma (HL). Methods: Adult pts with relapsed/refractory aggressive B cell lymphomas and adequate organ function were eligible. Pts with HIV or CNS involvement were ineligible. Pre-treatment evaluation included laboratory investigations, computed tomography (CT) scans, bone marrow aspirate/biopsy, and brain MRI/CT if indicated. Alemtuzumab 30 mg was infused first on day 1 over 12 hours before rituximab. EPOCH was infused over 5 days and dose-adjusted based on neutrophil nadir for up to 6 cycles. Responding pts were allowed to receive consolidation. Infective prophylaxis included trimethoprim-sulfamethoxazole, acyclovir, and fluconazole in all pts, and lamivudine for pts at risk of HBV reactivation. PCR for cytomegalovirus (CMV) was done at baseline and with every cycle. Tumor response was assessed per the revised 2014 International Working Group guidelines. CT scans were performed after cycles 4 and 6, and every 3 months for year 1, 4 months for year 2 and 6 months for years 3-5. Positron-emission tomography scans were performed after cycle 4 and 6. The primary endpoint of the study was overall response rate. Results: 50 pts were enrolled from November 2009 to March 2014. Two pts did not receive any chemotherapy due to congestive heart failure and rapid disease. 48 pts received 1 cycle and were included in the analysis. Median age was 45 years (range, 18-72) and 29 (60%) pts were male. Twenty-one (44%) pts had DLBCL (T-cell-histiocyte rich DLBCL (THRLBCL) in 4), 16 (33%) HL, 6 (13%) primary mediastinal B-cell lymphoma, 4 (8%) mediastinal grey zone lymphoma and 1 (2%) B-cell lymphoma NOS. Median lines of prior treatment was 2 (range 1-10). All pts received prior anthracycline and 10 (20%) received prior ASCT. Thirty-five (72%) were primary refractory to chemotherapy. In 46 pts evaluable for response, overall response rate (ORR) was 65% including a complete response (CR) rate of 33%. Of 30 responding pts, 13 (44%) received consolidation therapy (5 allogeneic HSCT, 7 radiation, 1 ASCT) and 17 received no further therapy with 7 long-term remissions. In 20 evaluable DLBCL pts, the ORR was 65% including a 30% rate of CR. All 4 THRLBCL responded and 3 had durable remissions after consolidative XRT (2) and allogeneic HSCT (1). In 15 evaluable HL pts, the ORR was 80% including a CR rate of 60%. After a median potential follow up of 84.6 months, median PFS and OS were 6.7 months (CI95: 4.1 - 10.4) and 18.1 months (CI95: 11.5 - not estimable), respectively. In DLBCL, the 2-year PFS and OS were 23% (CI95 9%-47%) (Figure 1A) and 41% (CI95 19%-66%), respectively, while in HL, the 2-year PFS and OS were 36% (CI95 15%-63%) (Figure 1B) and 60% (CI95 33%-82%), respectively. Febrile neutropenia, grade 4 thrombocytopenia, and CMV reactivation without infection occurred in 18%, 26%, and 53% of cycles, respectively. Grade 3 infection occurred in 18% of pts and included BK (3), HSV (1), and CMV (1). Overall, 27 deaths occurred, 3 during therapy (2 of sepsis, 1 of congestive heart failure) and 24 post-therapy (9 of PD, 5 of sepsis, 1 of hemorrhage, 1 of PTLD, and 8 of unknown causes). Conclusion: Alemtuzumab can safely be added to DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas without a significant increase risk of opportunistic infections or unexpected toxicity. Nearly half of patients were successfully bridged to consolidation therapy; however, selected pts, particularly those with significant T-cell infiltration, experience long-term durable remission. Figure 1 Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Alemtuzumab is not standard of care treatment of lymphoma. We have studied Alemtuzumab in combination with EPOCH in this study

Primary Mediastinal Nodal and Extranodal Non-Hodgkin Lymphomas: Current Concepts, Historical Evolution, and Useful Diagnostic Approach: Part 2.

Primary mediastinal non-Hodgkin lymphomas (PM-NHLs) represent ∼5% of all non-Hodgkin lymphomas (NHLs) and comprise lymphomas of B-cell and T-cell origin. PM-NHLs are defined as involvement of mediastinal lymph nodes, thymus, and/or mediastinal organs (heart, lung, pleura, pericardium) by NHL without evidence of systemic disease at presentation. The clinical scenario is variable and depends on the lymphoma subtype. The radiologic presentation is also variable ranging from a mediastinal mass with or without superior vena cava syndrome, a pleural or a cardiac mass associated with effusion, or as an effusion only. The diagnosis of PM-NHLs can only be established by microscopic evaluation, and therefore, general pathologists should be aware of these tumors and familiar with their diagnostic approach. The most common anterior mediastinal NHLs (90% to 95%) are primary mediastinal (PM) large B-cell lymphoma and T-lymphoblastic lymphoma. Thymic marginal zone lymphoma and mediastinal gray zone lymphoma are very rare. The remainder PM-NHLs involving middle or posterior mediastinum include diffuse large B-cell lymphoma (DLBCL) and rare cases of T-cell lymphoma, including anaplastic large cell lymphoma and breast implant-associated anaplastic large cell lymphoma extending to the anterior mediastinum. Primary pleural and cardiac NHLs are mostly DLBCLs. Other rare subtypes of PM-NHLs include DLBCL associated with chronic inflammation/pyothorax-associated lymphoma, fibrin-associated DLBCL (both Epstein-Barr virus positive), and pleural and/or pericardial primary effusion lymphoma (human herpesvirus-8 positive/Epstein-Barr virus positive). We review the historical aspects, epidemiology, clinicoradiologic features, histopathology, immunohistochemistry, differential diagnosis, and relevant cytogenetic and molecular features of the remaining mediastinal B-cell lymphomas, including primary thymic marginal zone lymphoma of the mucosa-associated lymphoid tissue type, other PM small B-cell lymphomas, PM plasmacytoma, and the most relevant PM T-cell lymphomas.

Primary Mediastinal Nodal and Extranodal Non-Hodgkin Lymphomas: Current Concepts, Historical Evolution, and Useful Diagnostic Approach: Part 1

Primary mediastinal non-Hodgkin lymphomas (PM-NHLs) represent ~5% of all NHLs and comprise lymphomas of B-cell and T-cell origin. PM-NHLs are defined as involvement of mediastinal lymph nodes, thymus, and/or mediastinal organs (heart, lung, pleura, pericardium) by NHL without evidence of systemic disease at presentation. The clinical scenario is variable and depends on the lymphoma subtype. The radiologic presentation is also variable ranging from a mediastinal mass with or without superior vena cava syndrome, a pleural or a cardiac mass associated with an effusion, or as an effusion only. The diagnosis of PM-NHLs can only be established by microscopic evaluation, and therefore, general pathologists should be aware of these tumors and familiar with their diagnostic approach. The most common anterior mediastinal NHLs (90% to 95%) are primary mediastinal large B-cell lymphoma and T lymphoblastic lymphoma. Thymic marginal zone lymphoma and mediastinal gray zone lymphoma are very rare. The remainder PM-NHLs involving middle or posterior mediastinum include diffuse large B-cell lymphoma (DLBCL) and rare cases of T-cell lymphoma, including anaplastic large cell lymphoma and breast implant-associated anaplastic large cell lymphoma extending to the anterior mediastinum. Primary pleural and cardiac NHLs are mostly DLBCLs. Other rare subtypes of PM-NHLs include DLBCL associated with chronic inflammation/pyothorax-associated lymphoma, fibrin-associated DLBCL (both EBV), and pleural and/or pericardial primary effusion lymphoma (HHV-8/EBV). We review the historical aspects, epidemiology, clinico-radiologic features, histopathology, immunohistochemistry, differential diagnosis, and relevant cytogenetic and molecular features of PM (thymic) LBCL, PM "nonthymic" DLBCL, BCL, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma (mediastinal gray zone lymphoma), DLBCL associated with chronic inflammation (pyothorax-associated lymphoma), fibrin-associated DLBCL, and primary effusion lymphoma. This review represents the first part of 2 manuscripts covering PM-NHLs.

EBV-Positive Primary Large B-cell Lymphoma: Highlighting the Role of XPO1 in the Diagnosis of Mediastinal Lymphomas

Abstract Background Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is described to be almost always negative for EBV in the current WHO. In the context of a mediastinal lymphoma, the distinction between PMBL, classic Hodgkin lymphoma (CHL), diffuse large B-cell lymphoma, and mediastinal gray-zone lymphoma can be very difficult; hence, EBV positivity often aids in pointing away from a diagnosis of PMBL. However, since EBV positivity can occur in rare PMBLs, it should not be the deciding factor in the diagnosis; assistance from molecular studies is emerging in these difficult cases. Case Presentation We present a 19-year-old male patient with a 2-week history of cough, vocal changes, and occasional dysphagia who was found upon imaging to have a 6-cm mediastinal mass. The biopsy of this mass was morphologically consistent with PMBL but the tumor was EBV positive by in situ hybridization. Methods We performed next-generation sequencing using Oncomine Comprehensive Assay v3 (ThermoFisher Scientific) on formalin-fixed, paraffin-embedded tumor tissue with a buccal swab sample for germline control. Variant calling, filtering, and annotation were performed by the Yale Tumor Profiling Laboratory. Results We found somatic mutations in XPO1, SMARCB1, and MYC. Along with classic immunophenotype of PMBL including positivity for MAL, OCT2, BOB1, BCL6, CD79a, MUM1, CD20, and subset weak CD30, the diagnosis was confirmed to be PMBL. Conclusion This is the first EBV-positive PMBL in which molecular profiling was performed. XPO1, specifically the mutation hotspot (E571K), found in our case is involved in PMBL and CHL. This was clinically helpful in confirming the histopathologic diagnosis and also opening up a targeted therapeutic option. Selective inhibitors of nuclear export (SINEs) that block the binding of XPO1 to its cargo are in clinical development as antineoplastic agents and have shown promising activity against some hematologic malignancies.

The utility of CD83, fascin and CD23 in the differential diagnosis of primary mediastinal large B-cell lymphoma versus classic Hodgkin lymphoma

Primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma (CHL) are the most common large cell lymphomas arising in the mediastinum and are thought to be closely related histogenetically. Although the distinction between PMBL and CHL is usually straightforward, in some cases it is challenging and rarely these neoplasms have intermediate features and qualify for the diagnosis of mediastinal gray zone lymphoma (GZL). CD83 and fascin are markers of CHL and CD23 is a marker of PMBL. In this study we assess the utility of this combination of these immunohistochemical markers to distinguish CHL from PMBL. We retrospectively collected cases of PMBL, CHL and GZL from three centers. Tissue sections were stained with CD83, fascin and CD23. CD83 was expressed in the neoplastic cells of 100% of CHL (22/22), 93% of GZL (16/18) and 41% of PMBL (9/22). Similarly, fascin was positive in the neoplastic cells of 100% of CHL (22/22), 86% of GZL (18/21) and 32% of PMBL (7/22). CD23 was positive in 95% of PMBL (21/22), 67% of GZL (12/18) and 9% of CHL (2/22). CD83 and fascin are sensitive markers for CHL but not specific whereas CD23 is sensitive for PMBL and uncommon in CHL. The GZL cases in this study had an intermediate immunophenotype, but the results were closer to CHL than PMBL. A large panel of immunohistochemical studies is recommended to distinguish CHL from PMBL entities and we suggest that CD83, fascin and CD23 add value to panels designed for this differential diagnosis.

Rearrangements of Immunoglobulin Genes in Tumor Cells of Patients with Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Background. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a malignant tumor with large atypical lymphoid cells expressing post-germinal differentiation markers. Rearrangements of immunoglobulin genes in PMBCL are revealed in 30-65 % of cases. Immunoglobulin molecules, however, are expressed neither on the surface, nor in cytoplasm of tumor cells. Aim. To assess cell clonality rate on the basis of rearrangements of immunoglobulin heavy/light chain genes; to determine rearrangement stability at the time of relapse development; to study the range of rearrangements and clonal relationship with primary tumor in metachronous development of mediastinal gray zone lymphoma. Materials & Methods. The assessment of rearrangements of immunoglobulin heavy/light chain genes was based on molecular analysis of 29 primary tumor biopsies and 4 tissue samples with histologically and immunohistochemically verified relapses or metachronous lymphoma development. Results. In 16 (55.2 %) out of 29 cases a rearrangement of immunoglobulin heavy chain genes was reported, in 7 (24.1 %) cases a rearrangement of light chain genes was identified, in 6 (20.7 %) cases no rearrangements of immunoglobulin heavy/light chain genes were found. On the basis of immunoglobulin gene analysis in 2 patients with early relapse a tumor clone was detected that was identical with the one identified at the onset of the disease. In 2 patients with complete remission a metachronous development of mediastinal gray zone lymphoma was reported, whereas molecular genetic analysis revealed a change/disappearance of initial clonal rearrangements of immunoglobulin genes. Conclusion. Total detection rate of B-cell clonality in PMB-CL was 79.3 %. Molecular genetic analysis confirmed that initial clonal rearrangements of immunoglobulin genes were preserved in early relapses, and invalidated tumor clonal relationship in a metachronous development of mediastinal gray zone lymphoma.

Dendritic Cell Markers and PD-L1 are Expressed in Mediastinal Gray Zone Lymphoma.

Mediastinal gray zone lymphoma (MGZL) is a rare entity with morphologic, immunophenotypic, and genetic features intermediate between classic Hodgkin lymphoma (CHL) and primary mediastinal large B-cell lymphoma (PMBL). It is challenging to differentiate from CHL and PMBL. A specific dendritic cell gene expression profile can distinguish CHL and MGZL from PMBL. We hypothesized that the dendritic markers fascin and CD123 may be helpful in distinguishing MGZL from CHL and PMBL. We also investigated programmed death-ligand 1 (PD-L1) expression in MGZL, which may have therapeutic significance in this difficulty to treat tumor. Representative sections from 89 CHL, 20 PMBL, and 7 MGZL cases were stained for fascin, CD123, and PD-L1, and scored on a scale from 0 to 3+. Most (71%) MGZLs stained for CD123, as well as some (23%) CHLs, and few (11%) PMBLs. All MGZLs stained for fascin, as well as most (90%) CHLs, and approximately half (53%) of the PMBLs. PD-L1 was positive in all MGZLs, most (77%) CHLs and most (66%) PMBLs. Our study is the first to show CD123 is positive in a subset of formalin-fixed, paraffin-embedded MGZLs and CHLs, in contrast to PMBL which is largely negative. Staining for fascin was not significantly different between the lymphomas, but was less likely to be positive in PMBL. These findings suggest a role for CD123 and fascin in supporting diagnoses of MGZL and CHL, and in ruling out PMBL. By immunohistochemistry, PD-L1 is positive in MGZL, pointing to its therapeutic potential.

Long-term complete remission following tandem autologous stem cell transplantation and consolidative radiotherapy for refractory mediastinal gray-zone lymphoma.

Mediastinal gray zone lymphoma (MGZL) is a provisional entity with intermediate features between classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma. Outcomes for patients with MGZL are reportedly poorer than those for patients with cHL or primary mediastinal large B-cell lymphoma. Additionally, no standard management guidelines for patients with MGZL are available, primarily due to its recent identification, rarity, and challenges in diagnosis. Although recent several studies have suggested dose-adjusted EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and rituximab) may improve outcomes in patients with MGZL, numerous patients still suffer from relapsed/refractory MGZL, and the optimal management for such patients remains uncertain. Here, we report the first case of successful treatment of refractory MGZL by tandem high-dose chemotherapy supported by autologous stem cell transplantations (auto-SCTs) and consolidative radiotherapy (RT). To date, the patient remains in CR 33 months after the completion of RT, with no significant complications. This case suggests that tandem auto-SCTs may be a promising therapeutic option for relapsed/refractory MGZL.

Primary mediastinal B-cell lymphoma: biology and evolving therapeutic strategies.

Primary mediastinal B-cell lymphoma (PMBCL) is recognized as a distinct clinicopathologic entity that predominantly affects adolescents and young adults and is more common in female subjects. Although PMBCL is considered to be a subtype of diffuse large B-cell lymphoma, its clinical, morphologic, and biological characteristics overlap significantly with those of nodular sclerosing Hodgkin lymphoma (NSHL). Over the past few years, the shared biology of these 2 entities has been highlighted in several studies, and mediastinal gray zone lymphoma, with features intermediate between PMBCL and NSHL, has been recognized as a unique molecular entity. Although there is a lack of consensus about the optimal therapeutic strategy for adolescent and young adult patients newly diagnosed with PMCBL, highly curative strategies that obviate the need for mediastinal radiation are favored by most. Progress in understanding the biology of PMBCL and its close relationship to NSHL have helped pave the way for the investigation of novel approaches such as immune checkpoint inhibition. Other strategies such as adoptive T-cell therapy and targeting CD30 are also being studied.

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.

Mediastinal gray zone lymphoma-morphollogically heterogenous group of lymphomas.

e19050 Background: Mediastinal Gray zone lymphoma (MGZL) could be refer to group of large B-cell lymphomas of mediastinum, where Hodgkin’s lymphoma and Diffuse large B-cell lymphoma also included. These kinds of lymphomas have common pathogenic mechanisms, but different epidemiological,clinical , morphological, IHC features, different therapy and prognosis. Methods: We analyzedhistological and IHC features of 11 patients with MGZL. Middle age of patients were 35 years old (25-42), Man(7 )and woman (4) ratio was 1,75:1. Results: We distinguished 5 types of MGZL: 1) Hodgkin’s lymphoma-like variant (ring-shaped fibrosis, expressed cellular polymorphism, large cells seems like Hodgkin’s and Reed-Shteinberg cells,mixed-cell background infiltrate; high expression of CD 20 and another B-lines antigens. 2) type, seems like primary mediastinum large B-cell lymphoma (PMBL-like) (about monotonous composition of the cells, diffuse alveolar stroma’sfibrosis, scarce background infiltrate, high diffuse expression of CD 30 and/or lack of LCA and CD 20 expression 3) mixed variant (mixture of cells PMBL and Hodgkin's lymphoma, irregularly expressed fibrosis, lack of zonality, transientimmunophenotype. 4) dual-component variant (well-defined zonality, Hodgkin's like areas and structuresspecific for PMBL with appropriate or changed immunophenotype 5) Metachronous variant (during progression or relapse we observedmodification of morphological and IHC features). Conclusions: MGZL is heterogenous group of neoplasms with different morphological and IHC features causes difficulties in differential diagnostics in large B-cell lymphomas of mediastinum group.Diagnostic algorithm should be used for high efficacy and accuracy. Clinical features and prognostic factors in these subtypes of MGZL is still unclear and need further investigations.

CheckMate 436: A phase 1-2 study to evaluate safety and efficacy of nivolumab plus brentuximab vedotin in patients with CD30-expressing relapsed/refractory non-Hodgkin lymphomas.

TPS7577 Background: Nivolumab (nivo) is a PD-1 immune checkpoint inhibitor that augments T-cell activation and host anti-tumor responses. PD-1 blockade has shown promise in B- and T-cell non-Hodgkin lymphoma (NHL),1 but many patients (pts) with NHL do not respond or progress after response. Combination therapy using anti-tumor agents with complementary mechanisms of action and low immunosuppressive impact may result in more frequent and durable responses. Brentuximab vedotin (BV) is an anti-CD30 antibody–drug conjugate that induces cell cycle arrest and apoptosis, with activity in a range of NHL tumors.2,3 Tumor cells undergoing BV-induced apoptosis have shown subsequent immune-mediated anti-tumor cytotoxicity.4 Therefore, nivo and BV may synergize if combined for relapsed/refractory (RR) NHL. Methods: CheckMate 436 (NCT02581631) is a phase 1–2, open-label, international, single-arm study evaluating nivo + BV for CD30-expressing RR NHL (study start: Dec 2015) in pts with RR diffuse large B-cell lymphoma, peripheral T-cell lymphoma (excluding anaplastic large cell lymphoma), and cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome); cohorts with primary mediastinal B-cell lymphoma (PMBL) and mediastinal gray zone lymphoma were made eligible in Sept 2016. Pts with PMBL must be aged ≥15 y (≥18 y for other histologies). All pts must have CD30-expressing disease, defined by CD30 on ≥1% of tumor cells or tumor-infiltrating lymphocytes by immunohistochemistry. In the phase 1 component, 6 pts will receive nivo and BV until disease progression or unacceptable toxicity. In the phase 2 component, ~130 more pts across the 5 histologies will be enrolled and treated at the recommended dose. Primary endpoints: safety, tolerability, and investigator-assessed objective response rate; secondary endpoints: duration of response and complete response (CR), CR rate, and progression-free and overall survival. Accrual is ongoing.

DIFFERENTIAL DIAGNOSIS OF LYMPHOMAS OF THE MEDIASTINUM: A VIEW OF THE ONCOLOGIST AND PATHOLOGIST

The clinic-rentgenological differential diagnosis is difficult especially in case of localized mediastinal disease. Just detailed histological diagnosis allows making a right tactic decision and choosing effective therapy. Furthermore, some indolent B-cell lymphomas and T-cell lymphomas can arise in mediastinum. Mediastinal tumors are frequent in young adults, and most of these neoplasms are lymphoproliferative disorders. The spectrum of mediastinal lymphoma is broad. The most often of them are large B-cell lymphomas: classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma and mediastinal grey zone lymphoma.

Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Primary mediastinal (thymic) large B-cell lymphoma (PMB-CL) is one of the primary extranodal tumors and originates from thymic medulla B cells. The disease is more common in young women and declares itself by mainly locally advanced growth within the anterior upper mediastinum with frequent involvement of chest organs. PMBCL has specific morphological, immunological, and genetic characteristics that permit to differentiate it from other similar diseases: diffuse large В-cell lymphoma, nodular sclerosis Hodgkin’s lymphoma, and mediastinal gray zone lymphoma. Immunochemotherapy with subsequent irradiation of the residual mediastinal tumor is the standard treatment of PMBCL. No benefits of one drug therapy over another have been demonstrated to date in controlled studies. Application of new imaging techniques (PET/CT) may result in withdrawal of the radiotherapy in some PMBCL patients without impairment of delayed survival rates.

Nivolumab Induces Remission in High- PD-L1 Expressing Aggressive B-Non Hodgkin Lymphoma: A Single Center Experience

Patients with relapsed or refractory aggressive B-cell Non-Hodgkin lymphoma (B-NHL) have a poor outcome. Nivolumab (NV) targeting the PD-1 receptor has shown promising results in several malignancies like melanoma, renal and lung carcinoma and Hodgkin lymphoma. Data for aggressive B-NHL are just emerging. PD-L1 expression does not necessarily correlate with response. Among lymphoma subtypes, the expression of PD-L1 seems to vary. So far there are no valid data on PD-L1 expression in aggressive lymphoma under NV treatment.We retrospectively analyzed seven patients who had aggressive B-NHL with a refractory or relapsed disease after at least 3 regimens and were thereupon treated with NV 3mg/kg once a fortnight. Treatment was initiated after signed informed consent for off-label use. The histologic specimens were analyzed for PD-L1 expression by immunohistochemistry (IHC).The median age at NV treatment start was 51 years (27-71). The histopathological diagnoses were primary mediastinal B-cell lymphoma (PMBL; n=2), composite lymphoma with diffuse large B-cell (DLBCL) and Hodgkin lymphoma components (n=2), follicular lymphoma transformed into a DLCBL (n=2) and one mediastinal grey zone lymphoma (MGZL). A median of 5 (3-7) prior therapy regimens were given including hematopoietic stem cell transplantation (HSCT) for 3 patients: autologous (n=2) and allogeneic HSCT (n=1), respectively. The lymphoma status was refractory in 2 patients and relapsed in 5 patients. PD-L1 expression was detected in 5 cases, 3 of them showing a positive staining of 10%, 30%, and 50%, respectively, and 2 cases even of 100% of the lymphoma cells. NV was mostly well tolerated (1 pneumonitis completely resolved after systemic steroid therapy, 1 unrelated death caused by septic shock) with a median of 3 (1-17) cycles administered. Response assessment (clinical examination, ultrasound, CT or PET-CT scans) were performed after a median of 3 cycles (2-7), showing regressive and refractory disease in 3 patients, respectively, while 1 patient died prior to response assessment. Among the three responders (2xCR, 1xPR) MGZL and PBML their tumors had high PD-L1 expression of 30% (n=1) and 100% (n=2), respectively. Two responders (one after autologous, one after allogeneic HSCT) are still under treatment. After 14 weeks, one responding patient showed signs of progression of a previously known cerebral lesion (or pseudo progression under immunotherapy). The third responder proceeded to allogeneic HSCT without relevant complications. The PD-L1 expression among the non-responders were 0% (n=2) with progressive disease being the cause of death and 10% (n=1) for the other who is currently receiving alternative therapy.In conclusion, NV induces remission in heavily pretreated, PD-L1 high expression aggressive B-NHL. The significance of these data are limited due to the small number of patients. Therefore, future results of current phase II trials (NCT02038933) will reveal the role of PD-1 blockade in aggressive B-NHL. DisclosuresViardot:Roche: Honoraria; Takeda: Other: travel support; Pfizer: Honoraria; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy.

A First-in-Human Study of Autologous T Lymphocytes with Antibody-Dependent Cell Cytotoxicity (ADCC) in Patients with B-Cell Non-Hodgkin Lymphoma (NHL)

Recent trials in patients with B-cell malignancies have demonstrated the clinical potential of chimeric antigen receptor (CAR)-directed T cells. We developed a chimeric receptor (antibody-coupled T-cell receptor, ACTR) consisting of high affinity CD16 V158, CD8α transmembrane domain, 4-1BB and CD3ζ (Kudo et al. Cancer Res 2014). Expression of ACTR conferred ADCC capacity to T cells. In vitro and in immunodeficient mice, ACTR T cells specifically killed B-NHL and chronic lymphocytic leukemia cells tagged with the anti-CD20 antibody rituximab. Trastuzumab induced ACTR-mediated T cell killing of breast and gastric cancer cells, and anti-GD2 of neuroblastoma and osteosarcoma cells. Thus, infusion of ACTR T cells might significantly augment the anti-tumor potential of immunotherapeutic antibodies, and expand options for cell therapy of cancer.To assess the safety of this strategy and explore its efficacy, we began a pilot study in patients with relapsed/refractory CD20+ B-NHL (ATTCK20; ClinicalTrials.gov No. NCT02315118). In this first-in-human study, ACTR expression is achieved by mRNA electroporation and, hence, is transient. In Phase 1a, 3 subjects receive one dose of autologous ACTR T cells (0.5 x 106/kg) 2 days after rituximab (500 mg/m2); a second dose of ACTR T cells at 0.5 x 107/kg 28 days later is allowed if there is no toxicity and evidence of response. Interleukin-2 (IL-2) is given subcutaneously at 1 million IU/m2/d x 3 during the first week after infusion. Phase 1b plans up to 4 infusions of ACTR T cells (0.5 x 107/kg) at 10 day intervals, each preceded by rituximab at 375 mg/m2; IL-2 (as in Phase1a) is given after the first 2 infusions only.Six subjects have been enrolled to date (3 in Phase 1a, 3 in Phase 1b) and received a total of 14 ACTR T cell infusions. All had advanced CD20+ B-NHL (2 diffuse large B cell lymphoma, 2 primary mediastinal B cell lymphoma, 1 mantle cell lymphoma, and 1 mediastinal grey zone lymphoma) and had failed multiple lines of therapy. As a lymphodepleting regimen prior to the first ACTR T cell infusion, 5 of the 6 patients received fludarabine (25 mg/m2/d x 5) plus cyclophosphamide (60 mg/kg/d x 1, n=3; 900 mg/m2/d x 1, n=2); the remaining patient received bendamustine (90 mg/m2/d x 2).After leukapheresis, T cells were cultured under cGMP conditions with anti-CD3 and -CD28 antibodies, and IL-2. After 10 days, cells were electroporated with ACTR mRNA using the MaxCyte GT system. The next day, median ACTR expression in T cells, as shown by flow cytometry, was 95.8% (range, 82.8%-99.3%; n=14). With Rituximab, this produced a median cytotoxicity of 77.5% (67.6%-97.6%; n=14) against CD20+ Daudi cells at a 4:1 effector : target ratio in 4 hours. As expected, ACTR expression in vitro remained high for the first 3-4 days, declining thereafter.We met or exceeded the estimated minimum target levels of CD3+ ACTR+ cells in 13 of the 14 infused cell products. CD3+ ACTR+ cells (mostly CD8+) were detectable in peripheral blood 1 day after infusion and reached their peak on day 3-4 when they represented 0.43-11.20 (median, 1.27) cells per µL. They became undetectable after day 6, reflecting the kinetics of ACTR expression in vitro.As of July 2016, 5 of the 6 patients are evaluable, with a median follow-up of 60 weeks (range, 6-83) after the last ACTR-T cell infusion; the remaining patient has received 3 of the 4 scheduled cycles. The main toxicities were grade 3-4 cytopenias: these were observed in all patients and likely due to the lymphodepleting regimen. There was no non-hematologic toxicity, nor evidence of cytokine release syndrome. In Phase 1a, 2 patients had progressive disease (PD) and 1 had stable disease (SD) on CT scan following the first and second infusions, with PET-CT showing reduced FDG avidity and central areas of photopenia suggestive of necrosis. Of the 2 Phase 1b patients evaluable for response, 1 had PD after the third infusion and was taken off study; the other had SD 1 month after 4 ACTR-T infusions; the 2nd month assessment was interpreted as PD.The initial results of this ongoing trial using autologous T cells with transient ACTR expression are encouraging and warrant additional studies with more potent formulations of this technology. To this end, a clinical trial for patients with relapsed/refractory CD20+ B-NHL in which ACTR is permanently expressed in autologous T cells via viral vector transduction is planned (ClinicalTrials.gov No. NCT02776813). DisclosuresCampana:Unum Therapeutics: Consultancy, Equity Ownership, Patents & Royalties; Juno Therapeutics: Patents & Royalties; Nkarta Therapeutics: Consultancy, Equity Ownership, Patents & Royalties.