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Concept: B-cell lymphoma

204

Background Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited. Methods We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery. Results A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64%; 95% confidence interval [CI], 44 to 81). Complete remission occurred in 6 of 14 patients with diffuse large B-cell lymphoma (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response (95% CI, 33 to 98) and 89% of patients with follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response. Severe cytokine-release syndrome occurred in 5 patients (18%). Serious encephalopathy occurred in 3 patients (11%); 2 cases were self-limiting and 1 case was fatal. All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later. Conclusions CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients. Transient encephalopathy developed in approximately one in three patients and severe cytokine-release syndrome developed in one in five patients. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02030834 .).

Concepts: Immune system, Protein, B cell, Types of cancer, Major histocompatibility complex, Lymphoma, Follicular lymphoma, B-cell lymphoma

171

A number of constitutively activated signaling pathways play critical roles in the survival and growth of primary effusion lymphoma cells (PELs) including NFkB and PI3/AKT kinase cascades. NFkBis constitutively activated in a number of malignancies, including multiple myeloma, Burkitt’s lymphoma and diffuse large cell B-cell lymphoma. However, its role in primary effusion lymphoma has not been fully explored.

Concepts: AIDS, Protein, Cancer, Signal transduction, Types of cancer, Hematology, Lymphoma, B-cell lymphoma

29

New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape. Like natural HDLs, biomimetic HDL-NPs target scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Functionally, compared with natural HDL, the gold NP template enables differential manipulation of cellular cholesterol flux in lymphoma cells, promoting cellular cholesterol efflux and limiting cholesterol delivery. This combination of scavenger receptor type B-1 binding and relative cholesterol starvation selectively induces apoptosis. HDL-NP treatment of mice bearing B-cell lymphoma xenografts selectively inhibits B-cell lymphoma growth. As such, HDL-NPs are biofunctional therapeutic agents, whose mechanism of action is enabled by the presence of a synthetic nanotemplate. HDL-NPs are active in B-cell lymphomas and potentially, other malignancies or diseases of pathologic cholesterol accumulation.

Concepts: AIDS, Cholesterol, Cancer, Nanoparticle, High-density lipoprotein, Lymphoma, Gold, B-cell lymphoma

28

Abstract Previous studies have suggested that CD30 may be expressed in diffuse large B-cell lymphomas (DLBCL). However, the prevalence of CD30+ DLBCLs and extent of CD30 expression within an individual tumor has not been fully evaluated. The aim of this study was to determine the frequency and extent of CD30 expression in DLBCLs, and explore possible relationships between CD30 expression and clinical and biologic variables. We retrospectively identified and analyzed 167 cases of CD30+ DLBCLs from our pathology archive. Twenty-one percent (95% CI: 14.8% - 27.1%) of these cases expressed CD30 and in 52% of them CD30 was positive in > 80% of tumor cells. CD30 expression was more frequent in DLBCLs with non-germinal center origin phenotype, BCL2+ DLBCLs and in patients ≤47 years old. There was significant interaction of BCL2 expression with age and subtype of DLBCL. A multivariate analysis performed in BCL2+ DLBCLs showed a higher frequency of CD30+ cases in non-GC DLBCLs (odds ratio [OR]: 6.5, 95% CI: 1.1 - 36.5) and in patients ≤47 years old (OR: 6.9, 95% CI: 1.5 - 29.5). These associations could suggest a common biologic pathogenesis. The effectiveness of anti-CD30 drugs in other lymphomas opens the possibility for its use in patients with CD30+ DLBCLs.

Concepts: Cancer, Medical statistics, B cell, Types of cancer, Lymphoma, Diffuse large B cell lymphoma, Anaplastic large cell lymphoma, B-cell lymphoma

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Canine lymphoma is the neoplasm most often treated by chemotherapy, yet there are few data to correlate response to therapy with its different subtypes. This study is based on biopsy specimens from 992 dogs for which lymphoma was the clinical diagnosis. All cases were phenotyped by immunohistochemistry for CD3 and CD79alpha. Cases with histiocytic proliferation were evaluated immunohistochemically for CD18. Clonality was verified in 12 cases by polymerase chain reaction (PCR). Survival (event time) data and complete survival information (cause of death or time to last follow-up) were available on 456 dogs. Additional covariate information when available included size, age, sex, phenotype, stage and grade of lymphoma, mitotic index, and treatment protocol. Because of the many subtypes of B- and T-cell lymphoma, the cases were grouped into 7 diagnostic categories: (1) benign hyperplasia; (2) low-grade B-cell; (3) high-grade B- and T-cell; (4) low-grade T-cell; (5) centroblastic large B-cell of all mitotic grades (subdivided by clinical stage); (6) immunoblastic large B-cell of all mitotic grades, and (7) high-grade peripheral T-cell. Grouping was determined by histological grade (based on mitotic rate/400× field, with low-grade 0-5, intermediate 6-10, and high-grade >10) and stage for survival function estimation. No association with survival was found for size (based on breed of dog) or sex. All diagnostic categories of indolent or low-grade type had low mitotic rates, whereas those with clinically high grades had high mitotic rates. The diagnostic category with the most cases was centroblastic large B-cell lymphoma. Compared with dogs in this largest represented group of lymphomas, dogs with high-grade lymphomas had significantly higher mortality rates, and dogs with low-grade T-cell lymphomas had significantly lower mortality rates. Treatments for high-, intermediate-, and low-grade lymphomas were divided into 4 groups: absence of treatment, chemotherapy with or without hydroxydaunorubicin, and only prednisone. Dogs with low-grade T-cell (T-zone) lymphomas had the longest median survival (622 days), whereas the shortest median survival was in dogs with T-cell high-grade (peripheral T-cell) subtype (162 days). The dogs with centroblastic large B-cell lymphomas had a median survival of 127 days with low stage, 221 days with intermediate stage, and 215 days with advanced stage. Dogs with T-zone lymphoma were probably diagnosed in later stages of disease because of the lack of signs associated with progression. As with human lymphomas, a histological diagnosis with immunophenotyping is a minimal requirement for diagnosis of a specific subtype.

Concepts: Cancer, Grade, B cell, Types of cancer, Lymphoma, Non-Hodgkin lymphoma, B-cell lymphoma, T-cell lymphoma

28

BACKGROUND: B-cell lymphomas with concurrent translocations of MYC and BCL2 or BCL6, also known as “double-hit” lymphomas (DHL), are rare malignancies characterized by aggressive clinical behavior and poor prognosis. Previous reports suggest that decreased CD20 and/or CD19 expression by flow cytometry is relatively common in DHL and may help to identify cases requiring additional cytogenetic analysis. METHODS: We conducted a retrospective analysis of 26 cases of DHL, and compared their flow cytometric characteristics to cases of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Cases were analyzed by four-color flow cytometry, and bivariate dot-plots were reviewed for light scatter characteristics, CD19, CD20, CD45, and surface light chain. RESULTS: Relatively few DHL cases showed dim expression of CD19 or CD20, and statistically significant differences were found only in the frequency of dim CD19 expression between DHL and BL or DLBCL. Although concomitant dim CD19 and CD20 expression was exclusive to DHL, it was present in only a minority of cases. CONCLUSIONS: We conclude that although a subset of DHL expresses aberrant levels of CD19 and/or CD20 by flow cytometry, these findings are of limited utility in identifying cases requiring cytogenetic analysis due to their low frequency. Until more sensitive pathologic parameters can be identified and validated, the decision to perform cytogenetic analysis should rest on a combination of clinical, morphologic, and immunophenotypic features suggestive of high-grade, aggressive disease. © 2013 International Clinical Cytometry Society.

Concepts: AIDS, Cancer, B cell, Types of cancer, Lymphoma, Flow cytometry, Diffuse large B cell lymphoma, B-cell lymphoma

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: Mantle cell lymphoma rarely affects the skin and is usually a secondary involvement. The present case illustrates a primary cutaneous mantle cell lymphoma of the leg, with blastoid morphology and aberrant expression of CD10 and bcl-6, which was misinterpreted at the beginning as diffuse large B-cell lymphoma. A larger panel of immunohistochemical markers, including cyclin-D1, and molecular investigation showing the typical translocation (t11;14), pointed toward the correct diagnosis. Cutaneous diffuse B-cell lymphomas with unusual morphology should be interpreted cautiously, and the diagnosis made on the basis of an appropriate panel of antibodies and molecular studies.

Concepts: Cancer, Types of cancer, Lymphoma, Skin, Diffuse large B cell lymphoma, Anaplastic large cell lymphoma, Mantle cell lymphoma, B-cell lymphoma

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Resistance to Fas-mediated apoptosis is associated with poor cancer outcomes and chemoresistance. To elucidate potential mechanisms of defective Fas signaling, we screened primary lymphoma cell extracts for Fas-associated proteins that would have the potential to regulate Fas signaling. An activation-resistant Fas complex selectively included nucleolin. We confirmed the presence of nucleolin-Fas complexes in B-cell lymphoma cells and primary tissues, and the absence of such complexes in B-lymphocytes from healthy donors. RNA-binding domain 4 and the glycine/arginine-rich domain of nucleolin were essential for its association with Fas. Nucleolin co-localized with Fas on the surface of B-cell lymphoma cells. Nucleolin knock-down sensitized BJAB cells to FasL- and Fas agonistic antibody-induced apoptosis through enhanced binding, suggesting that nucleolin blocks the FasL-Fas interaction. Mice transfected with nucleolin were protected from the lethal effects of agonistic anti-mouse Fas antibody (Jo2) and had lower rates of hepatocyte apoptosis, compared with vector and a non-Fas-binding mutant of nucleolin. Our results show that cell surface nucleolin binds Fas, inhibits ligand binding, and thus prevents induction of Fas-mediated apoptosis in B-cell lymphomas and may serve as a new therapeutic target.

Concepts: Immune system, Protein, Signal transduction, Apoptosis, B cell, Lymphoma, B-cell lymphoma, Fas receptor

27

Double-hit (DH) lymphomas with MYC and either BCL2 (DH-BCL2/MYC) or BCL6 (DH-BCL6/MYC) rearrangements are considered very aggressive, many of which are now included in the category B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) (DLBCL/BL). However, data describing the DH cases are largely based on DH-BCL2/MYC cases. To better characterize DH-BCL6/MYC cases, the clinical, morphologic, phenotypic, and cytogenetic features of 6 cases from University of Pittsburgh Medical Center and 17 cases from the Mitelman database were reviewed. In the University of Pittsburgh Medical Center cases, the median age was 83 years (range, 51 to 89 y) with 5/6 DLBCL/BL cases and 1 large B-cell lymphoma, not otherwise specified. Five of 6 had a germinal center phenotype, 1/6 was BCL2, and the median Ki-67 score was 98% (35% to 100%). The Mitelman DH-BCL6/MYC cases included 13 aggressive B-cell lymphomas (diagnosed as DLBCL-5, BL-5, BL-like lymphomas-2, and primary effusion lymphoma-1) and 4 other lymphoid/plasmacytic neoplasms. The median cytogenetic complexity score was 2.5 (range, 0 to 14) in 14 evaluable mature aggressive lymphomas with an immunoglobulin gene partner for MYC in 9/14 and for BCL6 in 7/14 cases. Ten of 13 cases involved extranodal extramedullary sites at presentation, and the median survival for the 10 patients with large cell neoplasms or BL and with available follow-up data was 9 months. Thus, DH-BCL6/MYC lymphomas are aggressive, frequently involve extranodal sites, and are often DLBCL/BL with a germinal center phenotype. Unlike DH-BCL2/MYC lymphomas, however, they are more likely to be CD10 but IRF4/MUM-1 (P=0.03) and, more like BL, only infrequently express BCL2 (P<0.001), and are cytogenetically less complex (P<0.04).

Concepts: AIDS, Cancer, Types of cancer, Lymphoma, Diffuse large B cell lymphoma, Anaplastic large cell lymphoma, B-cell lymphoma, BCL6

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Although almost any non-Hodgkin lymphoma can involve the spleen or an extranodal site as part of more widely disseminated disease, there is a group of small B-cell lymphomas that specifically arise in these locations. These are important to recognise as some appear to have a behaviour and prognosis that is distinct from their nodal counterparts. In addition, there are entities that are specific to extranodal locations (such as extranodal marginal zone lymphoma) and to the red or white pulp of the spleen. In this review, the characteristics of these entities will be presented as well as clues to help distinguish lymphoma from reactive infiltrates in extranodal sites and measure to distinguish between small B-cell lymphomas encountered in the spleen and at extranodal locations.

Concepts: Types of cancer, Lymphoma, Lymphatic system, Spleen, B-cell lymphoma, Marginal zone, T-cell lymphoma, White pulp