Daratumumab induces cell-mediated cytotoxicity of primary effusion lymphoma and is active against refractory disease.

Primary effusion lymphoma (PEL), an aggressive non-Hodgkin lymphoma caused by Kaposi sarcoma-associated herpesvirus (KSHV), lacks standard therapy and has a median survival of 10-22 months with combination chemotherapy. PEL is a tumor of plasmablast-like B cells generally expressing CD38, the target of daratumumab (Dara). Initially, we assessed PEL cells from eight patients and established that each expressed high levels of CD38 by flow cytometry. PEL cell lines were also evaluated and most had high CD38 expression. We then assessed Dara's effects on complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of PEL cell lines as well as its clinical benefits on two patients with PEL. Despite high CD38 expression, Dara did not induce CDC of PEL cell lines, due in part to high levels of the complement-inhibitory proteins, CD55 and CD59. However, Dara induced significant and dose-dependent increases in ADCC, particularly in those lines with high CD38 levels. Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC. Two patients with refractory PEL were treated with Dara alone or in combination with Pom. One patient with leptomeningeal PEL had a complete response to Dara and Pom combination treatment. Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL.

The spectrum of the cytopathological features of primary effusion lymphoma and human herpes virus 8-related lymphoproliferative disorders.

INTRODUCTION: Human herpes virus 8-related lymphoproliferative disorders are a complex and heterogeneous group of entities and some of them are eminently diagnosed by cytopathology. In a routine laboratory, these lesions account for less than 1% of the effusion fluids samples. However, they represent up to 30% of all the lymphoma diagnosis from effusion cytological samples and their consideration in the diagnostic flow chart is mandatory, especially in human immunodeficiency virus-positive patients. METHODS: A retrospective series of cytological specimens from cavity effusions (n = 605) were analysed. Five human herpes virus 8-related lymphoproliferative processes were recruited. A combination of morphological criteria (enhanced with May-Grünwald Giemsa staining), cell block-based immunocytochemistry and flow cytometry were undertaken for final characterisation. RESULTS: The identification of malignant cells may be difficult. Some specimens are particularly rich, easily leading to suspect a lymphoproliferative process, whereas in other cases, the presence of abundant reactive mesothelial cells, histiocytes, neutrophils, small reactive T and B lymphocytes may obscure the neoplastic process. The biological behaviour may be very heterogeneous and a standardised therapy for these cases is still lacking, although some patients may benefit from antiretroviral therapy in a human immunodeficiency virus setting. CONCLUSIONS: The present case series highlights some characteristic findings of these entities to reaffirm useful cytopathological diagnostic criteria, stressing the crucial role of the appropriate technical processing of effusion fluids to obtain the best performances.

High-dose Therapy and Autologous Hematopoietic Cell Transplantation as Consolidation Treatment for Primary Effusion Lymphoma.

BACKGROUND: Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma. The limited disease-free survival after chemotherapy has resulted in a poor prognosis. The outcomes data for high-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) for PEL are limited owing to the rarity of the disease. PATIENTS AND METHODS: The present study included 9 patients with PEL from 2 major academic centers. Of these patients, 4 had received auto-HCT after high-dose therapy. Of the 9 patients, 8 (89%) had immunodeficiency (7 with human immunodeficiency virus seropositivity; 1, a solid organ transplant recipient) at the diagnosis. Human herpesvirus-8 by immunohistochemistry was positive in 8 patients. Anthracycline-based combination chemotherapy was used as first-line treatment in 7 patients; 4 underwent auto-HCT after attaining first complete remission. RESULTS: The median follow-up of the surviving patients was 25 months (95% confidence interval [CI], 8%-29%). The 2-year progression-free and overall survival for the 8 patients who had received treatment was 58% (95% CI, 22%-95%) and 73% (95% CI, 41%-100%), respectively. The 2-year progression-free and overall survival for the patients who had received auto-HCT was 50% (95% CI, 1%-99%) and 75% (95% CI, 33%-100%), respectively. Of the 4 auto-HCT recipients, all had been in first complete remission at the time of autografting. The cumulative incidence of relapse was 50% (95% CI, 19%-100%). No deaths were attributable to auto-HCT at 2 years after autografting. CONCLUSION: Despite the small sample size, our data have shown that consolidative auto-HCT is safe and effective and should be considered for eligible patients with PEL after demonstration of an objective response to induction chemotherapy. However, the high relapse rate remains a concern and warrants the development of new strategies to mitigate post-transplantation relapse.

A 32-Year-Old Man With HIV Infection, Pleural Effusions, and Lymphadenopathy.

CASE PRESENTATION: A 32-year-old man presented with fever, nonproductive cough, diffuse lymphadenopathy, and polyarticular pain for 2 weeks. His medical history included HIV diagnosed 10 years ago, anal intraepithelial neoplasia, Kaposi sarcoma, and herpes simplex virus-2 infection. The patient was not receiving antiretroviral therapy or antibiotic prophylaxis, and his last known CD4 count a month before was 45 cells/mm3. He was prescribed a course of doxycycline by his primary care physician, which did not improve his symptoms.

Biology and management of primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a rare B-cell malignancy that most often occurs in immunocompromised patients, such as HIV-infected individuals and patients receiving organ transplantation. The main characteristic of PEL is neoplastic effusions in body cavities without detectable tumor masses. The onset of the disease is associated with latent infection of human herpes virus 8/Kaposi sarcoma-associated herpes virus, and the normal counterpart of tumor cells is B cells with plasmablastic differentiation. A condition of immunodeficiency and a usual absence of CD20 expression lead to the expectation of the lack of efficacy of anti-CD20 monoclonal antibody; clinical outcomes of the disease remain extremely poor, with an overall survival at 1 year of ∼30%. Although recent progress in antiretroviral therapy has improved outcomes of HIV-infected patients, its benefit is still limited in patients with PEL. Furthermore, the usual high expression of programmed death ligand 1 in tumor cells, one of the most important immune-checkpoint molecules, results in the immune escape of tumor cells from the host immune defense, which could be the underlying mechanism of poor treatment efficacy. Molecular-targeted therapies for the activating pathways in PEL, including NF-κB, JAK/STAT, and phosphatidylinositol 3-kinase/AKT, have emerged to treat this intractable disease. A combination of immunological recovery from immune deficiency, overcoming the immune escape, and the development of more effective drugs will be vital for improving the outcomes of PEL patients in the future.

Human herpes virus 8-unrelated primary effusion lymphoma-like lymphoma presenting with cardiac tamponade: A case report.

RATIONALE: Primary effusion lymphoma (PEL) is a rare disease of lymphomatous effusion in the body cavities in the absence of detectable mass and lymphadenopathy. PEL is predominantly related to the immunosuppressed patients infected with human herpes virus 8 (HHV-8). PEL-like lymphoma is negative for HHV-8 and human immunodeficiency virus (HIV) unlike PEL. The pathogenesis and prognosis of PEL-like lymphoma are unclear and there is no established treatment yet. PATIENT CONCERNS: A 73-year-old male patient was admitted for evaluation of dyspnea on exertion with 1-week duration. His relevant examinations were completed. DIAGNOSES: PEL-like lymphoma was diagnosed. INTERVENTIONS: The patient received chemotherapy including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), and palliative whole-brain radiotherapy, sequentially. OUTCOMES: He died 3 months after the diagnosis. LESSON: Although the prognosis of PEL-like lymphoma may be better than PEL, our case showed poor disease course despite chemotherapy.

Lymphoproliferative Disorders of the Lung.

This review aims to describe some of the most frequent lymphoproliferative disorders arising from the lung: pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma, lymphomatoid granulomatosis (LG), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and nodular lymphoid hyperplasia (NLH). Primary pulmonary lymphoma is defined as a clonal lymphoproliferative disorder affecting one or both lungs, without extrapulmonary involvement 3 months after diagnosis, and includes pulmonary MALT lymphoma and LG. MALT lymphoma is the most common pulmonary lymphoma. The disease is slow growing, most often asymptomatic, and revealed by chronic alveolar opacity on radiography. The diagnosis should involve minimally invasive techniques, and the prognosis is typically excellent. LG is a rare B-cell lymphoma driven by Epstein-Barr virus infection. The disease may mimic pulmonary vasculitis, often revealed by systemic signs. The diagnosis usually requires surgical lung biopsy. Its evolution is unpredictable, but median survival is poor and chemotherapy is usually proposed. MCD and PEL are both driven by Human herpesvirus 8 infection. Patients with MCD present with fever and lymphadenopathy associated with interstitial lung disease. PEL provokes a febrile, lymphocytic-exudative pleural effusion, without any pleural mass on CT. Specific chemotherapy is urgent for both MCD and PEL. NLH is a benign lymphoproliferative disorder of the lung that is usually asymptomatic and revealed by a single nodular opacity. The prognosis is good, without recurrence after surgical resection.

Primary effusion lymphoma: current concepts and management.

PURPOSE OF REVIEW: To summarize the current epidemiology, management, and outcomes of primary effusion lymphoma (PEL) and highlight possible future research efforts. RECENT FINDINGS: Cyclophosphamide, doxorubicin, vincristine, prednisone-based chemotherapy regimens alone or in combination with immunomodulatory agents (e.g., lenalidomide), or proteasome inhibitors (e.g., bortezomib), or targeted therapies, are commonly used to treat PEL. Highly active antiretroviral therapy should be continued or initiated in patients with HIV infection. Randomized controlled trials are lacking. Prognosis remains grim and there exists a need for further investigation into optimal treatment strategies. SUMMARY: PEL is an aggressive mature B-cell neoplasm primarily seen in young to middle aged men with HIV, though immunosuppression related to age and comorbidities such as cirrhosis or organ transplantation also predisposes to PEL. Classic cavitary PEL presents as an effusion in the pleural, pericardial, or peritoneal space. Human herpes virus-8/Kaposi's sarcoma herpes virus) is classically detected. Given its rarity, randomized controlled trials evaluating optimal treatment regimens are lacking, and cyclophosphamide, doxorubicin, vincristine, prednisone-based chemotherapy has been the mainstay of treatment. Advancement in knowledge of the oncogenic signaling pathways involved in Kaposi's sarcoma herpes virus-induced tumorigenesis may pave the way to develop targeted therapies. VIDEO ABSTRACT.

Kaposi sarcoma herpesvirus-associated cancers and related diseases.

PURPOSE OF REVIEW: This review discusses the pathogenesis and recent advances in the management of Kaposi sarcoma herpesvirus (KSHV)-associated diseases. RECENT FINDINGS: KSHV, a gammaherpesvirus, causes several tumors and related diseases, including Kaposi sarcoma, a form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These most often develop in patients infected with human immunodeficiency virus (HIV). KSHV inflammatory cytokine syndrome (KICS) is a newly described syndrome with high mortality that has inflammatory symptoms-like MCD but not the pathologic lymph node findings. KSHV-associated diseases are often associated with dysregulated human interleukin-6, and KSHV encodes a viral interleukin-6, both of which contribute to disease pathogenesis. Treatment of HIV is important in HIV-infected patients. Strategies to prevent KSHV infection may reduce the incidence of these tumors. Pomalidomide, an immunomodulatory agent, has activity in Kaposi sarcoma. Rituximab is active in KSHV-MCD but can cause Kaposi sarcoma exacerbation; rituximab plus liposomal doxorubicin is useful to treat KSHV-MCD patients with concurrent Kaposi sarcoma. SUMMARY: KSHV is the etiological agents of all forms of Kaposi sarcoma and several other diseases. Strategies employing immunomodulatory agents, cytokine inhibition, and targeting of KSHV-infected cells are areas of active research.

Management and Outcomes of HIV-Associated Primary Effusion Lymphoma: A Single Center Experience.

BACKGROUND: Primary effusion lymphoma (PEL) is a rare malignancy usually associated with HIV infection. Management and outcomes are poorly understood. METHODS: The medical records of all patients diagnosed with HIV-associated PEL at our institution between 1999 and 2014 were reviewed. Patients were followed till death, treatment failure or loss of follow-up. RESULTS: Twelve patients with PEL were identified during the 15 year study period; 9 had HIV infection. All 9 were male; median age was 45 years. All presented with local symptoms and were diagnosed with PEL a median of 11 years after HIV diagnosis. Location was pleural (3), pericardial (3), peritoneal (1) and extracavitatory (2). By definition, all had Ann Arbor stage 4 at diagnosis. Median follow-up was 34 months. Two patients had poor performance status and were unable to get chemotherapy. Seven patients had a complete remission (CR) and two died within 1 month of diagnosis. The median CD4 levels at PEL diagnosis in patients with poor versus good outcomes were 54 cells/mm3 (range, 26-82 cells/mm3) and 211 cells/mm3 (range, 73-800 cells/mm3). In contrast, the median lactate dehydrogenase (LDH) levels at PEL diagnosis with poor versus good prognosis were 1074 U/L (range, 703-1445 U/L) and 283 U/L (range, 156-760 U/L). CONCLUSIONS: Given its rarity, our knowledge of PEL relies solely on case reports and case series. Prompt HAART and chemotherapy may be effective in HIV- associated PEL and good outcomes are possible. LDH and CD4 may be possible prognostic factors in PEL.

PEGylated siRNA lipoplexes for silencing of BLIMP-1 in Primary Effusion Lymphoma: In vitro evidences of antitumoral activity.

Silencing of the B lymphocyte-induced maturation protein 1 (Blimp-1), a pivotal transcriptional regulator during terminal differentiation of B cells into plasma cells with siRNAs is under investigation as novel therapeutic approach in Primary Effusion Lymphoma (PEL), a HHV-8 related and aggressive B cell Lymphoma currently lacking of an efficacious therapeutic approach. The clinical application of small interfering RNA (siRNA) in cancer therapy is limited by the lack of an efficient systemic siRNA delivery system. In this study we aim to develop pegylated siRNA lipoplexes formed using the cationic lipid DOTAP and DSPE-PEG2000, capable to effectively stabilize anti-Blimp-1 siRNA and suitable for systemic administration. Two types of pegylated lipoplexes using a classic (C-PEG Lipoplexes) or a post-pegylation method (P-PEG-Lipoplexes) were formulated and compared in their physicochemical properties (size, zeta potential, morphology and structure) and efficiency on PEL cell lines. A stable siRNAs protection was obtained with post pegylation approach (2% molar of DSPE-PEG2000 with respect to lipid) resulting in structures with diameters of 300 nm and a complexation efficiency higher that 80% (0.08 nmol/10 nmol of lipid). In vitro studies on PEL cell lines suggested that empty liposomes were characterized by a low cell toxicity also after PEG modification (cell viability and cell density over 85% after treatment with 10 µM of lipid). We demonstrated that P-PEG-Lipoplexes were able to significantly reduce the levels of BLIMP-1 protein leading to reduction of viability (less that 15% after transfection with 100 nM of complexed siRNAs) and activation of apoptosis. In vitro efficiency encourages us to further test the in vivo potential of P-PEG-Lipoplexes in PEL therapy.

Primary effusion lymphoma in the absence of HIV infection--clinical presentation and management.

Primary Effusion Lymphoma (PEL) is a rare type of Non-Hodgkin's Lymphoma caused by human herpesvirus type 8, also termed Kaposi's sarcoma-associated herpesvirus. It usually occurs in human immunodeficiency virus (HIV)-infected patients. A subset of patients is not infected with HIV and their treatment remains poorly defined. To clarify treatment issues in HIV-negative PEL patients, we report on two such patients who represent two opposing ends in the spectrum of treatment and review the literature regarding treatment options and patient outcomes. Either repeated cycles of chemotherapy or, surprisingly, drainage of the malignant effusions alone, proved very effective in our patients. The literature reveals additional treatment options which may be effective including immunochemotherapy, stem cell transplantation, antiviral treatment and immunomodulatory and targeted biological therapy. However, no controlled trials were found due to the rarity of the condition. In the absence of controlled trials, treatment decisions in PEL not associated with HIV must remain individual and patient-tailored.

Human herpesvirus-8: Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma.

Human herpesvirus 8 (HHV8) is a gamma herpesvirus associated with Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma, lymphoproliferative diseases that are most commonly observed in immunocompromised individuals. The viral genome expresses genes responsible for inhibition of apoptosis, cell cycle entry, and angiogenesis. Viral homologs of human regulatory genes are expressed, providing stimuli for angiogenesis, B-cell proliferation, and immune evasion. Variations in expression of these factors give rise to the 3 known HHV8-associated malignancies. Identification of these pathogenetic mechanisms has led to exploration of targeted treatment approaches for all 3 of these disorders with success in Kaposi sarcoma and multicentric Castleman disease; primary effusion lymphoma remains a clinical challenge.

Self-limited effusion large B-cell lymphoma: two cases of effusion lymphoma maintaining remission after drainage alone.

We report two cases of human herpesvirus-8 (HHV-8)-negative large B-cell lymphoma involving pericardial and/or pleural effusion that regressed after drainage alone. Case 1 is a 70-year-old man showing massive pericardial effusion. Cytology of the drained effusion showed monotonous infiltration of CD3-, CD20+, CD79a+, and CD138- large B-cells. Monoclonality was shown by Southern blot analysis. Case 2 is a 70-year-old man with massive pericardial and bilateral pleural effusion. Cytology of pericardial effusion showed infiltration of CD20+, CD45RO-, CD138-, immunoglobulin lambda chain+, and kappa chain- large B cells. In both cases, effusion resolved after drainage and no relapse has been observed. HHV-8 was not demonstrated in either case. Clinical presentation of our two cases resembled primary effusion lymphoma (PEL), but cytomorphology, immunophenotype, and prognosis were clearly distinct from those of PEL. HHV-8-negative effusion lymphomas might include prognostically favorable self-limited tumors that could regress without any cytotoxic therapy.

Potent antitumor activity of zoledronic acid-induced Vγ9Vδ2 T cells against primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a subtype of aggressive and resistant non-Hodgkin lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the antitumor activity of zoledronic acid (Zol)-induced Vγ9Vδ2 T cells against PEL cells in vitro and in vivo. Vγ9Vδ2 T cells recognized endogenous mevalonate metabolites and MICA/B of PEL cell lines, inducing cytotoxicity via granule exocytosis and TRAIL-mediated pathway. Vγ9Vδ2 T cells suppressed the development of PEL cells and existed in a PEL xenograft mouse model. These results show that immunotherapy with Zol-induced Vγ9Vδ2 T cells could demonstrate an efficient strategy for PEL.

KSHV/HHV8-negative effusion-based lymphoma, a distinct entity associated with fluid overload states.

Human herpesvirus-8 (HHV8)-positive effusion-based lymphomas have been termed primary effusion lymphoma (PEL) in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Kaposi sarcoma herpesvirus (KSHV)/HHV8-negative effusion-based lymphomas (KSHV/HHV8-negative EBLs) resembling PELs have been reported in the literature and in many cases have been (mis)classified as PEL-like lymphomas. Herein, we present a series of cases and a review of KSHV/HHV8-negative EBLs. This lymphoma, although cytomorphologically resembling PEL, is a distinct entity with characteristic clinical and pathologic features. Patients are older, generally human immunodeficiency virus negative and not immunosuppressed, frequently hepatitis C positive compared with the population baseline, and often have an underlying medical condition leading to fluid overload. The lymphoma cells express pan-B-cell antigens in 86.7%, and CD20 is expressed in 71.1% of the cases. The lymphoma is often of germinal center B or mixed germinal center B/activated B-cell signature with the Hans classifier, and Epstein-Barr virus is positive in nearly 30% of cases. Rare T-cell lymphomas were also reported. Clinical outcomes and response to therapy, including isolated aspiration, are relatively favorable compared with cases of PEL. We suggest that HHV8-negative effusion-based lymphoma is a distinct entity associated with fluid overload states.

Disappearance of malignant cells by effusion drainage alone in two patients with HHV-8-unrelated HIV-negative primary effusion lymphoma-like lymphoma.

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma usually confined to the body cavities of predominantly immunosuppressed patients infected with human herpes virus-8 (HHV-8). In PEL, malignant cells are usually negative for B-cell markers, such as CD19, CD20, and CD79a, but are positive for activation and plasma cell-related markers, such as CD30, CD38, and CD138. It has been reported that HHV-8-unrelated PEL shows high expression of B-cell markers, which is referred to as PEL-like lymphoma. Here, we report two cases of HHV-8-unrelated HIV-negative PEL-like lymphoma in which malignant cells regressed spontaneously after effusion drainage alone. These cells expressed B-cell markers, such as CD20. No chemotherapy was given to either patient, as they were of an advanced age, and both achieved a complete response by effusion drainage alone. One showed a complete response for 16 months after effusion drainage, and the other has survived for 11 months with a complete response. This suggests that sufficient drainage of serous effusion may induce and maintain a complete response in some patients with HHV-8-unrelated HIV-negative PEL-like lymphoma, which represents an excellent treatment option for elderly patients with this disease.