Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

The Emerging Treatment Options of Plasmablastic Lymphoma: Analysis of 173 Individual Patient Outcomes.

Plasmablastic lymphoma (PBL) is a newly recognized aggressive subtype of non-Hodgkin lymphoma. Its rarity hinders testing effective treatment options in clinical trials. We conducted a systematic review of PubMed and our internal records to retrieve patients with a PBL diagnosis with evaluable treatment outcomes. Aggressive chemotherapy was defined as more intense regimens than CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). We compiled a meta-dataset of 173 patients. The median age at diagnosis was 48.5 years, 75% of patients were male, and stages III/IV accounted for 47% of the cohort. Of 138 patients with known response status after first-line chemotherapy, 63 (45%) achieved a complete response with a 2-year relapse-free survival of 71.6%. Sixty-nine (50%) patients received first-line CHOP. There was no significant difference in the objective response rate among the 2 most commonly used regimens, CHOP and DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) (69% vs. 79%; P = .4). The median follow-up was 9 months, and the 2-year overall survival (OS) was 47.4%. A univariate analysis identified factors associated with worse OS, including stage III/IV (hazard ratio [HR], 2.82; P < .001), human herpes virus-8-positive (HR, 3.30; P = .01), bone marrow (HR, 1.07; P = .035), and cardiorespiratory involvement (HR, 2.26; P = .015). Meanwhile, Epstein-Varr virus-encoded small RNA-positivity (HR, 0.31; P < .001) and involvement of head and neck (HR, 0.44; P = .009) were associated with better OS. Multivariate analysis showed that aggressive chemotherapy was significantly associated with better OS (HR, 0.22; P = .016). Patients with PBL with high-risk features, such as advanced stage, human herpes virus-8-positivity, bone marrow, and cardiorespiratory involvement, require more aggressive chemotherapy. Bortezomib and lenalidomide are promising add-on agents.

Survival analysis in treated plasmablastic lymphoma patients: a population-based study.

Herein we analyzed survival outcomes in chemotherapy-treated patients with plasmablastic lymphoma (PBL) diagnosed between 2010 to 2016 (n = 248). Data was acquired from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database (April 2019 release based on November 2018 submission). The majority of patients were male (81.9%) and younger than 60 years (71.0%). Oral and gastrointestinal (GI) sites were the most frequent primary extranodal locations (23% and 19.4%, respectively). Oral primary location was inversely associated with presence of B symptoms and advanced Ann-Arbor stage. The 3-year and 5-year overall survival (OS) rates of treated PBL patients were 54% (95% CI: 46.5%-60.8%) and 52.8% (95% CI: 45.2%-59.8%). Three-year conditional survival for 2-year and 3-year survivors were 90.3% and 97.8%, overlapping the survival of a general population matched by age, sex and calendar year. In a multivariable analysis, oral primary location was associated with not only better OS (HR 0.43; 95% CI: 0.21-0.88, P = .021) but also better lymphoma-specific survival (LSS) (SHR 0.36; 95% CI: 0.15-0.86, P = .022); age ≥60 years was associated with shorter LSS (SHR 1.73; 95% CI: 1.02-2.96, P = .043). Seven registries granted access to HIV status (n = 93) where HIV infection was detected in 52.7% of cases. The HIV status did not affect survival outcomes in unadjusted and adjusted analyses. We identified clinical characteristics associated with survival and showed that treated PBL patients may achieve long-term survival.

Plasmablastic lymphoma - single centre experience with infusional EPOCH chemotherapy.

BACKGROUND: Plasmablastic lymphoma (PBL) is a rare type of aggressive large B - cell non-Hodgkin Lymphoma (NHL) which was initially described in HIV positive individuals and later was also described in immune-competent individuals. It was included as a distinct entity in the WHO lymphoma classification in 2008. METHODS: The clinical features, HIV status, treatment details, and outcomes of patients diagnosed with plasmablastic lymphoma from January 2012 to December 2018 were retrospectively collected from the patient records and analyzed. The survival analysis was done by Kaplan Meier analysis and the comparison was done by the Log Rank test. RESULTS: The median age of 25 patients, included in the study was 41 years (Range 13-71 years). Males constituted 76 %. HIV positivity was 72 %. Stage IV disease was present in 76 %. Extranodal involvement was seen in 96 %. Out of 25 patients, seven did not receive any treatment and three received metronomic oral chemotherapy due to poor performance status at presentation. Fifteen patients received chemotherapy on a curative intent. Infusional EPOCH chemotherapy was given in 13 patients. CHOP and CHOEP chemotherapy was given in one patient each. The median number of cycles was 6 (Range: 3-8). The overall response rate of patients treated on a curative intent was 80 % (Complete response and partial response in 8 and 4 respectively). Three patients underwent high dose chemotherapy with autologous stem cell rescue at first remission. The median event-free survival (EFS) and median overall survival (OS) of the whole study population was 5.9 and 12.4 months respectively, with a median follow of 26.9 months. The median EFS was 13.8 months and the median OS was not reached in the curative-intent group. The factors adversely influencing the EFS and OS were Age > 40 years, high IPI, and non-curative intent of treatment. CONCLUSION: Plasmablastic lymphoma commonly presents as stage 4 disease with extranodal involvement and is more common in immune-deficient individuals. Infusional EPOCH chemotherapy is a promising option that induces long term remission.

Insurance status impacts overall survival in Burkitt lymphoma.

The impact of insurance status on clinical outcomes in Burkitt (BL) and plasmablastic (PBL) lymphomas remains unknown. We used the National Cancer Database to examine insurance status' effect on overall survival (OS) in adults diagnosed with these lymphomas between 2004 and 2014. BL patients with private insurance had significantly better OS compared to those without. In patients aged <65 years, hazard ratios were 1.4 for uninsured status (95% confidence interval 1.2-1.7), 1.2 for Medicaid (95% CI 1.0-1.4), and 1.5 for Medicare (95% CI 1.2-1.9). For patients aged >65 years, hazard ratio for uninsured status was 8.4 (95% CI 2.5-28.3). Conversely, underinsured PBL patients experienced no difference in OS. Thus, expanding insurance-related access to care may improve survival in BL, for which curative therapy exists, but not PBL, where more effective therapies are needed. Our findings add to mounting evidence that adequate health insurance is particularly important for patients with curable cancers.

Clinicopathological analysis of oral plasmablastic lymphoma: A systematic review.

BACKGROUND: Plasmablastic lymphoma (PBL) is a high-grade lymphoma that often affects the oral cavity of HIV-positive patients; however, its prognostic determinants remain unknown. PURPOSE: To integrate the available data on oral PBL to determine its clinicopathological features and to identify potential prognostic factors. METHODS: An electronic systematic review was performed using multiple databases with a specific search strategy in February 2018. Inclusion criteria comprised cases diagnosed as PBL affecting the oral cavity and gnathic bones with sufficient data to confirm the diagnoses. RESULTS: A total of 70 publications were included, representing 153 cases. Oral PBL predominantly affected HIV-positive males (76.4%). EBV was observed in 63.4% of the cases. The gingiva was the most involved site and the lesion usually presented as an asymptomatic swelling. Most cases were classified as stage I (21.6%), and chemotherapy alone was applied in 28.8% of the cases. There was a significant association between HIV and EBV infections, and cases affecting HIV-negative patients were more common in older individuals. Cumulative survival of the patients achieved 42.4% and 33.5% after 2 and 5 years, respectively. Although there were no statistically significant clinicopathological parameters in the univariate analysis, the multivariate Cox regression model demonstrated that EBV-positive status, presence of B-symptoms, and chemotherapy alone were independent prognostic determinants of a poor prognosis. CONCLUSION: Oral PBL is an aggressive neoplasm with low survival rates, which is influenced by the presence of EBV, presence of B-symptoms, and with the use of chemotherapy only.

Bortezomib in plasmablastic lymphoma: A glimpse of hope for a hard-to-treat disease.

Plasmablastic lymphoma (PBL) is a rare and hard to treat disease. With current standard chemotherapeutic regimens, PBL is associated with a median overall survival of 12-15 months. We performed a systematic review of the literature through March 31, 2017 looking for patients with a diagnosis of PBL who were treated with bortezomib, alone or in combination. We identified 21 patients, of which 11 received bortezomib in the frontline setting and 10 received bortezomib in the relapsed setting. Eleven patients were HIV-positive and 10 were HIV-negative. The overall response rate to bortezomib-containing regimens was 100% in the frontline setting and 90% in the relapsed setting. Furthermore, the 2-year overall survival of patients treated upfront was 55%, and the median OS in relapsed patients was 14 months. Although the sample size is small, we believe our results are encouraging and should serve as rationale to investigate bortezomib-based regimens in patients with PBL.

Plasmablastic lymphoma: Review of 60 Chinese cases and prognosis analysis.

BACKGROUND: Plasmablastic lymphoma (PBL) is a B-cell malignancy associated with human immunodeficiency virus (HIV). PBL could also influence the HIV-negative patients. The study aimed to identify prognostic factors for survival among Chinese PBL patients. MATERIALS AND METHODS: Eligible patients from literature and Peking Union Medical College Hospital (PUMCH) were included in this study. Clinical characteristics and immunophenotypic data were extracted. Kaplan-Meier curve was used to describe the survival status. Cox regression was used for multivariate analysis. RESULTS: A total of 60 Chinese PBL patients were included, including 54 patients from 36 published articles and 6 new patients that have not been reported. The median overall survival was 7 months (95% confidence interval 3.853-10.147 months). An overwhelming majority (79.31%) of the included cases were Ann Arbor stage IV patients. All the Chinese PBL patients were HIV-negative; 46.81% were Epstein-Barr virus-positive. CD38, CD138, or MUM1 was positively expressed in more than 80% of patients; CD20 expression was also found in 22.03% of cases. Kaplan-Meier curve revealed obvious differences in patient survival between patients in primary stages and advanced stages, as well as between patients with kidney involvement and those without kidney involvement. Cox regression analysis indicated that stage and age were 2 prognostic factors for patient survival. CONCLUSIONS: Advanced stage might be associated with poor prognosis among PBL HIV-negative patients in Chinese.

Immune-checkpoint expression in Epstein-Barr virus positive and negative plasmablastic lymphoma: a clinical and pathological study in 82 patients.

Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma commonly associated with Epstein-Barr virus co-infection that most often occurs in the context of human immunodeficiency virus infection. Therefore, its immune escape strategy may involve the upregulation of immune-checkpoint proteins allowing the tumor immune evasion. However, the expression of these molecules was poorly studied in this lymphoma. We have investigated 82 plasmablastic lymphoma cases of whom half were Epstein-Barr virus positive. Although they harbored similar pathological features, Epstein-Barr virus positive plasmablastic lymphomas showed a significant increase in MYC gene rearrangement and had a better 2-year event-free survival than Epstein-Barr virus negative cases (P=0.049). Immunostains for programmed cell death-1, programmed cell death-ligand 1, indole 2,3-dioxygenase and dendritic cell specific C-type lectin showed a high or moderate expression by the microenvironment cells in 60%-72% of cases, whereas CD163 was expressed in almost all cases. Tumor cells also expressed programmed cell death-1 and its ligand in 22.5% and 5% of cases, respectively. Both Epstein-Barr virus positive and negative plasmablastic lymphomas exhibited a high immune-checkpoint score showing that it involves several pathways of immune escape. However, Epstein-Barr virus positive lymphomas exhibited a higher expression of programmed cell death-1 and its ligand in both malignant cells and microenvironment as compared to Epstein-Barr virus negative cases. In conclusion, plasmablastic lymphoma expresses immune-checkpoint proteins through both malignant cells and the tumor microenvironment. The expression of programmed cell death-1 and its ligand constitutes a strong rationale for testing monoclonal antibodies in this often chemoresistant disease.

Doxorubicin-Based Chemotherapy and Radiation Therapy Produces Favorable Outcomes in Limited-Stage Plasmablastic Lymphoma: A Single-Institution Review.

BACKGROUND: Plasmablastic lymphoma (PBL) is an aggressive variant of diffuse large B-cell lymphoma. We sought to assess the treatment outcomes after combined-modality therapy for early-stage PBL. MATERIALS AND METHODS: We retrospectively reviewed the outcomes of 10 consecutive patients diagnosed with stage I-II PBL from February 2001 to December 2013 at a single institution. The baseline clinical characteristics, treatment modalities, overall outcomes, and treatment-related toxicity were assessed. RESULTS: The median age at diagnosis was 50.5 years. All patients had extranodal disease; 2 were positive for human immunodeficiency virus. Seven patients received hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based chemotherapy, 2 received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and 1 received dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). Radiotherapy (RT) was administered after a complete response to chemotherapy in 7 patients and a partial response in 1 patient. At a median follow-up period of 42 months, the estimated 2-year progression-free and overall survival rates were 90% and 100%, respectively. CONCLUSION: PBL can be successfully treated with aggressive chemotherapy followed by RT. The treatment was well tolerated and can result in long-term survival for patients with limited-stage disease.

Clinicopathologic features of plasmablastic lymphoma: Single-center series of 8 cases from Saudi Arabia.

BACKGROUND: Plasmablastic lymphoma (PBL) is a rare subtype of non-Hodgkin's lymphoma. Characterized by its aggressive nature and plasmacytic differentiation, PBL remains a therapeutic and diagnostic challenge; it generally has a poor prognosis with very few long-term survivors and most patients dying within 2 years from initial presentation. PBL has been reported in several other countries; however, there have been no reported cases from Saudi Arabia. Here, we report 8 cases of PBL depicting the clinical presentation, immunocompetency, immunphenotypic characterization, diagnostic challenges and treatment outcome. METHODS: The medical records were reviewed for clinical presentation, staging, laboratory data, radiological studies, treatments, and outcomes. A broad immunohistochemical panel consisting of CD45, CD3, CD20, CD79a, Pax5, CD38, CD138, MUM1, EMA, Kappa, Lambda, CD 56, CD30, Bcl-2, Bcl-6, Alk-1, Ki-67, EBV-LMP-1, and HHV8 was performed. RESULTS: The tumors predominantly exhibited immunoblastic/plasmablastic or plasmacytic morphologic features and had a plasma cell-like immunophenotype. All cases were immunoreactive for CD38, CD138 and MUM1 confirming plasma cell differentiation of the tumor cells. CD20 was negative for all cases; whereas CD79a and Pax5 were weakly positive in 2cases. All 8 cases were EBV-LMP-1/EBER-1 negative, and 1 case was HHV8 positive. Similar to previously published studies, PBL in Saudi Arabia is characterized by male predominance (6/8), median age 51.5 years (mean age 46 years), associated with early dissemination, poor response to therapy, and limited survival (average survival time, 6.4 months, median overall survival 5.5 months). However, it does have some unique features. It occurs more commonly in immunocompetent persons (6/8, 75%), is not associated with EBV infection (0/8), and nodal involvement (either primary or secondary) is common among patients (6/8). In addition, extra-oral sites are more common than oral/nasal cavities (7/8) and the c-myc gene is not common (1/8, 12.5%). CONCLUSION: It appears that PBL is heterogeneous in terms of clinical presentation and morphology. PBL is a therapeutic challenge with a clinical course that is characterized by its high rate of relapse and death. To date, treatment responses are usually partial and temporary. Therapies that are more intensive than CHOP do not seem to prolong survival. Further research is needed to understand the biology and molecular pathogenesis of PBL in order to improve therapies. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1465801416161912.