Eric S. Winer

Clinical and pathological differences between human immunodeficiency virus-positive and human immunodeficiency virus-negative patients with plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients. Several studies have reported the occurrence of PBL in HIV-negative patients, but comparative data are lacking. The goal of this study was to compare the characteristics of HIV-positive and HIV-negative patients with PBL. A MEDLINE search was undertaken through August 2009 for cases of PBL in HIV-positive and HIV-negative patients. Cases were identified and clinicopathological data were gathered. χ2 was used to compare categorical and t-test to compare continuous variables between groups. Calculated Kaplan–Meier survival estimates were compared using the log-rank test. Cox proportional-hazard regression was used for multivariate analysis. From 228 identified cases of PBL, 157 were HIV-positive and 71 HIV-negative. HIV-positive patients were younger, and more likely to be men, present with oral involvement, respond to chemotherapy, and express CD20, CD56, and EBV-encoded RNA than HIV-negative patients. In univariate analysis, age ≥60, advanced stage, bone marrow involvement, no chemotherapy, Ki-67 expression >80%, and HIV-negative status were associated with worse overall survival. In multivariate analysis, advanced stage and no chemotherapy were independent adverse prognostic factors. In conclusion, HIV-positive and HIV-negative patients with PBL have different clinicopathological characteristics, including a better response to chemotherapy and longer survival in HIV-positive patients.

CAL-101: a phosphatidylinositol-3-kinase p110-delta inhibitor for the treatment of lymphoid malignancies

Introduction: The management of lymphoid malignancies has greatly evolved in the last decade with the advent of targeted therapies, which have improved response and survival in patients with Hodgkins lymphoma (HL), non-Hodgkins lymphoma (NHL), chronic lymphocytic leukemia (CLL) and plasma cell myeloma (PCM). The PI3K pathway seems to play a seminal role in the development of lymphoid malignancies. CAL-101 is a highly selective PI3K p110δ inhibitor currently undergoing clinical development. Areas covered: The aims of this review are to summarize our understanding of the PI3K pathway, its role in lymphoid malignancies, the preclinical and clinical experience accumulated with CAL-101, a PI3Kδ inhibitor, and potential areas of future development. Expert opinion: CAL-101 is a novel drug that has shown preclinical activity against CLL, NHL, HL and PCM cells. There is early evidence of clinical efficacy in CLL and indolent NHL. Studies using CAL-101 alone or in combination are also ongoing in PCM, HL and aggressive NHL. However, additional studies are needed to prove CAL-101 is effective and safe as the goals of therapy for patients with lymphoid neoplasms are not only directed towards improving response and cure rates but also prolonging survival without affecting quality of life.

Prognostic Factors in Chemotherapy-Treated Patients with HIV-Associated Plasmablastic Lymphoma

BACKGROUND Plasmablastic lymphoma (PBL) is a variant of diffuse large B-cell lymphoma commonly seen in the oral cavity of HIV-infected individuals. PBL has a poor prognosis, but prognostic factors in patients who have received chemotherapy have not been adequately evaluated. METHODS An extensive literature search rendered 248 cases of PBL, from which 157 were HIV(+). Seventy cases with HIV-associated PBL that received chemotherapy were identified. Whenever possible, authors of the original reports were contacted to complete clinicopathological data. Univariate analyses were performed calculating Kaplan-Meier estimates and compared using the log-rank test. RESULTS The mean age was 39 years, with a male predominance. The mean CD4(+) count was 165 cells/mm(3). Advanced clinical stage was seen in 51% and extraoral involvement was seen in 43% of the cases. The expression levels of CD20 and Epstein-Barr virus-encoded RNA were 13% and 86%, respectively. The overall survival duration was 14 months. In a univariate analysis, early clinical stage and a complete response to chemotherapy were associated with longer survival. There was no apparent difference in survival with regimens more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). CONCLUSIONS Patients with HIV-associated PBL have a poor prognosis. Prognosis is strongly associated with achieving a complete clinical response to CHOP or CHOP-like chemotherapy. The role of more intensive regimens is currently unclear. Further research is needed to improve responses using novel therapeutic agents and strategies.

HIV-negative plasmablastic lymphoma: not in the mouth.

Plasmablastic lymphoma (PBL) is an aggressive variant of non-Hodgkin lymphoma initially reported in the oral cavity of HIV-positive individuals. Since its original description, several cases have been reported in patients who do not have HIV infection. However, despite its recognition as a distinct subtype of diffuse large B-cell lymphoma several years ago, comprehensive reviews of this entity are lacking. A MEDLINE search through June 2010 was performed to identify cases with a pathologic diagnosis of HIV-negative PBL based on morphology and minimal immunohistochemical criteria. Our study included a total of 76 cases. The median age was 57 years (range, 1 to 90 years) with a male-to-female ratio of 1.7. Seventy-four percent of cases did not have an apparent association with immunosuppression, 18% had a concurrent lymphoproliferative or autoimmune disorder and 9% developed PBL after solid organ transplantation. Oral involvement was observed in 21%, advanced stage in 60%, Epstein-Barr virus-encoded RNA expression was positive in 45% and Ki-67 expression of greater than or equal to 80% in 61% of the cases. Chemotherapy was documented in 43 patients, from which 43% received the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like regimens. The median and the 2-year overall survival for the whole group were 9 months and 10%, respectively. Patients who had HIV-negative PBL have distinct clinicopathological characteristics, such as short overall survival and lower rates of oral involvement and Epstein-Barr virus-encoded RNA expression than the previously reported in HIV-positive patients.

Nonengraftment Haploidentical Cellular Immunotherapy for Refractory Malignancies: Tumor Responses without Chimerism

Allogeneic bone marrow transplantation relies on immunosuppression, which controls graft-versus-host disease (GVHD) and allows engraftment at the expense of diminished graft versus-tumor (GVT) activity. Advances in hematologic transplantation have prompted the development of effective, less-toxic regimens that attempt to balance GVH and GVT immunoreactions. We analyzed the safety and efficacy of haploidentical transplantation in a Phase I/II nonimmunosuppressive, nonmyeloablative setting. A total of 41 patients with relapsed refractory cancer received 100 cGy of total body irradiation (TBI), along with an infusion of 1 x 10(6) to 2 x 10(8) CD3+ cells/kg; 29 patients received the highest dose. A postinfusional cellular graft rejection syndrome resembling engraftment syndrome was noted at the 2 highest CD3+ infusion cohorts. There were 26 patients with hematologic malignancies with 14 responses, 9 of which were major. Two of 6 patients with lymphoma remained free of disease at 76 months and 82 months, respectively; there were 5 durable complete responses and 4 partial responses in 13 patients with acute myelogenous leukemia (AML). All responses occurred outside of donor chimerism. TBI at 100 cGy followed by HLA-haploidentical immunotherapy is a biologically active therapy for patients with refractory AML and lymphoma. Possible mechanisms contributing to its effectiveness include initial GVT kill, breaking of host tolerance to tumor through cross-reactive alloreactive responses, persistent nondetectable microchimerism, or some combination of these.

PCI-32765: a novel Bruton's tyrosine kinase inhibitor for the treatment of lymphoid malignancies

Introduction: There has been a significant paradigm shift in the manner in which lymphoid malignancies are treated and managed. Treatment has been moving away from conventional chemotherapy and towards targeted therapy. The success of new classes of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further searches for novel pathways to inhibit. The Brutons tyrosine kinase (Btk) pathway is a downstream mediator of the B-cell receptor (BCR) pathway, which is crucial in B-cell production and maintenance, and a potential therapeutic target. Areas covered: This review will summarize the current knowledge of the Btk pathway and its role in lymphoid malignancies. It will also discuss the present data about PCI-32765 in both the preclinical and clinical setting. Expert opinion: PCI-32765 is an oral irreversible Btk inhibitor with high potency and both preclinical and clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkins lymphoma (NHL). Phase I studies have demonstrated that it is well tolerated and has an excellent safety profile. Further studies are ongoing as a single agent and in combination with other targeted and conventional therapies. PCI-32765 is a very promising targeted therapy, and the data from these trials will ultimately decide its future role and success.

Sites of extranodal involvement are prognostic in patients with diffuse large B-cell lymphoma in the rituximab era: An analysis of the Surveillance, Epidemiology and End Results database

Approximately a third of the patients with diffuse large B‐cell lymphoma present with extranodal involvement. Our study aims to identify primary extranodal sites of disease associated with prognosis in patients with diffuse large B‐cell lymphoma (DLBCL) in the rituximab era. A secondary objective is to describe epidemiological and clinical characteristics of patients with extranodal DLBCL. We included adult patients from the Surveillance, Epidemiology and End Results (SEER) database (2004–2009) in whom DLBCL was the first malignancy diagnosed. Extranodal primary sites were divided into 12 groups according to the topography code reported by SEER. Multivariate overall survival (OS) analyses were performed using Cox proportional‐hazard regression models adjusted for age, sex, race, and stage. From a total of 25,992 adult DLBCL patients included in our analysis, 32% presented with extranodal primary sites. Gastrointestinal tract (34%), head/neck (H&N; 14%), and skin/soft tissue (11%) were the most common. In comparison with nodal DLBCL, patients with extranodal involvement were older (with exception of skeletal sites) and presented with earlier stages. In the multivariate analysis, sites associated with worse OS rates were gastrointestinal (Hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.15–1.33; P <0.001), pulmonary (HR 1.59, 95% CI 1.38–1.83; P <0.001), and liver/pancreas (HR 1.58, 95% CI 1.35–1.85; P <0.001), whereas H&N was associated with better survival (HR 0.79, 95% CI 0.70–0.89; P <0.001). In this population‐based study, primary extranodal sites of involvement are associated with distinct outcomes in patients with DLBCL. Gastrointestinal, pulmonary, and liver/pancreas sites had a significant worse outcome than nodal sites. Am. J. Hematol. 89:310–314, 2014.

Bortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is a rare and aggressive CD20‐negative lymphoma. Despite improvements of the biology behind PBL, it still represents a challenge from the diagnostic and therapeutic perspectives for pathologists and clinicians. PBL is characterized by high rates of relapse and short median survival with standard approaches. Here, we report the use of the combination of bortezomib and infusional etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (V‐EPOCH) in three patients with PBL; two were HIV‐positive and one was HIV‐negative. All three patients obtained a durable complete response to V‐EPOCH with survival times of 24, 18 and 12 months respectively.

Prognosis in primary effusion lymphoma is associated with the number of body cavities involved.

Abstract Primary effusion lymphoma (PEL) is a rare lymphoma associated with Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), and characterized by a malignant body cavity effusion without solid organ or nodal involvement. Prognostic factors in patients with PEL have not been systematically studied. We conducted a literature search for patients with HHV8-positive PEL to identify potential prognostic factors for survival. Our search identified 147 patients, among which 104 patients were HHV8-positive. The median overall survival was 9 months. The median age was 57 years with a male predominance (6:1). Pathologically, 33% of the patients expressed CD20 and 69% expressed CD30. Patients with PEL with > 1 body cavity involved had a median overall survival (OS) of 4 months compared with 18 months in patients with only one cavity involved (p = 0.003). Additionally, in patients with one involved body cavity, pericardial involvement was associated with a longer median OS than pleural followed by peritoneal involvement (40, 27 and 5 months, respectively; p = 0.04). In conclusion, our study suggests that the number and location of body cavities involved are prognostic in patients with PEL.

Population‐based prognostic factors for survival in patients with Burkitt lymphoma: An analysis from the Surveillance, Epidemiology, and End Results database

Burkitt lymphoma (BL) is an aggressive but potentially curable lymphoma, previously described in small, single‐institution studies. This study evaluated prognostic factors for survival in adult patients with BL and a potential outcome improvement over the past decade in a population‐based cohort.