Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience.

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue. FUNDING: F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Trends in incidence, treatment and survival of aggressive B-cell lymphoma in the Netherlands 1989-2010.

Only a small number of patients with aggressive B-cell lymphoma take part in clinical trials, and elderly patients in particular are under-represented. Therefore, we studied data of the population-based nationwide Netherlands Cancer Registry to determine trends in incidence, treatment and survival in an unselected patient population. We included all patients aged 15 years and older with newly diagnosed diffuse large B-cell lymphoma or Burkitt lymphoma in the period 1989-2010 and mantle cell lymphoma in the period 2001-2010, with follow up until February 2013. We examined incidence, first-line treatment and survival. We calculated annual percentage of change in incidence and carried out relative survival analyses. Incidence remained stable for diffuse large B-cell lymphoma (n=23,527), while for mantle cell lymphoma (n=1,634) and Burkitt lymphoma (n=724) incidence increased for men and remained stable for women. No increase in survival for patients with aggressive B-cell lymphoma was observed during the period 1989-1993 and the period 1994-1998 [5-year relative survival 42% (95%CI: 39%-45%) and 41% (38%-44%), respectively], but increased to 46% (43%-48%) in the period 1999-2004 and to 58% (56%-61%) in the period 2005-2010. The increase in survival was most prominent in patients under 65 years of age, while there was a smaller increase in patients over 75 years of age. However, when untreated patients were excluded, patients over 75 years of age had a similar increase in survival to younger patients. In the Netherlands, survival for patients with aggressive B-cell lymphoma increased over time, particularly in younger patients, but also in elderly patients when treatment had been initiated. The improvement in survival coincided with the introduction of rituximab therapy and stem cell transplantation into clinical practice.

Histopathology of Hodgkin's lymphoma.

In the last few years, there has been a greater understanding of the spectrum and biology of Hodgkin's lymphoma. In standard texts, Hodgkin's lymphoma is classified as 2 distinct entities, namely nodular lymphocyte predominant Hodgkin's lymphoma and classical Hodgkin's lymphoma. However, recent evidence suggests that classical Hodgkin's lymphoma is not a single disease. Although the mixed cellularity and lymphocyte-depleted subtypes may be part of a biologic continuum, the nodular sclerosis subtype has a distinct epidemiology, clinical presentation, and histology. Nodular sclerosis Hodgkin's lymphoma, particularly those cases presenting with mediastinal disease, also seems related to primary mediastinal B-cell lymphoma. As Hodgkin's lymphoma is a B-cell neoplasm, there is also a better appreciation today of cases that may be borderline with conventional B-cell lymphomas. We present an update on the histopathological features of Hodgkin's lymphoma and the immunohistochemical tools available for diagnosis in the clinical setting.

Bcl-2-family proteins and hematologic malignancies: history and future prospects.

BCL-2 was the first antideath gene discovered, a milestone that effectively launched a new era in cell death research. Since its discovery more than 2 decades ago, multiple members of the human Bcl-2 family of apoptosis-regulating proteins have been identified, including 6 antiapoptotic proteins, 3 structurally similar proapoptotic proteins, and several structurally diverse proapoptotic interacting proteins that operate as upstream agonists or antagonists. Bcl-2-family proteins regulate all major types of cell death, including apoptosis, necrosis, and autophagy. As such, they operate as nodal points at the convergence of multiple pathways with broad relevance to biology and medicine. Bcl-2 derives its name from its original discovery in the context of B-cell lymphomas, where chromosomal translocations commonly activate the BCL-2 protooncogene, endowing B cells with a selective survival advantage that promotes their neoplastic expansion. The concept that defective programmed cell death contributes to malignancy was established by studies of Bcl-2, representing a major step forward in current understanding of tumorigenesis. Experimental therapies targeting Bcl-2 family mRNAs or proteins are currently in clinical testing, raising hopes that a new class of anticancer drugs may be near.

Pyothorax-associated lymphoma.

In Japan, EBV positive rate in immunocompetent patients with nodal lymphomas is less than 10% in B-cell and 20-50% in T cell lymphoma. Among extranodal lymphomas, EBV positive rate is higher in pyothorax-associated lymphoma (PAL), nasal NK/T-cell lymphoma, and adrenal lymphoma. PAL is non-Hodgkin's lymphoma that develops from chronic pyothorax resulted from artificial pneumothorax for the treatment of lung tuberculosis or tuberculous pleuritis. This disease was originally described by Dr. Aozasa as a distinctive clinicopathologic entity in 1987, and now listed as the disease entity in the WHO classification of Tumours, Pathology & Genetics, Tumours of the Lung, Pleura, Thymus and Heart (2004).