Hospitalization for Toxicity in Patients Treated With Rituximab.

OBJECTIVES: To estimate the rates of hospitalizations in patients within 12 months after the first rituximab administration. METHODS: Patients who received rituximab between 2001 and 2008 for either benign or malignant conditions were identified from Texas Medicare files. The hospitalization rates for these patients with any diagnoses that might represent toxicity were then compared in the 12 months before and after the first infusion of rituximab. Dose-response analyses were performed on the basis of the number of doses received in the 8 weeks after initiating rituximab and also using the cumulative number of doses as a time-dependent covariate. RESULTS: In all, 2623 patients received rituximab as a single agent for malignant indications and 1124 received it for benign indications. Overall inpatient admission rates did not differ significantly between the 12 months before and after rituximab initiation in patients with benign or malignant conditions. Those with malignant conditions had higher rates of hospitalizations for cardiovascular, infectious, pulmonary, and neurological diagnoses after rituximab initiation. In those with nonmalignant conditions, the only increase was in hospitalizations for infections. Neither group of patients showed any clear dose-response relationships with any toxicity. CONCLUSIONS: The increased hospitalizations for potential toxicities seen in patients with malignant disease were presumably because of the underlying disease process and not rituximab. Rituximab does not appear to be associated with hospitalizations for serious toxicity within 12 months after the first infusion, with the possible exception of infection.

Alternative therapy for epstein-barr virus related hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal condition characterized by excessive immune activation. HLH can occur as a familial or sporadic acquired disorder. Acquired HLH is more frequently found in adults and is commonly secondary to infections, malignancies, or autoimmune diseases. Diagnosing HLH is challenging because of the rare occurrence, variable presentation, and nonspecific findings of this disorder. Diagnosis of HLH can be based on the diagnostic criteria which were used in the HLH-2004 trial. Given the rarity of this disease, protocols for its treatment have developed slowly, and obtaining adequate short-term and long-term control of the disease continues to be a challenge. Conventional induction therapy for HLH is dexamethasone and etoposide (VP-16), followed by or with cyclosporine. Intrathecal methotrexate ± hydrocortisone is given to those with central nervous system disease. We are reporting a patient who was diagnosed with Epstein-Barr virus (EBV) related HLH. He achieved complete remission with rituximab alone. To our knowledge, this is the first case of an adult patient with EBV related HLH who went into remission with rituximab therapy alone, without using the conventional chemotherapy.

Durable hematological and major cytogenetic response in a patient with isolated 20q deletion myelodysplastic syndrome treated with lenalidomide.

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by ineffective hematopoiesis. It is characterized by peripheral blood cytopenia and significant risk of progression to acute myeloid leukemia result. Deletion of the long arm of chromosome 20 (20q deletion) is present in 3-7% of patients with MDS. Lenalidomide is an immunomodulatory agent with antiangiogenic activity. It is FDA approved for the treatment of anemia in patients with low or int-1 risk MDS with chromosome 5q deletion with or without additional cytogenetic abnormalities. Study of lenalidomide in patients with MDS without 5q deletion but other karyotypic abnormalities demonstrated meaningful activity in transfusion dependent patients; however, response of patients with isolated 20q deletion to lenalidomide is not known. We are reporting a patient with 20q deletion MDS treated with lenalidomide after he failed to respond to azacytidine; to our knowledge this is the first report of a patient with isolated 20q deletion treated with lenalidomide.

Rituximab: current status as therapy for malignant and benign hematologic disorders.

Rituximab is a chimeric monoclonal antibody targeting the pan-B-cell antigen CD20 and was the first monoclonal antibody approved for clinical use in the treatment of cancer. Since its first approval by the FDA in 1997, investigators have continued to explore a variety of clinical conditions in which rituximab has proven effective with minimal toxicity. Rituximab, as monotherapy or in combination with chemotherapy, has been studied extensively in untreated and relapsed/refractory settings as both induction and maintenance therapy for the treatment of CD20-positive lymphomas and chronic lymphocytic leukemia, in addition to non-malignant hematologic disorders including autoimmune hemolytic anemia and immune thrombocytopenic purpura. Here we discuss the clinical development of rituximab with a review of the efficacy data from clinical trials and its current status in the practice of hematology and oncology.

Expression and phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 in B-cell lymphomas and reactive lymphoid tissues.

CONTEXT: Cap-mediated messenger RNA translation controlled by the eukaryotic initiation factor 4F (eIF-4F) complex plays a key role in human cancer. eIF-4F activity is controlled by a repressor binding protein (4E-BP1), which promotes translation when phosphorylated. OBJECTIVE: To examine the level of expression and phosphorylation of 4E-BP1 in various subtypes of B-cell lymphoma and reactive lymphoid tissues. DESIGN: Archival formalin-fixed, paraffin-embedded B-cell lymphoma samples and reactive lymphoid tissues were immunostained and examined for expression of 4E-BP1 and phosphorylated 4E-BP1. Expression of components of the eIF-4F complex and unphosphorylated and phosphorylated 4E-BP1 was confirmed using Western immunoblotting on lysates of frozen lymphoma samples and reactive tissues. RESULTS: Immunohistochemical analysis demonstrated weak to undetectable 4E-BP1 staining within benign, reactive germinal centers (N = 10). In contrast, 4E-BP1 was consistently expressed (moderate to strong staining) in 98% of various subtypes of mature B-cell lymphoma (N = 50). 4E-BP1 expression was also demonstrable in all 4 lymph nodes with in situ or partial involvement by follicular lymphoma and in all 12 cases of BCL2-negative lymphoma. The level of phosphorylation of 4E-BP1 in lymphomas, evaluated by immunohistochemistry, was heterogeneous. CONCLUSIONS: The immunohistochemical expression pattern of 4E-BP1 exhibits regional and cellular specificity in reactive lymphoid tissues and may offer a diagnostic tool for distinguishing reactive follicles from neoplastic B-cell proliferations.

Prognostication of diffuse large B-cell lymphoma in the rituximab era.

Predicting the prognosis of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) has been a moving target over the last several years. While earlier prognostic models relied mainly on such clinical variables as age, stage of disease, and performance status, it has become evident from gene-expression microarray studies that DLBCL is a heterogeneous disease in terms of molecular pathogenesis and cell of origin. Despite providing considerable insight into disease biology, these techniques are not widely available and are, at least at present, not applicable to routine clinical practice. Furthermore, older prognostic models need to be revalidated and modified as improved therapeutic options become available. In this review, we discuss pertinent studies on individual biomarkers and pattern-based biomarker models, with an emphasis on markers evaluated in patients treated with rituximab-containing chemotherapy. We also discuss recent and ongoing therapeutic trials using drugs that target molecular markers and pathways involved in the pathogenesis of DLBCL or those that adversely influence prognosis. The ultimate goal of these efforts is to refine prognostication of DLBCL using widely available, reproducible, and consistently predictive biomarker models applicable to currently used chemoimmunotherapy, and to create a pathophysiologically based framework for the rational design of individually tailored therapy.

Therapeutic approaches to non-Hodgkin's lymphoma in the elderly patient.

The incidence of non-Hodgkin's lymphoma (NHL) is increasing among all age groups, with a median age at diagnosis of 67 years. With the increase in the geriatric population, there is a need for the development and validation of treatment strategies for NHL for these patients. Therapy in elderly patients is affected by multiple factors, especially comorbidities. Over the past decade, some treatment trials have included older patients. The disease incidence, characteristics and treatment approaches for both follicular and diffuse aggressive NHL histologies in elderly patients are reviewed, as well as the impact of aging on the care of these patients.

Posttransplant thrombopoiesis predicts survival in patients undergoing autologous hematopoietic progenitor cell transplantation.

The frequency and clinical significance of secondary thrombocytopenia following initial engraftment in autologous hematopoietic progenitor cell transplantation (HPCT) is unknown. An institutional review board approved retrospective study of thrombopoiesis was performed in 359 patients transplanted with autologous blood (97%) or marrow (3%) who achieved platelet engraftment to >50,000/microL. Idiopathic secondary posttransplant thrombocytopenia (ISPT) was defined as >50% decline in blood platelets to <100,000/microL in the absence of relapse or sepsis. ISPT occurred at a median of day +35 posttransplant in 17% of patients. Patients with ISPT had similar initial platelet engraftment (median 17 days) versus non-ISPT patients (18 days; P=NS) and recovered platelet counts (median 123,00 K/microL) by day 110 posttransplant. Four factors were independently associated with post-transplant death in a multivariate model: disease status at transplant; the number of prior chemotherapy regimens, failure to achieve a platelet count of >150,000/microL posttransplant, and the occurrence of ISPT. A prognostic score was developed based upon the occurrence of ISPT and posttransplant platelet counts of <150,000/microL. Survival of patients with both factors (n=25) was poor (15% alive at 5 years); patients with 1 factor (n=145) had 49% 5-year survival; patients with 0 factors (n=189) had 72% 5-year survival. Patients who failed to achieve a platelet count of >150,000/microL received significantly fewer CD34+ cells/kg (P<.001), whereas patients with ISPT received fewer CD34+CD38- cells/kg (P=.0006). The kinetics of posttransplant thrombopoiesis is an independent prognostic factor for long-term survival following autologous HPC. ISPT and lower initial posttransplant platelet counts reflect poor engraftment with long-term and short-term repopulating CD34+ hematopoietic stem cells, respectively, and are associated with an increased risk of death from disease relapse.