Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma.

BACKGROUND: The prognosis of T-cell lymphoma is poor. To explore the addition of the monoclonal antibody alemtuzumab, we studied the efficacy and tolerability of an intensified alemtuzumab-chemotherapy combination for aggressive T-cell lymphoma in a phase II study by Dutch-Belgian Hemato-Oncology Group (HOVON). PATIENTS AND METHODS: Patients (≤65 years) with newly diagnosed T-cell lymphoma received eight CHOP cycles (cyclophosphamide, doxorubicin, vincristine, prednisone) 2-weekly, each cycle with three doses of 30 mg alemtuzumab. Prophylaxis consisted of cotrimoxazole, fluconazole and valaciclovir. Cytomegalovirus (CMV) monitoring took place at least every fortnight. RESULTS: Twenty patients from 10 centers, median age 50 years, were included. Eighty-five percent received six or more cycles. The overall response was 90% [12 complete remissions (CRs), 1 CR unconfirmed, 5 partial remissions]. Median duration of follow-up of patients still alive was 29 months (range 19-41 months). Median overall survival (OS) and event-free survival (EFS) were 27 and 10 months, with 55%/27% OS/EFS at 2 years. Adverse events consisted of neutropenic fever (n = 8) and CMV reactivation (n = 7), with one CMV disease. Three patients developed secondary Epstein-Barr virus (EBV)-related lymphoma, all after end of treatment. CONCLUSIONS: Although intensified alemtuzumab-CHOP induces high responses, many patients relapse, and the scheme is associated with serious infection-related adverse events. EBV monitoring after end of treatment is required.

Storage-related changes in erythrocyte band 3: not a case for the Diego blood group antigens.

Removal of erythrocytes from the circulation is mediated by the immune system. Changes in structure and function of band 3, a major membrane protein of the erythrocyte, trigger the binding of antibodies to a band 3-derived neoantigen, senescent cell antigen, on erythrocytes aged in vivo. This mechanism probably is also involved in determining the survival of erythrocytes after transfusion. Band 3 is the carrier of the Diego blood group system, and subtle changes in the three-dimensional conformation of the same extracellular loops of band 3 determine Diego blood group activity as well as senescent cell antigen activity. Therefore we used the Diego blood group system to probe these changes with a combination of serological and immunochemical methods. Our data indicate that changes in band 3 structure during storage under blood bank conditions, as shown by immunoblot analysis, are not detectable as changes in expression of Diego antigens in intact cells. This makes it unlikely that immunological removal of erythrocytes after transfusion is mediated by reactions involving the Diego blood group system.

Survival of the fittest?--survival of stored red blood cells after transfusion.

During the last 90 years many developments have taken place in the world of blood transfusion. Several anticoagulants and storage solutions have been developed. Also the blood processing has undergone many changes. At the moment, in The Netherlands, red blood cell (RBC) concentrates (prepared from a whole blood donation and leukocyte-depleted by filtration) are stored for a maximum of 35 days at 4 degrees C in saline adenine glucose mannitol (SAGM). Most relevant studies show that approximately 20% of the RBCs is lost in the first 24 hr after transfusion. Even more remarkable is that the average life span is 94 days after a storage period of 42-49 days. Such observations create the need for a parameter to measure the biological age of RBCs as a possible predictor of the fate of RBCs after transfusion. The binding of IgG to RBCs can lead to recognition and subsequent phagocytosis by macrophages. This occurs during the final stages of the RBC life span in vivo. We determined the quantity of cell-bound IgG during storage, and found considerable variation between RBCs, but no significant storage-related change in the quantity of cell-bound IgG. The significance of this finding for predicting the survival of transfused RBCs in vivo remains to be established. Hereto we developed a flow cytometric determination with a sensitivity of 0.1% for the measurement of survival in vivo based on antigenic differences. This technique has various advantages compared with the 'classical' 51Cr survival method.

Progressive change in lymphocyte distribution and degree of hypergammaglobulinemia with age in children with hemophilia.

Fifty asymptomatic, pediatric hemophiliacs were examined for distribution of T-cell subsets, responsiveness to mitogen stimulation, interleukin-2 production, hypergammaglobulinemia, and the presence of antibody to virus including the human T-lymphotrophic virus type III (HTLV-III). Hemophilia A patients receiving factor VIII concentrate as replacement therapy had the most pronounced changes including decreased T4/T8 ratios and lower in vitro responsiveness to both phytohemagglutinin and pokeweed mitogen. Hemophilia A patients treated with cryoprecipitate and hemophilia B patients did not demonstrate these changes. Regardless of replacement therapy, hemophiliacs demonstrated a progressive decrease in the T4/T8 ratio and a progressive increase in the degree of IgG hypergammaglobulinemia as they aged. The amount of factor or cryoprecipitate or exposure to virus did not influence the T4/T8 ratio. These changes appear to be a result of chronic product exposure, which becomes more pronounced with increasing age.

HTLV-III status and abnormalities in T lymphocyte distribution in children with hemophilia A.

Children with hemophilia A are at risk for the acquired immunodeficiency syndrome (AIDS). Clinically asymptomatic hemophiliacs demonstrate many immune abnormalities that might represent exposure to the AIDS agent through blood products or be a natural reaction to their therapy. In this study, we examined lymphocyte subset distribution in children with hemophilia A who had been exposed to HTLV-III as determined by antibody seroconversion. Seroconversion to HTLV-III was confirmed using Western blot analysis. The lymphocyte subsets studied included T4+ and T8+ cells. The distribution of lymphocyte subsets in children with hemophilia A was independent of seroconversion to HTLV-III. Children with hemophilia A treated with commercial factor VIII concentrate had normal numbers of circulating T4+ lymphocytes and significantly increased numbers of circulating T8+ lymphocytes compared with their nontransfused age-matched counterparts. An increased number of T8+ lymphocytes was not observed, however, in children treated exclusively with cryoprecipitate. These results suggest that HTLV-III alone cannot account for changes in lymphocyte subsets in hemophiliacs. Higher antigenic protein loads in factor VIII concentrate or additional factors might account for the increased absolute numbers of T8+ lymphocytes and represent a natural response to therapy.