Deborah Hurst

A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma

Purpose: The incidence of non-Hodgkins lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)–bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. Experimental Design: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m2 (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). Results: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcγR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. Conclusions: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.

GROWTH RETARDATION IN SICKLE-CELL DISEASE TREATED BY NUTRITIONAL SUPPORT

The effect of increased nutritional intake was evaluated in 5 growth-retarded children with sickle-cell disease. Growth on recommended daily calorie and protein intakes had been inadequate in all 5. Fat absorption and intestinal mucosal morphology were normal in all 5. 2 children were given nutritional supplementation by nasogastric intubation, 1 received nightly oral formula supplements, and 2 were supplemented with zinc, iron, folate, and vitamin E only. Nutritional supplementation by the nasogastric route produced a rapid sustained increase in growth rate, associated with striking reductions in pain crises and infections which had previously necessitated many hospital admissions. Oral supplementation improved the clinical course but had no effect on growth rate. Mineral and vitamin supplements influenced neither the growth rate nor the clinical course. The observations indicate that nasogastric nutritional supplementation may accelerate growth and reduce the incidence and severity of complications in growth-retarded children with sickle-cell disease.

Transfusion of infants with activation of erythrocyte T antigen

A protocol for transfusion of infants with erythrocyte T-antigen activation was evaluated for safety and effectiveness in a prospective, 3-year, sequential series of 1672 infants admitted for intensive care. Erythrocyte T antigens are activated by enzymes produced by clostridia or other bacteria in infants with sepsis, often in association with necrotizing enterocolitis. Transfusion of these infants with blood products containing plasma carries the risk of causing intravascular hemolysis. Our transfusion protocol included testing for T-antigen activation, restricting transfusion of patients with activated T antigens to washed erythrocytes or washed platelets whenever possible, and selecting donors with low-titer anti-T when plasma-containing blood products were required. In this series, 10 patients had T-antigen activation, including four with clostridial infections. Severe hemolysis occurred in one patient who received plasma before T-antigen activation developed. Of five patients who received low-titer anti-T plasma, mild hemolysis occurred in three and no hemolysis in two. Four patients who received no plasma-containing blood products experienced no hemolysis. Used cautiously, this protocol allows a full range of transfusion therapy to infants with T-antigen activation.

Bleeding disorders in Noonan syndrome: three case reports and review of the literature.

PURPOSE Noonan syndrome (NS) is a congenital disorder characterized by various phenotypic features and congenital anomalies. Bleeding disorders are among the more serious, common, yet poorly defined complications associated with NS. As a means of focusing on these complications, we report three patients with stigmata of NS, each of whom had a combination of different hemostatic disorders, and review the literature on bleeding disorders in NS. PATIENTS AND METHODS The clinical course and hemostatic abnormalities in three patients with NS were studied, and a literature review on NS was undertaken. RESULTS The three patients we report had decreased coagulation factor levels (factors XI and II), von Willebrand disease, various levels of thrombocytopenia, and abnormal platelet function. The literature review on NS discloses multiple types of hemostatic abnormalities and a wide range of clinical presentations. A low level of coagulation factor XI is the most frequently described; thrombocytopenia and abnormal platelet function are also common. CONCLUSIONS The existence of various types of bleeding disorders within one syndrome is unusual and requires further investigation. Recognition of this common complication in children with NS would aid both clinical management and understanding of the spectrum, the frequency, and perhaps even the basis of the hemostatic defects in this syndrome. We recommend performing coagulation screening tests in every patient with NS.

Anemia and hemoglobinopathies in Southeast Asian refugee children.

Hematologic evaluations of 254 Southeast Asian refugee children from 163 families are reported. Hemoglobin E trait was common in Cambodians (19%) and Laotians (18%), but rare in Vietnamese (1%). beta-Thalassemia trait was most prevalent in Vietnamese (8%), and less common in Cambodians and Laotians (3%). alpha-Thalassemia was prevalent in all three groups. Hemoglobin concentrations and mean corpuscular volumes seen with hemoglobinopathies were compared with those of Southeast Asian children with normal hemoglobin. Both Hb AE and Hb EE were shown to be benign conditions resulting in microcytosis and mild, if any, anemia. In children with Hb AE, mean corpuscular volume ranged from 64 to 78 ft and Hb E from 27% to 34%. In those with Hb EE, microcytosis was more marked (50 to 63 ft). In 15 children with Hb EE, there was a delayed fall in fetal hemoglobin, which can cause diagnostic difficulties in infants.

Pathogenesis of renal failure in cirrhosis and fulminant hepatic failure

Acute renal failure in cirrhosis and fulminant hepatic failure represents a spectrum with ‘functional renal failure’ at one end and acute tubular necrosis at the other. In fulminant hepatic failure the development of renal failure is not necessarily a measure of the severity of liver damage. Functional renal failure is due to active renal vasoconstriction which may, at least in fulminant hepatic failure, be initiated by systemic endotoxaemia.

NUTRITION IN SICKLE CELL ANEMIA |[lpar]|HB SS|[rpar]|

To evaluate the role of nutrition in Hb SS we performed anthropometric and laboratory measurements on 95 Hb SS patients and determined the effects of caloric supplementation on these parameters and on clinical course. Height and weight were both below the 5th percentile in 17% of patients. Laboratory studies included vitamin C (ng/108 cells), vitamin E (mg/dl), zinc (μg/ml), selenium (ng/ml), and lipids (mg/dl).Immune status was measured as a reflection of nutritional adequacy. Total T cell (patient/control, 44%/78%), helper T cell (23%/55%), and suppressor T cells (17%/32%) as well as skin test reactivity were depressed. Two patients with marked growth retardation, multiple laboratory abnormalities and frequent sickle cell complications received dietary supplementation with nasal gastric hyperalimentation for 4-10 months. Improvements in growth, weight, skin test reactivity, T cell numbers, and clinical status were noted. We conclude that nutritional assessment and intervention may minimize complications associated with sickle cell disease.

PLASMA FVIII LEVELS MEASURED AFTER INFUSION OF RECOMBINANT F VIII (rFVIII) VARY SIGNIFICANTLY WITH DIFFERENT ASSAY METHODS - (WILL THE REAL FVIII LEVEL PLEASE STAND UP!). |[dagger]| 934

As part of a bioequivalence study comparing two lots of rFVIII(Kogenate®), 9 persons with hemophilia A were infused with rFVIII from each lot, and multiple plasma samples were then obtained from each subject for determination of FVIII assays over 48 hrs. Samples were assayed by 4 different methods: chromogenic, and one stage APTT method using 3 different types of activators (A)-micronized silica, ellagic acid, and kaolin. All samples were immediately centrifuged, snap frozen and stored at -70°C until assayed in duplicate. The same reference plasma standard was used throughout. Results, shown below, indicate a consistent difference in F VIII assay values, with those run by chromogenic substrate method being roughly twice as high as those run by one-stage APTT method with kaolin as A. One stage results with micronized silica or ellagic acid as A were comparable, and were consistently higher than those with kaolin. Most U.S. clinical labs use a one-stage assay, with micronized silica or ellagic acid A. Because significantly different results can be obtained depending on F VIII assay method used, multicenter studies must carefully standardize assay techniques and reagents in order to combine data for analysis. Additionally, such differences have significant cost implications (partially funded by Bayer). Figure