Intravenous Immune Globulin In Patients Research Articles

Use of Intravenous Immune Globulin in Patients with Immune Thrombocytopenia Before and After Romiplostim: Real-World Experience

AbstractAbstract 4641 Background:Thrombopoietin receptor agonists such as romiplostim have been shown to increase platelet counts in patients with immune thrombocytopenia (ITP) and reduce the need for concomitant therapies. However, their effect on the utilization of intravenous immune globulin (IVIG) has not been examined in the post-marketing or ‘real world' setting. The objective of this before-after study was to determine the effect of romiplostim on the utilization of IVIG outside of clinical trials. We determined the completeness of our dataset in this multi-center retrospective study. Methods:The charts of patients with ITP from 4 sites in Canada who had received romiplostim were reviewed until January 31, 2012. Patients were 18 years or older, had ITP according to ASH criteria and had at least 1 full year of data available prior to the first dose of romiplostim. A web-based electronic data capture system was used to collect platelet counts, IVIG use, bleeding as assessed by site and severity using an ITP-specific bleeding assessment tool, treatments and hospitalizations before and after the start of romiplostim treatment. IVIG use was compared after normalizing for the duration of time in observation. A pilot exercise was performed to optimize the quality of data extraction from charts. Results:Twenty-nine patients with ITP were included (15 females; median age 54 years, interquartile range [IQR] 45 – 63). Median platelet counts increased from 28 x109/L (IQR, 12 – 58) before romiplostim to 124 x109/L (IQR, 79 – 182) after romiplostim. The proportion of patients requiring other ITP treatments decreased from 25/29 (86%) to 17/29 (59%); the proportion of patients with any bleeding decreased from 24/29 (83%) to 11/29 (38%); and the proportion of patients with grade 2 or higher bleeding decreased from 13/29 (45%) to 6/29 (21%) after romiplostim. Of 29 patients, 16 (55%) had received IVIG before receiving romiplostim. IVIG use over time decreased in 14 of 16 (88%) patients, including 4 (25%) who did not require any IVIG after romiplostim administration. Two splenectomized patients with refractory ITP had received more IVIG in the period after romiplostim was initiated: One patient had discontinued romiplostim because of no platelet count response and subsequently developed intra-cerebral hemorrhage requiring multiple IVIG treatments; the other patient developed cyclical thrombocytopenia. Three additional patients received 1–3 infusions of IVIG only during the period after romiplostim. Of 128 IVIG infusion episodes, 106 were considered to have sufficient documentation since the dose, date of administration and preceding platelet count (within 1 week) were recorded in the chart. Conclusion:In this real-world cohort of patients with ITP, the proportion of patients who required IVIG decreased after starting romiplostim. A few refractory patients required more IVIG in the period after romiplostim. Retrospective data collection of treatment start and end dates and bleeding severity was limited. Disclosures:Arnold:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman-LaRoche: Research Funding.

Passive Transfer of Hepatitis B Core Antibody by Intravenous Immune Globulin in Patients with Immune Thrombocytopenic Purpura.

Abstract 2418Poster Board II-395 Background:Rituximab may reactivate remote hepatitis B infection. Thus, hepatitis B core antibody (HBcAb) seropositivity was an exclusion for a randomized trial of rituximab in patients with immune thrombocytopenic purpura (ITP) in Canada. During screening for this trial, we observed a high rate of HBcAb seropositivity at our centre. We investigated passive antibody transfer by intravenous immune globulin (IVIg) as a potential explanation. Methods:We performed a case-control study of consecutive ITP patients screened for eligibility for a randomized trial of rituximab. We compared the frequency of prior IVIg use and the IVIg product administered to patients who tested positive (n=11) and negative (n=13) for HBcAb. Total (IgG and IgM) HBcAb was tested using a microparticle enzyme immunoassay (MEIA) that measures the rate of inhibition compared with an internal cut-off value (AxSYM®, Abbott Laboratories, IL, USA). We calculated the odds ratio (OR) and 95% confidence interval (CI) for IVIg exposure. We also tested different lots of 2 IVIg products directly for HBcAb in the MEIA. Results:Of 24 consecutive patients with ITP screened, 11 (45.8%) were positive for HBcAb and thus were excluded from the randomized trial. The observed rate of HBcAb seropositivity in this cohort was 35 times higher than the expected seroprevalence in Canada of 1.3% (O'Brien Transfusion 2009). Of 11 HBcAb-positive patients, 10 (90.9%) had received prior IVIg [OR, 16 (95% CI, 1.54, 166.05)]. Of the 10 patients who received IVIg, 8 (80.0%) received Gamunex (10% human immune globulin, Talecris Biotherapeutics, Clayton, NC). HBcAb was repeated in 8 seropositive patients, of whom 4 were negative on repeat testing 7 to 104 weeks after the last dose of IVIg. Of the 13 HBcAb-negative patients, 5 (38.5%) had received prior IVIg; none were Gamunex. Seroconversion was documented in one patient serially tested after receiving Gamunex; MEIA rates decreased (became positive) rapidly, then gradually increased to normal after 7 weeks. Samples from 4 lots of Gamunex were reactive in the MEIA; whereas 3 lots of IGIVnex (Talecris Biotherapeutics) were non-reactive. Conclusions:False positive HBcAb results may occur due to the passive transfer of HBcAb from Gamunex, an IVIg product manufactured from donors who are not screened for HBcAb. HBcAb should be interpreted cautiously in any patient who received IVIg. We recommend HBcAb testing before IVIg administration so that treatments such as rituximab are not withheld unnecessarily. Disclosures:Arnold:Hoffman-LaRoche: Research Funding; Amgen: Consultancy, Honoraria. Meyer:The NCIC CTG is a clinical trials cooperative group. It receives its base grant support from the Canadian Cancer Society Research Institute. Many of its clinical trials include research support from industry. : Research Funding.

Efficacy, Safety and Tolerability of a New 10% Liquid Intravenous Immune Globulin [IGIV 10%] in Patients with Primary Immunodeficiency

The present clinical study was designed to evaluate the efficacy, pharmacokinetics and safety of a new 10% liquid intravenous immune globulin in patients with primary immunodeficiency diseases. Sixty-one adults and children with primary immuno-deficiency diseases received doses of 300-600 mg/kg body weight every 21-28 days for 12 months. No validated acute serious bacterial infections were reported. The 95% confidence interval for the annualized rate of acute serious bacterial infections (primary endpoint) was 0-0.060. A total of four predefined validated other bacterial infections commonly occurring in primary immunodeficiency disease subjects were observed; none were serious, severe or resulted in hospitalization. The median elimination half-life of IgG was 35 days. Median total IgG trough levels varied from 9.6 to 11.2 g/L. Temporally associated adverse experiences were determined for 72 h after each infusion and the most common adverse experience was headache, which was associated with 6.9% of infusions. The study met the primary endpoint for efficacy and demonstrated excellent tolerability of the new 10% liquid intravenous imunoglobulin preparation.

Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders

The safety and efficiency of a novel method of rapid-infusion IV immunoglobulin (IVIg) were retrospectively reviewed in 50 patients with neuromuscular disorders. There were 89 adverse events after 341 rapid infusions (26%), 3.5% of which were considered to be major (requiring hospitalization) and 66% minor. All patients recovered without sequelae, and there were no deaths. Fourteen of 17 patients (82%) receiving maintenance therapy preferred rapid IVIg infusion because of its convenience. Rapid-infusion IVIg can be given safely and conveniently in many patients with neuromuscular disorders.

New Uses for Intravenous Immune Globulin

The Physicians' Desk Reference and the package inserts state that intravenous immune globulin is indicated for patients who have primary antibody immunodeficiency or immune thrombocytopenic purpura, both fairly rare disorders. Why, then, will the pharmaceutical service at my medical center spend $1 million on intravenous immune globulin next year, placing it among the top four drug expenditures? The answer lies in the wide use of intravenous immune globulin in patients with many other conditions (notably, secondary antibody deficiencies, certain infections, and immunoregulatory disorders such as autoimmune and inflammatory diseases), coupled with its very high cost. Articles in this issue of . . .

Cost Effectiveness of Prophylactic Intravenous Immune Globulin in Chronic Lymphocytic Leukemia

A recent randomized controlled trial of intravenous immune globulin in patients with chronic lymphocytic leukemia and hypogammaglobulinemia demonstrated a statistically significant reduction in the rate of bacterial infections among patients who received intravenous immune globulin. We used decision-analysis techniques to determine whether prophylactic intravenous immune globulin is likely to result in an overall clinical benefit to patients who receive this treatment and to examine its cost effectiveness. We constructed a model to compare two strategies: treatment with intravenous immune globulin at a dose of 400 mg per kilogram of body weight every three weeks and no immune globulin therapy. Baseline estimates of the efficacy of intravenous immune globulin were derived from the published results of the randomized trial. The costs of treatment, complications, and infections were estimated on the basis of component costs. Health outcomes were measured in terms of gains in quality-adjusted life expectancy. Intravenous immune globulin therapy can result in a loss of quality-adjusted life expectancy when the inconvenience of treatment is taken into account. If the inconvenience of treatment is not considered, therapy results in a gain of 0.8 quality-adjusted days per patient per year of therapy at a cost of $6 million per quality-adjusted life-year gained. Decision-analysis modeling may be applied to the results of randomized controlled trials to assess the potential clinical and financial effects of adopting the intervention in medical practice. In the case of intravenous immune globulin therapy in patients with chronic lymphocytic leukemia and hypogammaglobulinemia, this type of analysis suggests that treatment might not result in improved quality or length of life and that it is extraordinarily expensive in comparison with other treatments generally accepted as cost effective.

Intravenous immune globulin in patients with acquired immune deficiency syndrome

Infection with the human immunodeficiency virus results in a progressive immune deficiency involving many components of the immune system. The major target cells for injection are CD4 antigen-bearing cells, which include predominantly, but not exclusively, the helper T cell subset and the monocyte-macrophage cell system. Hypergammaglobulinemia is a common and early-feature of human immunodeficiency viral infection but is often associated with an inability to mount specific antibody responses to neoantigens and decreased in vitro B cell differentiation responses. On the basis of our data and reports of others, a major component of B cell hyperactivity is related to the direct activity of the human immunodeficiency virus and its proteins. We and others have documented that B cells of these patients lose the capacity to respond to both T cell-dependent and T cell-independent stimuli in vitro. Thus the human immunodeficiency virus can profoundly influence B cells, causing both “stimulation” (vis-à-vis hypergammaglobulinemia) and “suppression” (poor specific antibody responses). However, the memory cells are probably not suppressed, and their dysfunction may be directly related to the extent of helper cell dysfunction. This explanation lends itself well to the clinical observation that children (who have not developed memory to recall antigens) with human immunodeficiency viral infection have more profound defects in specific antibody responses than do adults (who have an existing pool of memory cells). Thus the main rationale for intravenous immune globulin in acquired immune deficiency syndrome is to provide antibody replacement. We have used intravenous immune globulin in pediatric human immunodeficiency viral infection in the following situations: (1) children with recurrent bacterial infections: (2) children with cytomegaloviral diseases—here intravenous immune globulin is given along with a specific antiviral drug (e.g., ganciclovir): and (3) thrombocytopenia associated with human immunodeficiency virus in which intravenous immune globulin is given with azidothymidine. Currently, we are engaged in a double-blind, placebo-controlled, multicenter trial to test the efficacy of intravenous immune globulin in reducing infections and complications and to evaluate the long-term effects of intravenous immune globulin in children with human immunodeficiency viral infections.

Use of intravenous immune globulin in patients receiving bone marrow transplants

Patients undergoing bone marrow transplantation for acute leukemia or aplastic are a great risk for the development of interstitial pneumonia associated with the cytomegalovirus (CMV). Passive immunization with a CMV immune plasma has been found to be effective for the prevention of interstitial pneumonia after marrow transplantation. Because of the limited availability of high-titered CMV plasma, we studied the kinetics of CMV antibody in bone marrow transplant patients receiving immune globulin intravenous, 5%, in 10% maltose (IGIV). Several lots of IGIV had CMV radioimmunoassay (RIA) antibody titers (1:30,000) comparable to the CMV antibody titers in the CMV immune plasma. A single infusion of 20 cc/kg of IGIV produced a mean peak CMV RIA antibody titer of 1:9,500. This titer fell to 1:1,000 after seven days. These antibody titers were approximately two-to three-fold lower than the CMV RIA antibody titers achieved after a 10 cc/kg dose of the CMV immune plasma. Administration of IGIV at doses lower than 20 cc/kg produced correspondingly lesser increases in the CMV antibody titers of recipients. At all doses, IGIV was well tolerated and caused no significant biochemical abnormalities. Some patients experienced mild elevation of their serum glucose levels and asymptomatic glycosuria. We are presently evaluating the efficacy of IGIV (20 cc/kg given once every week) for the modification of CMV infection and prevention of interstitial pneumonia after bone marrow transplantation in a randomized, controlled study. The effects of IGIV on the incidence and outcome of bacterial, fungal, and other viral infections are also being analyzed.

Long term use of intravenous immune globulin in patients with primary immunodeficiency diseases: Inadequacy of current dosage practices and approaches to the problem

Thirty patients with well-defined primary immunodeficiency diseases seen at Duke University Medical Center between April of 1975 and November of 1981 were given modified immune serum globulin suitable for intravenous use (IGIV) for replacement therapy. Seven patients had infantile x-linked agammaglobulinemia (XAγ), three had x-linked immunodeficiency with hyper IgM (HypM), three had Wiskott-Aldrich syndrome, and 17 had common variable agammaglobulinemia (CVAγ). Twenty-two of the patients received a reduced and alkylated preparation (Gamimune®) over periods of up to five years and 21 have received a beta propriolactone-treated preparation (Intraglobulin®) over a period ranging to 7 months. Fourteen of the Gamimune-treated patients participated in the two-year crossover Phase II efficacy and safety study beginning in April of 1975 and 9 of these participated in the 6-month double-blind crossover study of 10% IGIV in glycine vs 5% IGIV in 10% maltose (Gamimune). Ten of the patients received Gamimune on a monthly basis for more than 5 years, with the other 12 receiving it for lesser periods of time. All patients received an initial loading dose of 200 mg/kg IgG and were maintained on 100 mg/kg/month thereafter. Adverse effects were most frequent with 10% IGIV in glycine and included primarily back and muscle pain, chills, nausea and vomiting; these have been rare with 5% IGIV in 10% maltose (Gamimune). No anaphylactic-type reactions occurred. No patient experienced adverse effects sufficiently severe to necessitate discontinuing a given infusion, and no patient dropped out of the study because of adverse effects. Patients participating in the two-year crossover study were given a choice as to the form of replacement therapy at the conclusion of the study: 10 elected to remain on Gamimune and the other four resumed plasma therapy; no patient elected to resume intramuscular ISG injections. Both intravenous preparations had excellent patient acceptability and have resulted in efficacy at least comparable to that of intramuscular ISG and plasma therapy. Patients with the Wiskott-Aldrich syndrome tolerated IGIV with no adverse effects and were cognizant of a reduction in their frequencies of pyogenic infections. A patient with persistent Echovirus meningoencephalitis was given 500 mg IgG/kg/month for 9 months but remained Echovirus positive.