Efficacy and tolerability of old and new drugs used in the treatment of immune thrombocytopenia: Results from a long-term observation in clinical practice.

BACKGROUND: Many patients with immune thrombocytopenia (ITP) may require special attention and long-term treatment. Little is known on the efficacy and tolerability of the drugs used in practice. MATERIAL AND METHODS: We retrospectively reviewed the results of therapy of 400 patients with chronic ITP. All Patients were treated at our institution between 1996-2016 under consideration of guidelines, general recommendations, and individual aspects, including gender, age, weight, comorbidity, patient's medical history and bleeding risk. RESULTS: Treatment was not required in 25% of patients (n = 100) during observation. In treated patients (n = 300), the rate of patients that responded and tolerated treatment with prednisolone was 59% (52/88), with azathioprine 32% (29/90), with eltrombopag 49% (31/63), with romiplostim 59% 27/45, with IVIG (intravenous immunoglobulines) 75% (94/126), with anti-D 37% (19/52) and with dexamethasone 60% (25/42) patients. Eighteen treated patients (6%) entered sustained remission after treatment with various drugs. Twenty-six patients underwent splenectomy (Splx) resulting in sustained remission in 15 cases (60%). Only two patients remained refractory to Splx and to all used drugs. DISCUSSION: None of the currently available drugs used in the treatment of ITP are invariably safe and effective. Responses, the duration of response, intolerability, and the course of disease are unpredictable. Although the treatment of ITP has considerably improved in the recent years, the currently available drugs may rarely cure affected patients. The need for safe and effective therapy in ITP is evident. Optimal treatment decisions for each patient remains a challenge in many cases.

Comparative treatment-related adverse event cost burden in immune thrombocytopenic purpura.

AIMS: Real-world evidence on the safety profile and costs associated with immune thrombocytopenic purpura (ITP) treatment in adults is lacking. This study quantifies and compares adverse event (AE) crude rates and costs associated with ITP treatments as found in claims data. MATERIALS AND METHODS: A retrospective claims-based analysis was conducted using IMS Pharmetrics Plus database. Included patients were ≥18 years old, with a diagnosis of ITP (2007-2012); an ITP-related claim for anti-D, intravenous immunoglobulin (IVIG), rituximab, romiplostim, or eltrombopag; and 1-year continuous enrollment (3-years for rituximab) during follow-up. AEs and event costs were identified during active treatment, defined from the first claim of each drug to a pre-defined treatment gap or end of study period. Descriptive statistics were reported with Wilcoxon rank-sum significance tests. RESULTS: A total of 2,518 patients were identified (mean age = 50.8 (±16.3 years); 55.8% male). Of all patients, 22.8% experienced any AE. Significantly fewer anti-D patients had any AE (13.8% vs IVIG: 21.1%, rituximab: 29.4%, romiplostim: 28.1%, eltrombopag: 22.4%). Nausea/vomiting and arthralgia/musculoskeletal pain were most common across treatments, and hemolytic events did not differ significantly across treatments. Most costly AEs were urinary tract infection, aseptic meningitis, and fever ($5000+/case); headache, nasal congestion, and hemolytic event were $4,000-5,000/case. Cost per AE did not differ by treatment. LIMITATIONS AND CONCLUSIONS: Although lower than trial-based AE rates, claims for ITP treatment-related AEs are common, with higher numbers for rituximab and lower numbers for anti-D. This disparity suggests a possible differential cost burden overall that future analysis should explore.

Disease outcomes in a cohort of women in Ireland infected by hepatitis C-contaminated anti-D immunoglobulin during 1970s.

BACKGROUND & AIM: In the mid-1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotype 1b infection, following administration of contaminated anti-D immunoglobulin in 1977-79. We aimed to describe their disease history and estimate the effect of selected host and treatment factors on disease progression. METHODS: We conducted a cohort study on the women infected with HCV. Information was collected from records at seven HCV treatment centres on demographics, treatment and health outcomes up to the 31st December 2013. We calculated cumulative incidence, case fatality, and sub hazard ratios (SHR) for disease progression using competing risks regression. RESULTS: Six hundred and eighty-two patients were included in the study. Among the chronically infected patients (n=374), 35% completed interferon-based antiviral treatment; 42% of whom had a sustained virological response. At the end of 2013, 19%, 1.9%, and 4.9% of chronically infected patients had developed cirrhosis, hepatocellular carcinoma, and liver-related death, respectively, compared with 10%, 0.8%, and 2.4% at the end of 2008. At the end of 2013, 321 (86%) of the chronically infected patients remained alive, 247 (77%) of whom were still chronically infected. Factors associated with increased cirrhosis rates included high alcohol intake (aSHR=4.9 [2.5-9.5]) and diabetes mellitus (aSHR=5.0 [2.9-8.8]). CONCLUSIONS: Development of liver-related outcomes accelerated with time, with the risk of cirrhosis, hepatocellular carcinoma, and liver-related death doubling in the last five years of follow-up, particularly in women with high alcohol consumption and diabetes mellitus. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of alcohol, and that data be collected on this cohort after a further five years to analyse the effect of subsequent antiviral treatment during this rapidly evolving period in HCV treatment history. LAY SUMMARY: In the mid-1990s, a group of women were diagnosed with chronic hepatitis C virus (HCV) infection following receipt of contaminated anti-D immunoglobulin between 1977 and 1979 in Ireland. Seventy-two (19%) developed cirrhosis and 18 had died from liver-related causes (5%) after 36years of infection. Disease progression accelerated in the last five years of follow-up, particularly in women with diabetes mellitus and high alcohol consumption. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of high alcohol consumption.

Anti-D immunoglobulin therapy for pediatric ITP: before and after the FDA's black box warning.

In March 2010, the Food and Drug Administration (FDA) issued a black box warning for anti-D immunoglobulin (anti-D), an approved treatment for immune thrombocytopenia (ITP). It is unknown if and how clinical practice at U.S children's hospitals has since changed. We sought to describe inpatient anti-D usage, laboratory monitoring, and anti-D complications before and after the FDA warning. Using the Pediatric Health Information System, we collected data from 41 children's hospitals. There was a modest but statistically significant decrease in anti-D usage from pre-warning to post-warning. Severe complication rates were very low and did not change appreciably.

Dermatofibrosarcoma protuberans arising at a Rho(D) immune globulin injection site.

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue tumor arising in the dermis. It is notorious for high rates of local recurrence despite its low metastatic potential. Although the etiology is unknown, DFSP often is considered to arise within scars and at sites of prior vaccination or trauma. Clinically, DFSP can be highly variable and mimic other soft tissue proliferations. We present a case of recurrent DFSP arising at the site of a Rho(D) immune globulin (Rhlg) injection that was administered 7 years prior. We also discuss the diagnostic challenges of DFSP as well as the indolent and locally recurrent nature of the tumor. This case serves to remind dermatologists of the highly variable clinical appearance of DFSP as well as to warn against presumptive diagnoses of lesions that mimic keloids and hypertrophic scars.

A single dose of anti-D immunoglobulin raises platelet count as efficiently as intravenous immunoglobulin in newly diagnosed immune thrombocytopenic purpura in Korean children.

OBJECTIVE: The aim of this study is to compare the efficacy and safety of a single dose of anti-D immunoglobulin (anti-D) at 50 mug/kg to intravenous immunoglobulin (IVIG) in Korean children with acute immune thrombocytopenic purpura (ITP). METHODS: We performed this study prospectively by randomly administering 2 consecutive doses of IVIG at a dose of 1.0 g/kg/dor a single dose of anti-D at 50 microg/kg to children upon initial diagnosis of acute ITP. The platelet count and adverse events, including hemoglobin concentration, were then serially evaluated, and the responses were compared. RESULTS: The likelihood of having a platelet count greater than 20x10/mm after 3 days of treatment in the IVIG and anti-D group was 93% and 92%, respectively. In addition, hemoglobin concentration in the anti-D group had declined more than that of the IVIG group (1.49 g/dL vs. 0.80 g/dL, P=0.014) 3 days after treatment. Fever, chills, and headache occurred less frequently in the anti-D group than the IVIG group, however, this difference was not statistically significant (25% vs. 45%, P=0.494). CONCLUSIONS: A single dose of 50 microg/kg of anti-D raised platelet count as efficiently as IVIG in newly diagnosed cases of ITP in Korean children. Although 50 microg/kg of anti-D had a greater effect on the hemoglobin concentration than IVIG, the adverse effects were found to be acceptable, and no serious events were observed.

Anti-D immunoglobulin-induced prolonged intravascular hemolysis and neutropenia.

Intravenous anti-D immunoglobulin (anti-D IVIG) is indicated for the treatment of immune thrombocytopenic purpura (ITP) in nonsplenectomized patients who are Rh(D)-positive. Recent reports have described episodes of intravascular hemolysis after anti-D IVIG. We report an adolescent boy with chronic ITP who required multiple transfusions of erythrocyte suspensions when intravascular hemolysis persisted for 6 months after anti-D IVIG treatment. He did not have hemolytic anemia before treatment. The features of our case suggest that pediatric patients treated with anti-D IVIG for ITP should be closely monitored for signs and symptoms of hemoglobinemia and/or hemoglobinuria, and clinically significant anemia. Our case proposes that persistence of immune hemolysis after this treatment may be related to presence of previously defined predisposing agents like tuberculosis and antituberculous therapy. Our observations suggest that steroid therapy can be effective in patients who developed prolonged hemolytic anemia and neutropenia after anti-D IVIG therapy.

Renal failure after anti-D globulin treatment of idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura (ITP) is a disorder of rapid destruction of antibody-coated platelets. Anti-D immune globulin has been used for treatment of ITP in the United States since 1995. Initial studies identified no significant side effects of treatment. However, a recent report highlighted occasional episodes of intravascular hemolysis after anti-D immune globulin. We describe two children with ITP who developed acute renal failure (ARF) after treatment with anti-D immune globulin and also analyze ten additional cases of ARF reported to the manufacturer, Cangene Corporation, through postmarketing surveillance. All episodes of ARF were associated with intravascular hemolysis. Four patients required dialysis. Patient age ranged from 1 to 82 years, but those requiring dialysis were all under age 15 years. Several patients with ARF had preexisting creatinine elevation. Three of the patients with ARF had serologic evidence of acute Epstein-Barr virus (EBV) infection. Renal biopsy in one patient showed acute tubular necrosis, with findings consistent with pigment nephropathy. Anti-D immune globulin, used to treat ITP, may be associated with intravascular hemolysis and resultant ARF. Renal function should be monitored in patients with evidence of intravascular hemolysis. Children and adolescents may have increased risk of ARF requiring dialysis.

Intravenous anti-D immune globulin-induced intravascular hemolysis in Epstein-Barr virus-related thrombocytopenia.

RhoD immune globulin intravenous (anti-D IGIV) increases platelet counts in patients who have not undergone splenectomy and are positive for RhoD with idiopathic thrombocytopenic purpura. After treatment, in most patients, anemia develops as a result of immune-mediated red cell destruction in the spleen. Although intravascular hemolysis (IVH) is not expected, life-threatening IVH has been recently reported by the Food and Drug Administration, and physicians are encouraged to report their experience with patients with idiopathic thrombocytopenic purpura in whom IVH develops after anti-D administration. Severe IVH was observed after treatment with anti-D IGIV in two adolescent girls with acute thrombocytopenia related to Epstein-Barr virus. They did not have hemolytic anemia before treatment. The authors believe that anti-D IGIV triggered an unusual virus-induced immune response causing hemolysis; therefore, anti-D IGIV should not be used in patients with Epstein-Barr virus-related thrombocytopenia, particularly during the acute phase of infection.

Changes in liver histopathology in women infected with hepatitis C through contaminated anti-D immunoglobulin injections in Ireland.

OBJECTIVE: To evaluate histological findings in untreated chronic hepatitis C patients at diagnosis 17 years after infection and to assess histological progression on repeat liver biopsy 2 years later. PATIENTS: Thirty patients infected with hepatitis C virus (HCV), genotype 1b, by contaminated anti-D immunoglobulin in Ireland in 1977 were studied. These patients were diagnosed in 1994 for the first time. All patients were positive for HCV-RNA by polymerase chain reaction (PCR). METHODS: Each patient underwent two liver biopsies approximately 2 years apart 17 and 19 years after initial infection. The liver biopsies were scored by two pathologists by the modified histological activity index using a numerical score. At first liver biopsy at time of presentation, eight patients had normal alanine aminotransferase (ALT), four had an ALT of more than 100 IU/I and 18 had an ALT level between 40 and 100 IU/I. RESULTS: In the initial (1994) biopsies, the median grade (inflammation) was 5/18, range 1-9 and the median stage (fibrosis) was 2/6, range 0-6. One patient showed cirrhosis (stage 6/6) and six patients (20%) had developed moderate fibrosis (stage 3-4/6). On the repeat biopsy, 2 years later, median grade (inflammation) was 5/18, range 2-9 and stage (fibrosis) was 1/6, range 0-6. CONCLUSION: This group of patients, infected with HCV genotype 1b and untreated for 19 years, allows evaluation of the natural history of this virus. The majority of patients showed mild chronic hepatitis. Only one patient had developed cirrhosis. There was no significant histological disease progression between the two biopsy specimens over a 2 year period. The results suggest that the prognosis in such cases could at least be guardedly optimistic and that sequential liver biopsy may be performed less frequently.

Risk of hepatitis C infection in neonates transfused with blood from donors infected with hepatitis C.

This look-back study was undertaken to identify newborn infants who had been infected with the hepatitis C virus (HCV) as a result of transfusions received before the introduction of routine screening in 1991 and to determine the transmission rates and persistence of transfusion-transmitted HCV infection acquired in the neonatal period. A total of 24 infants, transfused between 1980 and 1991, were identified as having received potentially infected blood from 11 blood donors. Ten of the donors had been administered batches of anti-D in 1977 known to have transmitted HCV genotype 1b infection. HCV RNA was detected in five of these donors when tested in 1994-95; the past donations of five of the donors, who had received anti-D immunoglobulin and had serological evidence of previous HCV infection but who were PCR negative when tested in 1994-95, were considered of lower risk. The source and time of acquisition of HCV infection for the one remaining donor in the study was not determined. Twenty-one (88%) of the 24 children were living at time of lookback. The median age at transfusion was 12 days. The median age at time of testing was 6.3 years. One child, who tested negative, was excluded from further analysis of HCV transmission, due to incomplete transfusion records. Overall, 12 of 20 (60%) children tested were positive for anti-HCV and seven (35%) were HCV RNA positive. Twelve (71%) of the 17 recipients of viraemic blood were ELISA positive and seven (41%) were PCR positive. Resolved HCV infection, as determined by ELISA pos, RIBA pos or indeterminate and PCR negativity, occurred in five of 12 (42%). In many instances there was more than one recipient per HCV infected donation. All of the reported children are clinically asymptomatic. However, the duration of HCV infection is relatively short and there is evidence of a degree of hepatitis in five of the seven children who are HCV RNA positive as judged by mildly elevated transaminase levels. The three who have undergone liver biopsy show mild hepatitis. The lower rates of persistence of HCV infection in this study may be due to the young age at exposure or to the source of infection which for all but one of the children was linked to one HCV genotype from female donors. Sharing of units of blood among multiple infants should be discouraged.

Hepatitis C virus liver disease in women infected with contaminated anti-D immunoglobulin.

Screening for hepatitis C virus (HCV) infection is carried out by detection of antibodies to the virus (enzyme-linked immunosorbent assay (ELISA) and recombinant immunoblot assay (RIBA)) with confirmation by identification of HCV RNA genome in serum (polymerase chain reaction (PCR)). We describe the histological features on liver biopsy in 88 women with chronic HCV infection (serum positive on ELISA, RIBA and PCR) acquired from virus contaminated anti-D immunoglobulin. For the majority of these patients the time interval from virus infection to presentation was between 17 and 18 years. We separately assessed necroinflammatory disease activity and architectural features on liver biopsy and applied a scoring system which permitted semi-quantitative documentation of abnormal features. Only three women showed liver biopsies within normal limits (+/-focal steatosis). The remaining 85 cases showed a predominantly mild or moderate degree of disease activity with interface hepatitis (56.8% of cases), spotty necrosis, apoptosis and focal inflammation (88.6% of cases) and portal inflammation (90.9% of cases). Confluent necrosis was an uncommon finding (2.3% of cases). Assessment of architectural features showed normal appearance in 35.2% of biopsies. The predominant architectural abnormality noted was portal tract fibrosis. Ten per cent of cases, however, showed significant fibrous band and/or nodule formation.

The use of anti-D to improve post-transfusion platelet response: a randomized trial.

Patients undergoing induction chemotherapy for acute leukaemia often become refractory to platelet transfusions. Increased clearance of transfused platelets due to alloimmune destruction has been identified as one of the primary mechanisms contributing to this refractory state. We performed a double-blind randomized trial to determine whether the administration of anti-D to Rh-positive individuals could prevent the refractory state and improve post-transfusion platelet response. Rh-positive patients with acute leukaemia undergoing induction chemotherapy and requiring platelet transfusions were allocated to weekly intravenous anti-D (20 micrograms/kg) or placebo. Platelets and red cell concentrates were administered according to standardized transfusion guidelines. Outcome measures included platelet transfusion utilization, red cell utilization, platelet recovery 18-24 h post-infusion, and the percentage of patients refractory to platelet transfusion. There were 43 patients studied: 21 received anti-D and 22 saline placebo. The mean number of platelet concentrates required per day of observation was 0.59 (SD 0.22) in the anti-D group and 0.61 (SD 0.22) in the placebo group, P = 0.86. No difference was detected between groups in terms of platelet recovery post-infusion, refractoriness to platelet transfusion or frequency of infection (P = 0.97). Red cell concentrate utilization was significantly increased in the anti-D group compared to the placebo group, 0.58 units per day versus 0.37 units per day respectively, P = 0.005. We conclude that the use of anti-D did not improve post-transfusion platelet response in Rh positive patients with acute leukaemia, but did result in an increased need for red cell transfusion.