Adrian C. Newland

International consensus report on the investigation and management of primary immune thrombocytopenia

Previously published guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) require updating largely due to the introduction of new classes of therapeutic agents, and a greater understanding of the disease pathophysiology. However, treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than high-quality clinical trial evidence. This consensus document aims to report on new data and provide consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. The inclusion of summary tables within this document, supported by information tables in the online appendices, is intended to aid in clinical decision making.

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial

BACKGROUND Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. METHODS In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336. FINDINGS A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. INTERPRETATION Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review

Whether the eradication of Helicobacter pylori infection can increase the platelet count in patients with immune thrombocytopenic purpura (ITP) is still a controversial issue. To provide evidence-based guidance, we performed a systematic review of the literature published in English, selecting articles reporting 15 or more total patients. We identified 25 studies including 1555 patients, of whom 696 were evaluable for the effects of H pylori eradication on platelet count. The weighted mean complete response (platelet count > or = 100 x 10(9)/L) and overall response (platelet count > or = 30 x 10(9)/L and at least doubling of the basal count) were 42.7% (95% confidence interval [CI], 31.8%-53.9%) and 50.3% (95% CI, 41.6%-59.0%), respectively. In 222 patients with a baseline platelet count less than 30 x 10(9)/L, the complete response rate was 20.1% (95% CI, 13.5%-26.7%) and the overall response rate was 35.2% (95% CI, 28.0%-42.4%). The response rate tended to be higher in countries with a high background prevalence of H pylori infection and in patients with milder degrees of thrombocytopenia. These findings suggest that the detection and eradication of H pylori infection should be considered in the work-up of patients with seemingly typical ITP.

Inhibition of autophagy abrogates tumour necrosis factor α induced apoptosis in human T-lymphoblastic leukaemic cells

The pattern and the sequence of tumour necrosis factor‐α (TNFα) induced cell death in the acute T‐lymphoblastic leukaemic cell line CCRF‐CEM and its vinblastine‐resistant subline CEM/VLB100 have been studied. Previously, we found that the CEM/VLB100 cell line was more sensitive to TNFα‐induced killing than its parental CCRF‐CEM cell line. TNFα‐induced cell death showed an apoptotic pattern, as detected by agarose electrophoresis, flow cytometry and transmission electron microscopy (TEM). TEM images revealed that autophagy and condensed mitochondria occurred earlier than nuclear fragmentation. The specific inhibitor of autophagy, 3‐methyladenine (3MA), inhibited the formation of autophagosomes. TNFα‐induced DNA fragmentation and cytolysis were completely inhibited by 10 mM 3MA. Inhibition of the fusion of lysosomes with autophagosomes by asparagine did not block TNFα‐induced apoptosis. In addition, amino acid and protein deprivation enhanced TNFα‐induced autophagy but not apoptosis. We propose that the early stages of autophagy are required for, but do not necessarily result in, TNFα‐induced apoptosis.

Platelets circulate in an activated state in inflammatory bowel disease

BACKGROUND/AIMS Platelets show proinflammatory as well as prothrombotic properties. Patients with inflammatory bowel disease are at increased risk of systemic thromboembolism, and multifocal microvascular infarction has been proposed as a pathogenetic mechanism in Crohns disease. The aim of this study was to determine if inflammatory bowel disease is associated with abnormal platelet behavior. METHODS Platelet activation and aggregability were assessed using flow cytometry, Born aggregometry, and the modified method of Wu and Hoak. Serum beta-thromboglobulin was measured in patients with Crohns disease and ulcerative colitis and, as controls, in healthy volunteers and patients with active rheumatoid arthritis. RESULTS Platelet surface expression of P-selectin and GP53 (markers of activation) were increased in Crohns disease (13 of 30 patients abnormal for P-selectin; 9 of 28 abnormal for GP53) (P < 0.01) and ulcerative colitis (9 of 21 for P-selectin; 10 of 21 for GP53) (P < 0.01) compared with healthy controls. Increased circulating platelet aggregates (15 of 24 patients with Crohns disease and 8 of 16 with ulcerative colitis) (P < 0.01), platelet aggregability in vitro, and serum beta-thromboglobulin were detected in active inflammatory bowel disease compared with healthy controls. Platelet behavior in active rheumatoid arthritis resembled that in healthy controls. CONCLUSIONS Increased platelet activation and aggregation are features of inflammatory bowel disease and may contribute to the risk of systemic thromboembolism and the pathogenesis of mucosal inflammation. Therefore, antiplatelet agents may be valuable in the management of inflammatory bowel disease.

An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura.

The objective of this open label, phase 1–2, multicentre trial was to evaluate the safety of AMG 531, a novel thrombopoiesis‐stimulating peptibody, and its effect on platelet counts in adults with immune thrombocytopenic purpura. Four patients were assigned to each of four unit‐dose cohorts: 30, 100, 300 or 500 μg, administered subcutaneously on days 1 and 15 (or day 22 if the day 15 platelet count was >50 × 109/l). Safety was assessed by adverse event (AE) monitoring, clinical laboratory studies and antibody assays. Platelet response was defined as a platelet count double the baseline value and between 50 and 450 × 109/l. Sixteen patients (10 women) were enrolled. The 500‐μg cohort was discontinued because the first patients platelet count became unacceptably high. AEs were generally expected and mild or moderate; the most frequent was headache (eight of 16 patients). Two patients experienced serious AEs related to AMG 531 (severe headache and elevated serum lactic dehydrogenase; thrombocytopenia). Platelet responses occurred with all doses and with a dose equivalent to ≥1 μg/kg in eight of 11 patients. In summary, patients tolerated AMG 531 well at the doses tested. No anti‐AMG or antithrombopoietin antibodies were detected. Doses equivalent to ≥1 μg/kg increased platelet counts.

Long‐term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy

Romiplostim was effective, safe, and well‐tolerated over 6–12 months of continuous treatment in Phase 3 trials in patients with immune thrombocytopenia (ITP). This report describes up to 5 years of weekly treatment with romiplostim in 292 adult ITP patients in a long‐term, single‐arm, open‐label study. Outcome measures included adverse events (including bleeding, thrombosis, malignancy, and reticulin/fibrosis), platelet response (platelet count >50 × 109 per litre), and the proportion of patients requiring rescue treatments. Treatment–related serious adverse events were infrequent and did not increase with longer treatment. No new classes of adverse events emerged. Thrombotic events occurred in 6·5% of patients and were not associated with platelet count. Median platelet counts of 50–200 × 109 per litre were maintained with stable doses of romiplostim (mean 5–8 μg/kg; generally self‐administered at home) throughout the study. A platelet response was achieved at least once by 95% of patients, with a platelet response maintained by all patients on a median 92% of study visits. There was a low rate of bleeding and infrequent need for rescue treatments. In conclusion, this study demonstrated that romiplostim was safe and well‐tolerated over 614 patient‐years of exposure in ITP patients, and that efficacy was maintained with stable dosing for up to 5 years of continuous treatment.

Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database

Background The risk of thromboembolic events in adults with primary immune thrombocytopenia has been little investigated despite findings of increased susceptibility in other thrombocytopenic autoimmune conditions. The objective of this study was to evaluate the risk of thromboembolic events among adult patients with and without primary immune thrombocytopenia in the UK General Practice Research Database. Design and Methods Using the General Practice Research Database, 1,070 adults (≥18 years) with coded records for primary immune thrombocytopenia first referenced between January 1st 1992 and November 30th 2007, and having at least one year pre-diagnosis and three months post-diagnosis medical history were matched (1:4 ratio) with 4,280 primary immune thrombocytopenia disease free patients by age, gender, primary care practice, and pre-diagnosis observation time. The baseline prevalence and incidence rate of thromboembolic events were quantified, with comparative risk modelled by Cox’s proportional hazards regression. Results Over a median 47.6 months of follow-up (range: 3.0–192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01–2.48), 1.37 (95% CI, 0.94–2.00), and 1.41 (95% CI, 1.04–1.91) were found for venous, arterial, and combined (arterial and venous) thromboembolic events, respectively, when comparing the primary immune thrombocytopenia cohort with the primary immune thrombocytopenia disease free cohort. Further event categorization revealed an elevated incidence rate for each occurring venous thromboembolic subtype among the adult patients with primary immune thrombocytopenia. Conclusions Patients with primary immune thrombocytopenia are at increased risk for venous thromboembolic events compared with patients without primary immune thrombocytopenia.

Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults

We conducted a retrospective analysis of 11 consecutive patients with various autoimmune cytopenias who failed to respond to conventional treatments and received a fixed-dose regimen of rituximab (100 mg weekly for 4 consecutive weeks). Sustained complete responses were achieved in 4 out of 7 patients with idiopathic thrombocytopenic purpura and in 1 patient with autoimmune pancytopenia. A partial response was observed in 1 patient with autoimmune hemolytic anemia. The immunotherapy had no effect in 1 patient with pure red cell aplasia or in 1 patient with autoimmune neutropenia. No infusion-related or delayed toxicities attributable to rituximab were experienced by any of the patients.

Angiogenesis and angiogenic mediators in haematological malignancies.

Neovascularization of solid tumours is suggested to be important for tumour growth and metastasis (Folkman et al, 1989). Various investigators have reported that tumours promote angiogenesis by secreting growth factors that stimulate endothelial cell migration and capillary proliferation (Folkman, 1995a,b; Mantovani et al, 1997; Nicosia, 1998) Indeed, angiogenic activity in a given tumour governs the potential for metastases and inhibition of angiogenesis may prove significant in suppressing neoplastic growth and invasiveness (Folkman, 1995b; Boehm et al, 1997; Cheresh, 1998; Benjamin et al, 1999). The role of angiogenesis in haematological malignancies is beginning to be identified (Vacca et al, 1995, 1997; Ribatti et al, 1996; Perez-Atayde et al, 1997). It is reported that the circulation within the bone marrow is similar to lymphoid tissues, i.e. lymph nodes, liver and spleen, and the lymphohaemopoietic tissue growth and function is dependent on its intravascular bed (Branemark, 1968; Bruyn et al, 1970). The prognostic role of neovascularization in lymphohaemopoietic malignancies remains contentious. This review focuses on the development of the microvascular bed, assessment of angiogenesis, its prognostic value and the possible therapeutic role of antiangiogeneic factors in haematological malignancies.