TOPIC:

Thrombopoietin-receptor agonists (Tpo-RAs) are highly effective in immune thrombocytopenia (ITP). Recently, cases of durable remission after Tpo-RA discontinuation in adult ITP have been reported. We aimed to describe the subset of patients in whom transient Tpo-RA therapy may induce a durable response. We studied all adults with primary ITP treated with at least one Tpo-RA over a 5-year period (n = 54) and seen at one of three participating referral centres in France. Tpo-RAs were discontinued in 20 of 28 patients who achieved a complete response. We excluded six patients because a previous treatment at the start of Tpo-RA treatment may have interfered with the response. Overall, eight patients with chronic ITP showed a sustained response [median follow-up: 13·5 months (range 5-27 months)]. We could not identify a predictive factor of sustained response. In conclusion, a substantial proportion of ITP patients receiving Tpo-RAs can maintain a durable response after treatment discontinuation.

www.ncbi.nlm.nih.gov/pubmed/24725224

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and inclusion bodies in leukocytes. Recent evidence links MHA to mutations in the MYH9 gene. MHA has not been reported in Taiwan before. We report a 25-year-old Taiwanese man who presented with prolonged bleeding after dental extraction. Examination of peripheral blood smear revealed thrombocytopenia (platelet = 35,000/μL), giant platelets, and Döhle-like cytoplasmic inclusions in neutrophils. A strong family history of thrombocytopenia favored hereditary macrothrombocytopenia over idiopathic thrombocytopenic purpura (ITP). Electron microscopy revealed a spindle shape and parallel order of filaments in the inclusions, consistent with the diagnosis of MHA. We performed mutational analysis using polymerase chain reaction followed by direct sequence of the MYH9 gene for the patient, his maternal uncle and cousin, and all showed the same heterozygous R1933X mutation in exon 40. MHA should be considered when a young patient has thrombocytopenia, frequently misdiagnosed as ITP. Morphological examination of peripheral blood smear, family history tracing and genetic studies are required to make an accurate diagnosis and avoid unnecessary and even harmful therapies such as corticosteroids and splenectomy.

www.ncbi.nlm.nih.gov/pubmed/23759689

Adults with newly-diagnosed or persistent Immunothrombocytopenia frequently relapse upon tapering steroids; adults and children with chronic disease have an even lower likelihood of lasting response. In adults with newly-diagnosed Immunothrombocytopenia, 2 studies showed that dexamethasone 40mg/dayx4days and 4 rituximab infusions were superior to dexamethasone alone. Studies have also shown 3 cycles of dexamethasone are better than one and patients with persistent/chronic Immunothrombocytopenia respond less well to either dexamethasone or rituximab. Therefore 375mg/m2x4 rituximab was combined with three 4-day cycles of 28mg/m2 (maximum40mg) dexamethasone at 2-week intervals and explored in 67 ITP patients. Best long-term response was assessed as complete (platelet count≥100x109/L) or partial (50-99x109/L). Only 5 patients had not been previously treated. Fifty achieved complete (43, 64%) or partial (7, 10%) responses. Thirty-five/50 responders maintained treatment-free platelet counts >50x109/L at median 17 months (range4-67) projecting 44% event-free survival. Duration of Immunothrombocytopenia <24 months, achieving complete responses, and being female were associated with better long-term response (p-values <0.01). Adverse events were generally mild-moderate, but 3 patients developed serum sickness and 2 colitis; there were no sequelae. Dexamethasone could be difficult to tolerate. Fourteen patients became hypogammaglobulinemic and half had increased frequency of minor infections; 9/12 evaluable recovered their IgG levels. Rituximab combined with 3 cycles of dexamethasone provides apparently better results to reported findings with rituximab alone, dexamethasone alone, or the combination with 1 cycle of dexamethasone. The results suggest medical cure may be achievable in immunothrombocytopenia, especially in women with and in patients within 2 years of diagnosis.

www.ncbi.nlm.nih.gov/pubmed/24747949

Patients with immune thrombocytopenia (ITP) paradoxically have an increased risk of thrombosis. The presence of antiphospholipid antibodies (aPL) has been observed in a substantial proportion of ITP patients, but its clinical significance remains to be established. This study retrospectively investigated the prevalence and clinical significance of aPL in ITP patients and assessed the risk factors for thrombosis. One hundred and sixty-five subjects with ITP were included in the study and followed for a mean period of 63·4 months. Sixty-nine (41·6%) patients were positive for aPL at diagnosis, and their clinical characteristics and course of ITP were not different from those of aPL-negative patients. Twenty-one (12·7%) patients developed a thrombotic event during follow-up and the cumulative incidence rate ratio of aPL-positive to aPL-negative patients for thromboembolism was 3·15 [95% confidence interval (CI) 1·21-8·17] after adjusting for confounding factors. Lupus anticoagulant and hypertension were identified by Cox regression analysis as independent risk factors for thrombosis [hazard ratio (HR) 4·1, 95% CI 1·4-11·9, P = 0·009 and HR 5·6, 95% CI 1·9-15·8, P = 0·001, respectively]. Our results showed that a substantial proportion of ITP patients were aPL-positive, and that lupus anticoagulant and hypertension were independent risk factors for thrombosis. Detection of aPL can provide useful information for identifying patients at high-risk for developing thrombosis.


www.ncbi.nlm.nih.gov/pubmed/23530551

It has been suggested that patients with ITP have an increased thrombotic risk compared to the general population and compared to those with other causes of acquired thrombocytopenia. The pro-coagulant role of microparticles in some clinical situations has been reported, yet, very little data is available about microparticles in ITP and their effect.
Aim of the work

To assess the levels of red cell microparticles (RMP), platelet microparticles (PMP) and their possible relation to some haemostatic parameters in ITP patients
Patients and methods

The levels of RMP and PMP in addition to FVIII, FIX, FXI, PC and aPTT were assessed in 29 patients with chronic ITP (8 of them had splenectomy). Ten apparently healthy volunteers served as controls. We compared the levels of the studied parameters in ITP patients with that in controls. Correlations of these parameters with each other and with the platelet count were studied.
Results

RMP (p = 0.0001), PMP (p = 0.0001), D- dimer (p = 0.048), FVIII (p = 0.049), FIX (p = 0.0001) and FXI (p = 0.0001) were significantly higher in ITP patients compared to controls. aPTT was significantly longer in ITP patients (p = 0.0001) but PC showed no significant difference. However, RMP was associated with shorter aPTT. Generally, the coagulation factors were negatively correlated with platelet count in ITP patients. Compared to controls, ITP patients preserved higher levels of RMP and PMP even in those with near-normal platelet count. Splenectomy was associated with lower FIX (p = 0.0001) and FXI (p = 0.028) and higher RMP (p = 0.0001).

In conclusion

Chronic ITP was associated with increased levels of RMP and PMP. FVIII, FIX and FXI were increased in ITP patients but showed a negative correlation with platelet count. Splenectomy was associated with increased levels of RMP and lower levels of FIX and F XI. The high level of microparticles in ITP might point towards a prothrombotic tendency.

www.sciencedirect.com/science/article/pii/S0049384812008420

Immune thrombocytopenia (ITP) results from platelet destruction and production suppression. Eltrombopag belongs to a new class of thrombopoietin-mimetic drugs that raise platelet counts in ITP patients. We performed a single-arm study to assess the response to a single course of dexamethasone (40 mg by mouth, days 1-4) in combination with eltrombopag (50 mg, days 5-32) in 12 adults with newly diagnosed ITP in an outpatient setting. Median follow-up was 12.5 months. After therapy (day 33), 100% of patients achieved at least ≥30 × 109/L platelets. Four patients relapsed. Complete response at 6 months (platelets ≥100 × 109/L) was achieved in 50% of patients and response at 6 months (platelets ≥30 <100 × 109/L) was achieved in another 25%; relapse-free survival was 66.7% at 12 months (median response duration of 8.3 months). In conclusion, eltrombopag/dexamethasone is a feasible frontline therapy for ITP. This trial is registered at www.clinicaltrials.gov as NCT01652599.

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bloodjournal.hematologylibrary.org/content/123/25/3906.abstract?sso-checked=1

Stimulation of platelet production by thrombopoietin-receptor agonists (TPO-RAs) is an effective second-line treatment in immune thrombocytopenia (ITP). This 28-day phase 2 study assigned subjects with ITP of ≥3 months to once-daily oral avatrombopag (2.5, 5, 10, or 20 mg), an investigational nonpeptide TPO-RA active in humans, or placebo; subjects completing randomized treatment could enroll in a 24-week extension study. Of 64 randomized subjects, 13% (avatrombopag 2.5 mg), 53% (5 mg), 50% (10 mg), and 80% (20 mg), vs 0% for placebo, achieved a platelet count (PC) response of ≥50 × 109/L with ≥20 × 109/L increase above baseline at day 28. Fifty-three subjects (83%) entered the extension: 52% and 76% had a durable (PC response at ≥75% of their platelet assessments over the last 14 weeks) and overall (stable response or response at any ≥2 consecutive visits) response, respectively. All subjects experienced ≥1 adverse event (AE) (most commonly fatigue, headache, and epistaxis); 19% (n = 12) reported ≥1 serious AE; 10 (16%) withdrew due to an AE (5 due to increased PC). Avatrombopag was active and generally well tolerated, with PC response rates and AE incidence comparable with other TPO-RAs. These studies were registered at www.clinicaltrials.gov as #NCT00441090 and #NCT00625443.

More at:

bloodjournal.hematologylibrary.org/content/123/25/3887.abstract?ct=

MONDAY, July 21, 2014 (HealthDay News) -- Scientists report they have discovered a new way to make fully functional human platelets, which are the blood cells that form clots.

Using human stem cells and a device called a bioreactor, which mimics the body's natural way of producing blood cells but on a larger scale, the researchers said their method eliminates risks and complications associated with donor blood transfusion. Those include a five-day shelf-life, contamination, rejection and infection. They added that their findings could help meet increasing global demand for donor blood.

"The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us to meet the growing need for blood transfusions," study author Jonathan Thon, from the division of hematology at Brigham and Women's Hospital in Boston, said in a hospital news release.

Blood cells, such as platelets, are made in bone marrow. The bioreactor, the researchers explained, combines the major components of bone marrow and models its composition and blood flow characteristics.

"By being able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation," study senior author Joseph Italiano Jr., of the division of hematology at Brigham and Women's Hospital and the Vascular Biology Program at Boston Children's Hospital, said in the news release.

The researchers hope to begin human clinical trials in 2017.

"The regulatory bar is appropriately set high for blood products, and it is important to us that we show platelet quality, function and safety over these next three years since we'll likely be recipients of these platelets ourselves at some point," Thon said.

One expert agreed the findings could change the way platelets are collected.

"A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research," Dr. William Savage, medical director of the Kraft Family Blood Donor Center at Dana Farber Cancer Institute/Brigham and Women's Hospital, said in the news release. He was not part of the study. "This study addresses that gap, while contributing to our understanding of platelet biology at the same time."

In the United States, more than 2.17 million platelet units from donors are transfused each year to treat trauma patients and those undergoing chemotherapy, organ transplants and surgery, the researchers noted.

The study, published July 21 in the journal Blood, was partially funded by the U.S. National Institutes of Health. Thon and Italiano are co-founders of Platelet BioGenesis, a company that aims to produce donor-independent human platelets from human stem cells.


consumer.healthday.com/circulatory-system-information-7/blood-disorder-news-68/scientists-discover-new-way-to-make-human-platelets-689938.html

A multi-centre, single-arm, open-label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R-ITP1000 study).
Tran H1, Brighton T, Grigg A, McRae S, Dixon J, Thurley D, Gandhi MK, Truman M, Marlton P, Catalano J.
Author information
Abstract

The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 × 109 /l and ≤50 × 109 /l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1-8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 × 109 /l) or partial response (PR; platelet count >50 × 109 /l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 × 109 /l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m2 four-dose schedule in relapsed/chronic ITP.

© 2014 John Wiley & Sons Ltd.

www.ncbi.nlm.nih.gov/pubmed/25041261

Abstract
OBJECTIVE:

This post hoc analysis evaluated romiplostim self-administration (SA group) versus romiplostim administration by a healthcare provider in a clinical setting (HCP group) in patients with chronic immune thrombocytopenia (ITP).
METHODS:

Outcomes from 3 ITP trials allowing self-administration in patients achieving a stable romiplostim dose for ≥3 consecutive weeks were compared. Evaluations were conducted for 12-week treatment intervals. Efficacy endpoints included percentage of patients and weeks with platelets within the target range of 50-200×109 /L and safety.
RESULTS:

Baseline characteristics suggested less severe disease in the SA groups (n=563) than in the HCP groups (n=241). The SA groups had greater proportions of patients achieving the target platelet range (55%-58% vs 40%-52%) and greater proportions of weeks with a platelet response (75%-88% vs 47%-76%) than the HCP groups. The rate of romiplostim discontinuation was 2- to 5-fold lower in the SA groups than in the HCP groups. Rates of duration-adjusted adverse events (AEs), serious AEs, and treatment-related AEs were also lower in the SA groups.
CONCLUSIONS:

In conclusion, in adults with ITP receiving romiplostim, self-administration was comparable to healthcare provider administration in terms of efficacy and safety profiles, suggesting that self-administration of romiplostim is a feasible option for certain patients with ITP. This article is protected by copyright. All rights reserved.

www.ncbi.nlm.nih.gov/pubmed/25039799

Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT.

More......

www.bloodjournal.org/content/124/6/e4.abstract?sso-checked=1

Abstract
BACKGROUND:

An increased risk of thrombosis has been reported in primary immune thrombocytopenia (ITP) and with the use of thrombopoietin (TPO) receptor agonists, on the basis of population studies using administrative databases.
OBJECTIVES:

To evaluate if the incidence of venous and arterial thrombosis in patients with primary ITP is higher than a clinically significant cut-off set at of 3% and 6.4%.
PATIENTS/METHODS:

We undertook a retrospective multicenter investigation in a large cohort of patients requiring at least one treatment for ITP, enrolled from the major tertiary Italian centers treating ITP. A total of 986 patients were analyzed.
RESULTS:

During a 3888 patient-year follow-up, 43 first thrombotic events occurred: 28 arterial and 15 venous, resulting in a cumulative incidence of 3.2% for arterial (95% CI, 2.0-5.0) and 1.4% (95% CI, 0.8-2.5) for venous thrombosis at 5 years. The annualized rates for 100 patient-years were 1.14 (95% CI, 0.84-1.54), 0.39 (95% CI, 0.23-0.65) and 0.71 (95% CI, 0.49-1.04) for total, venous and arterial thrombosis. Splenectomy, performed in 136 patients (13.7%), increased thrombotic risk (HR = 3.5, 95% CI) compared with non-splenectomized patients. Age > 60 years, more than two risk factors for thrombosis at diagnosis and steroid use were independently associated with an increased risk of thrombosis.
CONCLUSIONS:

In this study, we demonstrate that the 5-year cumulative incidence of venous and arterial thrombosis in ITP is well below the predefined thresholds. Venous and arterial thromboembolism are not frequent complications in ITP, except in particular settings, such as in splenectomized and elderly patients.

© 2014 International Society on Thrombosis and Haemostasis.


www.ncbi.nlm.nih.gov/pubmed/24942752

The title says:

Thrombotic risk in patients with primary immune thrombocytopenia is only mildly increased and explained by personal and treatment-related risk factors.

I am guessing that treatment-related risk factors would include not following the 50k platelet count target, but this factor was not mentioned in the abstract. Does anyone have access to the full text?

Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Conclusions R+3Dex provides clearly superior results to rituximab alone. Notably, there was a 75% response rate overall (50/67 pts) compared to 50% with R alone. The 5 year response rate was almost 50% of all patients and 3/5 of responders. In patients who had had ITP for ≤ 2 years, the response is comparable to what has been reported with splenectomy. Specifically the results in the ≤ 2 year group suggest that R+3Dex is an effective way to induce indefinitely normal platelet counts in pts with a “short” duration of ITP. R+3Dex was tolerable although patients had difficulty with 3 cycles of dex. The 21% rate of hypogammaglobulinemia, higher than that seen with R alone, is also evidence of the mechanism of R+3Dex affecting both B cells and plasma cells. The lasting, long-lived, unmaintained responses observed in this study suggest that this combination therapeutic strategy should be further tested in a controlled trial in patients with newly diagnosed, persistent, and early chronic ITP, whether or not they have been previously treated with other agents.
www.bloodjournal.org/content/122/21/2310

Abstract
Background and Objectives

This multicentre, open-label study investigated the safety and efficacy of Gammaplex, a 5% Intravenous Immunoglobulin (IVIg), in patients with idiopathic (immune) thrombocytopenic purpura (ITP).

Materials and Methods

Patients were between the ages of 6 and 70 years; had ITP for at least six months and had a platelet count ≤20×109/L. Eligible patients were dosed with 1 g/kg of Gammaplex on two consecutive days, followed by assessment of safety and efficacy on Days 3, 5, 9, 14, 21, 32 and 90. Response was defined as the increase in platelet count to a threshold of ≥50×109/L on or before Day 9 after the first dose of Gammaplex.
Results

All 35 patients received at least one infusion of Gammaplex. Twenty-nine (83%) patients responded to Gammaplex, similar to the historical control, with a 95% lower one-sided confidence interval of 68.9%. Median duration of response was 10.0 days, with an overall reduction in bleeding episodes. Gammaplex provided supranormal concentrations of total IgG; mean peak concentration (Cmax) of 45.3 g/L (4.53 g/dL), with a mean half-life of 28.5 days. Fifteen patients reported 63 Adverse Drug Reactions (ADRs); the most common were headache (10 patients), vomiting (6 patients) and pyrexia (5 patients). Five of these ADRs were considered serious, one patient had three concurrent Serious Adverse Events (SAEs); these were vomiting, dehydration and headache. Two other patients each had one SAE (headache). There were no unexpected Adverse Events (AEs) or thromboembolic episodes and no significant changes in vital signs, biochemical, haematological and virology results. Conclusion: Gammaplex achieved a very high concentration of serum IgG but was well-tolerated and effective in the treatment of ITP with a similar degree of efficacy to the pre-determined historical control group and the pre-set statistical criteria.
Trial Registration

ClinicalTrials.gov NCT00504075 Clinical Trials Registry India 000016
Go to:
Introduction

Idiopathic (immune) thrombocytopenic purpura (ITP) is an autoimmune disorder affecting both children and adults; it is characterised by a low platelet count, normal results on a bone marrow examination (except possibly for increased megakaryocytes) and the absence of specific causes of thrombocytopenia, such as leukaemia, aplastic anaemia or disseminated intravascular coagulation [1]–[3]. Childhood ITP is typically of acute onset. In more than 70% of children, spontaneous and permanent remission occurs within one year of onset [3], [4]. In contrast, the majority of adults have persistent ITP, although the natural history is less defined than that for ITP in children, and some patients do improve with time [5], [6]. Rarely, life-threatening bleeding occurs, but when it does, intracranial haemorrhage is the principal cause of death [7]. It is generally recognised that serious haemorrhage is most likely to occur when the platelet count falls below 20×109/L [2], [3], [6]. Other bleeding may occur and may result in acute or chronic anaemia. The use of IVIg to increase the platelet count rapidly has been shown in other studies to decrease signs and symptoms of haemorrhage. The first report of the efficacy of IVIg in the treatment of ITP appeared in 1981 [8]. More than 100 studies have subsequently confirmed the safety and efficacy of IVIg as treatment of ITP in children and adults [9]–[14]. A substantial and rapid platelet increase can be achieved with an IVIg dosage of 1 g/kg per day repeated for two consecutive days, and this is now the preferred regimen [11], [15], [16].

Gammaplex, a highly purified, unmodified IVIg, manufactured by BPL from human plasma which is processed by cold ethanol fractionation and chromatography. The process also includes three viral inactivation/removal steps, namely solvent/detergent treatment, nanofiltration (20 nm) and a terminal low pH incubation of the finished product to enhance safety [17].

The purpose of this study was to investigate the efficacy and safety of Gammaplex in patients with ITP. Response to Gammaplex treatment was assessed by the increase in platelet count to a threshold of ≥50×109/L and the duration of the response compared to historical controls [5], [7]–[18]. In addition, pharmacokinetic data are presented for Gammaplex after this high dosage in patients with ITP. Provan et al [19] and Rodeghiero et al [20] reported changes to the definition of types of ITP, following some international reviews. This manuscript briefly discusses these reviews and how this study (GMX02) complies with the revised guidelines.

The product used in this study was a ready-prepared solution for intravenous (IV) administration that contained 5 g human normal immunoglobulin and 5 g D-sorbitol (as a stabiliser) in 100 mL of buffer solution containing: 0.6 g glycine, 0.2 g sodium acetate, 0.3 g sodium chloride and approximately 5 mg Polysorbate 80.

See more:

www.ncbi.nlm.nih.gov/pmc/articles/PMC4043496/

SOUTH SAN FRANCISCO, Calif., July 16, 2014 /PRNewswire/ -- Rigel Pharmaceuticals, Inc. RIGL, +1.17% today announced the initiation of a Phase 3 clinical program for its oral SYK inhibitor, fostamatinib, in patients with ITP (immune thrombocytopenic purpura). The focus of these clinical studies is to evaluate the potential of fostamatinib to increase the platelet counts of patients with chronic ITP. Fostamatinib may provide a novel therapeutic for the underlying cause of this autoimmune disease of the blood.

"Based on our extensive clinical experience with this product candidate, which includes more than 4,500 patient-years of data, we hope to demonstrate that fostamatinib can provide a new treatment option for patients with chronic ITP," said James M. Gower, chairman and chief executive officer of Rigel. Results of Rigel's Phase 2 clinical study, published in Blood(volume 113, number 14), showed that fostamatinib significantly increased the platelet counts of certain ITP patients, including those who had failed other currently available agents.

Fostamatinib in ITP Phase 3 Program DesignA total of 150 ITP patients will be randomized into two identical multi-center, double-blind, placebo-controlled clinical studies. The patients will have been diagnosed with persistent or chronic ITP, and have blood platelet counts consistently below 30,000 per microliter of blood. Two thirds of the subjects will receive fostamatinib orally at 100 mg bid (twice daily), the other third will receive placebo on the same schedule. Subjects are expected to remain on treatment for 24 weeks. At week 4 of treatment, subjects who meet certain platelet count and tolerability thresholds will have their dosage of fostamatinib (or corresponding placebo) increased to 150 mg bid.

The primary efficacy endpoint of this program is a stable platelet response by week 24 with platelet counts at or above 50,000 per microliter of blood for at least 4 of the final 6 qualifying blood draws. Results are expected at year-end 2015.

Immune Thrombocytopenic PurpuraChronic ITP affects an estimated 60,000 – 125,000 people in the US. In patients with ITP, the immune system attacks and destroys the body's own blood platelets, which play an active role in blood clotting and healing. ITP patients can suffer extraordinary bruising, bleeding and fatigue as a result of low platelet counts. Current therapies for ITP include steroids, blood platelet production boosters (TPOs) and splenectomy. Fostamatinib is the only potential therapy that may address the autoimmune basis of the disease.

Taken in tablet form, fostamatinib blocks the activation of SYK kinase inside immune cells. ITP causes the body to produce antibodies that attach to healthy platelets in the blood stream. Immune cells recognize these antibodies and affix to them, which activates the SYK enzyme inside the immune cell, and triggers the destruction of the antibody and the attached platelet. When SYK is inhibited by fostamatinib, it interrupts this immune cell function and allows the platelets to escape destruction.

About Rigel (www.rigel.com)Rigel Pharmaceuticals, Inc. is a clinical-stage drug development company that discovers and develops novel, small-molecule drugs for the treatment of inflammatory and autoimmune diseases, as well as muscle disorders. Rigel's pioneering research focuses on intracellular signaling pathways and related targets that are critical to disease mechanisms. Rigel currently has five product candidates in development: fostamatinib, an oral SYK inhibitor in Phase 3 clinical trials for ITP and expected to enter into a Phase 2 clinical trial for IgA nephropathy in the second half of 2014; R348, a topical JAK/SYK inhibitor currently in Phase 2 clinical trials for dry eye; R118, an AMPK activator in Phase 1 development; and two oncology product candidates in Phase 1 development with partners BerGenBio and Daiichi Sankyo.

This press release contains "forward-looking" statements, including, without limitation, statements related to Rigel's clinical development plans, including the timing, design and nature of planned clinical trials and the timing and nature of results of those trials, as well as the potential activity of fostamatinib with respect to ITP and the ability of fostamatinib to provide a new treatment option for patients with chronic ITP. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "planned," "will," "may," "expect," and similar expressions are intended to identify these forward-looking statements. These forward-looking statements are based on Rigel's current expectations and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward looking statements as a result of these risks and uncertainties, which include, without limitation, the availability of resources to develop Rigel's product candidates, Rigel's need for additional capital in the future to sufficiently fund Rigel's operations and research, the uncertain timing of completion of and the success of clinical trials, market competition, risks associated with and Rigel's dependence on Rigel's corporate partnerships, as well as other risks detailed from time to time in Rigel's reports filed with the Securities and Exchange Commission, including its Quarterly Report on Form 10-Q for the quarter ended March 31, 2014. Rigel does not undertake any obligation to update forward-looking statements and expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein.



www.marketwatch.com/story/rigel-initiates-phase-3-studies-of-fostamatinib-in-itp-2014-07-16-8183350

www.nj.com/hudson/index.ssf/2014/07/hoboken_company_receives_fda_approval.html

Just another IVIG. I wonder what's special about it.

I don't know. Maybe better and longer response time? One could only hope.

Thrombopoietin (TPO) is the major regulator of megakaryopoiesis. Measurement of serum TPO levels may help distinguish between various causes of thrombocytopenia and predict treatment response to TPO receptor agonists. Serum TPO levels from 118 healthy volunteers and 88 patients with abnormal platelet counts were measured using a quantitative ELISA assay. The mean (range) TPO level in healthy volunteers was 39 (7-99) pg/mL. TPO values were correlated with the patient's diagnosis, platelet count, and response to TPO receptor agonists. 88 patients with history of consumptive thrombocytopenia (39) or hypoproliferative thrombocytopenia (49) were analyzed. Median (interquartile range) TPO level for consumptive thrombocytopenia patients was 63 (48-98) pg/mL with a corresponding median (interquartile range) platelet count of 73 (28-146) × 10(9) /L. In contrast, hypoproliferative thrombocytopenia patients had platelet counts [59 (30-117) × 10(9) /L] comparable with consumptive thrombocytopenia patients, but significantly higher serum TPO levels [706 (358-1546) pg/mL, P < 0.0001]. Analysis of 21 ITP patients treated with TPO receptor agonists demonstrated that a TPO level >95 pg/mL was associated with lack of clinical response (P < 0.002). TPO levels may have diagnostic utility in discriminating between patients with hypoproliferative and consumptive thrombocytopenia. Elevated TPO levels in ITP patients may predict a poor clinical response to treatment with TPO receptor agonists.

www.ncbi.nlm.nih.gov/pubmed/23913253

I understand the overall conclusion, that if your thrombopoietin (TPO) levels are highly elevated, then adding TPO receptor agonists (like Promactin and Nplate) is not going to help much.

I understand why having low platelets increases TPO levels as part of a feedback signal that is telling the body to produce more platelets.

What I do not fully understand is why TPO levels are substantially higher with hypoproliferative thrombocytopenia (poor platelet production) than with consumptive thrombocytopenia (platelet destruction).

One important aspect of the results seems paradoxical. If you have a problem with poor platelet production, then TPO agonists won't help. TPO agonists are only helpful if you are destroying platelets too quickly; presumably they cause platelets to be produced fast enough to keep up with platelet destruction.

Are thrombopoietin levels ever tested? I do not remember hearing of anyone being tested.

Have a read of this. It explains beautifully how TPO works and why ITP patients don't have an elevated level.

www.ncbi.nlm.nih.gov/pmc/articles/PMC2789970/

My understanding is that the TPO binds to the platelets and as the platelets are cleared quickly in ITP so is the TPO, so the TPO level goes down. The liver that makes the TPO makes it at a constant rate and is not designed to increase rate due to a low TPO, so the low TPO remains.

Thanks Ann. It helped pull together a lot of difficult concepts. A tough read but well worth it. It was a relief to get to page 15/25 and find the rest was footnotes!

What interested me most was to learn that TPO mimetics (Nplate and Promacta), in addition to stimulating platelet growth, also inhibit the destruction (apoptosis) of early stages of platelet growth (megakaryocyte progenitors).

It was a big surprise to me to learn that steroids act by increasing platelet production. I always thought they acted by suppressing autoimmune response. It was left unclear whether this increase was due to stimulating development or inhibiting apoptosis.

What I find the most interesting is that there may finally be a diagnostic tool to predict success of a certain treatment. As far as I know, testing TPO levels is not currently being done as a standard, but maybe it will be in the near future. This is huge as far as I'm concerned.

When I was first diagnosed in 1998, production problems were not even considered. As far as everyone knew, destruction was the only cause for low platelets and the only treatments were IVIG, steroids, Win-Rho and splenectomy.

I know people get discouraged about the information available, but geez, ITP has come so far so fast! Compared to other autoimmune disorders that can be truly disabling, ITP is pretty advanced.

Abstract

Bleeding is of particular clinical importance in the management of chronic immune thrombocytopenia (ITP), which involves impaired platelet production and accelerated destruction. We report the first comprehensive analysis of the impact of eltrombopag on bleeding in five clinical studies of adult chronic ITP: two 6-week phase 2 (TRA100773A) and phase 3 (TRA100773B) studies; a 6-month phase 3 study (RAISE); a phase 2 repeat-dose study (REPEAT); and a phase 3 extension study (EXTEND). Bleeding was assessed using the World Health Organization Bleeding Scale and categorized as no bleeding (grade 0), any bleeding (grades 1-4), and clinically significant bleeding (grades 2-4). Bleeding was also assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Across all studies, bleeding at baseline ranged from 50 to 73% for eltrombopag-treated patients; by week 2, bleeding had decreased, ranging from 26 to 39%. This trend was maintained throughout treatment. Similar results were observed for clinically significant bleeding. No such trend was seen in placebo-treated patients for any bleeding or clinically significant bleeding. For TRA100773B and RAISE, the odds of any bleeding across the entire treatment period were 51 and 76% lower for eltrombopag-treated versus placebo-treated patients (P=0.021, P<0.001). The odds of clinically significant bleeding in RAISE were 65% lower (P<0.001). In conclusion, analysis of prospective data from five clinical studies demonstrates that eltrombopag significantly reduces bleeding in adult patients with chronic ITP.

www.ncbi.nlm.nih.gov/pubmed/23492914

INTRODUCTION:

B-cell depletion with rituximab (RTX) is widely used to treat autoimmune diseases, especially as second-line therapy for immune thrombocytopenia (ITP). The incidence of RTX-induced hypogammaglobulinemia is unknown because of heterogeneous follow-up and confounding factors such as concomitant immunosuppressive treatments in most patients. We describe 3 cases and attempted to determine the incidence of RTX-induced hypogammaglobulinemia by a systematic review of the literature.

METHODS:

We retrospectively analyzed 189 ITP patients receiving RTX in 3 referral centers in France and conducted a systematic review of 32 studies (results published 2001-2014) reporting the use of RTX for ITP, particularly searching for symptomatic secondary hypogammaglobulinemia. We also searched for case reports of hypogammaglobulinemia after RTX initiation for ITP.
RESULTS:

Of the 189 patients, 3 showed symptomatic hypogammaglobulinemia more than 2years after RTX infusion (initial immunoglobulin level was normal). All 3 presented recurrent severe infections. In 2, the outcome suggested common variable immunodeficiency. In patient 3, the peripheral blood lacked CD19+CD20+ B cells and the bone-marrow B-cell precursor level was impaired. Among 1245 ITP patients in the literature who received RTX for ITP, gammaglobulin level was monitored before and after RTX initiation for 351 (28%). For 192 (55%), dosages were available and we identified 21 patients with secondary hypogammaglobulinemia, usually not symptomatic, 14 of whom had received concomitant dexamethasone. Finally, we found 4 case reports of ITP and symptomatic hypogammaglobulinemia possibly related to RTX according to the authors.

CONCLUSIONS:

This large analysis led us to recommend monitoring serum immunoglobulin level before and repeatedly after RTX initiation for ITP. Physicians should be aware of hypogammaglobulinemia as a rare but severe complication of RTX.

Copyright © 2014 Elsevier B.V. All rights reserved.


www.ncbi.nlm.nih.gov/pubmed/25183241

This last article is troubling. As I read it, a significant portion of ITP patients treated with Rituxan showed long term impairment of the immune system, an outcome Rituxan is supposed to avoid, in contrast with splenectomy.

Yes, it appears so. However, it doesn't seem as though that applies to everyone, and some may have been predisposed anyway. CVID can be common with ITP. This is another reason though why one treatment at a time is better and why people should avoid overuse of Rituxan.

Since Rituxan has only been around for about 12 years for ITP, the long-term affects are just now being seen.

Abstract

Background/Aim: Thrombopoietin receptor agonists (romiplostim and eltrombopag) have recently been licensed for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) with an insufficient response to corticosteroids, immunoglobulins or splenectomy. In the present case series, we present 4 nonresponding patients with chronic ITP who achieved maintenance of complete response (CR) for a period of at least 6 months on eltrombopag treatment administered in a modified regimen of 25 mg for 2, 3 or 5 days a week. Methods: The present study is a retrospective, nonconsecutive case series of 4 eltrombopag-treated patients with chronic ITP. Secondary ITP had been excluded in each patient, first-line therapy had failed and splenectomy had been refused. Furthermore, each patient was treated with eltrombopag, which resulted in a CR for a mean of 2 months. Consequently, decreased eltrombopag dosages have been able to maintain long-term CR. Results/Conclusion: Despite the low quality of evidence, our study results support the use of reduced-dose eltrombopag as a maintenance therapy after achieving CR. It seems a very promising strategy for the effective maintenance of response, improving health-related quality of life, lowering costs and possibly improving the safety in the treatment of ITP. © 2014 S. Karger AG, Basel.

www.ncbi.nlm.nih.gov/pubmed/25170628

Sept. 25, 2014--Platelets are an expensive biomedical commodity. These microscopic cells that come to the rescue when our blood vessels need to be repaired cannot be frozen and are stable for only three to five days at room temperature.

Although platelets are life-saving for accident victims, individuals undergoing chemotherapy, and people with diseases associated with a low platelet count, donated natural platelets are often in short supply, and their use comes with the risk of disease transmission between donors and recipients.

See more:


www.udel.edu/udaily/2015/sep/platelet-formation-092514.html