Stern v. Marshall Panel

The Stern v. Marshall Panel discussed the issues of the case and its potential impact on practitioners

Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura

Background: The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder. Methods: We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43. Results: In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups. Conclusions: Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.

Diagnosis of immune thrombocytopenia, including secondary forms, and selection of second-line treatment

This article summarizes our approach to the diagnosis of immune thrombocytopenia (ITP), its secondary forms, and choice of second-line treatment options. We very briefly summarize first-line treatment and then utilize a case-based approach. We first explore persistent, chronic ITP in a younger female. We consider many possibilities beyond primary ITP e.g., hypogammaglobulinemia, chronic infection, and anemia, and how to approach their diagnosis and management. The journey continues throughout pregnancy and the post-partum period and eventually includes fourth-line treatment after a late relapse. We then consider an older male, emphasizing differences in diagnostic considerations and management. The focus is on initiation and continuation of second-line treatment, the pros and cons of each option, and briefly the impact of treatment choices related to the endemic presence of severe acute respiratory syndrome coronavirus 2. During the review of potential second-line treatment options, we also briefly touch upon novel treatments. Finally, there is a short section on refractory disease drawn from our previous extensive review published in February 2020.1 The clinical nature of the discussions, replete with figures and tables and with the interspersion of pearls regarding efficacy and toxicity at different ages and genders, will serve the reader in the management of “typical” adult patients who develop persistent and chronic ITP

A disease-specific measure of health-related quality of life for use in adults with immune thrombocytopenic purpura: Its development and validation

BACKGROUND: No validated disease-specific measures are available to assess health-related quality of life (HRQoL) in adult subjects with immune thrombocytopenic purpura (ITP). Therefore, we sought to develop and validate the ITP-Patient Assessment Questionnaire (ITP-PAQ) for adult subjects with ITP. METHODS: Information from literature reviews, focus groups with subjects, and clinicians were used to develop 50 ITP-PAQ items. Factor analyses were conducted to develop the scale structure and reduce the number of items. The final 44-item ITP-PAQ, which includes ten scales [Symptoms (S), Bother-Physical Health (B), Fatigue/Sleep (FT), Activity (A), Fear (FR), Psychological Health (PH), Work (W), Social Activity (SA), Women's Reproductive Health (RH), and Overall (QoL)], was self-administered to adult ITP subjects at baseline and 7–10 days later. Test-retest reliability, internal consistency reliability, construct and known groups validity of the final ITP-PAQ were evaluated. RESULTS: Seventy-three subjects with ITP completed the questionnaire twice. Test-retest reliability, as measured by the intra-class correlation, ranged from 0.52–0.90. Internal consistency reliability was demonstrated with Cronbach's alpha for all scales above the acceptable level of 0.70 (range: 0.71–0.92), except for RH (0.66). Construct validity, assessed by correlating ITP-PAQ scales with established measures (Short Form-36 v.1, SF-36 and Center for Epidemiologic Studies Depression Scale, CES-D), was demonstrated through moderate correlations between the ITP-PAQ SA and SF-36 Social Function scales (r = 0.67), and between ITP-PAQ PH and SF-36 Mental Health Scales (r = 0.63). Moderate to strong inter-scale correlations were reported between ITP-PAQ scales and the CES-D, except for the RH scale. Known groups validity was evaluated by comparing mean scores for groups that differed clinically. Statistically significant differences (p < 0.01) were observed when subjects were categorized by treatment status [S, FT, B, A, PH, and QoL, perceived effectiveness of ITP treatment [S], and time elapsed since ITP diagnosis [PH]. CONCLUSION: Results provide preliminary evidence of the reliability and validity of the ITP-PAQ in adult subjects with ITP. Further work should be conducted to assess the responsiveness and to estimate the minimal clinical important difference of the ITP-PAQ to more fully understand the impact of ITP and its treatments on HRQoL

Results of bone marrow examinations in patients with chronic immune thrombocytopenic purpura treated with eltrombopag

Background: Bone marrow (BM) reticulin fibers can be increased in conditions such as neoplasms and autoimmune diseases (Frisch Haematol [Budap] 1982; Aharon Lupus 1997) and can lead to a clinical situation similar to osteomyelofibrosis. In healthy individuals, grade 1 and 2 reticulin have been reported in 27–70% and 4–20% of BM biopsies, respectively (Hultdin Med Onc 2007; Beckman Arch Path Int Med 1990; Bauermeister Am J Clin Path 1971). The presence of grade 1/2 reticulin was reported in the BM of up to 67% of patients with immune thrombocytopenic purpura (ITP) (Mufti J Supp Onc 2007). Theoretically, prolonged stimulation of megakaryocytes with TPO-R agonists might increase the risk of myelofibrosis (MF). Increased reticulin and peripheral nucleated RBCs have been reported in chronic ITP patients treated with romiplostim (Bussel Blood 2009). Eltrombopag, an oral, small molecule, TPO-R agonist, is approved in the United States for the treatment of chronic ITP. Objective: To determine whether eltrombopag treatment is associated with an increase in BM reticulin. METHODS Reports of BM biopsies performed prior to eltrombopag treatment were reviewed. In eltrombopag studies, complete blood counts (CBC) including white blood cell (WBC) differentials were performed at each visit. If a WBC differential indicated the presence of immature or dysplastic cells in the RAISE, REPEAT, and EXTEND studies, then a peripheral blood smear was performed. If the presence of immature or dysplastic cells on the blood smear was not consistent with the chronic ITP diagnosis, then a BM biopsy was performed. Additionally, a BM biopsy could be performed at any time at the investigator\u27s discretion. In EXTEND, a BM biopsy was required after 1 year on treatment. Reticulin was quantified using the modified MF scale (Thiele Haematologica 2005). Results: Prestudy BM biopsies were available for 64/446 patients subsequently exposed to eltrombopag; 51 reports did not mention reticulin or fibrosis. Of the 13 remaining prestudy reports, 4 (31%) had increased reticulin. Ninety-one patients (5 patients RAISE; 86 patients EXTEND) had a BM biopsy following treatment initiation; none of the BM biopsies were prompted by an abnormal peripheral blood smear. In a 6-month placebo-controlled study (RAISE), 1 placebo-treated patient had an on-treatment BM examination that showed myelodysplastic syndrome, and 4 eltrombopag-treated patients (2 on-treatment and 2 posttreatment) had BM examinations. One patient treated with eltrombopag for 41 days had a posttreatment marrow examination that showed grade 2 (Bauermeister) reticulin. None of the 4 showed hematologically relevant BM alterations. In an open-label extension study (EXTEND), 86 patients treated for a median of 12 months (range: 1–18 months) at the time of the procedure had BM biopsies; 83 had mention of reticulin fibers in the report and were evaluable for this analysis. Five patients had MF grade 2 reticulin with no clinical signs or symptoms of BM dysfunction (eg, abnormal WBC differential or peripheral blood smear); 2 reported collagen. One patient had a biopsy 2 years prior to EXTEND (grade 1/3). After 15 months on study, a biopsy showed grade 2/3; this patient was withdrawn. Of note, while on treatment the patient was not considered a responder (platelets \u3c50,000/μL) but did have decreased bleeding. The second patient was 81 years old with a history of 3 cancers. A similar degree of reticulin was observed when comparing the biopsy taken 6 years prior to EXTEND and after 14 months on study, but collagen was noted on the second BM. A patient with MF grade 1 reticulin reported collagen, but did not experience any adverse event or significant change in CBC and is continuing on study with good platelet response. Conclusion: There was no evidence of clinically relevant BM abnormalities or clinical findings typically associated with MF in patients treated for up to 18 months with eltrombopag. Systematic longitudinal evaluation of BMs in EXTEND will provide meaningful data regarding incidence of fibrosis during long-term treatment

Thrombopoietin receptor agonist therapy in primary immune thrombocytopenia is associated with bone marrow hypercellularity and mild reticulin fibrosis but not other stromal abnormalities

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Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study

Background: Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period. Methods: We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months’ duration who had baseline platelet counts lower than 30 000 per μL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤15 000 per μL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50 000–400 000 per μL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331. Findings: Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59–18·73; p\u3c0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag- treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (\u3c1%) patient treated with eltrombopag. Interpretation: Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatmen

CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance

Hyper-IgM (HIGM) syndromes are primary immunodeficiencies characterized by defects of class switch recombination and somatic hypermutation. HIGM patients who carry mutations in the CD40-ligand (CD40L) gene expressed by CD4+ T cells suffer from recurrent infections and often develop autoimmune disorders. To investigate the impact of CD40L–CD40 interactions on human B cell tolerance, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from three CD40L-deficient patients. Antibody characteristics and reactivity from CD40L-deficient new emigrant B cells were similar to those from healthy donors, suggesting that CD40L–CD40 interactions do not regulate central B cell tolerance. In contrast, mature naive B cells from CD40L-deficient patients expressed a high proportion of autoreactive antibodies, including antinuclear antibodies. Thus, CD40L–CD40 interactions are essential for peripheral B cell tolerance. In addition, a patient with the bare lymphocyte syndrome who could not express MHC class II molecules failed to counterselect autoreactive mature naive B cells, suggesting that peripheral B cell tolerance also depends on major histocompatibility complex (MHC) class II–T cell receptor (TCR) interactions. The decreased frequency of MHC class II–restricted CD4+ regulatory T cells in CD40L-deficient patients suggests that these T cells may mediate peripheral B cell tolerance through CD40L–CD40 and MHC class II–TCR interactions

Impact of chronic Immune Thrombocytopenic Purpura (ITP) on health-related quality of life: a conceptual model starting with the patient perspective

<p>Abstract</p> <p>Background</p> <p>Immune thrombocytopenic purpura (ITP), a condition characterized by autoimmune-mediated platelet destruction and suboptimal platelet production, is associated with symptoms such as bruising, epistaxis, menorrhagia, mucosal bleeding from the gastrointestinal and urinary tracts and, rarely central nervous system bleeding. The aim of this research is to develop a conceptual model to describe the impact of ITP and its treatment on patients' health-related quality of life (HRQoL).</p> <p>Methods</p> <p>A literature search and focus groups with adult ITP patients were conducted to identify areas of HRQoL affected by ITP. Published literature was reviewed to identify key HRQoL issues and existing questionnaires used to assess HRQoL. Focus group transcripts were reviewed, and common themes were extracted by grouping conceptual categories that described the impact on HRQoL.</p> <p>Results</p> <p>The literature synthesis and themes from the focus group data suggest that decreased platelet counts, disease symptoms, and treatment side effects influence multiple domains of HRQoL for ITP patients. Key areas affected by ITP and its treatments include emotional and functional health, work life, social and leisure activities, and reproductive health.</p> <p>Conclusion</p> <p>ITP affects various areas of HRQoL. This conceptual model will help inform the evaluation of therapeutic strategies for ITP.</p