Successful treatment of refractory secondary immune thrombocytopenia (antiphospholipid antibody syndrome-associated) with the combination of rituximab and romiplostim at the cost of severe bone pain: A case report and review of literature.

INTRODUCTION: Immune thrombocytopenia is an autoimmune disorder associated with increased thrombocyte destruction and impaired production in the bone marrow. Proposed mechanisms include an antibody or autoreactive T-cell-associated autoimmunity and thrombopoietin deficiency among others. Clinical manifestations are predominantly mucocutaneous hemorrhages including petechiae, purpura, mucosal bleeding in the urinary or the gastrointestinal tracts, menorrhagia, and epistaxis. The purpose of the treatment is to prevent bleeding rather than normalizing the platelet counts. First-line treatments include corticosteroids ± intravenous immunoglobulin and Anti-D which mainly decrease antibody-mediated platelet destruction and increase the number of peripheral Tregs. Second-line and subsequent therapies include splenectomy, chimeric anti-CD20 antibody (rituximab), which eliminates B cells and act as an immunomodulatory agent, and Thrombopoietin receptor agonists (romiplostim), which promote platelet production. CASE REPORT: We describe a 40-year-old male patient diagnosed with immune thrombocytopenia that was refractory to first-line corticosteroid and intravenous immunoglobulin and second-line romiplostim monotherapy treatments.Management and outcome: The patient was given the romiplostim and rituximab combination which not only successfully treated thrombocytopenia but also resulted in grade 3 bone pains and the patient's subsequent refusal to continue therapy. DISCUSSION: Common adverse effects of rituximab are infusion reactions and prolonged immunosuppression; those of romiplostim include thrombosis, headaches, arthralgia-myalgia, and gastrointestinal symptoms. This case shows that romiplostim has not caused any discernible side effects when given alone, while combination with rituximab resulted in severe bone and joint pains. We hypothesize that this combination regimen shows a synergistic effect both in terms of efficacy and adverse-effect probability and/or severity.

Assessment of romiplostim immunogenicity in adult patients in clinical trials and in a global postmarketing registry.

Antibodies to first-generation recombinant thrombopoietin (TPO) neutralized endogenous TPO and caused thrombocytopenia in some healthy subjects and chemotherapy patients. The second-generation TPO receptor agonist romiplostim, having no sequence homology to TPO, was developed to avoid immunogenicity. This analysis examined development of binding and neutralising antibodies to romiplostim or TPO among adults with immune thrombocytopenia (ITP) in 13 clinical trials and a global postmarketing registry. 60/961 (6·2%) patients from clinical trials developed anti-romiplostim-binding antibodies post-baseline. The first positive binding antibody was detected 14 weeks (median) after starting romiplostim, at median romiplostim dose of 2 µg/kg and median platelet count of 29.5 × 109 /l; most subjects had ≥98·5% of platelet assessments showing response. Neutralising antibodies to romiplostim developed in 0·4% of patients, but were unrelated to romiplostim dose and did not affect platelet count. Thirty-three patients (3·4%) developed anti-TPO-binding antibodies; none developed anti-TPO-neutralising antibodies. In the global postmarketing registry, 9/184 (4·9%) patients with spontaneously submitted samples had binding antibodies. One patient with loss of response had anti-romiplostim-neutralising antibodies (negative at follow-up). Collectively, anti-romiplostim-binding antibodies developed infrequently. In the few patients who developed neutralising antibodies to romiplostim, there was no cross-reactivity with TPO and no associated loss of platelet response.

Assessment of Self-Administration of Romiplostim in Patients with Immune Thrombocytopenic Purpura after Receipt of Home Administration Training Materials: a Cross-Sectional Study.

INTRODUCTION: Romiplostim is a subcutaneously administered thrombopoietin-receptor agonist approved in the European Union for self-administration (or administration by a caregiver) in selected adult patients with chronic primary immune thrombocytopenia refractory to other treatments. To mitigate the risk of medication errors due to self-administration, the manufacturer has implemented additional risk minimisation measures (RMM) in the form of a Home Administration Training (HAT) pack to support the training of both healthcare professionals (HCPs) (guide and checklist for patient selection and training) and patients (a preparation mat, quick guide booklet, step-by-step guide, self-administration diary and DVD/video). OBJECTIVE: The primary objective was to estimate the proportion of patients/caregivers who administered romiplostim correctly after HAT pack training. METHODS: A multicentre observational study was conducted to evaluate the effectiveness of the HAT pack by recording data on a standardised collection form during direct observation of patients/caregivers in the act of administering romiplostim at the first standard-of-care visit 4 weeks after training with the HAT pack. RESULTS: Among the 40 patients/caregivers enrolled across 12 study centres in eight European countries, 35 [87.5%; 95% confidence interval (CI) 73.9-94.5] administered romiplostim correctly, and five (12.5%; 95% CI 5.5-26.1) did not. CONCLUSION: The correct administration of romiplostim by most patients/caregivers supports the effectiveness of the HAT pack as an additional risk minimisation tool in the population and setting of this study.

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Effect of Romiplostim on Health-Related Quality of Life in Children with Primary Immune Thrombocytopenia and Associated Burden in Their Parents.

BACKGROUND: Chronic immune thrombocytopenia (ITP) in children can negatively impact their health-related quality of life (HRQoL) and impose a burden on their parents. This study sought to examine the effect of romiplostim on HRQoL and parental burden in children with primary ITP. PROCEDURE: This was a phase 3, randomized, double-blind, placebo-controlled study. Children aged <18 years with ITP ≥6 months were randomly assigned to receive romiplostim or placebo for 24 weeks. The Kids' ITP Tool (KIT) was used to measure HRQoL and was administered to patients and/or their parents at baseline and weeks 8, 16, and 25. Mean KIT scores at each assessment and mean changes in KIT scores from baseline were calculated overall by treatment group and platelet response status. Psychometric properties of the KIT were evaluated and the minimally important difference (MID) was estimated for different KIT versions. RESULTS: Sixty-two patients (42 romiplostim and 20 placebo) were enrolled. Changes in KIT scores by treatment group showed numerically greater and more often statistically significant improvements from baseline to each assessment for children receiving romiplostim versus placebo. Mixed-effects analysis demonstrated statistically significantly greater reduction in parental burden from baseline in the romiplostim group versus placebo. Ranges for the MID were estimated as 9-13 points for the Child Self-Report version and 11-13 points for the Parent Impact version. CONCLUSIONS: The treatment with romiplostim may be associated with improved HRQoL in children with primary ITP and reduced burden to their parents.

Comparative net cost impact of the utilization of romiplostim and intravenous immunoglobulin for the treatment of patients with immune thrombocytopenia in Québec, Canada.

OBJECTIVES: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by platelet destruction, sub-optimal platelet production, and mild-to-severe bleeding. Nplate® (romiplostim), a thrombopoietin receptor agonist, and intravenous immunoglobulin (IVIg), an expensive and occasionally scarce blood product, are used in the treatment of ITP. The objective of this study was to compare the total cost of treating patients with romiplostim vs IVIg in Québec, Canada. METHODS: A net cost impact model was developed to calculate the annual cost of romiplostim compared with IVIg based on actual practice observations in all patients (n = 95) treated for chronic ITP with IVIg from April 2010 to March 2011 in two participating hospitals. The model included costs of: drug acquisition, drug preparation and administration, patient monitoring, and indirect costs. Healthcare practitioners were consulted regarding romiplostim and IVIg treatment algorithms and the resources involved in patient monitoring. RESULTS: The average annual drug acquisition costs of romiplostim and IVIg were $48,024 and $98,868, respectively. Lower costs for drug preparation and administration ($309 vs $1245) and less time lost from work ($256 vs $2086) were attributed to romiplostim. The cost of follow-up monitoring was the same for both romiplostim and IVIg ($121). The total average annual per patient costs for romiplostim vs IVIg were, respectively, $48,710 and $102,320. The use of romiplostim was projected to save, on average, almost $54,000 per patient per year. LIMITATIONS: The study was conducted in two hospitals in Québec. Romiplostim may show different cost savings in other hospitals and other provincial and national jurisdictions. CONCLUSIONS: Scarce blood products must be used wisely. Romiplostim can allow for improved healthcare resource allocation by reserving IVIg for use in other areas of greater need while also providing cost savings for the overall provincial healthcare budget.