A single-arm, long-term efficacy and safety study of subcutaneous romiplostim in children with immune thrombocytopenia.

Romiplostim is a thrombopoietin (TPO) receptor agonist approved for children and adults with immune thrombocytopenia (ITP) for ≥6 months, recommended as second-line treatment. This phase 3b, single-arm, multicenter study investigated long-term efficacy and safety of romiplostim in children ≥1 to <18 years old with ≥6 months' ITP duration and platelet counts ≤30 × 109/L. Children received weekly subcutaneous romiplostim (1 µg/kg titrated to 10 µg/kg) to maintain platelets within 50 to 200 × 109/L. A subset underwent bone marrow examinations. The primary end point was percentage of time with platelet response during the first 6 months' treatment (counts ≥50 × 109/L without rescue medication within the preceding 4 weeks). Overall, 203 patients (median age, 10.0 years) received ≥1 dose of romiplostim, median treatment duration was ∼3 years, and median average weekly dose was 6.9 µg/kg. Ninety-five (46.8%) discontinued (lack of efficacy, n = 43 [21.2%]). Platelet responses were achieved a median (interquartile range) of 50.0% (16.7%-83.3%) of the time during the first 6 months, increasing to 78.2% (26.7%-90.4%) during the overall 36-month treatment period. Eleven patients (5.4%) achieved sustained responses (consecutive counts ≥50 × 109/L without ITP medications for ≥24 weeks). Treatment-related adverse events (AEs) occurred in 56 patients (27.6%), with 8 (3.9%) experiencing serious treatment-related AEs; all of these led to discontinuation, including 4 cases of neutralizing antibodies (romiplostim, n = 3; TPO, n = 1). Bleeding occurred in 141 patients (69.5%), decreasing over time; grade ≥3 bleeding events occurred in 20 (9.9%). At year 2, eight of 63 evaluable patients (12.7%) had grade 2 reticulin. Long-term romiplostim resulted in sustained on-treatment platelet responses with an overall safety profile consistent with previous studies. This trial was registered at www.clinicaltrials.gov as #NCT02279173.

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

Development of first-generation thrombopoietins (TPOs) was halted due to antibodies that neutralized endogenous TPO, causing protracted thrombocytopenia in some patients. The second-generation TPO receptor agonist romiplostim, having no homology to TPO, was developed to circumvent potential immunogenicity. We examined the development of binding and neutralizing antibodies to romiplostim and TPO among pediatric patients with primary immune thrombocytopenia (ITP) in 5 clinical trials and a global postmarketing registry. In the trials, 25 of 280 (8.9%) patients developed anti-romiplostim binding antibodies. The first positive result was detected 67 weeks (median) after romiplostim treatment was initiated. The median romiplostim dose was 8 µg/kg, and the median platelet count was 87 × 109/L. Most patients who developed anti-romiplostim binding antibodies (18 of 25 [72%]) had ≥90% of platelet assessments showing a response. Anti-romiplostim neutralizing antibodies developed in 8 of 280 (2.9%) patients. The development of anti-romiplostim neutralizing antibodies was unrelated to the romiplostim dose, and most patients who developed the antibodies (7 of 8 [88%]) had platelet response. Nine of 279 (3.2%) patients developed anti-TPO binding antibodies, and 1 (0.4%) developed transient anti-TPO neutralizing antibodies. In 8 patients who developed anti-romiplostim neutralizing antibodies, no TPO cross-reactivity was observed. In the postmarketing registry, 3 of 19 (15.8%) patients developed anti-romiplostim binding antibodies; 1 (5.3%) patient developed anti-romiplostim neutralizing antibodies. These results suggest that immunogenicity to romiplostim occurs infrequently in pediatric patients with ITP and is generally not associated with loss of platelet response or other negative clinical sequelae.

Lessons Learned Using Real-World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia.

Regulatory agencies are increasingly considering real-world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim vs. standard-of-care (SOC) therapy among patients with recently diagnosed (≤12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the end point of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary end point. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group vs. SOC, precision was limited because of small study size (median difference was 11 × 109 /L (95% CI: -59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit-for-purpose data sources with sufficient sample size, data elements, and follow-up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision makers and the data.

Effectiveness and Safety of Romiplostim Among Patients with Newly Diagnosed, Persistent and Chronic Immune Thrombocytopenia in European Clinical Practice.

INTRODUCTION: Romiplostim has been approved in Europe since 2009 to treat patients with chronic primary immune thrombocytopenia (ITP). Using real-world data from seven European countries, we measured the effectiveness and safety outcomes within 24 weeks following romiplostim initiation by duration of ITP: less than 3 months ("newly diagnosed"), 3-12 months ("persistent"), and more than 12 months ("chronic"). METHODS: Adults with ITP and ≥ 1 romiplostim administration between 2009 and 2012 were included. Endpoints included durable platelet response, median platelet count, rescue therapy, bleeding and adverse events. We used inverse probability of censoring weighted estimators to estimate cumulative risk of each outcome. There were 64 newly diagnosed, 50 persistent, and 226 chronic ITP patients at romiplostim initiation. RESULTS: Durable platelet response at 24 weeks ranged from 32% [confidence interval (CI): 18-46%] in newly diagnosed patients to 53% (CI 37-68%) in persistent patients. Median platelet count during follow-up ranged from 88 (CI 80-96) × 109/L in chronic patients to 131 (CI 102-160) × 109/L in newly diagnosed patients. CONCLUSION: Regardless of ITP duration, over half of patients discontinued concomitant ITP medications. Few adverse events were observed. Although only approved for chronic patients, estimates of the romiplostim treatment effect were similar across patients being managed in European clinical practice, regardless of ITP duration at romiplostim initiation.

Occurrence and Management of Thrombocytopenia in Metastatic Colorectal Cancer Patients Receiving Chemotherapy: Secondary Analysis of Data From Prospective Clinical Trials.

INTRODUCTION: Chemotherapy-induced thrombocytopenia (CIT) contributes to treatment dose delay and/or modification, often resulting in poorer survival and disease progression. We explored the incidence and clinical consequences of CIT among metastatic colorectal cancer (mCRC) patients. MATERIALS AND METHODS: Data from two prospective randomized phase 3 trials of mCRC patients receiving either first-line FOLFOX4 (fluorouracil, leucovorin, oxaliplatin) or second-line FOLFIRI (fluorouracil, leucovorin, irinotecan) were analyzed. Thrombocytopenia was defined by platelet count < 100 × 109/L (further categorized by grade) and by recorded adverse events (AEs). Co-occurrence of anemia (hemoglobin < 12 g/dL) and neutropenia (neutrophil count < 2 × 109/L) and clinical consequences of CIT were also evaluated. RESULTS: Among 1078 mCRC patients in the FOLFOX4 study, cumulative incidence of CIT based on platelet count was 37% (grade 3, 2%; grade 4, 1%) during an average 8 months' follow-up. Neutropenia or anemia were absent in 44% of CIT episodes; 62% of CIT AEs led to chemotherapy dose delay, change, and/or discontinuation. Among 1067 mCRC patients in the FOLFIRI study, cumulative incidence of CIT based on platelet count was 4% (grade 3, < 1%; grade 4, 0) during an average 4 months' follow-up. Neutropenia or anemia were absent in 22% of CIT episodes; 32% of CIT AEs led to chemotherapy dose delay, change, and/or discontinuation. With both regimens, transfusions and hospitalizations after CIT AEs were rare (< 3%). CONCLUSION: CIT was common among mCRC patients receiving the FOLFOX4 regimen. The most frequent consequence of CIT was a delay in chemotherapy, highlighting the unmet need in CIT management.

Romiplostim treatment for children with immune thrombocytopenia: Results of an integrated database of five clinical trials.

BACKGROUND: Treatment for chronic immune thrombocytopenia (cITP) in children is largely limited to immunosuppressive agents. Thrombopoietin receptor agonists (TRAs) have been used to treat cITP in adults for over a decade. The objective of this integrated analysis was to examine the safety and efficacy of the TRA romiplostim in children with ITP. METHODS: We examined efficacy and safety in children with ITP across five romiplostim trials: final data from two double-blind placebo-controlled trials and two open-label extensions, and interim data from an ongoing single-arm trial. RESULTS: Patients (n = 24 initially placebo; n = 262 initially romiplostim) had a median age of 10.0 years (Q1: 6.0, Q3: 13.0), ITP duration of 1.9 years (Q1: 1.0, Q3: 4.0), and baseline platelet count of 14.3 × 109 /L (Q1: 7.5, Q3: 23.0). Among 282 patients receiving romiplostim, median treatment duration was 65 weeks (range 8-471 weeks) and median weekly dose was 6.6 µg/kg (range 0.1-9.7 µg/kg). Overall, 89% of romiplostim-treated patients had platelet responses. Nineteen patients (7%) maintained treatment-free responses for ≥6 months while withholding all ITP therapy. Grade 3 and 4 adverse events of bleeding occurred in 10% and <1% of romiplostim-treated patients, respectively. Twenty-five percent of patients had a serious adverse event, most commonly epistaxis (6%). Seven patients (2%) had neutralizing antibodies against romiplostim postbaseline and none had neutralizing antibodies against endogenous thrombopoietin. Efficacy and safety results appeared similar between children with ITP for ≤12 months and >12 months at baseline. CONCLUSIONS: Across five pediatric clinical trials, romiplostim was well tolerated. Most patients had a platelet response; some maintained responses for at least 6 months while withholding all ITP therapy.

The incidence and clinical burden of immune thrombocytopenia in pediatric patients in the United States.

Immune thrombocytopenia (ITP) is the most common bleeding disorder diagnosed in children. Characterized by low platelet counts, it leads to reduced clotting abilities and an increased tendency to bleed. The disorder in children is often self-limiting. However, approximately 25% of children develop persistent or chronic ITP, and bleeding associated with thrombocytopenia can be life-threatening. The current incidence of ITP in the US and the characterization of the illness among children being managed in routine clinical practice are sparsely reported. This retrospective cohort study leveraged a large US-based commercial claims database to estimate the current incidence of pediatric ITP, the uptake of ITP treatments, and the occurrence of clinical outcomes of interest. Overall, the incidence of ITP in patients <18 years was 8.8 (95% confidence interval; 8.5-9.1) per 100,000 person-years from 2011 to 2016. Within two years of ITP onset, >31% of patients received IVIg and/or oral corticosteroids. Other ITP therapies were less common. During this same time period, 50% had at least one bleeding event (ecchymosis, epistaxis, gastrointestinal hemorrhage, etc.), 24% were hospitalized for a bleeding event, and 62% had at least one ITP-related hospitalization. The majority of patients experiencing these events did so within the first month following ITP onset. Our findings confirm the rarity of ITP and relatively low likelihood of chronic disease in young patients, but reveal that for a significant proportion of patients in the newly diagnosed phase, clinical consequences can be serious. Further study of improved treatment methods throughout the disease course is warranted.

Long-term treatment with romiplostim and treatment-free platelet responses in children with chronic immune thrombocytopenia.

Children with immune thrombocytopenia for ≥6 months completing a romiplostim study received weekly subcutaneous romiplostim (1-10 µg/kg targeting platelet counts of 50-200×109/L) in this extension to examine romiplostim's long-term safety and efficacy. Sixty-five children received romiplostim for a median of 2.6 years (range: 0.1-7.0 years). Median baseline age was 11 years (range: 3-18 years) and platelet count was 28×109/L (range: 2-458×109/L). No patient discontinued treatment for an adverse event. Median average weekly dose was 4.8 mg/kg (range: 0.1-10 mg/kg); median platelet counts remained >50×109/L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50×109/L, no rescue medication in the previous 4 weeks), 72% had responded at ≥75% of visits, and 58% had responded at ≥90% of visits. Treatment-free response (platelets ≥50×109/L ≥24 weeks without immune thrombocytopenia treatment) was seen in 15 of 65 patients while withholding romiplostim doses. At onset of treatment-free response, the nine girls and six boys had a median immune thrombocytopenia duration of four years (range: 1-12 years) and had received romiplostim for two years (range: 1-6 years). At last observation, treatment-free responses lasted for a median of one year (range: 0.4-2.1 years), with 14 of 15 patients still in treatment-free response. Younger age at first dose and platelet count >200×109/L in the first four weeks were associated with treatment-free responses. In this 7-year open-label extension, three-quarters of the patients responded ≥75% of the time, and romiplostim was well tolerated, with no substantial treatment-related adverse events. Importantly, 23% of children maintained treatment-free platelet responses while withholding romiplostim and all other immune thrombocytopenia medications for ≥6 months. (Registered at clinicaltrials.gov identifier: 01071954).

Romiplostim in adult patients with newly diagnosed or persistent immune thrombocytopenia (ITP) for up to 1 year and in those with chronic ITP for more than 1 year: a subgroup analysis of integrated data from completed romiplostim studies.

The thrombopoietin receptor agonist romiplostim is approved for second-line use in chronic immune thrombocytopenia (ITP), but its effects in patients with ITP for ≤1 year are not well characterized. This analysis of pooled data from 9 studies included patients with ITP for ≤1 year (n = 311) or >1 year (n = 726) who failed first-line treatments and received romiplostim, placebo or standard of care. In subgroup analysis by ITP duration, patient incidences for platelet response at ≥75% of measurements were higher for romiplostim [ITP ≤1 year: 74% (204/277); ITP >1 year: 71% (450/634)] than for placebo/standard of care [ITP ≤1 year: 18% (6/34); ITP >1 year: 9% (8/92)]. Of patients with ≥9 months on study, 16% with ITP ≤1 year and 6% with ITP >1 year discontinued romiplostim and maintained platelet counts ≥50 × 109 /l for ≥6 months without ITP treatment (treatment-free remission). Independent of ITP duration, rates of serious adverse events and bleeding were lower with romiplostim than placebo/standard of care and thrombotic events occurred at similar rates. In this analysis, romiplostim and placebo/standard of care had similar safety profiles and romiplostim increased platelet counts in patients with either ITP ≤1 year or ITP >1 year, with more treatment-free remission in those with ITP ≤1 year.

Appropriateness of granulocyte colony-stimulating factor use in patients receiving chemotherapy by febrile neutropenia risk level.

OBJECTIVE: Inappropriate granulocyte colony-stimulating factor use with myelosuppressive chemotherapy has been reported. Using the Oncology Services Comprehensive Electronic Records electronic medical record database, prophylactic granulocyte colony-stimulating factor (pegfilgrastim/filgrastim) use in cancer patients was assessed by febrile neutropenia risk level. METHODS: Patients with nonmetastatic or metastatic breast, head/neck, colorectal, ovarian/gynecologic, lung cancer, or non-Hodgkin's lymphoma who received myelosuppressive chemotherapy from June 2013 to May 2014 were included. Prophylactic granulocyte colony-stimulating factor use with high-risk, intermediate-risk, and low-risk chemotherapy and distribution of National Comprehensive Cancer Network risk factors with intermediate-risk regimens were assessed. RESULTS: Overall, 86,189 patients received ∼4.2 million chemotherapy cycles (high risk, 9%; intermediate risk, 48%; low risk, 43%). Prophylactic granulocyte colony-stimulating factor was given in 24% of cycles (high risk, 59%; intermediate risk, 29%; low risk, 11%). For nonmetastatic solid tumors, granulocyte colony-stimulating factor was given in 78% (high risk), 31% (intermediate risk), and 6% (low risk) of cycles. For metastatic solid tumors or non-Hodgkin's lymphoma, granulocyte colony-stimulating factor was given in 50% (high risk), 27% (intermediate risk), and 11% (low risk) of cycles. Among patients receiving intermediate-risk regimens with granulocyte colony-stimulating factor, febrile neutropenia risk factors were identified in 56% (95% confidence interval, 51.1-60.9%) of patients with nonmetastatic solid tumors (n = 400) and in 70% (64.5-73.5%) of patients with metastatic solid tumors or non-Hodgkin's lymphoma (n = 400). CONCLUSION: Prophylactic granulocyte colony-stimulating factor use was appropriately highest for high-risk regimens and lowest for low-risk regimens yet still potentially underused in high risk regimens, overused in low-risk regimens, and not appropriately targeted in intermediate-risk regimens, indicating a need for further education on febrile neutropenia risk evaluation and appropriate granulocyte colony-stimulating factor use.

Cost per response analysis of strategies for chronic immune thrombocytopenia.

OBJECTIVES: This analysis estimated the cost per response and the incremental cost per additional responder of romplostim, eltrombopag, and the "watch-and-rescue" (monitoring until rescue therapies are required) strategy in adults with chronic immune thrombocytopenia (ITP). STUDY DESIGN: The decision tree is designed to estimate the total cost per response for romiplostim, eltrombopag, and watch and rescue over a 24-week time horizon; cost-effectiveness was evaluated in terms of incremental cost per additional responder. METHODS: Model inputs including response rates, bleeding-related episode (BRE) rates, and costs were estimated from registrational trial data, an independent Bayesian indirect comparison, database analyses, and peer-reviewed publications. Costs were applied to the proportions of patients with treatment response and nonresponse (based on platelet count). The total cost per response and the incremental cost per additional responder for each treatment were calculated. Sensitivity analyses and alternative analyses were performed. RESULTS: With higher total costs and greater treatment efficacy, romiplostim and eltrombopag had a lower 24-week cost per response and a lower average number of BREs than watch and rescue. Eltrombopag was weakly dominated by romiplostim. The incremental cost-effectiveness ratio of romiplostim versus watch and rescue was $46,000 per additional responder. The model results are most sensitive to response rates of romiplostim and watch and rescue and the BRE rate for splenectomized nonresponders. Alternative analyses results were similar to the base case. CONCLUSIONS: In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag; both romiplostim and eltrombopag had lower costs per response than watch and rescue.

Safety and efficacy of romiplostim in splenectomized and nonsplenectomized patients with primary immune thrombocytopenia.

Primary immune thrombocytopenia is an autoimmune disorder characterized by increased platelet destruction and insufficient platelet production without another identified underlying disorder. Splenectomy may alter responsiveness to treatment and/or increase the risk of thrombosis, infection, and pulmonary hypertension. The analysis herein evaluated the safety and efficacy of the thrombopoietin receptor agonist romiplostim in splenectomized and nonsplenectomized adults with primary immune thrombocytopenia. Data were pooled across 13 completed clinical studies in adults with immune thrombocytopenia from 2002-2014. Adverse event rates were adjusted for time of exposure. Results were considered different when 95% confidence intervals were non-overlapping. Safety was analyzed for 1111 patients (395 splenectomized; 716 nonsplenectomized) who received romiplostim or control (placebo or standard of care). At baseline, splenectomized patients had a longer median duration of immune thrombocytopenia and a lower median platelet count, as well as a higher proportion with >3 prior immune thrombocytopenia treatments versus nonsplenectomized patients. In each treatment group, splenectomized patients used rescue medications more often than nonsplenectomized patients. Platelet response rates (≥50×109/L) for romiplostim were 82% (310/376) for splenectomized and 91% (592/648) for nonsplenectomized patients (P<0.001 by Cochran-Mantel-Haenszel test). Platelet responses were stable over time in both subgroups. Exposure-adjusted adverse event rates were higher for control versus romiplostim for both splenectomized (1857 versus 1226 per 100 patient-years) and nonsplenectomized patients (1052 versus 852 per 100 patient-years). In conclusion, responses to romiplostim were seen in both splenectomized and nonsplenectomized patients, and romiplostim was not associated with an increase in the risk of adverse events in splenectomized patients. clinicaltrials.gov Identifier: 00111475(A)(B), 00117143, 00305435, 01143038, 00102323, 00102336, 00415532, 00603642, 00508820, 00907478, 00116688, and 00440037.

Thromboembolism in patients with immune thrombocytopenia (ITP): a meta-analysis of observational studies.

This meta-analysis describes the incidence rate of arterial and venous thromboembolism (ATE and VTE) in patients with immune thrombocytopenia (ITP), and the relative risk of ATE and VTE in patients with ITP and comparable populations without ITP. MEDLINE and EMBASE were systematically searched for observational studies reporting incidence rates of ATE and VTE in populations with and without ITP between 1996 and 2013 [follow-up completed before thrombopoietin receptor (TPOr) agonists were commercially available]. Three large, population-based studies were identified from Denmark, the United Kingdom, and the United States. The incidence of ATE per 100 patient-years among patients with ITP ranged from 1.0 to 2.8, and among populations without ITP ranged from 0.7 to 1.8; the summary relative risk adjusted for matching factors (aRR) was 1.5 [95 % confidence interval (CI) 1.3, 1.8]. The incidence of VTE per 100 patient-years among patients with ITP ranged from 0.4 to 0.7, and among populations without ITP ranged from 0.1 to 0.4; the summary aRR (95 % CI) was 1.9 (1.4, 2.7). The risk of ATE and VTE among patients with ITP, based on evidence from three large, population-based observational studies, should be considered when evaluating the risk of thromboembolism attributed to ITP treatments, such as TPOr agonists.

Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study.

BACKGROUND: The thrombopoietin receptor agonist romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months' duration. METHODS: In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 10(9)/L or less (mean of two measurements during the screening period) with no single count greater than 35 × 10(9)/L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly romiplostim or placebo for 24 weeks stratified by age (1 year to <6 years, 6 years to <12 years, 12 years to <18 years), adjusting the dose weekly from 1 µg/kg to 10 µg/kg to target platelet counts of 50-200 × 10(9)/L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 10(9)/L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18-25). This study is registered with ClinicalTrials.gov, NCT 01444417. FINDINGS: Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9-43·2]). Durable platelet response rates with romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the romiplostim group, were considered treatment related. No patients withdrew due to adverse events. INTERPRETATION: In children with chronic immune thrombocytopenia, romiplostim induced a high rate of platelet response with no new safety signals. Ongoing romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia. FUNDING: Amgen Inc.

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.

Hospitalizations in pediatric patients with immune thrombocytopenia in the United States.

To examine utilization and outcomes in pediatric immune thrombocytopenia (ITP) hospitalizations, we used ICD-9 code 287.31 to identify hospitalizations in patients with ITP in the 2009 HCUP KID, an all-payer sample of pediatric hospitalizations from US community hospitals. Diagnosis and procedure codes were used to estimate rates of ITP-related procedures, comorbidity prevalence, costs, length of stay (LOS), and mortality. In 2009, there were an estimated 4499 hospitalizations in children aged 6 months-17 years with ITP; 43% in children aged 1-5 years; and 47% with emergency department encounters. The mean hospitalization cost was $5398, mean LOS 2.0 days, with 0.3% mortality (n = 13). With any bleeding (15.2%, including gastrointestinal 2.0%, hematuria 1.3%, intracranial hemorrhage [ICH] 0.6%), mean hospitalization cost was $7215, LOS 2.5 days, with 1.5% mortality. For ICH (0.6%, n = 27), mean cost was $40 209, LOS 8.5 days, with 21% mortality. With infections (14%, including upper respiratory 5.2%, viral 4.9%, bacterial 1.9%), the mean cost was $6928, LOS 2.9 days, with 0.9% mortality. Septic shock was reported in 0.3% of discharges. Utilization included immunoglobulin administration (37%) and splenectomies (2.3%). Factors associated with higher costs included age >6 years, ICH, hematuria, transfusion, splenectomy, and bone marrow diagnostics (p < 0.05). In conclusion, of the 4499 hospitalizations with ITP, mortality rates of 1.5%, 21%, and 0.9% were seen with any bleeding, ICH, and infection, respectively. Higher costs were associated with clinically significant bleeding and procedures. Future analyses may reveal effects of the implementation of more recent ITP guidelines and use of additional treatments.

Case study of remission in adults with immune thrombocytopenia following cessation of treatment with the thrombopoietin mimetic romiplostim.

OBJECTIVES: In adults, immune thrombocytopenia (ITP), characterized by platelet counts <100 × 10(9)/l, is typically chronic, with remission reported infrequently ≥3 years post-diagnosis. The thrombopoietin mimetic romiplostim increases platelet counts and reduces use of concomitant ITP medications in chronic ITP. While often perceived as a long-term treatment, dose-adjustment rules allow romiplostim to be discontinued when hemostatic platelet counts are reached, as reported in Amgen trials. METHODS: Eight romiplostim trials were examined for remission, defined as ≥26 consecutive weeks of platelets ≥50 × 10(9)/l without treatment. RESULTS: Remission was identified in 27 patients; median (quartile 1 [Q1], quartile 3 [Q3]) ITP duration of 2.1 (0.5, 4.2) years, 17/27 (63%) having ITP for >1 year, mean baseline platelets 20.9 × 10(9)/l, median preremission maximum dose 3.0 µg/kg, 12/27 (44%) were splenectomized at baseline, and there were 40-276 cumulative weeks of romiplostim with median time to remission 7.1 months. DISCUSSION/CONCLUSION: No clear-cut predictors of remission were apparent; however, a number of patients had ITP for <1 year and received romiplostim for <1 year.

Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study.

In anecdotal reports, some patients with immune thrombocytopenia (ITP) maintained platelet counts after discontinuing romiplostim. Here, we examined rates of platelet response (≥50 × 10(9) /l), remission, splenectomy and adverse events in patients with primary ITP duration ≤6 months who were treated with romiplostim for ≤12 months. The starting dose of romiplostim was 1 µg/kg; concomitant and rescue treatments were permitted to maintain platelet counts. Patients with platelet counts ≥50 × 10(9) /l at the end of 12 months entered a dose taper in which the romiplostim dose was decreased as long as platelet counts were maintained. Remission (platelet count ≥50 × 10(9) /l for 24 consecutive weeks with no ITP treatments) was evaluated in patients once romiplostim was discontinued. Over the 12 months, a high response rate (>90%) was observed. Platelet response occurred quickly (median, ~2 weeks) and was observed for a cumulative median of 11 months. Remission was observed in 24 patients (32%); there were no significantly predictors of remission. Most (20/24) patients had remission start before the forced taper. No new safety signals were identified. Thus, in patients with early-stage ITP, romiplostim was well tolerated and induced rapid responses, with remission occurring in approximately one-third of patients (NCT01143038, Amgen 20080435).

Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP).

BACKGROUND: Treatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12-16-week study, 15/17 romiplostim-treated patients achieved platelet counts ≥50 × 109 /L, and romiplostim treatment was well tolerated. In a subsequent open-label extension (≤109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 × 109 /L. Twelve patients continued in a second extension (≤127 weeks). Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP. PROCEDURE: Patients received weekly subcutaneous romiplostim, adjusted by 1 µg/kg/week to maintain platelet counts (50-200 × 109 /L, maximum dose 10 µg/kg). Bone marrow examinations were not required. RESULTS: At baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 × 109 /L; 73% were male; and 36% had prior splenectomy. Median romiplostim treatment duration was 167 weeks (Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 µg/kg (Q1, Q3: 4.3, 8.0 µg/kg). Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy. None withdrew because of adverse events (AEs). After the first 12 weeks, median platelet counts remained >50 × 109 /L. Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy. Seven patients (31.8%) reported serious AEs, and two (9.1%) reported life-threatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities. CONCLUSIONS: Long-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Pediatr Blood Cancer 2015;62:208-213. © 2014. The Authors. Pediatr Blood & Cancer published by Wiley Periodicals, Inc.