Romiplostim Group Research Articles

Thrombopoietin receptor agonists for the treatment of severe persistent and chronic immune trombocytopenia in children: clinical data of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology

Thrombopoietin receptor agonists (TPO-RA) – romiplostim and eltrombopag – changed considerably the therapeutic options for severe persistent and chronic immune thrombocytopenia (ITP). The article presents the results of a retrospective study of TPO-RA efficacy and safety in patients under 18 years of age. The study was approved by the Independent Ethics Committee and Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Sixty-eight children had a total of 89 courses of TPO-RA (44 romiplostim and 45 eltrombopag). Their median age was 6.5 years. The median ITP duration was 15.8 months. All patients received previous ITP therapy (1–6 lines). Before the initiation of TPO-RA, the majority of patients had thrombocytopenia with bleeding. In most cases, the platelet response was achieved within the first 2 months of treatment. The average effective doses of romiplostim and eltrombopag were 10 mg/kg per week and 75 mg per day, respectively. Half of patients in romiplostim group and 62% of patients in eltrombopag group did not require extra therapy. The majority of patients (75.6–81.8%) achieved an overall response, but only near 50% achieved a durable (more than 24 weeks) platelet response. Six patients sustained the response after TPO-RA discontinuation. The most common adverse events (AE) of TPO-RA therapy were transient elevation in hepatic enzymes in eltrombopag group (28.9%) and thrombocytosis (18.2–22.2%) in both groups. In 6 cases the therapy was discontinued due to AEs. Two AEs were serious. Our results demonstrate that TPO-RA could safely increase platelet counts and decrease the risk of spontaneous life-threatening bleeding in nearly half of children with severe persistent and chronic ITP. TPO-RA could help to avoid long-term immunosuppressive therapy and splenectomy or delay them and the ITP remission is possible in some cases.

Thrombopoietin-Receptor Agonist Romiplostim Attenuates Hematopoietic System Injury By Promoting the Recovery of Early Hematopoiesis and the Hematopoietic Environment in the Bone Marrow and Spleen of Mice Exposed to Lethal Total Body γ-Irradiation

High-dose radiation exposure, usually caused by radiological accidents or nuclear disasters, can cause lead to acute radiation syndrome (ARS), which is a life-threatening condition. The International Atomic Energy Agency recommends the use of a combination of various cytokines or bone marrow (BM) transplant for treating high-dose exposure, depending on the degree of radiation exposure and ARS. Therefore, drugs that respond quickly, which can be used to treat a large number of radiation-associated casualties represent a good treatment option. However, certain hematopoietic cytokines, such as the granulocyte macrophage-colony stimulating factor and interleukin-3, which are effective against hematopoietic dysfunction and have been used in previous accidents, are not approved as pharmaceutical drugs in Japan. Although granulocyte-colony stimulating factor is only approved domestically for the treatment of ARS, it has been found that a single dose is insufficient to improve the survival rate of individuals exposed to lethal ionizing radiation. We have previously demonstrated that an effective protocol of drug therapy, based on approved pharmaceutical drugs in Japan, is the administration of romiplostim (RP), a thrombopoietin-receptor myeloproliferative leukemia virus proto-oncogene (c-mpl) agonist, at a dose of 50 μg/kg body weight/day for 3 consecutive days. This regimen achieved 100% survival at 30-days in 8-weekold female C57BL/6JJcl mice when administered immediately following exposure to a lethal dose (7 Gy) of 137Cs γ-rays. In the present study, we assessed the mechanisms by which RP ameliorated radiation-induced hematopoietic damage in mice after lethal total body γ-irradiation (TBI) by focusing on the recovery and regeneration of BM and spleen. Mice were divided into 4 groups: control group, RP group, TBI group, and TBI + RP group. On days 4, 10, 18, and 30 after TBI, morphological and histological changes of BM and spleen and antigen expression changes of cells isolated from both tissues were assessed. While the body weight of animals in the TBI group decreased significantly by day 18 compared to controls, that of mice receiving RP remained comparable. Similarly, on day 18, leukocyte, platelet, erythrocyte, and hemoglobin levels were the lowest in TBI mice. Conversely, these values markedly recovered in the TBI + RP group. Splenic atrophy was assessed by weighing the spleen after TBI, and it was observed that while the spleen contracted significantly following TBI, mice in the RP + TBI group showed a 3 to 4-fold increase in spleen weight and in cell numbers on day 18. Endogenous colonies, which are indicators of hematopoiesis, were also observed in the spleen after day 10. In addition, TBI induced severe myelosuppression that resulted in the loss of hematopoietic function. On day 18 after irradiation, while the BM exhibited obvious myeloablation, that of the RP + TBI treated mice was comparable to controls. Further, the number of BM cells in mice RP + TBI treated mice continued to increase till 30 days after TBI but did not attain pre-TBI levels. Additionally, analysis of cell-surface antigen expression in BM and spleen cells showed that, compared to the TBI group, RP administration promoted the recovery of hematopoietic stem cells, multipotent progenitor cells, and common lymphocyte precursor cells. In particular, a dramatic increase in the number of common myelo-erythroid progenitors were observed in the spleen on day 18 in the TBI + RP treated mice, accompanied with the disappearance of splenic cyst structures and acceleration of megakaryocyte hematopoiesis. These results suggest that thrombopoietin-receptor agonist RP promotes the recovery of early hematopoiesis and hematopoietic environment in both BM and spleen of lethal TBI mice, especially the promoting megakaryocytopoiesis in the spleen. As a result, treating lethally-irradiated mice with RP results in 100% survival. DisclosuresNo relevant conflicts of interest to declare.

Proteomic changes by radio-mitigative thrombopoietin receptor agonist romiplostim in the blood of mice exposed to lethal total-body irradiation

Purpose The thrombopoietin receptor agonist romiplostim (RP) is a therapeutic agent for immune thrombocytopenia that can achieve complete survival in mice exposed to a lethal dose of ionizing radiation. The estimated mechanism of the radio-protective/mitigative effects of RP has been proposed; however, the detailed mechanism of action remains unclear. This study aimed to elucidate the mechanism of the radio-protective/mitigative effects of RP, the fluctuation of protein in the blood was analyzed by proteomics. Materials and Methods Eight-week-old female C57BL/6J mice were randomly divided into 5 groups; control at day 0, total-body irradiation (TBI) groups at day 10 and day 18, and TBI plus RP groups at day 10 and day18, consisting of 3 mice per group, and subjected to TBI with 7 Gy of 137Cs γ-rays at a dose rate of 0.74 Gy/min. RP was administered intraperitoneally to mice at a dose of 50 µg/kg once daily for 3 days starting 2 hours after TBI. On day 10 and day 18 after TBI, serum collected from each mouse was analyzed by liquid chromatography tandem mass spectrometry. Results Nine proteins were identified by proteomics methods from 269 analyzed proteins detected in mice exposed to a lethal dose of TBI: keratin, type II cytoskeletal 1 (KRT1), fructose-1, 6-bisphosphatase (FBP1), cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1), peptidyl-prolyl cis-trans isomerase A (PPIA), glycine N-methyltransferase (GNMT), glutathione S-transferase Mu 1 (GSTM1), regucalcin (RGN), fructose-bisphosphate aldolase B (ALDOB) and betain–homocysteine S-methyltransferase 1 (BHMT). On the 10th day after TBI, KRT1 was significantly increased (p < 0.05) by 4.26-fold compared to the control group in the TBI group and significantly inhibited in the TBI plus RP group (p < 0.05). Similarly, the expression levels of other 8 proteins detected at 18th day after TBI were significantly increased by 4.29 to 27.44-fold in the TBI group, but significantly decreased in the TBI plus RP group compared to the TBI group, respectively. Conclusion Nine proteins were identified by proteomics methods from 269 analyzed proteins detected in mice exposed to a lethal dose of TBI. These proteins are also expected to be indicators of the damage induced by high-dose radiation.

Efficacy of romiplostim in the treatment of ITP in children: a meta-analysis.

We aimed to analyze the efficacy and safety of romiplostim in the treatment of primary immune thrombocytopenia (ITP) in children. PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, Chinese biomedical literature database (CBM), Chinese Journal Full Text Database (CNKI), Wanfang and VIP database were searched. The bibliography was screened according to the inclusion and exclusion criteria and the target literature was selected. The data were extracted, and the quality of included literature was evaluated. RevMan 5.3 software was used to carry out the meta-analysis. The rate of effective, adverse and bleeding events was collected, and meta-analysis was performed. 3 out of 43 papers met the inclusion criteria. Meta-analysis showed that there was a statistical significance in effective rate and median time to platelet rise to response criteria of in romiplostim group, RR=5.05, [95% CI (2.21, 11.53), p<0.01] and RR=9.67, [95% CI (1.89, 49.46), p<0.01]. Similar results occurred in the rate of adverse event and serious adverse event, [RR=0.95, 95% CI (0.69,1.31), p>0.05] and [RR=1.65, 95% CI (0.53,5.31), p>0.05]; bleeding event of the two groups was similar [RR=1.27, 95% CI (0.92,1.75), p>0.05]. On the aspect of treating ITP, romiplostim is more effective and safer than placebo.

Thrombopoietin Receptor Agonists in the Treatment of Chronic Resistant Primary Immune Thrombocytopenia: Efficacy and Safety Data in Real Clinical Practice.

To analyze the long-term efficacy and safety of ATR in adult patients with primary resistant ITP in real-world clinical practice. The article contains long-term results analysis of ATR application under real clinical practice conditions in 138 patients (40 men and 98 women) whose median age at the beginning of therapy was 59 (18-86) years. Two ATR medicines-romiplostim (100 patients) and eltrombopag (38 patients) were used. During the first month of therapy, the median platelet count in the romiplostim group increased from 17·109 / L to 60·109 / L (9-600·109 / L), and the elethrombopag from 16.109 / L to 56.109 / L (9-400·109 / L). The minimal response (reaching platelet counts over 30·109 / L) was achieved in 92% of cases in both groups. Partial response (achievement of platelet count more than 50·109 / L) was achieved in 91 and 84% of patients in the rhombostim and eltrombopag groups, respectively. The frequency of complete response (an increase in platelet counts above 100·109 / L) was noted somewhat more often in the rhy- ploistim group-69% compared to 47% in the eltrombopag group (P = NS). Most patients demonstrated a long-term stable effect in the form of an increase in blood platelet count to a safe level during months and years of ATR treatment. The achievement of at least partial remission for 3 months or more was 70 and 71% in romiplostim and elthrombopag groups, respectively. Patients who started ATR- therapy are currently continuing treatment: 51% - in romiplostim group and in eltrombopag group-39%. The main reason of discontinuation the initially effective therapy were the loss of platelet response, toxicity, withdrawal from treatment (withdrawal with preservation of remission) and patients death. The tolerability of drugs with long-term admission was satisfactory. The most common AE were headache, bone pain, thrombosis, increased blood pressure and petechial hemorrhagic eruptions. The overall incidence of complications did not differ significantly between the romiplostim and eltrombopag groups -15.6 and 15.8%, respectively. Long-term ATR-therapy using in patients with resistant chronic ITP is an effective and largely safe treatment option.

Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial

Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0·0001) and increased International Working Group-defined haematological improvement-platelet rates (p<0·0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2·5; the subsequent 58-week acute myeloid leukaemia HR was 1·2 (95% CI 0·4-3·8). This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18-90 years, and had platelets of 20 × 109 per L or less with or without a history of bleeding or 50 × 109 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (≥20 × 109 per L or <20 × 109 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 μg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523. Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1·06 [95% CI 0·48-2·33]; p=0·88) and proportions who died (93 [56%] vs 54 [54%]; HR 1·03 [0·72-1·47]; p=0·89) were not significantly different between the two groups. Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns. Amgen Inc.

Eltrombopag versus romiplostim in treatment of children with persistent or chronic immune thrombocytopenia: a systematic review incorporating an indirect-comparison meta-analysis

In absence of direct comparison, we conducted an indirect-comparison meta-analysis to evaluate the efficacy and safety of thrombopoietin-receptor agonists(TPO-RAs) in treatment of pediatric persistent or chronic immune thrombocytopenia(ITP). PubMed, Embase, Cochrane Library, Clinical Trials.gov, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database were searched from their earliest records to May 2017. Randomized controlled trials comparing the TPO-RAs with placebo in pediatric ITP were included. Outcomes included overall response rate(primary), durable response, overall or clinically significant bleeding, the proportion of patients receiving rescue medication, and safety. Five randomized placebo-controlled studies(N = 261) were analyzed. The overall response[Risk Ratio(RR) 0.57, 95% confidence interval(CI) 0.21–1.56], the incidence of adverse events (RR 0.96, 95%CI 0.66–1.39), durable response(RR 2.48, 95%CI 0.31–19.97), and the proportion of patients receiving rescue treatment(RR 0.73, 95%CI 0.20–2.73) were similar between eltrombopag and romiplostim group. Nevertheless, eltrombopag might have lower risk of overall bleeding(RR 0.43, 95%CI 0.23–0.80) and clinically significant bleeding(RR 0.33, 95%CI 0.12–0.89) than romiplostim. This meta-analysis suggests that eltrombopag might be similar to romiplostim in efficacy and safety, but seems to reduce the risk of bleeding compared to romiplostim. Furthermore, cost of the treatment, comorbidity of patients and drug compliance should also be considered in clinical decision making.

Thrombopoietin-receptor agonists for children with immune thrombocytopenia: a systematic review

ABSTRACTObjective: We conducted a systematic review to assess the efficacy and safety of Thrombopoietin-receptor agonists (TPOras) for pediatric immune thrombocytopenia (ITP).Methods: We searched PubMed, Embase and Cochrane Library from their earliest records to January 2017. Randomized controlled trials (RCTs) were included. Primary outcomes were durable response and clinically significant bleeding. Secondary outcomes were overall response, overall bleeding events, the use of rescue medication and adverse events (AEs).Results: Five randomized RCTs (261participants) were included. Compared with placebo group, the proportion of patients achieving durable platelet response was significantly higher in Eltrombopag (P = 0.0004) or Romiplostim (P = 0.002) group, so was the overall response in Eltrombopag [RR = 2.64, 95% CI (1.58, 4.44)] or Romiplostim [RR = 5.05, 95% CI (2.21, 11.53)] group. Both clinically significant bleeding (P = 0.04) and total bleeding (P = 0.01) in Eltrombopag group were significantly less frequent than those in placebo group, while no significant difference between Romiplostim and placebo group. The proportion of patients receiving rescue medication, the incidence of overall AEs and serious AEs between TPO-receptor agonists and placebo group were not significantly different.Conclusion: TPOras might improve both durable and overall platelet response in pediatric ITP, compared with placebo.

Thrombopoietin Receptor Agonists in Treatment of Idiopathic Thrompocytopenic Purpura (Primary Immune Thrombocytopenia): Efficacy and Safety in Everyday Clinical Practice

Background &amp; Aims. The use of thrombopoietin receptor agonists (aTPO-r) is a new approach to the treatment of patients with idiopathic thrompocytopenic purpura (ITP) irresponsive to other methods. Data on the efficacy and safety of aTPO-r outside the frames of clinical trials are limited. The aim of the study is to evaluate the efficacy of the therapy in the routine clinical practice as the second and subsequent lines of therapy, as well as the frequency and nature of complications of the treatment in chronic ITP patients. Methods. Data on 58 adult patients (median age: 56 years) with chronic ITP were retrospectively evaluated; 43 (74 %) of them were treated with romiplostim and 15 (26 %) patients received eltrombopag. Two or more lines of prior therapy were ineffective in 19 (33 %) patients (14 from the romiplostim group and 5 from the eltrombopag group). aTPO-r was prescribed and adjusted according to the prescription guidelines. The efficacy of the treatment was assessed based on the platelet response and the possibility of achieving a sustained response after discontinuation of the therapy. Hemorrhagic manifestations were classified according to the WHO bleeding scale. The safety assessment is conducted by identifying adverse events (AEs) and lab test abnormalities. Treatment-related adverse events was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Results. The therapy with aTPO-r was effective in 49 (84 %) patients, including 36 patients (84 %) treated with romiplostim and 13 patients (87 %) with eltrombopag. The median dose to maintain a response was 3.7 ng/kg and 44 mg, respectively. A stable remission was achieved in 4 patients after discontinuation of romiplostim and 1 patient after discontinuation of eltrombopag. aTPO-r resistance was diagnosed in 9 (16 %) patients: 7 (16 %) of them were from the romiplostim group and 2 (13 %) from the eltrombopag group. Complete arrest of bleeding was achieved in 43 (88 %) responders and its reduction to grade I was achieved in the remaining 6 (12 %) of them. The most frequent AEs of romiplostim therapy were headache, arthralgia and dermatitis; and the treatment with eltrombopag caused hepatotoxicity, headache, and nausea. The severity of events did not lead to complete discontinuation of the therapy in any case. Different types of thrombotic complications were diagnosed in 3 patients (5.2 %). Conclusion. The therapy with aTPO-r is an effective and safe method for the treatment of patients with chronic ITP in the second and subsequent lines of therapy.

Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

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

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. 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. 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. 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. Amgen Inc.

Romiplostim in Thrombocytopenic Patients (Pts) with Low-Risk or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndrome (MDS) Results in Reduced Bleeding without Impacting Leukemic Progression: Updated Follow-up Results from a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Romiplostim in Thrombocytopenic Patients (Pts) with Low-Risk or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndrome (MDS) Results in Reduced Bleeding without Impacting Leukemic Progression: Updated Follow-up Results from a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Effect of Romiplostim on Health-Related Quality of Life in Children with Immune Thrombocytopenia and Associated Burden in Their Parents: Results from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study

▪Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count levels and increased risk of bleeding. Symptomatic ITP in children can have a negative impact on their health-related quality of life (HRQoL) and increase their parents' burden. The effect of romiplostim (a thrombopoietin receptor agonist) on HRQoL and parental burden was evaluated in a phase 3 study of children with ITP.Methods: In a phase 3, randomized, double-blind, placebo-controlled study on efficacy and safety of romiplostim, children (<18 years) with ITP ≥ 6 months were randomized to weekly romiplostim or placebo for 24 weeks. The Kids' ITP Tool (KIT), a psychometrically-valid disease-specific HRQoL instrument (Klaassen Ped Blood Cancer2007), was administered to children and/or their parents at baseline, weeks 8, 16, and 25. All three KIT versions were used: Child self-report (to assess HRQoL of children ≥7 years), Parent/Proxy (to assess HRQoL of children <7 years via parent proxy), and Parent self-report (to assess impact of children's ITP on parental burden, for children of all ages). Each KIT version contains 26 items, summarized in a single score ranging from 0 to 100. Higher Child or Parent/Proxy KIT scores reflect better HRQoL of a child with ITP, and higher Parent KIT scores reflect less parental burden.Among efficacy endpoints of the study, overall platelet response was defined as achieving a weekly platelet response (platelet count ≥ 50 x 109/L) for ≥ 4 weeks during weeks 2 to 25, and durable platelet response was defined as achieving a weekly platelet response for ≥ 6 weeks during weeks 18 through 25.As exploratory endpoints of the study, changes in KIT scores from baseline to each follow-up assessment were estimated separately by treatment group (romiplostim or placebo) and by overall/durable platelet response status (yes/no). A mixed effects repeated measures analysis was conducted to estimate the difference in changes of Child and Parent KIT scores between romiplostim group and placebo group, controlling for baseline score, child's age, child's gender, and child's race (analysis of Parent/Proxy data was not conducted due to small sample size).Results: Sixty-two patients were enrolled and randomized to receive romiplostim (42 patients) and placebo (20 patients). Mean age was 9.6 years (range: 3-17, 16 patients <7 years), 57% were female, and 66% were white. Overall and durable platelet response was achieved by 34 and 24 patients, respectively.In general, changes in KIT scores by treatment group and overall platelet response status showed numerically greater and more often statistically significant improvements from baseline to each assessment for children receiving romiplostim (vs placebo) and for platelet responders (vs non-responders) (see Tables 1 and 2). Results based on durable response status were similar to those based on overall response status (data not shown).In the mixed effects analysis, greater improvement from baseline to week 8/16/25 on Parent KIT score was found in the romiplostim group vs placebo (by approximately 8 points, p-value<0.05); no significant difference was found between groups for Child KIT score.Conclusion: Romiplostim treatment is associated with reduced parental burden (measured by Parent KIT score). In some instances sample sizes were small for other KIT versions; therefore, results should be interpreted with caution.Table 1Mean Change from Baseline in KIT Scores by Treatment ArmKIT VersionAssessment week (sample size for romiplostim, placebo)Romiplostim Mean (95% CI)PlaceboMean (95% CI)Child8 (n=28,11) 16 (n=27,10) 25 (n=28,11)9 (4, 15) 11 (5, 16) 14 (7, 20)9 (1, 18) 8 (-3, 20) 10 (-1, 20)Parent/Proxy8 (n=8,2) 16 (n=8,3) 25 (n=9,3)-0.9 (-7, 5) -0.4 (-12, 11) 8 (2, 13)-40 (-108, 23) -1 (-86, 84) -10 (-80, 59)Parent8 (n=40,16) 16 (n=39,17) 25 (n=37,16)13 (10, 17) 15 (10, 21) 18 (12, 23)4 (-6, 13) 12 (4, 20) 13 (4, 22)Table 2Mean Change from Baseline in KIT Scores by Overall Platelet ResponseKIT VersionAssessment week (sample size for responders, non-responders)Responders Mean (95% CI)Non RespondersMean (95% CI)Child8 (n=23,17) 16 (n=22,16) 25 (n=23,16)11 (4, 18) 11 (4, 18) 16 (8, 24)4 (-5, 12) 8 (1, 15) 8 (1, 15)Parent/Proxy8 (n=7,5) 16 (n=8,5) 25 (n=8,6)0.9 (-7, 9) 4 (-10, 18) 9 (1, 17)-15 (-44, 13) -4 (-31, 22) -3 (-23, 17)Parent8 (n=30,26) 16 (n=30,26) 25 (n=29,24)11 (7, 14) 14 (7, 20) 17 (10, 24)10 (3, 18) 15 (9, 21) 15 (9, 21) DisclosuresMathias:Amgen: Research Funding. Li:Amgen: Employment, Other: Stock Ownership. Eisen:Amgen Inc: Employment, Other: stock ownership. Carpenter:Amgen: Employment, Other: Stock Ownership. Crosby:Amgen: Research Funding. Blanchette:Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Other: Data Safety Monitoring Board; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Treatment with Romiplostim, a Thrombopoietin-Receptor Agonist, in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (Int-1) Risk Myelodysplastic Syndrome (MDS): Updated Follow-up Results for Acute Myeloid Leukemia (AML) and Survival from a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Treatment with Romiplostim, a Thrombopoietin-Receptor Agonist, in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (Int-1) Risk Myelodysplastic Syndrome (MDS): Updated Follow-up Results for Acute Myeloid Leukemia (AML) and Survival from a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Pooled Analysis of Safety and Efficacy of Romiplostim in Splenectomized and Nonsplenectomized Patients (pts) with Immune Thrombocytopenia (ITP)

Introduction: Romiplostim is a thrombopoietin receptor agonist approved for use in adult pts with ITP. Pooled analyses of combined pt data from romiplostim ITP clinical studies have previously been reported. Here we report updated safety and efficacy data according to baseline splenectomy status.Methods: Data from adult pts in 13 completed ITP studies with romiplostim were analysed up to June 2014. Pts received romiplostim, placebo or medical standard of care (SOC) and data from the placebo/SOC arms were pooled. All 13 studies were included in analyses of baseline pt characteristics and safety endpoints; 4 early dose-finding studies were excluded from analyses of efficacy endpoints as they do not reflect the current dosing of romiplostim. Adverse events were adjusted for time spent on study and reported as rates per 100 pt-years. For pts who started their parent study in the placebo/SOC group and then went on to receive romiplostim in an extension study, all data from the first dose of romiplostim were included in the romiplostim group. A platelet response was defined as a platelet count ≥50x109/L without rescue medication in the previous 8 weeks; a platelet response for 9 out of any 12 consecutive weeks on-study was considered a sustained platelet response. All analyses were descriptive and no statistical testing was performed.Results: Data from 1,111 pts were analysed, 395 splenectomized and 716 nonsplenectomized. The splenectomized and nonsplenectomized groups were similar in age (median 52 vs 53 years) and sex (female 64% vs 60%), but in the splenectomized group median baseline platelet counts were slightly lower (14 vs 19x109/L) and a higher proportion of pts were known to have received >3 prior ITP treatments (38% vs 12%) than the nonsplenectomized group. Rates of AEs, serious AEs, fatal AEs, treatment-related AEs, thrombotic events, and hemorrhages were lower in nonsplenectomized than splenectomized pts and were in general lower in romiplostim than placebo/SOC-treated pts in both groups. Bone marrow reticulin occurred in 17 romiplostim-treated pts and one placebo-treated pt, at a slightly increased rate in splenectomized vs nonsplenectomized pts. Bone marrow collagen was reported in one romiplostim-treated nonsplenectomised pt. Data from 1,024 pts were analysed for efficacy (376 splenectomized, 648 nonsplenectomized). The median (Q1, Q3) most frequent weekly dose was 4 µg/kg (2, 9) in splenectomized and 3 µg/kg (2, 7) in nonsplenectomized pts. A platelet response was achieved in 82% of splenectomized and 91% of nonsplenectomized pts and a sustained platelet response in 66% and 79%, respectively. The median time to first response was 2.1 weeks for splenectomized and 2.0 weeks for nonsplenectomized pts. Platelet responses were maintained in those who responded: after the first response the median (Q1, Q3) proportion of time with a response was 97% (79%, 100%) for splenectomized and 100% (91%, 100%) for nonsplenectomized pts.Conclusions: A relatively large number of nonsplenectomized pts have received romiplostim in clinical studies. Safety of romiplostim was comparable in splenectomized and nonsplenectomized patients with no new safety signals observed, and platelet response rates were high and of sustained duration in both groups.Abstract 4199. TableNumber of events (rate per 100 pt-years)SplenectomizedNonsplenectomizedPlacebo/SOC N=27 Pt-yr=11.2Romiplostim N=391 Pt-yr=702.0Placebo/SOC N=106 Pt-yr=97.7Romiplostim N=655 Pt-yr=1129.7All AE208 (1861.1)8609 (1226.3)1028 (1052.6)9624 (851.9)Serious AE15 (134.2)478 (68.1)92 (94.2)498 (44.1)Fatal AE3 (26.8)11 (1.6)5 (5.1)31 (2.7)Treatment-related AE15 (134.2)864 (123.1)152 (155.6)928 (82.1)Treatment-related serious AE0 (0)65 (9.3)18 (18.4)59 (5.2)Treatment-related fatal AE0 (0)2 (0.3)0 (0)3 (0.3)Thrombotic events1 (8.9)44 (6.3)5 (5.1)52 (4.6)Hemorrhage events54 (483.2)1868 (266.1)233 (238.6)1591 (140.8)Fatal hemorrhage events1 (3.7)0 (0)0 (0)5 (0.8)Bone marrow reticulin /collagen events*1 (8.9)11 (2.0)0 (0)7 (0.8)Hematologic malignancies/MDS0 (0)6 (0.9)4 (4.1)8 (0.7)Any malignancies0 (0)24 (3.4)9 (9.2)43 (3.8)* Bone marrow collagen reported in one romiplostim-treated nonsplenectomized pt. Excludes study NCT00907478 as bone marrow evaluations were collected differently than in other studies; in the romiplostim arms the N/pt-yrs were 331/560.6 for splenectomised and 546/866.7 for nonsplenectomised pts. DisclosuresRodeghiero:GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Suppremol: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Steurer:Amgen: Honoraria. Godeau:Amgen: Consultancy. Carpenter:Amgen: Employment, Equity Ownership. Kreuzbauer:Amgen: Employment, Equity Ownership.

Results of a randomized, double‐blind study of romiplostim versus placebo in patients with low/intermediate‐1–risk myelodysplastic syndrome and thrombocytopenia

BACKGROUNDThrombocytopenia in patients with myelodysplastic syndrome (MDS) is associated with shortened survival and an increased risk of evolution to acute myeloid leukemia (AML). In this study, the authors evaluated the efficacy of romiplostim in patients who had thrombocytopenia with low-risk/intermediate-1–risk MDS.METHODSPatients who had thrombocytopenia with low-risk/intermediate-1–risk MDS (N = 250) were randomized 2:1 to receive romiplostim or placebo weekly for 58 weeks.RESULTSThe primary endpoint— the number of clinically significant bleeding events (CSBEs) per patient—had a hazard ratio for romiplostim:placebo of 0.83 (95% confidence interval, 0.66-1.05; P = .13). CSBEs were reduced significantly in the romiplostim group for patients who had baseline platelet counts ≥20 × 109/L (P < .0001). For patients who had baseline platelet counts <20 × 109/L, there was no difference in the number of CSBEs, but the platelet transfusion rates were higher in the placebo group (P < .0001), which may have affected the overall CSBE results in this group with severe thrombocytopenia. The incidence of bleeding events was reduced significantly in the romiplostim group (relative risk, 0.92), as were protocol-defined platelet transfusions (relative risk, 0.77). Platelet response rates according to 2006 International Working Group criteria were higher for the group that received romiplostim (odds ratio, 15.6). On the basis of interim data, an independent data monitoring committee advised halting study drug because of concerns regarding excess blasts and AML rates with romiplostim (interim hazard ratio, 2.51). At 58 weeks, the AML rates were 6% in the romiplostim group and 4.9% in the placebo group (hazard ratio, 1.20; 95% confidence interval, 0.38-3.84), and the overall survival rates were similar.CONCLUSIONSRomiplostim treatment in patients with low-risk/intermediate-1–risk MDS increased platelet counts and decreased the number of bleeding events and platelet transfusions. Although study drug was discontinued because of an initial concern of AML risk, survival and AML rates were similar with romiplostim and placebo.

DI-062 Romiplostim and eltrombopag in the treatment of Idiopatic Thrombocytopenic Purpura

BackgroundRomiplostim and eltrombopag have a novel mechanism of action that expands treatment options for idiopathic thrombocytopenic purpura (ITP). Both have proven effective in increasing platelet counts in splenectomised patients.PurposeTo describe...

Treatment With Romiplostim, a Thrombopoietin-Receptor Agonist, In Thrombocytopenic Patients With Low Or Intermediate-1 Risk Myelodysplastic Syndrome: Updated Follow-Up Results For Acute Myeloid Leukemia and Survival From a Randomized, Double-Blind, Placebo-Controlled Study

▪ BackgroundThrombocytopenia in myelodysplastic syndrome (MDS) occurs in approximately 50% of patients with low/intermediate-1 MDS and is associated with reduced survival; few therapies are available. In a randomized placebo-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or placebo. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events (HR 0.83, 95% CI: 0.66, 1.05, P = 0.13) and platelet transfusions (RR 0.77, 95% CI: 0.66, 0.88), and increased IWG HI-P incidence (OR 15.6, 95% CI: 4.7, 51.8). Increases in peripheral blast counts to >10% were more frequent with romiplostim (25/167, 15%) than placebo (3/83, 3.6%), and in most cases resolved after discontinuation. Due to concerns of the data monitoring committee that the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to acute myeloid leukemia (AML) and that transient increases in blast cell counts might put patients at risk for diagnosis of and treatment for AML, treatment with study drug was discontinued in February 2011. Patients were then moved into the long-term follow-up (LTFU) portion of the study. Previously reported (July 2012) 58-week incidence of AML was romiplostim: 6.0% (10 patients), placebo: 4.9% (4 patients), HR 1.20 (95% CI: 0.38, 3.84). This report provides data on long-term follow-up of these patients to March 2013, with a particular emphasis on AML incidence. MethodsEligible patients had IPSS low/intermediate-1 MDS and platelets 1) ≤20x109/L or 2) ≤50x109/L with a history of bleeding, and were receiving only supportive care. Disease progression to AML was defined as 1) ≥20% blasts in the bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim, 2) pathology consistent with leukemia including chloroma or leukemia cutis, or 3) anti-leukemic treatment initiation. Results are presented by treatment group. ResultsOf 250 patients in the study, 210 entered LTFU, and 98 of these patients remained on study as of March 2013; the median (Q1, Q3) follow-up was 25.5 (10.8, 33.1) months. Reasons for discontinuation during LTFU were similar in the romiplostim and placebo groups: death (46.7%, 98 patients); lost to follow up (4.8%, 10 patients), and consent withdrawal (1.9%, 4 patients).During the active study period or during LTFU, death was reported in 44.3% (74 patients) in the romiplostim group and 44.6% (37 patients) in the placebo group (HR 1.04, 95% CI: 0.70, 1.54) (Figure). AML was reported in 10.7% (18 patients) in the romiplostim group and 9.8% (8 patients) in the placebo group (HR 1.14, 95% CI: 0.49, 2.62) (Figure). The proportions of patients who either died or developed AML were 46.1% (77 patients) in the romiplostim group and 45.8% (38 patients) in the placebo group (HR 1.07, 95% CI: 0.72, 1.58). Thirteen of the 26 AML cases occurred in patients who were RAEB-1 and 5 cases were diagnosed by anti-AML treatment alone (Table). In LTFU, patient-reported use of MDS therapy (e.g., azacitidine or cyclosporine) in the romiplostim group was 40.6% and in the placebo group, 28.2%. Reported use of AML therapy (e.g., chemotherapy) was 8.8%, romiplostim and 7.0%, placebo.TableProgression to AML to DateStudy-defined AMLRomiplostimN = 18PlaceboN = 8TotalN = 26Baseline IPSS classificationRAEB-1/-210 (55.6%)3 (37.5%)13 (50.0%)Non-RAEB8 (80.0%)5 (62.5%)13 (50.0%)AML diagnosis byBone marrow/peripheral blast >20%15 (83.3%)6 (75.0%)21 (80.7%)Anti-AML therapy alone3 (16.7%)2 (25.0%)5 (19.2%) ConclusionFollowing the 2011 decision to stop study drug, results have been updated with more observational time on study. Specifically, the HRs for death or progression to AML are 1.04 and 1.14, respectively, compared with 2012 HRs of 1.09 (95% CI: 0.71, 1.68) and 1.15 (95% CI: 0.47, 2.85) respectively. In LTFU, more patients in the romiplostim group than in the placebo group received MDS therapy. As LTFU continues, additional data will be evaluated. Safety concerns regarding risk of disease progression to AML are still being investigated. [Display omitted] Disclosures:Kantarjian:Amgen Inc.: Research Funding. Off Label Use: Romiplostim is indicated for treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Treatment of thrombocytopenia due to MDS, which is the subject of a study described in this abstract, is not an approved indication. Mufti:Novartis: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Fenaux:Amgen Inc.: Research Funding. Sekeres:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen Inc.: Honoraria. Kuendgen:Celgene: Research Funding. Gaidano:Amgen Inc.: Consultancy, Honoraria. Wiktor-Jedrzejczak:Amgen Inc.: Research Funding. Meibohm:Amgen Inc.: Consultancy. Lopez:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

Short Term Treatment With Thrombopoietin-Receptor Agonists For Patients With Immune Thrombocytopenic Purpura (ITP) Before Splenectomy

The thrombopoietin-receptor agonists (romiplostim and eltrombopag) were approved recently as treatments for patients with immune thrombocytopenic purpura (ITP). Splenectomy remains a common second line treatment for ITP with the highest remission rate compared with alternative therapies. It has been reported that splenectomy can be safely performed in patients with a platelet count of 40-50,000 per cubic millimeter but many patients do not reach these values. Intravenous immune globulins (IVIG) are often used before splenectomy in order to increase the platelet count before surgery.The aim of this study was to determine whether a short course of thrombopoietin-receptor agonists can be used as a reliable and safe treatment to increase the platelet count in patients with ITP before splenectomy.Between 2010 and 2012, fifteen patients with ITP, all refractory to steroids, were scheduled for splenectomy. Treatment with thrombopoietin-receptor agonists (romiplostim or eltrombopag) was started 3 weeks before splenectomy. Eight patients received eltrombopag at a dose of 50 mg/day orally until 3 days before splenectomy. For romiplostim, a subcutaneous injection of 3 mcg/kg was given weekly to 7 patients. The last injection was given one week before splenectomy. Complete blood count was repeated every week and the dose of romiplostim was adjusted (up to 10 mcg/kg or down to 1 mcg/kg) based on the platelet count increment. Response was defined as a platelet count of 50,000 or more per cubic millimeter.Mean platelet count before treatment was 11,000±8,000 cells per cubic millimeter. All patients, except one patient on romiplostim, responded to the treatment with a mean platelet count of 74± 25 cells per cubic millimeter on the day of splenectomy (p<0.01). Similar effect was noticed among responders of the two drugs. Four patients from the romiplostim group responded to a 3 mcg/kg dose. Two patients responded to increased doses of 7 and 10 and 10 mcg/kg. One patient did not respond to 10 mcg/kg of romiplostim but later responded to IVIG. The two drugs were well tolerated with no side effects except for mild liver function abnormalities in one patient in the eltrombopag group. No thromboembolic complications or excessive bleeding were reported for these patients.In summary, we report that a short course of thrombopoietin-receptors agonists can effectively and safely increase the platelet count in steroid resistant ITP patients before splenectomy. Disclosures:No relevant conflicts of interest to declare.

A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide

BackgroundLenalidomide treatment in myelodysplastic syndrome (MDS) may lead to thrombocytopenia and dose reductions/delays. This study evaluated the safety and tolerability of the thrombopoietin mimetic romiplostim and its effects on the incidence of clinically significant thrombocytopenic events (CSTEs) in lower risk MDS patients receiving lenalidomide.MethodsPatients were assigned to weekly placebo (n = 12) or romiplostim 500 μg (n = 14) or 750 μg (n = 13) for four 28-day lenalidomide cycles.ResultsThe treatment groups were generally similar with respect to baseline disease characteristics. Del(5q) abnormalities were noted in 1 (8%) patient in the placebo group, 3 (21%) in the romiplostim 500 μg group, and two (15%) in the 750 μg group. CSTEs were noted in 8 (67%) patients in the placebo group, 4 (29%) in the romiplostim 500 μg group, and 8 (62%) in the romiplostim 750 μg group. Throughout the study, median platelet counts trended lower in placebo-treated than in romiplostim-treated patients. Thrombocytopenia-related adjustments in lenalidomide occurred in 6 (50%) patients in the placebo group, 5 (36%) in the romiplostim 500 μg group, and 2 (15%) in the 750 μg group. Although the percentages of patients who received platelet transfusions were similar across treatment groups, there was a trend toward lower numbers of transfusions in both romiplostim groups during each treatment cycle. There were two serious treatment-related adverse events during the treatment period (cerebrovascular accident, placebo; worsening thrombocytopenia, romiplostim 500 μg). Two patients (romiplostim 500 and 750 μg, respectively) had an increase in bone marrow blasts to >20% during treatment, but had no post-treatment biopsy to confirm or exclude the diagnosis of progression to AML.ConclusionsThese data suggest that romiplostim administered to MDS patients during lenalidomide treatment may decrease the frequency of dose reductions/delays due to thrombocytopenia. Additional study is needed to confirm the results of this preliminary trial.Trial registrationClinicalTrials.gov NCT00418665