Romiplostim Dose Research Articles

Long-term safety and effectiveness of romiplostim for chronic idiopathic thrombocytopenic purpura in real-world settings.

Idiopathic thrombocytopenic purpura (ITP), an autoimmune hematologic disorder characterized by severe platelet count reduction, can be treated with romiplostim. However, post-marketing safety and effectiveness data for romiplostim in Japan are scarce. This prospective, observational, post-marketing Specified Use-Results Survey evaluated the real-world safety and effectiveness of romiplostim for 2years. All patients treated with romiplostim during the survey period were eligible. Of the 1622 patients in the safety analysis set, 94.08% (1526/1622) had chronic ITP. The mean single dose of romiplostim was stable after 12weeks and remained < 6μg/kg in approximately 70% of patients until 104weeks. Within 2years, 14.92% of patients discontinued romiplostim because of adverse events, while 6.47% discontinued because of suspected adverse drug reactions. In contrast, 14.00% of patients discontinued romiplostim because of symptom improvement. Before romiplostim initiation, platelet count was < 2.0 × 104/µL in 60.54% of patients, and the mean platelet count was 2.84 ± 5.76 × 104/µL. Platelet count was 9.19 ± 13.01 × 104/µL after 4weeks, and remained between 10.34 ± 10.72 and 12.38 ± 12.63 × 104/µL from 8 to 104weeks of treatment. No specific concerns were revealed regarding the safety and effectiveness of romiplostim in chronic ITP; the findings demonstrated a favorable risk-benefit balance for romiplostim in this population. Trial registration: UMIN000047864 ( www.umin.ac.jp/ctr ).

Platelet response to romiplostim amongst patients with newly diagnosed, persistent, and chronic immune thrombocytopenia in routine clinical practice in Denmark, Sweden, and Norway.

Patient characteristics and platelet responses at romiplostim initiation according to the duration of immune thrombocytopenia (ITP) are poorly understood. Amongst romiplostim-exposed adults with ITP lasting ≥6 months during 2009-2018 in Denmark, Sweden, and Norway, we examined characteristics at romiplostim initiation, romiplostim dosage, and durable platelet response (≥75% of measurements ≥50 × 109/L at 14-24 weeks) for subcohorts with newly diagnosed (duration <3 months), persistent (3-12 months), or chronic (>12 months) ITP initiating romiplostim. The 285 romiplostim initiators comprised 81 (28%) with newly diagnosed, 47 (16%) with persistent, and 157 (55%) with chronic ITP. More patients with newly diagnosed ITP than longer ITP duration, had low comorbidity levels, two or more prior ITP therapies, and previous bleeding requiring hospitalisation. The median romiplostim doses were similar across subcohorts. During treatment, median platelet counts were similar across subcohorts (75-76 × 109/L), and the durable platelet response was 64.6%, 52.9%, and 52.7% for newly diagnosed, persistent, and chronic ITP, respectively. After treatment cessation, the median platelet count was 138 × 109/L, 68 × 109/L, and 71 × 109/L, respectively. In conclusion, newly diagnosed patients, compared with romiplostim initiators with longer disease duration, had more severe ITP, higher frequency of durable platelet response, and higher median platelet count after cessation.

Romiplostim for Treatment of Children and Young Adults With Severe Aplastic Anemia and Myelodysplastic Syndrome.

Thrombopoietin receptor agonists (TPO-RAs) induce trilineage hematopoiesis under conditions with acquired hematopoietic failure. We evaluated safety, tolerability, and preliminary efficacy of a TPO-RA, romiplostim (Nplate), with or without standard-of-care immunosuppressive therapy (±IST) for children (ages < 21y) with newly diagnosed and relapsed/refractory severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS). Data were collected from an observational study and a single arm interventional pilot study. The safety outcome was treatment-related adverse events (AEs). Efficacy was evaluated by complete hematopoietic response (CHR) at week 24. Romiplostim was commenced at 5µg/kg/week, with dose escalation of 2.5µg/kg/week (maximum, 20µg/kg/dose) based on platelet response. Romiplostim was continued until CHR was observed. Ten subjects (SAA, 9 [IST, 4; without IST, 5]; MDS, 1) completed the study (median age: 9.2y). Median romiplostim dose was 10µg/kg/week (range: 5 to 17.5µg/kg/week). The cumulative incidence of CHR was 70.4% (95% CI, 20.2%-92.6%). Among 21 AEs (Grade 1 to 3), 3 were attributed to romiplostim. At a median posttherapy follow-up of 10.9 months (range: 0.7 to 77.5), no clonal evolution, bone marrow fibrosis or mortality was reported. This proof-of-concept study provides data about short-term safety, tolerability, and preliminary efficacy of romiplostim (±IST) for treatment of pediatric SAA/MDS.

Romiplostim for treatment of thrombocytopenia in dogs: A retrospective assessment and clinical outcomes.

Romiplostim, a thrombopoietin analog, is commonly used to treat immune-mediated thrombocytopenia (ITP) in humans, but its use in dogs remains limited. Evaluate the effects and adverse events of romiplostim administration in dogs with thrombocytopenia caused by various underlying diseases. Forty-two client-owned dogs with naturally occurring thrombocytopenia at 2 referral animal hospitals. Retrospective, multi-institutional analysis to evaluate the outcomes of romiplostim treatment in dogs. Among the dogs treated with romiplostim, 27 experienced an increase in platelet count and 26 maintained a platelet count within the reference range. Platelet count improvement was observed in various conditions: primary ITP (90%, n = 18/20), pancytopenia of unknown etiology (42.9%, n = 3/7), chemotherapy-induced thrombocytopenia (50%, n = 3/6), babesiosis (100%, n = 1/1), radiotherapy-induced thrombocytopenia (0%, n = 0/1), and disseminated intravascular coagulopathy (33.3%, n = 2/6). The median time for platelet recovery (>50 000/μL) after romiplostim administration was 4 days, and the median time for platelet count normalization was 7 days. Median hospitalization time for the improvement group (I) was 5 days. The survival-to-discharge rates were 85%, 40%, and 28.6% for dogs with primary ITP, secondary thrombocytopenia, and thrombocytopenia of unknown etiology, respectively. Romiplostim is a well-tolerated and promising treatment for primary ITP in dogs, suggesting its potential as a valuable therapeutic option for dogs with thrombocytopenia caused by various underlying conditions. These findings emphasize the need for further research to optimize romiplostim dosing and understand its role in treating secondary thrombocytopenia and pancytopenia of unknown etiology.

Proteomic Screening Identifies Megakaryocyte Derived PF4/Cxcl4 As a Critical Driver of Myelofibrosis

Background: Despite advances in understanding the genomic landscape of Myeloproliferative Neoplasms (MPNs), the precise pathological mechanisms driving fibrotic progression in MPNs remain incompletely understood. Previous research has shown that Megakaryocytes (Mks) play a role in MPN pathology by promoting inflammation and extracellular matrix (ECM) deposition by activated stromal cells. However, the specific factors derived from Mks that contribute to the inflammatory milieu and myelofibrosis progression are not well defined. Aims: To investigate the events that drive bone marrow (BM) fibrosis due to abnormal megakaryocyte-stromal crosstalk, we employed mass spectrometry-based proteomics in a myelofibrosis-like mouse model. Our goal was to identify differentially expressed proteins involving Mks, platelets and BM cells in fibrotic versus non-fibrotic conditions. Methods: We induced myelofibrosis in mice through repeated injections of supra-pharmacological doses of the thrombopoietin-mimetic Romiplostim (TPO high). Subsequently, we isolated Mks, BM cells and platelets from TPO high and control mice (injected with saline) and analyzed protein extracts using LC-MS/MS assay. Cytokine levels in plasma and BM cell-free fluids of treated mice were assessed using cytokine arrays. To evaluate fibrosis-related markers, we analyzed the expression of myofibroblasts markers (a-SMA, Vimentin) and ECM synthesis (Fibronectin, Type III Collagen) in mouse embryonic fibroblasts (mEFs) and human BM mesenchymal stromal cells after stimulation with recombinant PF4 using western blot. mEFs were co-cultured with BM-derived Mks in direct and indirect co-culture systems in the presence of increasing TPO concentrations. In some experiments, Mks were transfected with siRNA specifically targeting CXCL4 gene or control siRNA before co-culture with mEFs. Additionally, we quantified plasma PF4/Cxcl4 levels using ELISA assay in a large cohort of MPN patients and normal controls. We also sorted CD41/CD61 Mks from BM aspirates of MPN patients and evaluated CXCL4 mRNA levels through qPCR. Results: We observed that signaling pathways related to cytoskeletal reorganization, cell adhesion and inflammation, were commonly activated in Mks, platelets and BM cells of TPO high mice compared to control mice. The MSP-RON signaling pathway and the Unfolded Protein Response were specifically activated in Mks and platelets, respectively. Among the differentially expressed proteins,the chemokine PF4/Cxcl4 was up regulated exclusively in the proteasomes of the TPO high mice. We confirmed Increased levels of PF4/Cxcl4 in plasma and BM cell-free fluids of fibrotic mice using cytokine arrays. In vitro stimulation of BM-derived Mks with high TPO concentrations resulted in increased synthesis and secretion of PF4/Cxcl4. Recombinant PF4/Cxcl4 was rapidly internalized through surface glycosaminoglycans by mEFs and human BM mesenchymal stromal cells, leading to myofibroblast differentiation. Importantly, we demonstrated that these mechanisms were interconnected during Mk-mEF cross-talk in co-culture systems with high TPO concentrations. Genetic down-regulation of CXCL4 in Mks, prior to co-culture in TPO-saturated conditions, mitigated the profibrotic phenotype of mEFs in terms of ECM synthesis and myofibroblast markers expression. Finally, we found higher plasma levels of circulating PF4/Cxcl4 and increased expression in BM-sorted Mks in patients with MPNs. Conclusions: Our findings identify a crucial role of Mk derived PF4 in the fibrosis progression of MPNs, providing further support for the potential therapeutic strategy of neutralizing PF4.

Patient Outcomes after Initial High Dose Versus Low Dose Romiplostim for Inpatient Management of Immune Thrombocytopenia

Introduction: Romiplostim is a thrombopoietin receptor agonist approved by the US FDA for chronic immune thrombocytopenia (ITP) in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The recommended dose is 1 mcg/kg/week subcutaneously, escalated weekly by increments of 1 mcg/kg to achieve and maintain a platelet count of 50 x 10 9 /L g ( Kuter et al 2021). It has been postulated that starting at the maximum recommended dose of 10 mcg/kg/week in patients with severe bleeding may swiftly increase platelets and minimize bleeding ( Roumier et al 2021). However, this approach may also increase the risk of major thrombotic events (TE). It is unclear if the more aggressive dosing strategy results in more rapid, robust responses and a tolerable safety profile compared to the FDA approved approach. Methods: This retrospective chart review included adult patients who initiated romiplostim while admitted for ITP at a Mayo Clinic Enterprise site from May 2018 to May 2022. Outcomes included rate of TE at 30 days and 90 days and time to first TE in patients receiving initial romiplostim doses of &amp;lt; 5 mcg/kg (low dose, LD) and &amp;gt; 5 mcg/kg (high dose, HD), median time to platelet response (defined as platelets &amp;gt; 30 x10 9/L and &amp;gt; 50 x10 9/L on 2 separate checks) in LD vs HD, and cost to the institution comparing LD to HD. Outcomes were summarized using descriptive statistics. Statistical analysis was done using BlueSky. Fischer's exact test and chi-squared were performed for categorical data, and Wilcoxon rank sum test were done for continuous variables. Results: Forty-five patients met eligibility criteria: 33 (73%) received initial romiplostim doses &amp;lt; 5 mcg/kg and 12 (27%) received doses &amp;gt; 5 mcg/kg. The majority of patients (43/45 (96%)) presented with platelets &amp;lt; 50 x 10 9/L. The median age was 65 years (68 in LD vs 57 HD). There were 24 (73%) males in the LD group vs five (42%) in the HD group. At baseline, 64% (n = 21) of LD patients and 75% (n = 9) of HD patients presented with bleeding. Major bleeding (defined by 2019 ASH ITP guidelines) was present in 21% (n= 7) vs 17% (n = 2) of patients, LD versus HD, respectively ( Neunert et al 2019). The overall incidence of TE in this study was 24% (n = 11): LD 5 (15%) and HD 6 (50%) (p = 0.044) at 90 days. Median days to TE was 21 days, 12 days in LD group (range 5-21) vs 24.5 days (range 14-58) in HD group (p = 0.067). TE included deep vein thrombosis (DVT, n = 6), DVT with pulmonary embolism (n = 1), portal vein thrombus (n = 1), multiple brain infarcts (n = 1), splenic vein thrombus (n = 1), and left atrial appendage thrombus (n = 1). The median platelet count at the time of TE was 304 x 10 9/L, 415 x 10 9/L (range 58-900) in the LD group vs 323 x 10 8/L (range 33-1427) in the HD group (p = 0.79). Thirty-two (71%) out of 45 patients had a response to romiplostim: 22 in the LD group (71%) vs 10 (83.3%) in the HD group (p = 0.698). Of the patients that responded, the median time to response was 6 days in the LD group vs 11.5 days in the HD group (p = 0.09) The median dose at time of initial response was 2 mcg/kg in the LD group and 6 mcg/kg in the HD group. Wholesale Acquisition Cost (WAC) was used to determine the cost per dose, rounded to the nearest vial size. The average WAC for the initial dose in LD patients was $1806.80 compared to $6061.79 in HD patients. Conclusion:There was a significantly increased incidence of thrombosis in patients admitted with ITP that received initial romiplostim doses &amp;gt; 5 mcg/kg, with no differences in the time to platelet response. Careful consideration of risks versus benefits should be given prior to initiating romiplostim at doses higher than recommended doses.

Thrombocytopenia Associated with Elemental Mercury Poisoning in Two Siblings - Connecticut, July 2022.

Two siblings aged 5 and 15 years from Connecticut were hospitalized with petechial rash, oral mucositis, and severe thrombocytopenia approximately 10 days after they played with a jar of elemental mercury they found in their home. Before the mercury exposure was disclosed, the siblings were treated with platelet transfusions, intravenous immune globulin (IVIG) for possible immune thrombocytopenic purpura, and antibiotics for possible infectious causes. When their conditions did not improve after 6 days, poison control facilitated further questioning about toxic exposures including mercury, testing for mercury, and chelation with dimercaptosuccinic acid. The older sibling soon recovered, but the younger child required a prolonged hospitalization for severe thrombocytopenia, ultimately receiving repeated doses of IVIG, steroids, and romiplostim, a thrombopoietin receptor agonist. Close collaboration among multiple agencies was required to identify the extent of mercury contamination, evaluate and treat the other family members, and decontaminate the home. These cases demonstrate the importance of ongoing public health outreach to promote early detection of elemental mercury toxicity, and the need to evaluate for environmental exposures when multiple close contacts experience similar signs and symptoms.

Immunomodulation with romiplostim as a second-line strategy in primary immune thrombocytopenia: The iROM study.

Thrombopoietin receptor agonists (TPO-RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first-line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end-points included the sustained remission off-treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)-4, IL-9 and IL-17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor-β levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation.

Antithrombotic and hemostatic stewardship: Evaluation of romiplostim for treatment of thrombocytopenia at a large academic medical center.

Romiplostim is indicated for immune thrombocytopenia (ITP), though is often used off-label for other indications such as chemotherapy-induced thrombocytopenia (CIT) and thrombocytopenia post hematopoietic stem cell transplantation (HSCT). Although romiplostim is FDA approved at a starting dose of 1 mcg/kg, it is often initiated at 2-4 mcg/kg depending on the severity of thrombocytopenia in clinical practice. Given the limited data, but interest in higher doses of romiplostim for indications other than ITP, we aimed to assess our inpatient romiplostim utilization at NYU Langone Health.This was a single-center, retrospective review of 84 adult patients from January 2019 to July 2021. The top three indications were ITP (51, 60.7%), CIT (13, 15.5%), and HSCT (10, 11.9%). The median initial romiplostim dose was 3.8 mcg/kg (range, 0.9-10.8). 51% of patients achieved a platelet count of ≥50 × 109/L by the end of week 1 of therapy. For patients achieving goal platelets by the end of week 1, the median dose of romiplostim was 2.4 mcg/kg (range, 0.9-10.8). There was 1 episode of thrombosis and 1 episode of stroke.We found that higher than FDA-recommended initial doses should be considered to achieve a platelet response. It appears to be safe to initiate romiplostim as higher doses, and to increase doses by greater increments than 1 mcg/kg in order to achieve a platelet response. Future prospective studies are needed to confirm the safety and efficacy of romiplostim in off-label indications and should evaluate clinical outcomes such as bleeding and need for transfusions.

Efficacy and Safety of Long-Term Romiplostim Use for Refractory Aplastic Anemia

Introduction: Aplastic anemia (AA) is a life-threatening bone marrow failure syndrome characterized by pancytopenia and hypocellular bone marrow caused by the destruction of hematopoietic stem cells by lymphocytes. About one-third of patients with severe AA who cannot undergo allogeneic hematopoietic stem cell transplantation from a matched sibling donor are refractory to single or repeated immunosuppressive therapy courses. Romiplostim (ROMI), a thrombopoietin receptor agonist, signals and activates intracellular transcriptional pathways via the thrombopoietin receptor, resulting in stimulation of hematopoietic stem and progenitor cells. Our previous research, a phase II/III, multicenter, open-label interventional study, showed that ROMI induced the recovery of at least one lineage of blood cells in >80% of patients with refractory AA. However, data on the long-term efficacy and safety of ROMI in refractory AA beyond 52 weeks are scarce. Additionally, the pretreatment baseline factors of patients who achieve hematological response during treatment and maintain response after discontinuing ROMI are unclear. To address these issues, we report the results at the end of the extension phase (June 2020) of the aforementioned phase II/III study. Methods: We conducted a long-term follow-up analysis of the efficacy and safety of ROMI 10 μg/kg administered subcutaneously once weekly for 4 weeks (Weeks 1-4), followed by 1-step titration to 5, 10, 15, and 20 μg/kg once weekly up to 52 weeks (Weeks 5-52) depending on platelet response. The extension study was started from Week 56 after a 4-week suspension period. The patients continued to receive the same dose of ROMI they received on Week 52 until its commercially available date for the treatment of AA in the study country or the end of June 2020 (end of the extension phase), whichever occurred first. Results: Of the 31 patients enrolled in the phase II/III study, 27 completed the 53-week assessment. Twenty-five hematological responders (any cell lineage) and 2 non-responders entered the extension phase. ROMI was administered for 2 years in 23 patients, 3 years in 7 patients, and 3.5 years in 6 patients in this extension study. The median dose of ROMI was 20 μg/kg at Week 53, which was reduced to 15 μg/kg at 2 years, and 7.5 μg/kg at 3.5 years (Figure 1). Of the 2 non-responders, 1 patient showed platelet response at 2 years, which was sustained thereafter, while the other failed to respond by the end of the extension study at 103 weeks. Of the patients who failed to achieve the platelet (n=7) and erythrocyte (n=6) responses at 1 year, 3 (43%) and 1 (17%) showed responses at 2 years; the mean platelet count increased from 38.3 to 76.7 ×109/L in the 3 platelet responders, and the hemoglobin level increased from 8.0 to 9.2 g/dL in the erythrocyte responder (Figure 2). Of the 23 patients who needed blood transfusions at baseline, 4 and 2 of them still required erythrocyte and platelet transfusions at 1 year, and 4 and 5 of them did so at 2 years, respectively. Five patients remained in response after discontinuing ROMI lasting 29-111 weeks even after discontinuing treatment. These 5 patients had relatively high baseline reticulocyte counts (45.8-93.8 ×109/L, median 57.5 ×109/L) compared with the remaining 22 patients (2.7-114.7 ×109/L, median 46.5 ×109/L). The most common adverse drug reactions included headache (3 cases, 9.7%) and muscle spasms (2 cases, 6.5%); cytogenetic abnormality (-7) led to discontinuation of the study drug in 1 case. Two patients presented with chromosomal abnormalities of unknown significance, including 46,XX,t(11;17) at Week 108 and 46,XX,add(10) at Week 134. No transformation to acute myeloid leukemia or myelodysplastic syndromes occurred. Conclusions: The up to 3.5-year follow-up study of ROMI administration in adult patients with refractory AA demonstrated its safety and efficacy during the extension period. The dose of ROMI was on a downward trend during the long-term follow-up. Nearly half the patients who did not achieve platelet or erythrocyte responses to ROMI at Week 52 eventually achieved responses by continuing the administration until the end of the study, demonstrating the efficacy of prolonged ROMI administration. High reticulocyte counts at ROMI initiation may predict achievement of response after discontinuing ROMI. Further studies with larger sample sizes should confirm these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Enzalutamide for Primary Immune Prostate Cancer in Routine Clinical Practice: Results from a Rare Metastasis Study in Japan

Introduction: The effectiveness and safety of romiplostim were evaluated by immune thrombocytopenia (ITP) phase (newly diagnosed/persistent/ chronic) at romiplostim initiation. Methods: This is a post hoc analysis of a prospective, Japanese, multicentre, observational study in adults with ITP who received ≥1 dose of romiplostim. Follow-up data were collected for ≤2 years. Outcomes included overall platelet response (≥1 platelet count ≥50 × 109/L at 2–24 weeks after romiplostim initiation) or durable platelet response (≥75% of measurements ≥50 × 109/L at 14–24 weeks) and adverse drug reactions (ADRs), evaluated by ITP phase.

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

AbstractRomiplostim 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.

Effect of Thrombopoietin Receptor Agonist on Pregnant Mice.

Thrombopoietin receptor agonists (TPO-RAs) are an effective treatment for refractory immune thrombocytopenia (ITP). However, the use of TPO-RAs is limited for ITP in pregnant women due to concerns about fetal toxicity. In this study, we examined the effects of romiplostim, one of the TPO-RAs, on pregnant mice. The mice were injected subcutaneously with romiplostim (1, 5, 10, 30, and 100 μg/kg) on gestational days (GD) 1, 8, and 15. We evaluated maternal and fetal platelet and megakaryocyte counts (MK), fetal weight at birth, placental morphology, and miscarriage rates. Romiplostim increased platelet and MK counts in pregnant mice at all doses and in fetuses at doses above 10 µg/kg. Fetal weight at birth was slightly reduced at a dose of 100 μg/kg, but there were no significant differences in placental weight, spiral artery wall thickness, placental growth factor signal changes, or the rate of resorption at that dosage. The dose of romiplostim used clinically for ITP patients (1–10 μg/kg) did not show any adverse effects on pregnant mice. Although the results of the present study are encouraging, until there are more conclusive data, the use of romiplostim should be evaluated individually in severe, life-threatening cases, and all relevant ethical aspects should be considered.

Implementation, utilization, and evaluation of a pharmacist-driven romiplostim dosing service for patients with immune thrombocytopenia at a multisite cancer centre

Introduction Romiplostim is a thrombopoietin receptor agonist approved for the treatment of patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immune globulin, or splenectomy. Dose adjustments of romiplostim are based on platelet counts and follow a dosing schema that requires frequent monitoring. As a quality improvement initiative to increase clinical efficiency and promote clinical pharmacy services at our institution, we developed a collaborative practice agreement and implemented a novel pharmacist-driven romiplostim dosing protocol. Methods A retrospective chart review was conducted to evaluate the acceptance, utilization, and impact of the pharmacist-driven romiplostim dosing service. The primary outcome of our analysis was the adoption rate by providers of the romiplostim pharmacist dosing service. Secondary endpoints were focused on patients newly initiating romiplostim on the dosing service and included platelet responses and number of dose adjustments by a pharmacist Results A total of 54 patients received romiplostim in our analysis: 25 patients who had already been receiving romiplostim and 29 patients who newly initiated romiplostim during the study period. Of the 29 patients newly initiating romiplostim, 27 (93%) had their dosing managed by a pharmacist Twenty-one patients (84%) and 18 patients (75%) achieved an initial and durable response with romiplostim, respectively. Pharmacists made a median of 3 dose adjustments to romiplostim per patient. Conclusion The implementation of a pharmacist-driven romiplostim dosing service led to a significant adoption and utilization by physicians at our health system.

Chemotherapy-induced thrombocytopenia in Ewing sarcoma: Implications and potential for romiplostim supportive care.

Maintaining dose-dense, interval-compressed chemotherapy improves survival in patients with Ewing sarcoma but is limited by myelosuppression. Romiplostim is a thrombopoietin receptor agonist that may be useful in the treatment of chemotherapy-induced thrombocytopenia (CIT). Patients aged between 3 and 33years with Ewing sarcoma from 2010 to 2020 were reviewed. CIT was defined as a failure to achieve 75,000 platelets per microliter by day 21 after the start of any chemotherapy cycle. Fisher's exact test was used for univariate analysis and Pearson's correlation coefficient was used for the association between continuous variables. Twenty-seven out of 42 patients (64%) developed isolated CIT, delaying one to four chemotherapy cycles per patient. CIT occurred during consolidation therapy in 24/27(88.9%) and with ifosfamide/etoposide cycles in 24/27 (88.9%). Univariate analysis failed to identify risk factors for CIT. The use of radiation approached significance (p-value=.056). Ten patients received romiplostim. The median starting dose was 3μg/kg (range 1-5). Doses were escalated weekly by 1-2 to 4-10μg/kg and continued throughout chemotherapy. A higher romiplostim dose was associated with a higher change in average platelet counts from baseline, r=.73 (p=.04). No romiplostim-related adverse events were identified aside from mild headache. CIT is the primary reason for the inability to maintain treatment intensity in Ewing sarcoma. The concurrent use of romiplostim with chemotherapy was safe and feasible, and efficacy was associated with higher romiplostim doses.

Romiplostim for Primary Immune Thrombocytopenia in Routine Clinical Practice: Results from a Multicentre Observational Study in Germany

Introduction: The effectiveness and safety of romiplostim were evaluated by immune thrombocytopenia (ITP) phase (newly diagnosed/persistent/chronic) at romiplostim initiation. Methods: This is a post hoc analysis of a prospective, German, multicentre, observational study in adults with ITP who received ≥1 dose of romiplostim. Follow-up data were collected for ≤2 years. Outcomes included overall platelet response (≥1 platelet count ≥50 × 10⁹/L at 2–24 weeks after romiplostim initiation) or durable platelet response (≥75% of measurements ≥50 × 10⁹/L at 14–24 weeks) and adverse drug reactions (ADRs), evaluated by ITP phase. Results: Data from 96 patients were analysed (newly diagnosed, n = 18; persistent, n = 25; chronic, n = 53). During the 2- to 24-week follow-up, overall platelet response was achieved in 100% (95% confidence interval: 81.5–100), 100% (86.3–100), and 96.2% (87.0–99.5) of patients with newly diagnosed, persistent, or chronic ITP, respectively, and platelet responses were durable in 88.2% (63.6–98.5), 65.0% (40.8–84.6), and 69.4% (54.6–81.7) of patients. During the 2-year follow-up, ADRs occurred in 24.0–35.8% of patients across phases. Two patients with chronic ITP experienced bone marrow ADRs; no thrombotic ADRs occurred. Conclusion: Romiplostim was effective and well tolerated in patients with newly diagnosed, persistent, or chronic ITP in routine clinical practice.

Investigating the Potential Impact of Dosing Tolerance to Facilitate Use of Nplate Self-Administration in Adult Patients with ITP

Background and Objective: Romiplostim, is a TPO agonist approved for the treatment for adult ITP. It follows a weight-based and platelet response-guided dose titration algorithm to maintain patients' platelet counts (PC) between 50 and 200x10 9/L, after which a maintenance dose is administered once weekly to keep platelet counts within the target range. While self-administration of romiplostim maintenance dose has been approved in EU for adult patients, in the US romiplostim is only approved for weekly administration by a healthcare provider (HCP) using an 0.01 mL graduation syringe to ensure dosing accuracy; a dose tolerance margin of romiplostim has never been investigated before. The following work explores the impact of dosing tolerance on PC to assess the feasibility of romiplostim self-administration in adult ITP patients.Methods: The analysis was based on a previously developed pharmacodynamic model of romiplostim in ITP patients (Perez-Ruixo et al, 2012, Gibiansky et al, 2021). Previous romiplostim clinical studies in patients with ITP were leveraged to develop an updated model of 475 ITP patients (>50 kg, weekly romiplostim total dose > 100 µg and between 1 and 10 µg/kg stable maintenance dose for at least 1 month, self-administration) and assess potential differences in PC between ITP patients who qualify for self-administration and the general adult ITP population. Comparison of observed and model predicted PC and romiplostim dose over time confirmed the adequacy of the model to assess the impact of varying dose tolerances on PC that may occur with self-administration.Under the proposed guidelines for romiplostim self-administration eligibility, an adult patient would self-administer up to 4 weekly stable maintenance doses of romiplostim between two platelet measurements 1 month apart. To evaluate the impact on PC over 1 month when patients self-administered all four weekly doses versus patients receiving the same prescribed dose by a healthcare provider, three dosing scenarios were considered: (1) exact titrated dose (no dose deviation), (2) titrated dose plus 0.03 mL or 15 µg of romiplostim, and (3) titrated dose minus 0.03 mL or 15 µg of romiplostim. To further characterize the number of ITP patients with clinically meaningful platelet deviations, the predicted number of virtual patients with a PC below 30 x10 9/L or above 400 x10 9/L were also summarized for each simulated scenario.Lastly, the simulated population was divided into four groups based on the magnitude of their prescribed dose and used to evaluate whether the prescribed romiplostim dose influences platelet excursion rates following the investigated dose scenarios.Results: Simulations suggest that 4 successive weekly doses of ± 0.03 mL (or ± 15 µg) the prescribed romiplostim dose is unlikely to cause a significant change in platelet excursion rates relative to continuous administration of the exact prescribed dose. No meaningful increase (0.1 - 0.4%) was observed in the predicted excursion rates across these thresholds for either the under- or overdosing scenarios (Figure 1).This results also show that while there is a slight trend between the magnitude of the prescribed dose and the fraction of subjects that experience a platelet excursion, it does not result in a meaningful increase (<4%) in platelet excursions in any of the evaluated subgroups. Specifically, we observed minimal changes in the fraction of patients with a platelet excursion outside the potentially clinically meaningful thresholds across all simulated dose groups and dosing scenarios (Table 1).The results from this analysis suggest that possible dosing variance expected from the self-administration of romiplostim by an eligible lay person (± 0.03 mL or 15 μg) with monthly PC evaluation will not lead to a significant increase in the rate of platelet count excursions for patients who achieve a stable romiplostim dose and meet the proposed eligibility criteria. [Display omitted] DisclosuresSerrano Castillo: Amgen: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company. Wang: Amgen Inc: Current Employment, Current equity holder in publicly-traded company. Zhang: Amgen: Current Employment, Current equity holder in publicly-traded company. Chow: Amgen: Current Employment, Current equity holder in publicly-traded company. Doshi: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment.

Assessing Romiplostim Dose and Platelet Response-Guided Titration to Support Use of Romiplostim in ITP Patients Less Than 12 Months from Diagnosis

Background: Romiplostim, a subcutaneous treatment for adult ITP, uses a platelet response-guided dose adjustment algorithm (USPI dosing, Table 1) to maintain patients' platelet count (PC). Romiplostim was recently approved for patients with ITP ≤ 12 months from diagnosis.Objectives: The primary objective of this analysis was to confirm the appropriateness of romiplostim dose and platelet response-guided titration for patients with ITP ≤ 12 months from diagnosis using a model based approach.Methods: Data from 268 adult patients with ITP ≤ 12 months from diagnosis was extracted from 7 previously conducted clinical studies and used to develop a model based on a previously published model of romiplostim dose-response in ITP patients (Perez-Ruixo et al, 2012). Following the model update, patient characteristics (time from diagnosis, PC at baseline, sex, age, weight, number of prior therapies, region, and use of rescue medications) were assessed to identify any potential factors influencing dose or platelet response in ITP patients ≤ 12 months from diagnosis. The model was qualified for simulation using standard methods modified to account for response-guided dosing. Additionally, observed and predicted platelet responses (incidence of durable response, sustained response, and duration of response) were compared for patients stratified by time from ITP diagnosis (<3, 3 to ≤ 6, and 6 to ≤ 12 months). Simulations were then conducted using prescribed dosing guidance to predict PC and romiplostim doses over 52 weeks of treatment in patients ≤ 6 months and > 6 to ≤ 12 months from diagnosis.Results: The analysis dataset included 7854 PC from 268 patients (with median baseline PC of 18 x 10 9/L and median time since diagnosis of 3 months) receiving romiplostim weekly for up to 3 years at doses ranging from 1 to 15 mg/kg.The updated model (Figure 1) consisted of a drug-sensitive progenitor cell compartment (Pre), 4 maturation compartments (Transit), and a peripheral blood compartment (Circ). Romiplostim increased production of platelet precursors in Pre in 2 ways: 1. linearly with romiplostim exposure (immediate response), and 2. as a function of cumulative administered dose. Response to romiplostim was bimodal with approximately 50% of patients more sensitive to romiplostim treatment with drug sensitivity proportional to time since diagnosis. In the other 50% of patients, immediate response was reduced and there was no cumulative effect of romiplostim dosing on platelet response over time. Age was associated with average platelet transit time where a patient of 30, 60, or 90 years would have a platelet transit time of 6.3, 7.5, and 8.3 days respectively. No other covariates were found to influence any model parameters.Model predicted and observed platelet responses were similar for ITP patients stratified by time from ITP diagnosis (<3, 3 to ≤ 6 and 6 to ≤ 12 months). Simulations (Figure 2) showed that romiplostim prescribed dosing is effective in maintaining PC of 50 - 250 x 10 9/L following titration (approximately 65% of subjects) and minimizing the proportion <20 or >400 x 10 9/L regardless of time since ITP diagnosis or sensitivity to romiplostim treatment. The predicted <35% of subjects above 400 x 10 9/L is consistent with what was observed in the adult ITP safety datasets.Conclusions: An updated model of romiplostim dose and platelet response was developed using data from ITP patients ≤12 months from diagnosis. Clinical trial simulations using the updated model predicted that weekly dosing of romiplostim according to the dose titration rules in the label adequately maintained platelet counts in patients with ITP ≤ 12 months from diagnosis. [Display omitted] DisclosuresGibiansky: Amgen: Consultancy. Serrano Castillo: Amgen: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company. Chow: Amgen: Current Employment, Current equity holder in publicly-traded company. Doshi: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment.

Romiplostim for the Treatment of Adult Patients with Newly Diagnosed or Persistent Immune Thrombocytopenia: Subgroup Analysis from a Phase 2 Study

Background: The clinical course of immune thrombocytopenia (ITP) can be categorized into three phases: newly diagnosed (<3 months post-diagnosis), persistent (≥3-≤12 months) or chronic (>12 months). Having previously been restricted to use in patients with chronic ITP, romiplostim (a thrombopoietin receptor agonist) was recently approved in the USA and Europe for use across all phases of ITP in adult patients refractory to 1st line treatments. Its efficacy and safety in adult patients with ITP diagnosed for ≤6 months have been reported in a Phase 2 study (Newland, BJH 2016); however, its effect in patients with newly diagnosed ITP is not well characterized. Here we report post hoc analyses from the same Phase 2 romiplostim study stratified by duration of ITP diagnosis (<3 months and ≥3-≤12 months).Methods: Adult patients with primary ITP diagnosed within 6 months prior to study entry and an insufficient response to first-line therapies (corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin or vinca alkaloids) were enrolled in a Phase 2, interventional, single-arm study (NCT01143038). Patients had to have a single platelet count ≤30 × 10 9/L at any time during the 4-week screening period. Splenectomized patients, those who received rituximab, and those who had previously received romiplostim or other platelet-producing agents were excluded. Patients were to receive 12 months of romiplostim therapy at a starting dose of 1 µg/kg, with dose adjusted to target platelet counts ≥50-<200 ×10 9/L. Concomitant and rescue treatments were permitted to maintain platelet count. Following the 12-month treatment period, romiplostim dose was tapered for patients maintaining platelet count ≥50 × 10 9/L. Tapering could also begin earlier during the 12-month treatment period according to platelet counts and dose adjustment rules.Efficacy outcomes included the duration (expressed as a percentage of months) with platelet response (defined as median platelet count ≥50 × 10 9/L during a month without rescue medication use in the previous 8 weeks) during the 12-month treatment period; treatment-free remission (TFR; weekly platelet count ≥50 × 10 9/L for 24 consecutive weeks with no ITP treatments); time to platelet response; durable platelet response (platelet response for ≥6 of the last 8 weeks of treatment during the first 24 weeks); and sustained platelet response (platelet response for 9 weeks in any 12-week period). Safety was assessed throughout the study. Post hoc analyses were performed by subgroups of ITP duration (newly diagnosed ITP: <3 months; persistent ITP ≥3-≤12 months).Results: Of 75 patients enrolled, 45 had newly diagnosed ITP, 30 had persistent ITP. Baseline demographic are shown in the Table. Mean (standard deviation; SD) duration of platelet response was 80.1% (35.4) of months for patients with newly diagnosed ITP and 80.9% (29.9) for patients with persistent ITP (Table). Median (range) weeks to first platelet response was 2.1 (0-11) in the newly diagnosed group and 2.1 (1-25) in the persistent ITP group. In the newly diagnosed ITP group 21 (46.7%) and 31 (68.9%) patients had durable and sustained platelet response, respectively; in the persistent ITP group, 16 (53.3%) and 24 (80.0%) patients had durable and sustained platelet response, respectively. TFR was achieved by 17 (37.8%) newly diagnosed patients and 7 (23.3%) persistent ITP patients. Median (range) weeks to TFR was 21 (6-57) in the newly diagnosed group and 43 (9-53) in the persistent ITP group. The safety profile of romiplostim was broadly similar across the two groups.Conclusion: In this Phase 2 study of patients with primary ITP and disease duration of ≤6 months, romiplostim demonstrated efficacy irrespective of whether patients had newly diagnosed (<3 months duration) or persistent (≥3-≤12 months) disease. Efficacy outcomes were generally similar in both groups of patients, with rapid time to platelet response (~2 weeks) observed and around half of patients achieving a durable platelet response. Respective TFR rates were 37.8% and 23.3% in patients with newly diagnosed and persistent ITP. Safety was consistent across groups and no new safety signals were observed. This subgroup analysis was consistent with the previously reported overall findings of the study and supports the use of romiplostim for adult patients with primary ITP, including those with newly diagnosed and persistent disease. [Display omitted] DisclosuresNewland: GSK: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; BMS: Research Funding; Argenx: Consultancy, Speakers Bureau; Angle: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; UCB Biosciences: Consultancy; Roche: Speakers Bureau; Octapharma: Research Funding. Viallard: LFB: Consultancy; Grifols: Consultancy; Novartis: Consultancy; Amgen: Consultancy. López Fernández: Amgen: Honoraria. Eisen: Amgen: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company. Hippenmeyer: Amgen: Current Employment, Current equity holder in publicly-traded company. Godeau: Novartis: Consultancy; Sobi: Consultancy; Amgen: Consultancy; Grifols: Consultancy.

Efficacy and Safety of Extended Use of Romiplostim Treatment for Chemotherapy-Induced Thrombocytopenia

Background: Chemotherapy induced thrombocytopenia (CIT) is common, adversely impacts chemotherapy relative dose intensity, and may adversely impact cancer control. There is no approved therapy for CIT. In our recent phase II study of solid tumor patients with CIT (Soff et al, J. Clin. Onc., 2019), romiplostim lead to correction of platelet counts in 85% of participants within 3 weeks. While on romiplostim maintenance, only 6.8% of participants experienced chemotherapy dose reduction or delay as a result of recurrent CIT within a minimum of two cycles of chemotherapy or 8 weeks. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT.Objectives: This is an extension analysis of the phase II study for patients receiving romiplostim maintenance for 12 months or longer.Patients/Methods: In the phase II study, 44 patients successfully met the primary endpoint of correction of their platelet count within 3 weeks and resumed chemotherapy with romiplostim maintenance. 21 patients (48%) remained on romiplostim for 12 months or longer. Data were collected from one month prior to initiation of romiplostim to one month after the last dose of drug. Data extracted included complete blood count, chemotherapy doses and dates, romiplostim doses and dates, body weight, cancer diagnosis, age, gender, date of death and thrombotic events. Efficacy was demonstrated by persistent maintenance of platelet counts during long-term chemotherapy and avoidance of episodes of reduced chemotherapy dose intensity. Safety was assessed by two methods: tracking the rates of venous or arterial thrombosis; as well as development of marrow fibrosis and/or secondary hematologic malignancy. The mean romiplostim doses and lab values are calculated by month of study participation.Results: All participants had metastatic disease. Breast (N=6) and colorectal (N=6) were the most common cancers. No participant discontinued romiplostim therapy due to an adverse event or futility. One patient received romiplostim at our institution, but chemotherapy at an outside hospital; details of his chemotherapy were not available for this analysis. 14 of the 20 (70%) of the analyzable participants experienced no episode of CIT; 4 subjects experienced a single chemotherapy dose delay due CIT. No patient experienced multiple delays in chemotherapy due to CIT. Two patients required a chemotherapy dose reduction.The mean monthly platelet counts remained controlled throughout the period of analysis. (Figure 1A). The mean romiplostim doses were in the range of 3-5 mcg/kg through 35 months. There were insufficient participants beyond month 36 to allow meaningful interpretation of platelet counts or mean romiplostim doses. There was no evidence of adverse impact on absolute neutrophil count or hemoglobin levels (Figure 1B). No patient developed leukoerythroblastic changes indicative of marrow fibrosis, and no cases of secondary hematologic malignancy were identified. Two participants experienced thrombosis. One individual experienced a deep vein thrombosis. A second participant with an established history of congenital thrombophilia, experienced multiple tumor associated infarctions. The thrombotic events did not lead to discontinuation of participation in the trial for either participant. Of the 44 patients in the phase 2 study who resumed chemotherapy, 21 were alive at 12 months (48%) and 12 were alive at 24 months (27%).Conclusions: In this long-term analysis, romiplostim was effective and safe in the treatment of CIT with no evidence of drug resistance, marrow fibrosis, or secondary hematologic malignancy. The rates of thrombosis were no higher than expected for this patient demographic. There are some limitations to our analysis which includes our inability to accurately capture non-parenteral chemotherapy (oral or investigational agents) which were excluded from our analysis. We are unable to assess an impact on overall survival or cancer progression. However, the fact that half the participants were alive at 12 months and a quarter at 24 months is a reassuring signal. The analysis also is limited to the patients who were eligible for the initial phase 2 trial and corrected their platelet count within 3 weeks. Within these limitations, the extension study provides reassurance for long-term efficacy and safety of romiplostim treatment for CIT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Romiplostim is approved to increase platelet counts in ITP and pre-surgery. We are describing the results of a clinical trial.