Thrombopoietin Receptor Agonists Romiplostim Research Articles

Romiplostim in chemotherapy-induced thrombocytopenia: A review of the literature.

Chemotherapy-induced thrombocytopenia (CIT) is a common challenge of cancer therapy and can lead to chemotherapy dose reduction, delay, and/or discontinuation, affecting relative dose intensity, and possibly adversely impacting cancer care. Besides changing anticancer regimens, standard management of CIT has been limited to platelet transfusions and supportive care. Use of the thrombopoietin receptor agonist romiplostim, already approved for use in immune thrombocytopenia, has shown promising signs of efficacy in CIT. In a phase 2 prospective randomized study of solid tumor patients with platelet counts <100 × 109/L for ≥4 weeks due to CIT, weekly romiplostim corrected the platelet count to >100 × 109/L in 93% (14/15) of patients within 3 weeks versus 12.5% (1/8) of untreated patients (p < 0.001). Including patients treated with romiplostim in an additional single-arm cohort, 85% (44/52) of all romiplostim-treated patients responded with platelet count correction within 3 weeks. Several retrospective studies of CIT have also shown responses to weekly romiplostim, with the largest study finding that poor response to romiplostim was predicted by tumor invasion of the bone marrow (odds ratio, 0.029; 95% CI: 0.0046-0.18; p < 0.001), prior pelvic irradiation (odds ratio, 0.078; 95% CI: 0.0062-0.98; p = 0.048), and prior temozolomide treatment (odds ratio 0.24; 95% CI: 0.061-0.96; p = 0.043). Elsewhere, lower baseline TPO levels were predictive of romiplostim response (p = 0.036). No new safety signals have emerged from romiplostim CIT studies. Recent treatment guidelines, including those from the National Comprehensive Cancer Network, now support consideration of romiplostim use in CIT. Data are expected from two ongoing phase 3 romiplostim CIT trials.

Complications of thrombopoietin receptor agonists therapy in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and decreased platelet production. The formation of antibodies to platelet and megakaryocyte glycoproteins plays a major role in the pathophysiology of ITP. All treatment strategies for ITP attempt to increase platelet count and reduce the risk of bleeding complications. Corticosteroids remain the most commonly used first-line therapy for ITP, but their long-term use is limited due to the development of severe complications. Today the new treatment methods including the use of thrombopoietin receptor agonists (TPO-RA) romiplostim, eltrombopag and avatrombopag with a number of advantages over standard therapy are of great interest. These drugs are recommended for use in the second-line therapy and show high efficacy in patients with ITP, particularly in real clinical practice. In most cases TPO-RA provide stable and long-term remission of the disease, allowing you to reduce or discontinue the use of glucocorticosteroids and avoid splenectomy. Many studies of the mechanism of action, efficacy and toxicity of TPO-RA have been performed. the research results significantly expand our knowledge about these agents. This review provides comparative data of the TPO-RA safety and the main aspects of their clinical use. The features of the new drug avatrombopag, recently approved for use in the Russian federation, are described. the overview presents the advantages and limitations of each drug, possible adverse events and methods for their control.

SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice.

Heterozygous mutation targeting proline 95 in Serine/Arginine-rich Splicing Factor 2 (SRSF2) is associated with V617F mutation in Janus Activated Kinase 2 (JAK2) in some myeloproliferative neoplasms (MPNs), most commonly primary myelofibrosis. To explore the interaction of Srsf2P95H with Jak2V617F, we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl) gene promoter. In transplantation experiments, Srsf2P95H unexpectedly delayed myelofibrosis induced by Jak2V617F and decreased TGFβ1 serum level. Srsf2P95H reduced the competitiveness of transplanted Jak2V617F hematopoietic stem cells while preventing their exhaustion. RNA sequencing of sorted megakaryocytes identified an increased number of splicing events when the two mutations were combined. Focusing on JAK/STAT pathway, Jak2 exon 14 skipping was promoted by Srsf2P95H, an event detected in patients with JAK2V617F and SRSF2P95 co-mutation. The skipping event generates a truncated inactive JAK2 protein. Accordingly, Srsf2P95H delays myelofibrosis induced by the thrombopoietin receptor agonist Romiplostim in Jak2 wild-type animals. These results unveil JAK2 exon 14 skipping promotion as a strategy to reduce JAK/STAT signaling in pathological conditions.

Safety of romiplostim and eltrombopag for children with immune thrombocytopenia: a pharmacovigilance study of the FDA adverse event reporting system database

ABSTRACT Background Romiplostim and eltrombopag are thrombopoietin receptor agonists (TPORAs) that have been approved by the FDA on 22 August 2008 and 20 November 2008 for pediatric immune thrombocytopenia (ITP). However, postmarketing pharmacovigilance of TPORAs in children still attracts much attention. We aimed to evaluate the safety of the TPORAs romiplostim and eltrombopag using data from the Adverse Event Reporting System database of FDA (FAERS). Research design and methods We conducted a disproportionality analysis and analyzed data from the FAERS database to characterize the key features of adverse events (AEs) associated with TPO-RAs approved for children under 18 years of age. Results Since their approval in the market in 2008, 250 and 298 reports of romiplostim and eltrombopag use in children have been published in the FAERS database, respectively. The most frequent AE associated with romiplostim and eltrombopag was epistaxis. Neutralizing antibodies and vitreous opacities showed the strongest signals for romiplostim and eltrombopag, respectively. Conclusions The labeled AEs for romiplostim and eltrombopag in children were analyzed. Unlabeled AEs may reflect the potential of new clinical individuals. Early recognition and management of AEs that appear in children treated with romiplostim and eltrombopag are of key importance in clinical practice.

Retrospective, Observational, Multicenter Study Assessing the Thrombopoietin Receptor Agonist (TPO-RA) Romiplostim and Other Treatments for Patients with Newly Diagnosed or Persistent Primary Immune Thrombocytopenia (ITP) in Routine Clinical Practice in the United Kingdom (UK)

Background: The clinical course of ITP can be categorized into three phases: newly diagnosed (<3 months post-diagnosis), persistent (≥3-≤12 months) or chronic (>12 months). Romiplostim (a TPO-RA) is now approved in the USA and Europe for use across all phases of ITP in adults refractory to 1st line treatments. This extended indication is aligned with treatment guidelines, which recommend TPO-RAs at earlier stages to help patients avoid adverse events associated with prolonged steroid use (>8 weeks) (Neunert et al. Blood Adv 2019; Provan et al. Blood Adv 2019). To guide future recommendations and improve patient outcomes, further real-world data on romiplostim use in the earlier phases of ITP are warranted. Methods: A retrospective, observational, UK wide multicenter study of real-world treatment patterns in adult patients diagnosed with newly diagnosed or persistent primary ITP between 2 July 2015-23 March 2020 was undertaken. The study population was divided into two patient groups depending on what treatments they received during the 1st year from ITP diagnosis - Group 1: received romiplostim; Group 2: received other ITP treatments (excluding TPO-RAs). TPO-RAs, including eltrombopag, could be received in either group post 12 months. Patients in either group were able to receive the following therapies throughout the observation period: azathioprine, cyclosporine, danazol, dexamethasone, IVIg, methylprednisolone, mycophenolate (MMF), prednisolone, and/or rituximab. Exclusion criteria were: clinical trial participation in the observation period and eltrombopag within 12 months of ITP diagnosis. At baseline, data were collected on patient demographics and clinical characteristics. For the 24-month period following ITP diagnosis (observation period), data were collected on prescribed ITP treatments, platelet counts, rescue therapies, bleeding episodes and hospitalizations. All analyses were descriptive. Results: Overall, 78 patients were enrolled at 7 sites in the UK (Group 1: n=14; Group 2: n=64). Baseline demographics are shown in the Table. In Group 1, romiplostim was initiated at a median of 7 weeks from diagnosis and was continuing in 57% of patients (8/14) at the end of the 24-month observation period. Two patients (14%) discontinued romiplostim before 24 months as treatment-free remission was achieved (defined by investigator). The median duration of romiplostim was 46 weeks. The Table summarizes non-TPO-RA treatments received in both groups. The median duration of prednisolone was shorter for Group 1 vs 2 (3 vs 10 weeks for patients who discontinued prednisolone). A similar trend was seen for MMF (18 vs 54 weeks). During the 2nd year of observation, 4 patients in Group 2 received eltrombopag (none in Group 1) and 1 received romiplostim. At ITP diagnosis (i.e. baseline), the median platelet counts were 4 and 8 ×109/L in Groups 1 and 2, respectively. By the end of the 24-month treatment period, the median (interquartile range [IQR]) platelet counts had increased to 192 (81-279) and 121 (80-196) ×109/L in Groups 1 and 2, respectively. During the observation period in Groups 1 and 2, respectively, bleeding episodes occurred in 50% and 63% of patients, rescue therapies were required by 36% and 31%, and hospitalizations in 50% and 46% (81% and 60% were day cases, the rest inpatient stays). The mean number of rescue therapies/patient was 0.7 and 0.6 in Group 1 and 2, respectively. Thromboembolic events occurred in 1 patient in each group (Group 1: sub-acute left lower limb arterial ischemia; Group 2: stroke). Conclusion: In this real-world observational study, median platelet counts increased to 192×109/L after 24 months of observation in patients receiving romiplostim in the 1st 12 months of ITP diagnosis. Over the same period, patients receiving other treatments in the 1st year of ITP diagnosis had median platelet counts of 121×109/L. For patients who discontinued prednisolone, the duration of this steroid was 3 vs 10 weeks in those who received romiplostim in the 1st year vs those who did not. At the time of study data collection, romiplostim was not approved in the UK for use in patients with ITP <1 year from diagnosis. In accordance with treatment guidelines, these findings support further exploring the earlier use of romiplostim for adult patients with primary ITP, including the possibility of reducing prolonged exposure to steroids such as prednisolone. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chemically modified in-vitro-transcribed mRNA encoding thrombopoietin stimulates thrombopoiesis in mice

The use of messenger RNA (mRNA) enables the transient production of therapeutic proteins with stable and predictable translational kinetics and without the risk of insertional mutagenesis. Recent findings highlight the enormous potential of mRNA-based therapeutics. Here, we describe the synthesis of chemically modified thrombopoietin (TPO) mRNA through in vitro transcription and in vivo delivery via lipid nanoparticles (LNPs). After delivery of TPO mRNA in mice, compared with normal physiological values, plasma TPO protein levels increased over 1000-fold in a dose-dependent manner. Moreover, through a single intravenous dose of TPO mRNA-loaded LNPs, both reticulated and total platelet count increased significantly in mice, demonstrating that TPO protein derived from the exogenous mRNA was able to maintain normal activity. Submicrogram quantity of N1-methylpseudouridine-modified TPO mRNA showed a similar effect in promoting thrombopoiesis as that by the TPO receptor agonist romiplostim. In addition, a therapeutic value was established in anti-GPIbα (CD42b) antibody-induced thrombocytopenia mouse models that showed a fast recovery of platelet count. Our study demonstrated chemically modified in-vitro-transcribed TPO mRNA as a potentially safe therapeutic intervention to stimulate thrombopoiesis.

Addition of romiplostim to conditioning prior to HSCT allows chemotherapy reduction while maintaining engraftment levels

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment approach for certain benign and malignant hematologic diseases. The actual HSCT is preceded by a conditioning therapy that reduces host-vs-HSCT graft rejection and creates niche space for transplanted hematopoietic stem and progenitor cells (HSPCs). Conditioning consists of chemotherapy with or without irradiation and is a major cause of side effects in HSCT. However, reduction of the intensity of cytotoxic conditioning leads to higher rates of engraftment failure and increased rates of relapse. We here tested if the addition of an HSC cycling inducing agent during conditioning allows to diminish the dose of conditioning drugs without reducing subsequent transplanted HSC engraftment in a mouse HSCT model. The thrombopoietin receptor agonist romiplostim was shown to induce cell cycling activity in hematopoietic stem cells (HSCs). We thus tested if the addition of romiplostim to the clinically applied conditioning chemotherapy regimen cyclophosphamide and busulfan leads to increased efficacy of the chemotherapeutic regimen. We found that romiplostim not only sensitizes HSCs to chemotherapy but also enables a reduction of the main chemotherapeutic component busulfan by half while HSC engraftment levels are maintained in long-term, serial transplantation assays.

An Analysis of the Serum Metabolomic Profile for the Radiomitigative Effect of the Thrombopoietin Receptor Agonist Romiplostim in Lethally Whole-Body-Irradiated Mice.

The thrombopoietin receptor agonist romiplostim (RP) was recently approved by the US Food and Drug Administration for improving survival in patients acutely exposed to myelosuppressive doses of radiation. Our previous studies with mice have shown that RP administration after lethal irradiation not only completely rescues irradiated mice but also shows mitigative effects on their hematopoiesis and multiple organ injury, including that of the lung, bone marrow, small intestine, and liver. However, the mechanism by which RP functions as a radiomitigator remains unclear. In the present study, we applied a metabolomics approach, which has the ability to reflect the status of an organism directly and accurately, helping to elucidate the biology of treatment responses. Our results showed that the disruption of several metabolites and pathways in response to total body irradiation was partially corrected by RP administration. Notably, RP-corrected metabolites and pathways have been reported to be indicators of DNA damage and lung, bone marrow, small intestine, and liver injury. Taken together, the present findings suggested that the radiomitigative effect of RP is partially involved in the recovery of organ injury, and the identified metabolites may be a useful biomarker of the survival likelihood following radiation exposure.

Treatment of Immune Thrombocytopenia (ITP) with Eltrombopag - Results of the 4 th Interim Analysis of the German Non-Interventional Trial RISA

Background: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder with increased platelet destruction and impaired platelet production. Patients present with bleeding complications of various severity. Another common symptom of ITP is fatigue, which can severely affect patient's quality of life. Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, which is proved to be effective and safe in the treatment of ITP. In Europe, it is approved for the therapy of patients who were diagnosed with ITP at least 6 months ago and who have not responded to other treatments. Here we present data from the 4 th interim analysis of the RISA study.Methods: RISA is a prospective multicenter non-interventional trial in Germany. It was launched in December 2015, and it will be continued until December 2023. In accordance with the inclusion criteria, adults with persisting or chronic pITP (primary ITP) have been enrolled. Patients with pre-treatment could only be included if it was terminated 4 weeks prior to the patient's consent to participate in the study. Exclusion criteria comprised pregnancy, hepatitis C infection and severe aplastic anaemia. Dosage of EPAG and treatment of patients follows the SmPC and the routine of treating physicians. According to the study protocol, patient questionnaires must be completed at 0,1,3,6,9,12,18 and 24 months. Fatigue is assessed using the FACIT-F score, which includes a score range from 0 to 52, with score values <30 indicating severe fatigue. Statistical elaboration is predominantly descriptive. Calculations of confidence intervals and significance values are performed only for explorative purposes.Results: Data cutoff for this 4 th interim analysis was 23.02.2021. 275 patients were enrolled. 261 of them received at least one dose of EPAG and completed one post baseline assessment. Mean duration of participation was 5.2 years. Mean±SD age was 62.7±17.6 years. 54.8% of the patients were female. Median (range) duration of ITP at baseline was 5.3 (0.0-44.9) years. Comorbidity was present in 80.5% of all patients. 79 (28.7%) patients completed all scheduled visits before data cutoff. Median treatment duration was 395.0 days. Treatment with EPAG was carried out at a median dosage of 50 mg daily.In 255 patients, baseline platelet counts were available. The proportion of patients with a platelet count ≥50x10 9/L was 30.6% at baseline. With EPAG treatment, it increased to 75.4% within the first month (N=224) and to 89.0% within 24 months (N=73) from baseline. 12.6% of the patients who completed at least one assessment visit after baseline were pre-treated with the thrombopoietin receptor agonist romiplostim. Within this subgroup as well, platelet counts responded well to EPAG treatment.In 35.6% of patients, at least one bleeding event had occurred in the 12 months prior to baseline. During EPAG therapy, the incidence of bleeding events per patient year was reduced from 1.40 before baseline to 0.60 and 0.13 within the first and second treatment year respectively. This corresponds to a relative reduction in bleeding events of 57% and 91% respectively. Over the entire two years treatment period, the average incidence of bleeding events per patient year accounted for 0.44, which is 69% below the incidence at baseline. Bleeding events were mostly of low severity. (Tab.)Median FACIT-F score was 37.0 at baseline (N=202; mean 36.0±11.0) and 42.5 after 24 months (N=48; mean 38.1±12.1). This difference was not statistically significant. According to exploratory calculations, severity of fatigue was not correlated to platelet count, hemoglobin concentration or incidence of bleeding events.Discussion: In line with previously published randomized controlled trials (Birocchi et al. Platelets 2021), this non-interventional study confirmed the effectiveness of EPAG in adults with persistent or chronic ITP in a routine care setting. During treatment with EPAG, the prevalence and severity of thrombocytopenia, as well as the incidence of bleeding events, decreased. We could also confirm that fatigue is a significant issue in patients with ITP. A FACIT-F score of 37.0 is comparable to average score values in cancer patients (Montan et al. Value Health 2018). Under treatment with EPAG, we observed a decrease in fatigue that was clinically relevant but not statistically significant. Further research is needed to explore possible additional effects of EPAG, for example on fatigue. [Display omitted] DisclosuresMeyer: Swedish Orphan Biovitrum: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Stauch: Novartis: Honoraria, Research Funding; Amgen: Honoraria. Willy: Novartis Pharma: Current Employment.

Surveillance Program of Romiplostim Use Connected to Pregnancy

Surveillance Program of Romiplostim Use Connected to Pregnancy

Efficacy and Thrombotic Adverse Events of Romiplostim Use in Patients with Thrombocytopenia Related to Underlying Malignancies

Background: Chemotherapy-Induced Thrombocytopenia (CIT) often results in treatment delay, dose reduction, or need for alternate cancer therapy. There is no validated or approved treatment of CIT. At our institution, the thrombopoietin-receptor agonist romiplostim, is being tested in a phase II clinical trial to treat CIT (being reported separately). Further, since there is no alternative, some oncologists have been using romiplostim off-label/off study to treat CIT and prevent recurrence of CIT when chemotherapy is resumed. Raising the platelet count could potentially increase the risk of thrombosis. Therefore, as a Quality Assessment initiative, we conducted a retrospective analysis of all use of romiplostim in cancer patients at MSKCC to determine the efficacy for treatment of CIT, as well as rates of thrombosis.Methods: We performed a retrospective review of all romiplostim use in cancer patients at MSKCC from 1/1/2010 to 4/14/2017. Patients without cancer or patients whose thrombocytopenia was due to an unrelated indication, such as ITP, Evans syndrome, underlying cirrhosis, or hereditary thrombocytopenia syndromes, were not included in this analysis. All medical records, radiology reports, and romiplostim administration records were reviewed by one or more study investigator. The study was approved by the IRB.Results: From 1/1/2010 through 4/14/2017, romiplostim use was documented in 292 patients. We derived 239 patients with cancer-associated indications. 185 (77.4%) of patients had thrombocytopenia related to chemotherapy and/or radiation therapy. Other causes of thrombocytopenia included primary or metastatic cancer of the liver (n=21, 8.8%), bone metastases (n=16, 6.7%), immune thrombocytopenia related to lymphoma (n=11, 4.6%), or other (n=6, 2.5%). 184 patients had solid tumors (77%) and 55 had hematologic malignancy (23%).We performed an analysis of efficacy response to romiplostim in the cohort of solid tumor patients and lymphoid malignancies (lymphoma/myeloma), the two groups with the most patients (Table 1A). The analysis of lymphoma/myeloma below does not include stem cell transplant patients. One solid tumor patient died before any followup labs were available and is not included in the analysis.For both solid tumor and lymphoid malignancies, the mean platelet counts at least doubled by day 14. Resumption of chemotherapy was at the discretion of the treating oncologist, and beyond Day 14 the platelet counts reflected the competing effects of maintenance romiplostim support of the platelet counts and platelet suppression by chemotherapy. The majority of patients tolerated resumption of chemotherapy without reoccurrence of CIT (Data not shown).We analyzed the rates of thrombosis, adjusted for time of exposure to romiplostim (Table 1B). The cumulative romiplostim use in the 239 patients was 129 years. There were a total of 15 venous thromboembolic events (DVT and/or PE). This calculated to 11.6% VTE events per patient-year, well within the historical rate of thrombosis in patients with metastatic cancer or lymphoma on chemotherapy (i.e. Khorana AA et al, Cancer 2013;119:648-55). In addition, no episodes of ischemic stroke or myocardial infarction were identified in the cancer patients while on romiplostim.Discussion: In this retrospective analysis of romiplostim use in cancer patients, we found evidence of efficacy in patients with solid tumors and lymphoid malignancies. Platelet counts increased over two-fold within 14 days of initiation of romiplostim. And importantly, we did not find evidence of increased thrombotic rates compared with historical experience. How to optimally utilize romiplostim in cancer patients with thrombocytopenia is the focus of ongoing clinical research. [Display omitted] DisclosuresSoff:Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

Comparison of the Effects of the Thrombopoietin (TPO) Receptor Agonist Romiplostim in Patients with Immune Thrombocytopenia (ITP) for ≤1 Year Vs. >1 Year

Comparison of the Effects of the Thrombopoietin (TPO) Receptor Agonist Romiplostim in Patients with Immune Thrombocytopenia (ITP) for ≤1 Year Vs. >1 Year

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.

Thrombopoietin Receptor Agonists (TPO-RAs): Drug Class Considerations for Pharmacists.

The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)- and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient’s treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia.

Platelets prevent the development of monocrotaline-induced liver injury in mice

Destruction of liver sinusoidal endothelial cells (LSECs) is an initial event in sinusoidal obstruction syndrome (SOS) that leads to accumulation of platelets in the liver. Herein, we explored the role of platelets during progression of experimental SOS induced by monocrotaline (MCT) in mice. Depletion of platelets using an anti-CD41 antibody or anti-thrombocyte serum exacerbated MCT-induced liver injury in C57BL/6 mice, as indicated by an increase in the alanine transaminase (ALT) level, which was associated with hemorrhagic necrosis. Thrombocytosis induced by thrombopoietin (TPO) or the TPO receptor agonist romiplostim (ROM) attenuated MCT-induced liver injury, as evidenced by lower levels of ALT and mRNA encoding matrix metalloproteinase (MMP) 9, and higher levels of mRNA encoding vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3. The level of activated hepatic platelets was higher in TPO- and ROM-treated mice than in saline-treated mice. Co-culture with a high number of platelets increased the viability of LSECs and their mRNA levels of CD31, VEGFR2, and VEGFR3, and decreased their mRNA level of MMP9. The level of VEGF-A was increased in the culture medium of LSECs co-cultured with platelets. These results indicate that platelets attenuate MCT-induced liver injury by minimizing damage to LSECs.

Treatment lines of childhood chronic ITP: A retrospective single-center analysis

Immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia in children. Approximately 20–25% of children develop a chronic course of the disease. Many treatment options are available, including chronic use of first-line therapies, e.g., corticosteroids, intravenous immunoglobulin or anti-Rh-D, and second-line therapies, including dexamethasone, high-dose methylprednisolone, intensive immunosuppressants, rituximab, thrombopoietin receptor agonists (TPO-RAs), splenectomy, and many others; however, none of these treatments have been determined to be the best. In this study, we retrospectively reviewed the course, response to different treatment lines and outcome of children with chronic ITP over a period of ten years to compare the efficacy of different treatment options, aiming to determine a scale of priority for selecting the most costeffective treatment. A retrospective study was conducted and included children diagnosed with chronic ITP from January 2008 until December 2018 who were followed at the Pediatric Hematology Unit of Mansoura University Children Hospital, Mansoura, Egypt. The study proposal was approved on February 14, 2017 (approval No 17.02.59) by the Institutional Review Board (IRB) of the Faculty of Medicine, Mansoura University, Egypt. All research steps were conducted according to the Declaration of Helsinki. The diagnosis of chronic ITP was based upon the persistence of thrombocytopenia lasting for more than 1 year with or without therapy. Bone marrow aspiration was performed for all patients to confirm the diagnosis of chronic ITP and exclude other causes of thrombocytopenia. Data relevant to chronic ITP patients diagnosed from 2008 to 2018 were retrieved from the Electronic Data System of Hospital Management of Mansoura University Children Hospital, including age, sex, diagnosis date, duration of chronicity, treatment given during the chronic phase and response. Treatment regimen was immune modulatory therapies (high-dose dexamethasone, IV rituximab or low-dose dexamethasone + azathioprine), thrombopoietin receptor agonists (TPO-RAs) (eltrombopag or romiplostim). Out of 405 newly diagnosed ITP patients in a period of 10 years in our center, 103 progressed to chronic disease, of whom 29 were lost to follow-up, while 74 patients were followed at the hematology outpatient clinic and enrolled in the current study (32 males and 42 females, median age – 10 years, median initial platelet count – 16 × 109 /l). Approximately one-third of patients (25~33.8%) were managed conservatively; of them, 19 patients achieved sustained remission, and 6 patients needed another treatment line. Forty-six (62%) patients received immunomodulatory therapies. Twentyeight patients (37.8%) were treated with TPO-RAs. No differences were observed between the 3 types of immunomodulatory therapies regarding relapse-free survival and duration of remission (р value: 0.7). Additionally, no differences were noted according to relapse-free survival among those treated with eltrombopag and romiplostim (р value: 0.7). The number of male children who had a sustained response was significantly higher than that of female children among patients receiving immunomodulatory therapies (71.4% vs 28.6%, respectively) (р value 0.01). There were significantly more patients on TPO-RA with a sustained response than patients on immune modulators, and consequently, the number of patients who relapsed on immunomodulators was higher than that of those on TPO-RA (67.9% vs 30.4% compared to 69.9% vs 32.1%, р value 0.01). Many of our patients who received immunomodulators and failed to achieve or lost a response before 2015 were switched to TPO-RAs with comparable efficacy apart from sustainability, which was in favor of the latter. Additionally, among the types of immunomodulators, rituximab did not show superior efficacy compared to other types, with lower costs for the latter, leading to the abandonment of its use, particularly in limited resource countries such as ours.

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.

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

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

Biomarkers of Response to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome (MDS) and Thrombocytopenia - Results of the Europe Trial By the Emsco Network

Biomarkers of Response to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome (MDS) and Thrombocytopenia - Results of the Europe Trial By the Emsco Network

A Multicenter Study of Romiplostim to Treat Chemotherapy-Induced Thrombocytopenia in Solid Tumors and Lymphoid Malignancies

Introduction : Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients causing chemotherapy treatment delays, dose reductions, and discontinuation. A major unmet clinical need, there is no FDA-approved agent available to manage CIT. Given this, we developed clinical pathways to treat CIT at 4 large academic hospitals. Data using romiplostim to manage CIT is limited to small single-center studies and case series of solid tumor patients only. We performed the first large multicenter study of romiplostim for CIT, including both solid tumor and non-myeloid hematologic malignancy patients. Methods : We retrospectively collected demographics, cancer and chemotherapy data, romiplostim dosing, weekly platelet counts (Plt), and outcomes of romiplostim support for patients treated on institutional romiplostim CIT pathways from 2009-2019. For solid tumor patients, 2 institutions utilized intracycle dosing (romiplostim administered on average twice monthly on chemotherapy-off weeks) and 2 utilized standard weekly romiplostim dosing, facilitating comparison of dosing strategies. Romiplostim response was defined as a median on-romiplostim Plt of ≥75×109/L and at least 30×109/L higher than baseline. Baseline characteristics were analyzed for predictors of romiplostim non-response using multivariate logistic regression. Wilcoxon signed-rank and Mann-Whitney U tests compared paired and unpaired groups and Chi square and Fisher's exact tests compared categorical outcomes. Results : 173 patients (153 solid tumor, 20 lymphoid malignancy) were treated for CIT with romiplostim to facilitate ongoing chemotherapy administration, with 170 (98%) receiving a median (range) of 4 (1-36) additional chemotherapy cycles over 10 (2-125) weeks of romiplostim support. A total of 61.3 patient-years of romiplostim treatment of CIT were analyzed for effectiveness and safety. Table 1 lists baseline patient characteristics and Table 2 details chemotherapy regimens precipitating CIT and supported on romiplostim. Median per-patient Plt on romiplostim was significantly higher than baseline (all patients, 112×109/L vs. 54×109/L, P&amp;lt;0.001; solid tumor patients, 116×109/L vs. 60×109/L, P&amp;lt;0.001), Figure 1. Median romiplostim starting dose was 3 µg/kg/week, which was also the median optimized romiplostim dose (dose achieving Plt &amp;gt;100×109/L). While on romiplostim, bleeding occurred in 7.5% of patients and venous thromboembolism occurred in 4.6% (at Plt 65-306×109/L). Compared with intracycle romiplostim dosing, weekly romiplostim dosing resulted in higher median Plt (Figure 2) and fewer chemotherapy delays/dose reductions with no difference in bleeding or thrombotic events (Table 3). Characteristics of solid tumor patients predicting non-response to romiplostim per multivariate regression included biopsy-proven bone marrow invasion by tumor (P&amp;lt;0.001), prior pelvic irradiation (P=0.029), and prior temozolomide (P=0.031) (Figure 3), with only 23%, 20%, and 46% of patients, respectively, achieving a romiplostim response compared with 82% of all other solid tumor patients. Plt improvement with romiplostim was modest in patients with myeloma (N=7, median per-patient Plt 39×109/L with romiplostim vs. 19×109/L at baseline, P=0.078) and aggressive lymphoma (N=13, 47×109/L with romiplostim vs. 23×109/L at baseline, P=0.033), Figure 3, with only 35% receiving more than 1 additional chemotherapy cycle on romiplostim. All myeloma and lymphoma patients were dosed weekly and had extensive bone marrow involvement by malignancy. Conclusions : We present results of romiplostim treatment of CIT in a large cohort of 173 cancer patients, including lymphoid malignancies. Dosing strategies were compared and predictors of non-response were evaluated. Romiplostim was highly effective in solid tumor patients with CIT, allowing chemotherapy administration. Bleeding and thrombosis rates were similar to the general cancer patient population. Both weekly and intracycle dosing were effective and equally safe, but weekly dosing maintained higher Plt overall and higher Plt nadirs with fewer chemotherapy dose reductions or treatment delays. Bone marrow invasion, pelvic irradiation, and prior temozolomide predicted romiplostim non-response. Romiplostim had modest effectiveness to manage CIT in lymphoid malignancy patients with underlying bone marrow involvement. Disclosures Al-Samkari: Moderna: Consultancy. Parnes:Sunovion: Consultancy, Other: Safety monitoring board; Hoffman LaRoche: Research Funding; Genentech: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Geron Corporation: Other: owning stock . Connors:Portola: Other: scientific ad boards; Abbott: Consultancy; Bristol Myer-Squibb: Consultancy, Other: Scientific Ad boards; Eli Lilly: Consultancy. Kuter:Up-to-Date: Consultancy, Honoraria, Patents &amp; Royalties: 3 Up-to-Date chapters; Shinogi: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Kezar: Research Funding. OffLabel Disclosure: Off-label use of the thrombopoietin receptor agonist romiplostim to treat chemotherapy-induced thrombocytopenia is discussed.