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 < 21 y) 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 5 µg/kg/week, with dose escalation of 2.5 µg/kg/week (maximum, 20 µg/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: 9.2 y). Median romiplostim dose was 10 µg/kg/week (range: 5 to 17.5 µg/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.

Treatment patterns in adults with immune thrombocytopenia before, during and after use of thrombopoietin receptor agonists: a longitudinal prescription database study from Germany.

OBJECTIVE: To assess real-world treatment patterns in patients with immune thrombocytopenia (ITP) who received thrombopoietin receptor agonists (TPO-RAs) in Germany. METHODS: This was a longitudinal, retrospective study using anonymized patient-level data (IQVIA healthcare prescription database, covering 82% of German statutory prescriptions). Eligible patients (aged ≥18 years) had received ≥1 TPO-RA prescription (romiplostim/eltrombopag) from July 2016 to June 2019 (treatment duration ≥30 days). ITP medication use was assessed for 18 months prior to, during and for ≥6 months after TPO-RA treatment. RESULTS: A total of 3553 patients (median age 64 years) were included. Median persistence on TPO-RAs was 12 months (range 1-34). In the periods before, during and after TPO-RA treatment, oral corticosteroids were the most commonly used therapy (64.4%, 43.4% and 36.1% of patients, respectively); median cumulative doses across each period were 2521.9, 2000.0 and 2277.8 mg. The median total duration of corticosteroid use before, during and after TPO-RA therapy was 15, 18 and 32 weeks, respectively. The total median cumulative corticosteroid dose was 6799.7 mg. CONCLUSION: We identified a potential overuse of corticosteroids in patients with ITP in Germany. Earlier use of TPO-RA therapy after a short course of corticosteroids could avoid side effects associated with long-term use.

Novel oncolytic adenovirus expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitor activates multiple immune effector populations leading to enhanced tumor killing in vitro, in vivo and with patient-derived tumor organoids.

BACKGROUND: Despite the success of immune checkpoint inhibitors against PD-L1 in the clinic, only a fraction of patients benefit from such therapy. A theoretical strategy to increase efficacy would be to arm such antibodies with Fc-mediated effector mechanisms. However, these effector mechanisms are inhibited or reduced due to toxicity issues since PD-L1 is not confined to the tumor and also expressed on healthy cells. To increase efficacy while minimizing toxicity, we designed an oncolytic adenovirus that secretes a cross-hybrid Fc-fusion peptide against PD-L1 able to elicit effector mechanisms of an IgG1 and also IgA1 consequently activating neutrophils, a population neglected by IgG1, in order to combine multiple effector mechanisms. METHODS: The cross-hybrid Fc-fusion peptide comprises of an Fc with the constant domains of an IgA1 and IgG1 which is connected to a PD-1 ectodomain via a GGGS linker and was cloned into an oncolytic adenovirus. We demonstrated that the oncolytic adenovirus was able to secrete the cross-hybrid Fc-fusion peptide able to bind to PD-L1 and activate multiple immune components enhancing tumor cytotoxicity in various cancer cell lines, in vivo and ex vivo renal-cell carcinoma patient-derived organoids. RESULTS: Using various techniques to measure cytotoxicity, the cross-hybrid Fc-fusion peptide expressed by the oncolytic adenovirus was shown to activate Fc-effector mechanisms of an IgA1 (neutrophil activation) as well as of an IgG1 (natural killer and complement activation). The activation of multiple effector mechanism simultaneously led to significantly increased tumor killing compared with FDA-approved PD-L1 checkpoint inhibitor (Atezolizumab), IgG1-PDL1 and IgA-PDL1 in various in vitro cell lines, in vivo models and ex vivo renal cell carcinoma organoids. Moreover, in vivo data demonstrated that Ad-Cab did not require CD8+ T cells, unlike conventional checkpoint inhibitors, since it was able to activate other effector populations. CONCLUSION: Arming PD-L1 checkpoint inhibitors with Fc-effector mechanisms of both an IgA1 and an IgG1 can increase efficacy while maintaining safety by limiting expression to the tumor using oncolytic adenovirus. The increase in tumor killing is mostly attributed to the activation of multiple effector populations rather than activating a single effector population leading to significantly higher tumor killing.

Rapid blood cell recovery with immunosuppressive therapy combined with romiplostim in a patient with very severe hepatitis-associated aplastic anemia who underwent liver transplantation.

Patients with hepatitis-associated aplastic anemia (HAA) who undergo living-donor liver transplantation (LDLT) have a poor prognosis with infections and bleeding complications. Rapid recovery of blood cells is critical for preventing these complications and improving the outcome. Immunosuppressive therapy (IST) combined with thrombopoietin receptor agonists is considered effective for aplastic anemia. However, there are no data on the benefits of adding thrombopoietin receptor agonists to IST for HAA. We present the case of a child with severe HAA who underwent LDLT, and who achieved rapid blood cell recovery with IST combined with romiplostim, a thrombopoietin receptor agonist. In addition, despite having undergone LDLT, the patient had no adverse events such as serious liver dysfunction or thrombosis. This case suggests that IST combined with thrombopoietin receptor agonists may be a promising treatment option for HAA patients undergoing LDLT.

Real-world use of thrombopoietin receptor agonists in older patients with primary immune thrombocytopenia.

The efficacy and safety of thrombopoietin receptor agonists (TRAs) in older patients with primary immune thrombocytopenia (ITP) are unknown. We investigated TRA response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROTs) in 384 patients with ITP aged ≥60 years. After 3 months, 82.5% and 74.3% of eltrombopag- and romiplostim-treated patients, respectively, achieved a response; 66.7% maintained the response (median follow-up, 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; although no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. Thirty-four major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, while on TRAs and were associated with thrombosis history (subdistribution hazard ratio, 2.04, P = .05) and platelet count <20 × 109/L (subdistribution hazard ratio, 1.69; P = .04), respectively, at TRA start. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but 1 during persisting TRA treatment (incidence rate, 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRAs; 53 (13.8%) patients maintained SROTs, which were associated with TRA discontinuation in complete response (P < .001). Very old age (≥75 years; 41.1%) was associated with the more frequent start of TRAs in the persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in older patients with ITP, with no fatal hemorrhages and with SROTs in a significant portion of patients. Caution is warranted in patients with a history of thrombosis, and a careful risk/benefit balance should be considered.

Clinical overview and practical considerations for optimizing romiplostim therapy in patients with immune thrombocytopenia.

The fundamental treatment goal for patients with immune thrombocytopenia (ITP) is reduced or ameliorated bleeding. Although various treatment options exist for the management of ITP, recent advances have led to the approval of three thrombopoietin receptor agonists (TPO-RAs; romiplostim, eltrombopag, and avatrombopag) in the United States and European Union. Current treatment guidelines for ITP indicate that medical therapy is preferred over surgical therapy and support the use of TPO-RAs as early as 3 months after disease onset. More recent data are available on the use of romiplostim in patients who have had ITP for <1 year, and romiplostim is now indicated for the treatment of adults who have not responded adequately to initial treatment, as well as children aged ≥1 year who have had ITP for ≥6 months. Here we review the role of romiplostim in the management of ITP, with a focus on efficacy and safety data, emerging data on early use (beginning within 3 months of disease onset) and treatment-free remission, and practical considerations for optimal management of ITP.

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

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

Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study.

A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.

Regulation of Antioxidant Stress-Responsive Transcription Factor Nrf2 Target Gene in the Reduction of Radiation Damage by the Thrombocytopenia Drug Romiplostim.

Ionizing radiation induces severe oxidative stress, resulting in individual death by acute radiation syndrome. The nuclear factor-erythroid-2-related factor 2 (Nrf2) plays an important role in the antioxidant response pathway. Recently, romiplostim (RP), an idiopathic thrombocytopenic purpura therapeutic drug, was reported to completely rescue mice exposed to lethal total-body irradiation (TBI). However, the details underlying the mechanism for reducing radiation damage remain largely unknown. To elucidate the involvement of the master redox regulator Nrf2 in the radio-mitigative efficacy of RP on TBI-induced oxidative stress, expression of Nrf2 target genes in hematopoietic tissues such as bone marrow, spleen, and lung from mice treated with RP for three consecutive days after 7 Gy of X-ray TBI was analyzed. RP promoted the recovery of bone marrow cells from day 10 and the significant up-regulation of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1 (Nqo1), glutamate-cysteine ligase catalytic subunit (Gclc) and glutamate-cysteine ligase modifier subunit (Gclm) was observed compared to the TBI mice. RP also promoted the recovery of splenic cells on day 18, and the significant up-regulation of Nqo1, Gclc and Gclm in spleen both on day 10 and 18 and Nqo1 and Gclm in lung on day 10 was observed compared to the TBI mice. The present study suggests that the radio-mitigative effects of RP indicates on the activation of Nrf2 target genes involved in redox regulation and the antioxidative function, especially Nqo1, Gclc and Gclm. It is indicating the importance of these genes in the maintenance of biological homeostasis in response to radiation-induced oxidative stress.

Romiplostim is effective for eltrombopag-refractory aplastic anemia: results of a retrospective study.

Eltrombopag (EPAG) and romiplostim (ROM), thrombopoietin receptor-agonists with demonstrated efficacy against aplastic anemia (AA) in prospective controlled studies, were authorized in Japan for use in adults with aplastic anemia in 2017 and 2019, respectively. So far, no data are available on the potential contribution of switching from ROM to EPAG or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles of ten patients, who failed to respond to the maximum dose of EPAG and then switched to ROM, were evaluated. All ten patients received a maximum dose of ROM (20 µg/kg/week). At a median follow-up of twelve months, seven of ten patients (70%) had achieved either neutrophil, erythroid, or platelet response, including one complete response. No patients showed platelet count fluctuations that were reported during ROM treatment for immune thrombocytopenia. In univariate analysis of the relationship between efficacy and demographics, the response had a correlation with neither factors. None of the patients stopped the ROM treatment because of adverse events. Although a larger number of patients and a longer follow-up period are needed to confirm our findings, our results show the efficacy of ROM in patients with EPAG-refractory AA.

Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study.

Management of immune thrombocytopenia (ITP) during pregnancy can be challenging because treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess the safety and efficacy of off-label use of Tpo-RAs during pregnancy, a multicenter observational and retrospective study was conducted. Results from 15 pregnant women with ITP (pregnancies, n = 17; neonates, n = 18) treated with either eltrombopag (n = 8) or romiplostim (n = 7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks (range, 1-39 weeks); the indication for starting Tpo-RAs was preparation for delivery in 10 (58%) of 17 pregnancies, whereas 4 had chronic refractory symptomatic ITP and 3 were receiving eltrombopag when pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed, except for 1 case of neonatal thrombocytosis. Response to Tpo-RAs was achieved in 77% of cases, mostly in combination with concomitant ITP therapy (70% of responders). On the basis of these preliminary findings, temporary off-label use of Tpo-RAs for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and is likely to be helpful, especially before delivery.

Treatment-free remission after thrombopoietin receptor agonist discontinuation in patients with newly diagnosed immune thrombocytopenia: an observational retrospective analysis in real-world clinical practice.

Thrombopoietin receptor agonists (TPO-RAs) are used for treatment of chronic immune thrombocytopenia (ITP). Several studies have shown that TPO-RAs induce remission and sustained response, despite long-term discontinuation of therapy. Furthermore, TPO-RAs are effective in patients with newly diagnosed ITP. Here, we retrospectively assessed all patients with ITP who received TPO-RAs in our hospital, focusing on newly diagnosed, non-splenectomized patients who had discontinued TPO-RAs due to sustained complete response (CR, platelet count ≥ 100 × 109/L). Moreover, we explored predictive factors related to sustained treatment-free remission (TFR) without additional ITP treatment. Seventy-seven consecutive patients with ITP received TPO-RAs from 2011 to 2018. Twenty-seven newly diagnosed patients achieved CR and discontinued TPO-RAs. The overall response and discontinuation rates in all patients with ITP were 79.2% and 41.6%, respectively. In newly diagnosed patients who discontinued TPO-RAs, the 2-year TFR rate, cumulative incidence of loss of CR, and response (R) rate (platelet count ≥ 30 × 109/L) were 66.4%, 46.7%, and 34.0%, respectively. Patients who achieved R within 14 days from the start of TPO-RA administration exhibited a higher 2-year TFR rate, compared with patients who did not (87.5% vs. 48.5%, p = 0.0106). In conclusion, patients with newly diagnosed ITP who achieve sustained response should consider discontinuation of TPO-RAs.

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

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

Safety and efficacy of self-administered romiplostim in patients with immune thrombocytopenia: Results of an integrated database of five clinical trials.

Romiplostim self-administration by patients or caregivers may offer time/cost savings to healthcare professionals (HCPs) and convenience for patients who avoid weekly clinic visits. We performed an integrated analysis of five clinical trials to evaluate the efficacy and safety of romiplostim self-administration. Data were analyzed from adults with immune thrombocytopenia (ITP) who received weekly romiplostim via self-administration or from an HCP. Patients who achieved a stable romiplostim dose for ≥3 weeks (HCP group ≥5 weeks to provide an appropriate index date to enable comparisons with the self-administration group) with platelet counts ≥50 × 109 /L were eligible. In the self-administration (n = 621) vs HCP (n = 133) groups, respectively, median age was 53 vs 58 years, median time since primary ITP diagnosis was 3.7 vs 2.5 years, and median baseline platelet count at ITP diagnosis was 19.0 vs 20.0 × 109 /L. In the self-administration and HCP-dosed groups, median romiplostim treatment duration was 89 vs 52 weeks and median total number of doses was 81 vs 50, respectively. In the self-administration and HCP groups, respectively: 95.0% and 100.0% of patients achieved ≥1 platelet response (defined as weekly platelet count ≥50 × 109 /L without rescue medication in previous 4 weeks); the median percentage of weeks with a response was 94.5% and 95.9%; and rescue medication was used in 36.7% and 39.8% of patients. Self-administration did not adversely affect safety; duration-adjusted rates for all treatment-emergent adverse events (TEAEs) and bleeding TEAEs were numerically lower with self-administration. Romiplostim self-administration appears effective and well tolerated in eligible patients with ITP.

Romiplostim for thrombocytopenia following allogeneic stem cell transplantation: A case series.

Thrombocytopenia is a relatively common complication following allogeneic hematopoietic stem cell transplantation and is associated with increased bleeding, transfusion requirements, chronic graft-versus-host disease, and all-cause mortality. There are currently no approved treatments outside of supportive transfusions. We report on the outcomes of five patients at our institution who received romiplostim for either primary engraftment failure or secondary failure of platelet recovery following stem cell transplantation. In total, four out of the five patients demonstrated a response to romiplostim, which was defined as seven consecutive days of platelet count >50 × 109/L with transfusion independence, with two ongoing responses (>365 days each) at the conclusion of the study period. Responses to romiplostim were sustained in the absence of significant bone marrow disease, which was found to contribute to recurrent thrombocytopenia. Additionally, romiplostim was well-tolerated overall; one patient developed minimal fibrotic changes on bone marrow biopsy postromiplostim. Although these results are promising, data from randomized clinical trials are needed to fully understand the role of romiplostim after stem cell transplantation.

Use of Romiplostim during pregnancy as a rescue therapy in primary immune thrombocytopenia: Literature review and case description.

Thrombocytopenia could appear during pregnancy, in up to 8-10% of the cases, where 3-5% is related to an autoimmune process so-called immune thrombocytopenia (ITP). We present a 34-year-old woman debuted at 13 weeks gestation, with a platelet count of 19 × 109/L and petechiae. She did not respond to initial treatment with corticosteroids and intravenous immunoglobulin. At this point, considering the limited treatment options due to toxicity and/or teratogenesis of other drugs proven to be effective against ITP like azathioprine, rituximab, cyclophosphamide, etc. and the risk of bleeding symptoms, either from mother or fetus, we decided to begin treatment with Romiplostim (thrombopoietin receptor agonist). On reviewing the literature at this matter, only eight cases with ITP were treated during pregnancy with Romiplostim and only one of those, the ITP, was refractory to Romiplostim. In a retrospective study, Romiplostim used as a bridge to surgery in 47 patients stated a platelet count increment higher than 100 × 109/L in 79% cases after two doses of Romiplostim. According to bibliography, we decided to start Romiplostim to our patient at 35 weeks of gestation with a spectacular platelet count recovery of 158 × 109/L within 1 week of treatment, at 36th week, and after induced labor, she had on the very next day an eutocic vaginal childbearing without major bleeding complications.