Immunomodulation with Romiplostim in Young Adult Primary Immune Thrombocytopenia (ITP) As Second-Line Strategy (iROM-study)

Introduction : To date most treatment strategies of primary immune thrombocytopenia (ITP) are symptomatic, preventing premature platelet destruction and increasing their production. New strategies should focus on targeting the immune dysregulation, rather than the platelet count. Rituximab and dexamethasone have the potential to induce tolerogenic mechanisms, however with moderate long-term results (<30%). Thrombopoietin-receptor agonists (TPO-RAs) obviously have the potential to affect the course of the disease with up to 30% treatment-free remission. Possible mechanisms could be exposure to high-dose antigen and/or the innate immune activity of platelets, especially the release of TGF-ß, which may stimulate or restore regulatory T cells (Tregs). Tregs play a fundamental role in the maintenance of immune tolerance. Previous studies have shown lower and impaired function of Tregs in the peripheral blood of ITP patients. Methods: The iROM study is a national multi-center, open label, single arm pilot study that aims to explore possible immunomodulatory effects of romiplostim administered as second line drug in young adults with ITP. Patients who failed, did not tolerate or relapsed after first-line treatment with steroids and/or intravenous immunoglobulin (IVIG) were included, irrespective of disease duration. Romiplostim was administered subcutaneously for 22 weeks and then stopped. The dose was adjusted every week depending on platelet response, following the product information (target platelet count 50-200x10 9/l). Follow-up was performed until week 52. Immunologic investigations were done at weeks 1, 6, 12, 22 and 52. Tregs (CD4 +, CD25 +, CD127 low) were investigated by flow cytometry and reported as percentage Tregs/CD3. Because of comedication at week 1 (IVIG, steroids), week 6 was defined as the initial immunological state. Confirmatory tests were performed using a paired samples Wilcoxon test at a two-sided alpha of 5%. The p-values are adjusted using the Holm method for all secondary analyses. Results: Between 2016 and 2020, 15 patients were enrolled, including two dropouts. Of the 13 patients analyzed, 9 had newly diagnosed ITP (<3 months), median age 31 years (IQR 8), and 4 chronic ITP (>12 months), median age 31.5 years (IQR 8.75), with a median platelet count at enrollment of 26x10 9/l (IQR 41) and 49.5x10 9/l (IQR 88.5), and at week 52, 168x10 9/l (IQR 88) and 96x10 9/l (IQR 23.5), respectively. All patients were on ITP treatment at enrollment (steroids and/or IVIG). In 6 out of 9 patients with newly diagnosed ITP, discontinuation of romiplostim was successful with sustained treatment-free complete remission (TFR) at 1 year, whereas all patients with chronic ITP relapsed and restarted various treatments. Interestingly, romiplostim dose titration was lower and platelet count response higher and more stable in patients achieving TFR (Fig 1). Platelet counts in patients with relapse showed a very jagged curve over the 22 weeks of treatment. Tregs increased between weeks 6 and 22 (end of treatment), so as between weeks 6 and 52 (end of study) in the whole group of patients with a median change of 0.62 (CI95 (0.14, 1.26)) (p=0.017) at end of study. Tregs variation for patients with sustained TFR versus no remission is shown in Fig 2a, and for the 9 patients with newly diagnosed ITP in Fig 2b. Conclusion : These results support the assumption that early treatment of ITP with TPO-RAs, e.g. romiplostim, could positively influence the natural course of ITP. Induction of tolerance may be more successful in the early stage of an autoimmune disorder because of autoimmune expansion and epitope spreading. We also assume that induction of tolerance may be more successful in younger patients because of potentially reduced immunosenescence. In this small trial only 3 out of 9 patients (33%) with newly diagnosed ITP relapsed after stopping treatment according to the iROM protocol. In contrast, all 4 patients with chronic ITP relapsed after stopping treatment. Our observation of a higher increase of platelets and a more stable increase of Tregs in patients with sustained TFR in comparison to those with relapse corroborate the hypothesis that the tolerogenic stimulus may be supported by the platelet mass. Limitations of the study were the small sample size, the heterogeneity of the patient population regarding ITP duration, and preceding medications overlapping the first study weeks. Figure 1 Figure 1. Disclosures Schifferli: Sobi: Honoraria; Novartis: Honoraria, Research Funding. Rovo: Novartis: Research Funding; AG Alexion: Honoraria; BMS: Honoraria; OrPhaSwiss GmbH: Honoraria; Swedish Orphan Biovitrum AG: Honoraria; Amgen: Other: Financial support for congresses and conference travel; AstraZeneca: Other; BMS: Other; Sanofi: Other; Roche: Other; AstraZeneca: Honoraria; Novartis: Honoraria; CSL Behring: Research Funding; AG Alexion: Research Funding. Kuehne: Novartis: Research Funding; UCB: Honoraria; SOBI: Honoraria; Amgen: Research Funding.

Approaches to Establishing Tolerance in Immune Mediated Diseases

The development of rational approaches to restore immune tolerance requires an iterative approach that builds on past success and utilizes new mechanistic insights into immune-mediated pathologies. This article will review concepts that have evolved from the clinical trial experience of the Immune Tolerance Network, with an emphasis on lessons learned from the innovative mechanistic studies conducted for these trials and new strategies under development for induction of tolerance.

The Microbiota and Kidney Transplantation: Influence on the Graft

The gut microbial community may be associated with complications after kidney transplantation. The indigenous microbiota has a significant and protective function that influences the transplant recipient response. Genetic or environmental factors may modify the indigenous microbiota and pathobionts appear. In this condition, several disturbances of the kidney graft may be observed. These include acute rejection, infection, diarrhoea, disturbance in the induction of tolerance, and modification of immunosuppressive drug metabolism. Recently, the use of prebiotics, probiotics, and synbiotics has been demonstrated to be effective in normalising these conditions and in restoring the generation of the normal indigenous microbiota. An improved understanding of the function and composition of the indigenous microbiota may help in finding further solutions to stabilise the microbiota after kidney transplantation.

Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes

Antigen-specific immunotherapy (ASIT) offers a targeted treatment of autoimmune diseases that selectively inhibits autoreactive lymphocytes, but there remains an unmet need for approaches that address their limited clinical efficacy. Soluble Antigen Arrays (SAgAs) deliver antigenic peptides or proteins in multivalent form, attached to a hyaluronic acid backbone using hydrolysable linkers (hSAgA) or stable “click” chemistry linkers (cSAgA). They were evaluated for the ability to block the spontaneous development of disease in the non-obese diabetic mouse model of Type 1 diabetes (T1D). Two peptides, a hybrid insulin peptide and a mimotope, efficiently prevented the onset of T1D when delivered in combination as SAgAs, but not individually. Relative to free peptides administered at equimolar dose, SAgAs (particularly cSAgA) enabled a more effective engagement of antigen-specific T cells with greater persistence and induction of tolerance markers such as CD73, IL-10, PD-1, KLRG-1. Anaphylaxis caused by the free peptides was attenuated using hSAgA and obviated using cSAgA platforms. Despite similarities, the two peptides elicited largely non-overlapping and possibly complementary responses among endogenous T cells in treated mice. Thus, SAgAs offer a novel and promising ASIT platform superior to soluble peptides in inducing tolerance while mitigating risks of anaphylaxis for the treatment of T1D.

Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes

Antigen-specific immunotherapy (ASIT) offers a targeted treatment of autoimmune diseases that selectively inhibits autoreactive lymphocytes, but there remains an unmet need for approaches that address their limited clinical efficacy. Soluble Antigen Arrays (SAgAs) deliver antigenic peptides or proteins in multivalent form, attached to a hyaluronic acid backbone using hydrolysable linkers (hSAgA) or stable “click” chemistry linkers (cSAgA). They were evaluated for the ability to block the spontaneous development of disease in the non-obese diabetic mouse model of Type 1 diabetes (T1D). Two peptides, a hybrid insulin peptide and a mimotope, efficiently prevented the onset of T1D when delivered in combination as SAgAs, but not individually. Relative to free peptides administered at equimolar dose, SAgAs (particularly cSAgA) enabled a more effective engagement of antigen-specific T cells with greater persistence and induction of tolerance markers such as CD73, IL-10, PD-1, KLRG-1. Anaphylaxis caused by the free peptides was attenuated using hSAgA and obviated using cSAgA platforms. Despite similarities, the two peptides elicited largely non-overlapping and possibly complementary responses among endogenous T cells in treated mice. Thus, SAgAs offer a novel and promising ASIT platform superior to soluble peptides in inducing tolerance while mitigating risks of anaphylaxis for the treatment of T1D.

Use of Alfentanil in Palliative Care

Alfentanil is used for chronic pain relief in palliative care. However, there is a dearth of data on its use. For this reason, a decision was made to review the use of alfentanil in palliative care. Retrospective study was carried out in a palliative care service. The files of patients who received alfentanil as an intravenous or subcutaneous continuous infusion for pain relief, between January 2018 and April 2019. In total, 111 patients received alfentanil out of 113 admissions. Of them, 56 were male, and the median age was 70 years. The median number of days on alfentanil was 6 (range 1 to 129). The most frequent primary reasons for switching to alfentanil was uncontrolled pain in 52 (46%) patients and renal impairment in 24 (21%) patients. The median 24-h initial dose of alfentanil was 4 mg (1–20), and the median final 24-h dose of alfentanil was 5 mg (1–60), (p < 0.001). The initial 24-h median number of rescue doses was 2 (0–8), and the final median number of rescue doses was 1 (0 to 8), (p = 0.025). In 56 patients who were on alfentanil for at least 7 days, the dose decreased in 3 (5%), remained stable in 10 (18%) and increased in 43 (77%). The patient on alfentanil for 129 days maintained the same dose throughout that period. Alfentanil can be a useful second-line opioid. The induction of tolerance does not seem to be particularly rapid with alfentanil.

Long induction of tolerance to imatinib

Imatinib is used to treat several haematological and solid malignancies. Cutaneous side effects could often limit the use of this medication. We present a case of a 62-year-old woman with a history of a gastrointestinal stromal tumour that developed a delayed cutaneous adverse reaction 10 days after starting imatinib 400 mg daily. She developed the same symptoms with reintroduction at a dose of 100 mg and with an alternative tyrosine kinase inhibitor, nilotinib 50 mg/day. Given that imatinib was considered her best treatment, she underwent a long induction of drug tolerance (IDT) protocol to imatinib. Patient tolerated the medication without further reactions for 6 months and had improvement of her cancer per last imaging studies. IDT should be considered in delayed hypersensitivity reactions to imatinib after a failed reintroduction of the drug or when no other equally effective agents are available.