Romiplostim for Primary Immune Thrombocytopenia (ITP) 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: 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 x 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 2–24-week follow-up, overall platelet response was achieved in 100% (95% confidence interval [CI]: 81.5–100), 100% (86.3–100), and 96.2% (87.0–99.5) of patients with newly diagnosed, persistent, or chronic ITP, respectively; 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.

Immunomodulatory and immunosuppressive drug protocols in the treatment of canine primary immune thrombocytopenia, a scoping review

Primary immune thrombocytopenia (ITP) is a cause of severe thrombocytopenia in dogs. Immunosuppressive corticosteroid drugs are frequently used in the management of ITP, but treatment failure may occur. Immunomodulatory and non-corticosteroid immunosuppressive drugs might improve outcomes from therapy either alone or in combination with corticosteroids. The objectives of this scoping review were (1) to evaluate the current evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP, and (2) to answer the clinical question, whether or not therapy with immunomodulatory or non-corticosteroid immunosuppressive drugs alone or in combination with corticosteroids could improve outcome, compared to therapy with corticosteroids alone. A literature search was performed in the electronic databases of Agricola, CAB Abstracts, Embase, Medline and Web of Science for publications in November 2019 and again February 1, 2021. Selection criteria were relatively strict and included peer-reviewed research papers reporting outcome measures from immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP with a pre-therapeutic mean or median platelet count < 50,000/µL as a strict criterion for inclusion. Studies were evaluated if they had an appropriate diagnostic work up to exclude underlying conditions. Outcome measures and adverse events were compared between drug protocols both within studies and between studies. The search identified 456 studies, with six studies being eligible for inclusion. The studies were mostly case series while two were randomized controlled trials. Level of evidence varied with an overall uncertain subject enrollment, small groups, inadequate description and variable use of drug protocols or outcome measures. For outcomes such as platelet recovery time and duration of hospitalization, an improvement was observed using adjunctive therapy (human intravenous immunoglobulin) compared to therapy with corticosteroids alone. For outcomes of complete platelet recovery time, survival (6-month), mortality and relapse, no improvement was observed using adjunctive drugs compared to corticosteroids alone. Specifically, therapy with mycophenolate mofetil alone and adjunctive azathioprine were associated with more severe adverse events compared to other drug protocols. Evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP was of variable quality. Future larger case-controlled trials are required for determination of optimal treatment protocols in canine ITP.

Splenectomy for Primary Immune Thrombocytopenia Revisited at the Era of Thrombopoietin Receptor Agonists: New Insights for an Old Treatment

Introduction Although splenectomy is still considered as the most effective curative treatment for primary immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the emergence of thrombopoietin receptor agonist (TPO-RAs) and anti-CD20 monoclonal antibodies 1-3. The main objective of our study was to evaluate if splenectomy was still as effective in the modern era, particularly for patients who failed to respond to TPO-RAs and rituximab. One of the secondary objectives was to assess, among patients who did not respond to or relapse after splenectomy, the pattern of response to subsequent intervention with treatments used before splenectomy and particularly TPO-RAs. Methods This multicentre retrospective observational study involved adults who underwent surgical splenectomy for primary ITP in France from 2011 (authorization of TPO-RAs in France) to 2020. To be included in the study, patients had to fulfil the following criteria : age ³18 years, primary ITP diagnosis defined according to the usual international criteria 2. Patients with abnormal spleen histology (other than reactional lymphoid hyperplasia, white-pulp hypoplasia or red pulp hyperplasia) or yet definite secondary ITP were excluded. Response was defined according to international criteria 4. Sustained response was defined as the absence of ITP relapse at last visit. We performed univariable and multivariable logistic regression procedures to calculates the odds ratio associated with a sustained response. Results In total,185 patients, 98 (53 %) women, with median age at splenectomy of 43.3 [interquartile range 27.6-64.3] years, were included in 18 French university and general hospitals from the French reference center network. Most of the patients were splenectomised at the chronic phase of ITP (n=150, 81.1%) and only two patients had undergone surgery within 3 months after ITP onset. Of note, 100 (54.1%) and 135 (73.0%) patients received TPO-RAs and/or rituximab prior to the splenectomy, respectively. The median time of follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) of patients had an initial response and 23 patients (12.4%) relapsed during follow-up leading to an overall rate of sustained response of 65.4%, similar to the one observed in the pre-TPO-RA's era 1. Characteristics of patients according to the period during which occurred the splenectomy is available in Table 1. Among the 14 patients who failed to respond to both eltrombopag and romiplostim prior to splenectomy a sustained response after splenectomy was observed in 7 (50%). Among the 13 patients who had failed after both TPO-RAs and rituximab, we observed a sustained response in 6 (46%). In the multivariate analysis, an older age (60-75 years: OR 0,39 [0,17-0,86], p=0.02; &gt;75 years: OR 0,28 [0,10-0,75], p=0.013) and a history of more than 4 treatment lines for ITP before splenectomy (OR 0.25 [0.08-0.66], p=0.010) were significantly associated with a lack of sustained response after splenectomy. TPO-RAs were used for 57/64 (89.1%) patients who failed to respond to splenectomy. Among them, 21 were treated with one TPO-RA (i.e. eltrombopag or romiplostim) which was previously used before splenectomy without any efficacy and a response was observed in 13 (62%) of them. Conclusions In conclusion, splenectomy seems to be still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients who fail to respond or relapse after splenectomy should be re-challenged with TPO-RAs. 1. Kojouri, K., Vesely, S. K., Terrell, D. R. & George, J. N. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term 2. Provan, D. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 3.Neunert, C. et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 3, 3829-3866 (2019). 4. Rodeghiero, F. et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113, 2386-2393 (2009). Figure 1 Figure 1. Disclosures Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ebbo: Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Attendance Grant; Sobi: Other: Attendance Grant. Viallard: Novartis: Consultancy; Amgen: Consultancy; Grifols: Consultancy; LFB: Consultancy. Jeandel: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for congress; Sobi: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Support for congress; GSK: Other: Support for congress; Pharming: Other: support for congress. Michel: Amgen: Consultancy; Novartis: Consultancy; Rigel: Honoraria; UCB: Honoraria; Alexion: Honoraria; Argenx: Honoraria. Godeau: Grifols: Consultancy; Sobi: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Comont: Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Delayed Plasma Clot Lysis in Adult Patients with Primary Immune Thrombocytopenia (ITP)

Introduction: Primary immune thrombocytopenia (ITP) is an orphan disease characterized by very low platelet counts. Patients have heterogeneous bleeding phenotypes, which are not only determined by platelet counts, also a paradoxically increased thrombotic risk has been observed. Aim: To investigate, whether the fibrinolysis inhibitors plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin are associated with impaired plasma clot lysis in primary ITP patients in comparison to non-immunologic thrombocytopenic controls (TPC) and healthy controls (HC). Furthermore, associations with bleeding severity and previous thrombotic events were investigated. Methods: Patients from the Vienna ITP biobank (EC 1843/2016), a multi-centric study including adult patients with primary ITP were investigated and compared to age- and sex-matched control groups: TPC with thrombocytopenia after chemotherapy and HC. Informed consent was obtained from all individuals before study inclusion. A clot formation and lysis assay (CLA) was performed according to the recommendations of the ISTH SSC. Platelet poor plasma samples were measured in duplicates for each patient and control. PAI-1 (PAI-1 Actibind ELISA, Technoclone, Vienna, Austria) and α2-antiplasmin by the chromogenic STA Stachrom antiplasmin assay (Diagnostic Stago, Asnieres, France) were measured. Bleeding severity was measured using the ITP-specific ITP-ISTH BAT (Rodeghiero et al. 2013). Results: In total, 37 primary ITP patients, 18 TPC and 156 healthy controls were analyzed (Table 1). Primary ITP patients had a higher BMI than HC. Bleeding severity was higher and more ITP patients had a thrombosis history compared to HC, whereas there was no difference in comparison to TPC. PAI-1 activity was highest in ITP patients, with a statistically significant difference in comparison to HC. α2-antiplasmin activity was higher in ITP patients than in TPC, whereas there was no difference in comparison to HC. After adjustment for sex, age, BMI and fibrinogen, primary ITP patients had a reduced clot formation rate (V max) and significantly delayed plasma clot lysis compared to TPC and HC (Table 2). Also, the lag phase and time to peak absorbance (TTP) were prolonged with a significant difference in comparison to HC. To investigate outliers of PAI-1 and α2-antiplasmin, we calculated cut-offs at the 75 th percentile of healthy controls (PAI-1: ≥ 3.1 U/mL, α2-antiplasmin: ≥ 107.0 %). 14 (37.8 %) ITP patients had PAI-1 levels and 10 (27.0 %) ITP patients had α2-antiplasmin activity above the cut-off. ITP patients with high PAI-1 levels had mildly delayed clot lysis in comparison to those below with a significantly lower maximal lysis rate (mLR). ITP patients with α2-antiplasmin activity above the cut-off had a significantly shorter lag phase, faster V max and shorter TTP than patients below the cut-off, whereas there was no difference in clot lysis. No differences between ITP patients above or below the respective cut-offs of PAI-1 and α2-antiplasmin regarding their bleeding severity and thrombosis incidence were observed (Table 3). Conclusion: Primary ITP patients have a tendency towards increased PAI-1 activity, which is associated with considerably delayed plasma clot lysis. Albeit an association with the bleeding score could not be identified, this impaired lysis could be seen as a counter-regulation and at least contribute to the relatively mild bleeding tendency in patients with ITP. Figure 1 Figure 1. Disclosures Pabinger: CSL Behring: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Daiichi Sanchyo: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Safety, Pharmacokinetics and Preliminary Efficacy of HMPL-523 in Adult Patients with Primary Immune Thrombocytopenia: A Randomized, Double-Blind and Placebo-Controlled Phase 1b Study

Background: Primary immune thrombocytopenia (ITP) is characterized by increased platelet destruction and impaired platelet production, resulting in decreased platelet counts and increased bleeding risk. Spleen Tyrosine Kinase (Syk) plays a pivotal role in the regulation of downstream signals in immune receptors, including B cell receptors (BCRs) and has been implicated in autoantibody production. On the other hand, all activating Fc receptors signal via Syk, which has roles in cellular proliferation, differentiation, survival, immune regulation, and cytoskeletal rearrangements during phagocytosis. This randomized, double-blind, placebo-controlled phase 1b study (NCT03951623) aimed to assess the safety, pharmacokinetics (PK), determine the recommended phase 2 dose (RP2D) and evaluate preliminary efficacy of HMPL-523, a novel, potent and highly selective Syk inhibitor, in patients with ITP. Methods: Relapsed/refractory ITP patients with platelet counts less than 30×10 9/L were eligible for the study. This randomized study (3:1) consists of two stages with dose escalation (DES) and dose expansion (DEX). Four dose groups were set (100, 200, 300 and 400mg QD) and patients were randomized to either HMPL-523 or placebo in each dose group (n=8) to determine the RP2D in DES. Additional 12 patients were enrolled at RP2D to further assess the safety and efficacy in DEX. Each patient received an 8-week double blind treatment (8w-DB), followed by a 16-week, open-label HMPL-523 treatment (16w-OL), except for all patients of 100mg cohort and 2 patients of 200mg cohort (only received 8w-DB per protocol v1.0). Treatment-emergent adverse events were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. The efficacy of overall response rate was defined as the proportion of patients with at least one platelet counts ≥50×10 9/L, and durable response rate was defined as the proportion of patients with platelet counts ≥50×10 9/L for at least 4 of the last 6 scheduled visits. Results: As of data cutoff (June 23, 2021), 33 patients (24:9) were enrolled in DES at 100-400mg. And 300mg QD was determined as RP2D. Additional 12 patients (10:2) were enrolled in DEX at 300mg QD. Main baseline patient characteristics are shown in Table 1. During 8-w DB treatment period, the overall response rate was 3 (50.0%), 2 (33.3%), 11 (68.8%) and 2 (33.3%) at 100-400mg dose cohorts, respectively, compared to 1 (9.1%) in the placebo. The durable response rate at 300mg was 5 (31.3%), compared to 1 (9.1%) in placebo. For all patients enrolled in 300mg cohort with at least one dose of HMPL-523 (n=20), including both 8w-DB and 16w-OL treatment period, the overall response rate was 80%; the durable response rate was 27.8% in the durable response-evaluable set (defined as patients received HMPL-523 treatment and completed at least 6 scheduled visits or discontinued during HMPL-523 treatment, n=18). No DLTs were observed at 100-400mg dose cohorts. The most common TEAEs (≥2 patients) related with HMPL-523 in 8w-DB were LDH increased (6 [17.6%]), ALT increased (5 [14.7%]), amylase increased (5 [14.7%]), AST increased (4 [11.8%]), neutrophil count decreased (3 [8.8%]), hypokalemia (3 [8.8%]), urine protein detection (3 [8.8%]), WBC count decreased (3 [8.8%]), gamma-glutamyl transferase (2 [5.9%]), asthenia (2 [5.9%]), dizziness (2 [5.9%]), total bile acid increased (2 [5.9%]), diarrhea (2 [5.9%]), abdominal pain (2 [5.9%]), hypertriglyceridemia (2 [5.9%]) and hyperlipidemia (2 [5.9%]). For all patients enrolled in 300mg cohort (n=20) throughout HMPL-523 treatment period (up to 24 weeks), ALT increased (5 [25.0%]), LDH increased (5 [25.0%]), AST increased (4 [20.0%]), total bile acid increased (4 [20.0%]), amylase increased (3 [15.0%]), TBiL increased (2 [10.0%]), hyperlipemia (2 [10.0%]) and hypertension (2 [10.0%]) were the most frequently reported HMPL-523-related TEAEs (≥2 patients). At the dose of 100-400mg QD, the exposure of HMPL-523 (C max and AUC tau) in plasma increased dose proportionally. Median T max was 4 h and mean T 1/2 was 11-13 h across all four dose levels. Conclusion: HMPL-523 was well tolerated at all dose levels within the range of 100 mg to 400 mg. HMPL-523 300mg QD for ITP treatment is an efficacious and safe dose and recommended as RP2D. A randomized phase 3 study will commence to further confirm the efficacy of HMPL-523 in primary ITP. Figure 1 Figure 1. Disclosures Shi: HUTCHMED: Current Employment. Yin: HUTCHMED: Current Employment. Fan: Hutchmed: Current Employment.

Contribution of Next Generation Flow (NGF) Cytometry in Primary Immune Thrombocytopenia (ITP): Utility for the Differential Diagnosis with Myelodysplastic Syndromes

Background: Primary immune thrombocytopenia (ITP) is an immune-mediated acquired disorder characterized by impaired production and increased destruction of platelets with an elevated risk of bleeding. At present, diagnosis of primary ITP still remains one of exclusion with a need to discard other causes of isolated thrombocytopenia, in the absence of robust and accurate clinical and laboratory diagnostic criteria. For the diagnosis of ITP, a bone marrow (BM) study may be useful to differentiate between ITP and other diseases, such as myelodysplastic syndromes (MDS). Next generation flow (NGF) has emerged as a potential useful tool in these settings. Aim: In this study (FCR-PTI-2017-01) we prospectively evaluated the potential utility of NGF analysis of BM and peripheral blood (PB) for more accurate diagnosis of ITP vs MDS. Methods: 62 patients presenting with isolated thrombocytopenia and classified as ITP (n=20), MDS (n= 11) or inconclusive, i.e. unclassifiable, (n= 25) by BM cytomorphology, were studied. PB (n=47) and BM (n=62) analysis by NGF was blindly performed in parallel for the ITP, MDS and unclassifiable patient groups using the EuroFlow 8-colour AML/MDS classification antibody panel followed by automated analysis against pre-existing flow cytometry databases of normal healthy donor PB and BM immunophenotypic profiles. NGF BM and PB results were then compared with the BM cytomorphological diagnosis. In parallel, epidemiological data from patients were recorded in an electronic case report form (eCRF) and analyzed afterwards. Results: By cytomorphology, expert hematologists were able to conclude an ITP or MDS diagnosis in only 31 cases (55.3%). 62 BM and 48 PB samples with isolated thrombocytopenia were evaluated by NGF. Our 62 patients were allocated in 4 immunophenotypic groups attending to different BM variables observed: maturation blockades, abnormal antigen expression and cross lineage markers. Thus, we observed normal phenotype cases (n=10), isolated (unilineage) alterations (n=24), mild multilineage (&gt;1) alterations (n=20) and severe multilineage (MDS-like) phenotypes (n=8). Cytomorphology diagnosed our cases as ITP, MDS or unclassifiable with a median number of alterations observed by BM NGF of 4 (IQR, 3-6), 2 (IQR, 1-6) and 4 (IQR, 3-5) respectively. For ITP cytomorphology group, NGF demonstrated numerous BM alterations being monocytic alterations (n=17, 94%) the most frequent finding observed. MDS presumed cases were also associated with monocytic alterations (50%) with a frequent decrease in neutrophil precursors (40%). On the contrary, when cytomorphology was not capable to establish a diagnosis, NGF showed a mixture of alterations with no clear predominance of none of them (table 1). Similarly to our work with BM NGF, we looked into a potential correlation of cytomorphology with PB NGF phenotypes. Thus, we observed a median number of alterations of 4 (IQR, 3-5), 4 (IQR, 2-4) and 4 (IQR, 3-5) in ITP, MDS and inconclusive cytomorphology groups. Increased platelet size and upregulated CD41, CD61 and CD63 glycoprotein (GP) expression were the most characteristic findings of ITP cohort. MDS subtype depicted an increased platelet size and overexpression of CD41. Downregulation of GP was restricted to patients with MDS-like phenotypes. (table 2). Nearly statistical significant differences at significance level of 90% were observed between cytomorphology and BM NGF results (p=0.179) (table 3), between platelet score and BM NGF findings (p=0.118) and also, among morphology, BM NGF and platelet score (p=0.179). Nevertheless, cytomorphology and PB NGF showed no statistical differences between them (p=0.206) (table 4). Conclusions: Limitations of BM cytomorphology when facing an isolated thrombocytopenia were demonstrated here. However, normal or unilineage BM NGF alterations may lead us to an ITP diagnosis while mild or severe multilineage BM phenotypes may correlate good with MDS. PB platelet GP expression allowed us to classify our patients in six groups (Gonzalez-Lopez/Matarraz platelet score) which may help ITP diagnosis when this score is low. Comparison of BM cytomorphology, BM NGF and PB NGF techniques at diagnosis showed statistically nearly comparable results (p=0.179), with a bigger amount of patients needed to confirm this trend. All these NGF findings may lead us to better address ITP at diagnosis. Figure 1 Figure 1. Disclosures Gonzalez-Lopez: Novartis: Other: Advisoryboard and speakers honoraria, Research Funding; Amgen: Other: Advisory board and speakers honoraria, Research Funding; Sobi: Other: Advisory board honoraria; Grifols: Other: Advisory board honoraria.