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Autoimmune thrombocytopenia: Current treatment options in adults with a focus on novel drugs

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European Journal of Haematology
Authors:
Michał Witkowski
Michał Witkowski
Michał Witkowski
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Magdalena Witkowska at Medical University of Lodz
Magdalena Witkowska
Tadeusz Robak at Medical University of Lodz
Tadeusz Robak
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Abstract and Figures

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet destruction and reduced platelet production resulting in decreased platelet level and an increased risk of bleeding. Based on the immunologic mechanism of ITP, front‐line standard therapy consists of corticosteroids and intravenous immunoglobulins (IVIG). If patients do not respond to the first‐line treatment, or if continuous therapy is required, the disorder is called refractory ITP, and second‐line therapy is indicated. This treatment may consist of rituximab, thrombopoietin receptor agonists, splenectomy, or cytotoxic drugs. Despite significant advances, many patients do not respond to any the treatments listed below, and new treatment options need to be developed for this relapsed and refractory group. Recent clinical studies have indicated promising outcomes for novel drugs, either as single agents or in combination with traditional drugs. This review discusses the latest and the most promising novel drugs for ITP in adults.
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Eur J Haematol. 2019;103:531–541. wileyonlinelibrary.com/journal/ejh  
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 531
© 2019 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
|
Immune thrombocytopenia (ITP) is an acquired autoimmune phe‐
nomenon resulting in isolated thrombocytopenia (defined as periph‐
eral blood platelet count <100 × 109/L) and increased bleeding risk.1
The total count of platelets in a healthy patient is dictated by the
equilibrium between the rates of platelet production and destruc‐
tion, with an imbalance typically resulting in a decreased level of
platelets.1 ITP is believed to arise as a result of autoimmune attacks
on platelets and megakaryocytes by IgG autoantibodies targeting
very abundant sur face antigens such as glycoprotein (GP) αIIbβ3
(GPIIbIIIA) and GPIb‐IX‐V.2 Platelets attached to autoantibodies are
able to bind to the Fcγ receptors expressed on tissue macrophages
of the reticuloendothelial system and can be cleared from the circu‐
lation. Such uptake has been found to occur primarily in the spleen
and liver. In ITP patients, autoreactive CD4+ T cells can recognize
several distinct epitopes on GPIIbIIIa, resulting in the expansion
of the autoimmune response and accelerated platelet destruction.
Although the trig ger for initiating the autoantibody response is un‐
known, autoreactive T helper cells that interact with antibody‐pro‐
ducing B cells are believed to play a key role.3 In addition, platelet
maturation may be inhibited, and their destruction accelerated, by
autoantibodies that bind to megakaryocytes. Thrombopoietin (TPO),
a liver‐derived glycoprotein hormone that drives thrombopoiesis, is
not able to normalize platelet levels: it has been found that even 60%
of patients with ITP present with normal or decreased TPO plasma
levels, indicating that a functional deficit of TPO may also contribute
to the pathophysiology of the disease.4
Although ITP is usually a primary disease, it can also act as sec‐
ondary condition if it is associated with infection, drugs, autoim‐
mune disorders, or malignant disease among others.5 There are no
typical signs and symptoms for ITP patients. Although many cases
have no symptoms or only minimal bruising, others can experience
life‐threatening bleeding such as gastrointestinal or intracranial
Received:31July2019 
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  Revised:21A ugust2019 
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  Accepted:22August2019
DOI : 10.1111 /ejh .13319
REVIEW ARTICLE


1|1,2|1,3
1Copernicus Memorial Hospital, Lodz,
Poland
2Department of Experimental
Hematol ogy, Medical Unive rsity of Lodz,
Lodz, Poland
3Department of Hematology, Medical
University of Lodz, Lodz, Poland

Tadeusz Robak, Copernicus Memorial
Hospit al, Medi cal Universit y of Lodz,
Ciolkowskiego 2, 93‐0510 Lodz, Poland.
Email: robaktad@umed.csk.pl

The study was supported in part
by grant s fundin g from the Medica l
University of Lodz, Polan d: No. Klinika
503/1‐093‐01/503‐11‐004‐18 and
503/8‐093‐01/503‐81‐001‐18.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet
destruction and reduced platelet production resulting in decreased platelet level and
an increased risk of bleeding. Based on the immunologic mechanism of ITP, front‐
line standard therapy consists of corticosteroids and intravenous immunoglobulins
(IVIG). If patients do not respond to the first‐line treatment, or if continuous therapy
is required, the disorder is called refractory ITP, and second‐line therapy is indicated.
This treatment may consist of rituximab, thrombopoietin receptor agonists, splenec‐
tomy, or cytotoxic drugs. Despite significant advances, many patients do not respond
to any the treatments listed below, and new treatment options need to be devel‐
oped for this relapsed and refractory group. Recent clinical studies have indicated
promising outcomes for novel drugs, either as single agents or in combination with
traditional drugs. This review discusses the latest and the most promising novel drugs
for ITP in adults.

avatrombopag, eltrombopag, immune thrombocytopenia, indirubin, receptor antagonist,
rituximab, romiplostim, rozanolixizumab, rozrolimupab, thrombopoietin
... Steroids are the gold standard for the management of patients with primary immune thrombocytopenia [2,3]; nevertheless, one-third of patients relapse or do not achieve a complete response [3][4][5]. These patients can be classified as resistant to corticosteroid therapy if they do not show a response after at least 3 months of treatment, and a secondline therapy should be considered according to the patient's clinical situation [1]. ...
... Steroids are the gold standard for the management of patients with primary immune thrombocytopenia [2,3]; nevertheless, one-third of patients relapse or do not achieve a complete response [3][4][5]. These patients can be classified as resistant to corticosteroid therapy if they do not show a response after at least 3 months of treatment, and a secondline therapy should be considered according to the patient's clinical situation [1]. ...
... The decision to choose which therapy to follow must be individualized and will depend on the duration of ITP, the frequency of bleeding episodes that require hospitalization or rescue medication, comorbidities, the age of the patient, adherence to the medication, medical and social support networks, patient values and preferences, cost, and availability; the complications of each therapy should also be considered, that is, whether the long-term benefits are greater than the risks [1]. Both TPO-Ras and rituximab are high-cost treatments with limited access, especially in developing countries such as Mexico [2][3][4]6]; on the other hand, a splenectomy is an irreversible procedure that carries operation risks as well as risks of infection and thrombosis [1]. ...
Evaluation of the Effects of Atorvastatin and N-Acetyl Cysteine on Platelet Counts in Patients with Primary Immune Thrombocytopenia: An Exploratory Clinical Trial
Article
Full-text available
Objective: We aimed to evaluate the efficacy of the combination of atorvastatin and N-acetyl cysteine in increasing platelet counts in patients with immune thrombocytopenia who were resistant to steroid therapy or had a relapse after treatment. Material and Methods: The patients included in this study received oral treatment of atorvastatin at a dose of 40 mg daily and N-acetyl cysteine at a dose of 400 mg every 8 h. The desired treatment duration was 12 months, but we included patients who completed at least 1 month of treatment in the analysis. The platelet counts were measured prior to the administration of the study treatment and in the first, third, sixth, and twelfth months of treatment (if available). A p value < 0.05 was considered statistically significant. Results: We included 15 patients who met our inclusion criteria. For the total treatment duration, the global response was 60% (nine patients); eight patients (53.3%) had a complete response and one patient (6.7%) had a partial response. Six patients (40%) were considered as having undergone treatment failure. Of the responder group, five patients maintained a complete response after treatment (55.5%), three patients maintained a partial response (33.3%), and one patient (11.1%) lost their response to the treatment. All of the patients in the responder group had significant increases in their platelet counts after treatment (p < 0.05). Conclusion: This study provides evidence of a possible treatment option for patients with primary immune thrombocytopenia. However, further studies are needed.
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... Additionally, the prognosis in pediatric ITP varies widely; some children recover spontaneously, while others develop chronic disease. Thus, identifying biomarkers that can predict clinical outcomes is essential for improving disease management and patient care [3]. Several studies suggest that platelet apoptosis contributes to ITP pathogenesis [4][5][6]; however, limited research has focused on apoptosis markers in ITP patients [7][8][9][10]. ...
... Immune thrombocytopenia is an acquired bleeding disorder characterized by extreme clinical heterogenicity and considerable variability in therapeutic protocols worldwide. Several pathophysiological mechanisms have been implicated in this heterogeneity [3]. Previous studies have suggested that the disruption of normal apoptotic pathways plays a role in the pathogenesis of autoimmune disorders [6]. ...
Differential Expression of BCL2 and IGFBP2 in Childhood Immune Thrombocytopenic Purpura Clinical Subtypes: Implications for Predicting Disease Progression and Apoptotic Regulation
Article
  • Feb 2025
  • PEDIATR BLOOD CANCER
Background Immune thrombocytopenic purpura (ITP), which poses challenges in treatment response, is an autoimmune-mediated bleeding disorder with an extremely complex pathogenesis and unpredictable clinical progression. Dysregulation of apoptotic pathways may influence both the pathogenesis and prognosis of ITP. This study aimed to evaluate the expression patterns of the apoptotic protein insulin-like growth factor-binding protein 2 (IGFBP2) and the anti-apoptotic protein B-cell lymphoma 2 (BCL2) as potential predictive or prognostic biomarkers for disease progression in childhood ITP. Patients and Methods The expression levels of BCL2 and IGFBP2 were assessed in peripheral blood samples from 40 pediatric ITP patients and 30 age- and sex-matched healthy controls using enzyme-linked immunosorbent assays. Results Plasma levels of BCL2 and IGFBP2 were higher in ITP patients than in control subjects. Although the difference in IGFBP2 expression was not statistically significant (p = 0.910), BCL2 expression was significantly elevated (p < 0.001). Notably, chronic ITP patients had significantly lower levels of both IGFBP2 and BCL2 markers compared to patients who achieved spontaneous recovery (p < 0.001). Conclusion BCL2 and IGFBP2 appear to be promising noninvasive biomarkers for predicting disease outcomes in newly diagnosed ITP, emphasizing the need for validation in large-scale, multicenter longitudinal studies.
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... [79] Although the exact mechanisms of immunoglobulins in ITP are still under investigation, several have been suggested, including competing autoreactive T cells, action on Fc receptors, and immunomodulation via dendritic cells. [80] Other proposed immunomodulatory mechanisms include FccR blockade, saturation of FcRn, inhibition of the complement cascade, and neutralization of pathogenic antibodies. [80] Thus, the American Society of Hematology recommends IVIG as one of the first-line therapies in ITP. ...
... [80] Other proposed immunomodulatory mechanisms include FccR blockade, saturation of FcRn, inhibition of the complement cascade, and neutralization of pathogenic antibodies. [80] Thus, the American Society of Hematology recommends IVIG as one of the first-line therapies in ITP. [81] In warm autoimmune hemolytic anemia (AIHA), immunoglobulins are occasionally used as second-line treatment, usually in combination with glucocorticoids and mycophenolate mofetil. ...
Use of Immunoglobulin Replacement Therapy in Clinical Practice: A Review
Article
Full-text available
  • Dec 2024
Immunoglobulins (Igs) are produced by B lymphocytes and play a key role in humoral immunity. Igs are classified into five isotypes (IgG, IgA, IgM, IgE, and IgD). Their primary function is to recognize and bind to foreign antigens. When Igs bind to antigens, they facilitate phagocytosis and promote clearance mediated by other immune cells. It is an essential component in protecting the host from outside pathogens. Hypogammaglobulinemia predisposes an individual to severe and recurrent infections. Therefore, replacement therapy is recommended to maintain optimal Ig level. In addition, Igs can modulate immune responses by to neutralizing proteins such as endotoxins or receptor-binding antibodies. They can be used to manage excessive immune reactions and autoimmune-related diseases. In this review, we aimed to summarize the clinical indications for Ig therapy for practicing oncologists.
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... diopathic thrombocytopenic purpura (ITP) is an acquired immune-mediated disease characterized by a peripheral blood platelet count of <100000 μL [1]. Although many patients with ITP have no symptoms or show only minor bruises, others might develop serious bleeding, such as gastrointestinal or intracranial hemorrhage [2]. In children, 85% to 90% of ITP occurrences are acute and resolve within 6 months, while 10% progress to the chronic form [3,4]. ...
... ITP is an autoimmune disorder that causes isolated thrombocytopenia [2]. The precise mechanism by which autoimmunity leads to ITP is yet unknown; however, it involves an imbalance between effector and regulatory cells [12]. ...
The effect of vitamin D on platelet count in children with idiopathic thrombocytopenic purpura
Article
Full-text available
  • Sep 2024
Objectives: Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disease associated with immune dysregulation and autoantibody production. Numerous studies have shown that vitamin D has a protective effect against autoimmune diseases. As vitamin D deficiency has been identified in the majority of children with chronic ITP, this study evaluates the effects of vitamin D supplementation on the platelet count of such children. Methods: This was a quasi-clinical trial study and the study population consisted of children with chronic ITP who were referred to Afzalipur Hospital in Kerman City, Iran, from August 2020 to September 2021. All patients' vitamin D levels were measured and subjects with levels below 30 mg/dL were treated while the remaining children received the standard vitamin D supplementation. Subsequently, after a 3 and 9-month interval, patients' vitamin D levels and platelet counts were assessed. Results: As a result, the mean serum vitamin D level increased significantly from 21.34±5.87 mg/dL to 34.25±5.64 mg/dL throughout the study. The mean serum platelet count was 18085.71±1292.10 µL at the start of the trial, 26628.57±1727.72 µL after 3 months, and 32114.28±1127.77 µL after 9 months, which showed a significant increase. Discussion: In conclusion, vitamin D boosts platelet count in chronic ITP patients. Thus, all children with chronic ITP should be evaluated and treated for vitamin D insufficiency.
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... Recent studies suggest that the immune factors may include Fc receptor (FcR)-mediated enhancement of phagocytosis and T cell-mediated immune imbalance, which may further lead to megakaryopoiesis and thrombopoiesis destruction. [16][17][18] FcR-mediated enhancement of phagocytosis-induced PTR can be treated with IVIG and steroids 19,20 ; yet, no recognized treatment scheme for PTR mediated by T cell dysregulation is currently available. ...
... 34 The main mechanism of PTR treatment using steroids and IVIG is their binding to FcR on the platelet surface to reduce macrophagephagocytosis thrombocytopenia. 19,20 The refractory PTR patients enrolled in our research did not respond to steroid or IVIG treatment. Therefore, Figure 3. Efficacy on platelet transfusion independence between two groups. ...
Avatrombopag for the salvage treatment of platelet transfusion refractoriness
Article
Full-text available
  • Mar 2024
Background Platelet transfusion refractoriness (PTR) is a life-threatening and intractable condition in hematological patients. Thrombopoietin receptor agonists such as avatrombopag promote platelet production and modulate immune intolerance. However, its application in PTR has not been extensively studied. Objectives We aimed to compare the platelet response (PR) as well as bleeding events and mortality rate between the best available therapies (BATs) and avatrombopag (Ava) treatments in refractory PTR patients. Design A total of 71 refractory PTR patients were enrolled at Nanfang Hospital. Intravenous immunoglobulin, steroids, and human leucocyte antigen-matched platelet transfusions were administered to 30 patients in the BATs group. The Ava group included 41 patients. Methods Data of refractory PTR patients were retrospectively collected. The primary endpoint was PR (defined as an increase of platelet count to ⩾50 × 10⁹/L without platelet transfusion support for 7 consecutive days). Secondary endpoints included platelet-transfusion independence rate, cumulative platelet transfusion units, World Health Organization bleeding grades, adverse events, overall survival (OS), and bleeding event-free survival (EFS). Results There were 75.6% and 13.3% refractory PTR patients who reached PR within 3 months in Ava and BATs groups. The median platelet counts were significantly higher in Ava group from day 7. Platelet-transfusion independence rate in Ava was higher than BATs group. The median cumulative platelet transfusion unit in Ava was lower than that of BATs group. The OS and bleeding events-free EFS rate of Ava group improved within 3 months as compared to BATs group. Cox proportional hazards regression analysis revealed that Ava therapy was a protective factor for the OS and EFS. No primary disease progression or termination of avatrombopag was observed due to intolerability. Conclusion Our study suggests that avatrombopag is an effective and safe treatment option for refractory PTR patients.
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... 6 However, when tapering first-line steroids, 70%-90% of patients experience relapse. 7 For >10 years, thrombopoietin receptor agonists (TPO-RAs) have been used as a platelet-enhancing therapy for ITP patients. 8,9 In many countries, TPO-RAs are approved as second-line treatments. ...
Immunomodulation with romiplostim as a second‐line strategy in primary immune thrombocytopenia: The iROM study
Article
Full-text available
Thrombopoietin receptor agonists (TPO‐RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first‐line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end‐points included the sustained remission off‐treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)‐4, IL‐9 and IL‐17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor‐β levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation.
View
... La prednisona y la dexametasona son los fármacos principalmente utilizados, siendo el ultimo preferido en casos de PTI severa, puesto que ha demostrado mayores tasas de respuesta(1). Sin embargo, un 20% de los pacientes con PTI tratados con esteroides son resistentes a esta terapia, por lo que se recurre al uso de IGIV, reservado para estos pacientes dada una rápida pero corta respuesta, aunque no exenta de importantes efectos adversos y su costo elevado (9). ...
Trombocitopenia inmune primaria refractaria y el uso de terapia combinada, reporte de caso
Article
Full-text available
  • Sep 2023
La trombocitopenia inmune primaria es un trastorno autoinmune adquirido, caracterizado por una destrucción plaquetaria excesiva, derivada de la producción de anticuerpos contra la membrana plaquetaria, conllevando a un alto riesgo de hemorragia para el paciente. Actualmente, la piedra angular del tratamiento sigue siendo el uso de agentes de primera línea como los glucocorticoides y la inmunoglobulina intravenosa. Sin embargo, en algunos casos los pacientes pueden ser refractarios a estos, con el requerimiento de terapias de segunda y tercera línea. Se presenta el caso clínico de una paciente de 25 años con historia de trombocitopenia inmune primaria con presentación severa por la presencia de sangrado gastrointestinal y estado anémico asociado, con refractariedad a diferentes estrategias de tratamiento, incluida la esplenectomía, requiriendo posterior manejo combinado con Rituximab, con el cual se logró mantener un recuento plaquetario adecuado. Consideramos que este caso toma interés clínico dado los escasos reportes de casos de esta condición y la limitada evidencia que se tiene ante las terapias secuenciales en pacientes refractarios a tratamiento de primera línea.
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... 6 Cyclosporine is a widely used potent immunosuppressant that can effectively act on both humoral and cellular immunity. 7 Multiple studies demonstrated that cyclosporine plays an important role in regulating multiple immune cell types and related inflammatory factors, and the drug can inhibit the activities of helper T cells and CD8 þ T lymphocytes. It can suppress the proliferation and differentiation of T lymphocytes by inhibiting IL-2 and regulate protein expression in dendritic cells, macrophages, and neutrophils. ...
Efficacy and safety of cyclosporine-based regimens for primary immune thrombocytopenia: a systematic review and meta-analysis
Article
Full-text available
Objective To conduct a meta-analysis assessing the efficacy and safety of cyclosporine-based combinations for primary immune thrombocytopenia (ITP). Methods Randomized controlled clinical trials were collected by systematically searching databases (PubMed®, MEDLINE®, EMBASE, The Cochrane Library, China National Knowledge Infrastructure) from inception to June 2022. All studies included patients with ITP who received cyclosporine-based regimens. We performed comprehensive analyses of the overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, relapse rate, platelet count, and adverse drug reaction (ADR) rate. Results Seven studies (n = 418) were ultimately included. According to a fixed-effects model, cyclosporine-based combinations improved the ORR and CR rate and reduced the relapse rate. The ADR rate was not increased in the cyclosporine-based combination group. Cyclosporine-based regimens effectively increased the platelet count. Subgroup analysis illustrated that cyclosporine-based combinations were linked to higher ORRs in both children (odds ratio [OR] = 5.74, 95% confidence interval [CI] = 1.79–18.41) and adults (OR = 5.46, 95% CI = 2.48–12.02) and a higher CR rate in adults (OR = 2.97, 95% CI = 1.56–5.63). Conclusion Cyclosporine exhibited efficacy in the treatment of ITP without increasing the risk of ADRs.
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... Immune thrombocytopenia is an acquired disease characterized by the autoimmune destruction of platelets and megakaryocytes by IgG autoantibodies targeting surface antigens such as glycoprotein (GP) αIIbβ3 (GPIIbIIIA) and GPIb-IX-V [98]. Patients with B-cell malignancies treated with irreversible BTKis such as ibrutinib, acalabrutinib, zanubrutinib, and tirabrutinib often demonstrate mild bleeding [21]; however, no bleeding has been reported in the clinical trials of tolebrutinib, evobrutinib, branebrutinib, BMS-986142, fenebrutinib, and rilzabrutinib. ...
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Idiopathic thrombocytopenic purpura (ITP) – new era for an old disease
Article
Full-text available
  • Jun 2019
Immune thrombocytopenia is an autoimmune hematological disorder characterized by severely decreased platelet count of peripheral cause: platelet destruction via antiplatelet antibodies which may also affect marrow megakaryocytes. Patients may present in critical situations, with cutaneous and/or mucous bleeding and possibly life-threatening organ hemorrhages (cerebral, digestive, etc.) Therefore, rapid diagnosis and therapeutic intervention are mandatory. Corticotherapy represents the first treatment option, but as in any autoimmune disorder, there is a high risk of relapse. Second line therapy options include: intravenous immunoglobulins, thrombopoietin receptor agonists, rituximab or immunosuppression, but their benefit is usually temporary. Moreover, the disease generally affects young people who need repeated and prolonged treatment and hospitalization and therefore, it is preferred to choose a long term effect therapy. Splenectomy – removal of the site of platelet destruction – represents an effective and stable treatment, with 70-80% response rate and low complications incidence. A challenging situation is the association of ITP with pregnancy, which further increases the risk due to the immunodeficiency of pregnancy, major dangers of bleeding, vital risks for mother and fetus, potential risks of medication, necessity of prompt intervention in the setting of specific obstetrical situations – delivery, pregnancy loss, obstetrical complications, etc. We present an updated review of the current clinical and laboratory data, as well as a detailed analysis of the available therapeutic options with their benefits and risks, and also particular associations (pregnancy, relapsed and refractory disease, emergency treatment).
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Prognostic Factors for Immune Thrombocytopenic Purpura Remission after Laparoscopic Splenectomy: A Cohort Study
Article
Full-text available
Background and Objectives: Laparoscopic splenectomy (LS) has become the gold standard for patients with immune thrombocytopenic purpura (ITP). The total remission rate after splenectomy is 70%–90%, of which 66% is long-term. Despite this high response rate, some patients do not benefit from surgery. It is therefore important to try to identify risk factors for an unsatisfactory clinical response. The aim of this study was to assess long-term outcomes of LS for ITP and identify factors associated with increased disease remission rates. Materials and Methods: We retrospectively studied consecutive patients with ITP undergoing LS in a tertiary referral surgical center prospectively recorded in a database. Inclusion criteria were: Elective, laparoscopic splenectomy for diagnosed ITP, and complete follow-up. The cohort was divided into two groups—Group 1 (G1) patients with ITP remission after splenectomy and Group 2 (G2) patients without remission. There were 113 G1 patients and 52 G2 patients. Median follow-up was 9.5 (IQR: 5–15) years. Results: In univariate analysis, patient’s age, body mass index (BMI), preoperative platelet count, the need for platelet transfusions, and presence of hemorrhagic diathesis were shown to be statistically significant factors. Next, we built a multivariate logistic regression model using factors significant in univariate analysis. Age <41 years (odds ratio (OR) 4.49; 95% CI: 1.66–12.09), BMI < 24.3 kg/m² (OR: 4.67; 95% CI: 1.44–15.16), and preoperative platelet count ≥97 × 10³/mm³ (OR: 3.50; 95% CI: 1.30–9.47) were shown to be independent prognostic factors for ITP remission after LS. Conclusions: The independent prognostic factors for ITP remission after LS revealed in our study are: age <41 years, BMI < 2 4.3 kg/m², and preoperative platelet count ≥97 × 10³/mm³. Duration of the ITP and the time of treatment are not related to remission after LS.
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Optimal use of thrombopoietin receptor agonists in immune thrombocytopenia
Article
Full-text available
  • Apr 2019
The thrombopoietin receptor agonists (TPO-RAs) are a class of platelet growth factors commonly used to treat immune thrombocytopenia (ITP). There are three agents that have been investigated for the treatment of chronic ITP: the peptide agent romiplostim and the small molecule agents eltrombopag and avatrombopag. These agents offer a higher clinical response rate than most other ITP therapies but may require indefinite use. This review is a critical appraisal of the TPO-RAs in adult ITP, defining the optimal patient groups to receive these agents and assisting the hematologist with agent choice, goals of treatment, dosing strategies, and toxicity management. Use of endogenous thrombopoietin levels to predict response to eltrombopag and romiplostim treatment is discussed and alternative dosing protocols suited for certain patient subgroups are described. Finally, indications for discontinuation and combination therapy with other agents are considered.
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Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura [see comments]
Article
  • Jan 1995
Autoimmune thrombocytopenic purpura (AITP) is generally a chronic disorder in affected adults. Twenty-five percent of these patients will become refractory to routine therapy (corticosteroids and splenectomy), as well as most other available agents. Intravenous pulse cyclophosphamide therapy was used to treat 20 patients with severe refractory AITP who had previously failed to achieve a sustained remission with a mean of 4.8 agents (range 2 to 8). Patients received 1 to 4 doses (mean 2.0) of 1.0 to 1.5 g/m2 intravenous cyclophosphamide per course. Of the 20 patients treated with pulse cyclophosphamide therapy, 13 patients (65%) achieved a complete response (CR), four (20%) a partial response (PR), and three patients (15%) failed to respond. Of the 13 complete responders, eight have remained in remission with stable platelet counts during followup intervals of 7 months to 7 years (median 2.5 years). Five patients developed recurrent AITP 4 months to 3 years following a CR. Of these, two patients responded to subsequent courses of pulse cyclophosphamide therapy with current remissions of 1 and 4 years. Of the four patients who obtained a PR, two remain in partial remission after 10 months and 4 years; one relapsed after 18 months and, after retreatment, is still in remission at 6 months. Of the patient characteristics examined, duration of disease was most strongly associated with response to pulse cyclophosphamide. Side-effects of treatment included neutropenia (three patients, one of whom developed staphylococcal sepsis), acute deep venous thrombosis (two patients), and psoas abscess (one patient). Intravenous pulse cyclophosphamide should be strongly considered in the treatment of patients with refractory AITP. There is a relatively low incidence of side-effects, and it can be administered easily on an out- patient basis.
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Anti-RH immunoglobulin therapy for human immunodeficiency virus-related immune thrombocytopenic purpura
Article
  • May 1988
The potential hazards of steroids in human immunodeficiency virus (HIV)- infected patients led us to evaluate the effectiveness and safety of anti-D and anti-c Ig in 17 adults with severe HIV-related immune thrombocytopenic purpura (platelet count less than 20 x 10(9)/L). The 14 Rh+ patients received 12 to 25 micrograms/kg of anti-D IgG intravenously on two consecutive days. A significant platelet rise above 50 x 10(9)/L was obtained in nine patients. Repeated boosters were performed in six cases and were effective in all cases. The 3 Rh- patients had a good response after they were given 20 mL x 2 of plasma containing potent anti-c antibodies. Therapy was well tolerated, and only one patient had significant hemolysis. These data suggest that anti-Rh IgG can be effective and safe in HIV-related thrombocytopenic purpura and that a specific interaction between the RBC antigens and the anti-Rh antibodies is required.
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Ultrastructural changes of endothelium associated with thrombocytopenia
Article
  • Oct 1975
In a study of the relationship between thrombocytopenia and increased vascular fragility, changes in the endothelium of capillaries and postcapillary venules of the tongue were examined by electron microscopy. Adult male albino rabbits (4 kg) were maintained thrombocytopenic (platelets less than 20,000/cu mm) up to 24 hr by one to three injections of guinea pig antirabbit platelet serum. Within 6 hr the normal projections and folds of the lumenal surface of the endothelial surface were largely effaced. In addition, the endothelium became thinner. In places, pores and membranous diaphragms were observed. Endothelial junctions appeared normal. Identical findings were observed if rabbits were made thrombocytopenic by administration of intraperitoneal busulfan. Intravenously administered Thorotrast was observed in endothelial cells and in the extravascular spaces within 3 min after injection into thrombocytopenic animals, while it was seen only intravascularly in control rabbits. With the spontaneous restoration of circulating platelets, the endothelium reverted to normal.
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Tapering Eltrombopag in Patients with Chronic ITP: How Successful Is This and in Whom Does It Work?
Article
  • Dec 2015
Background: Thrombopoietin receptor agonists (TPO-RA) eg eltrombopag (Epag), are highly effective treatments of ITP as demonstrated in multiple randomized studies. Studies have shown effective and safe long-term use; toxicity appears tolerable with thromboembolism the most common serious adverse event. An important question is if there will be an indefinite long-term need for treatment with these agents once initiated. The aim of this study is to taper eltrombopag in a single arm study to determine how many and which patients will be able to discontinue treatment over time. It specifically targets patients with adequate counts ie 50-100,000/uL, not waiting for patients whose counts spontaneously increase to high levels and thus indicate that they are being over-dosed. Methods: All patients on eltrombopag at doses of 75 mg daily or less for at least 4 months were offered study entry; only one refused. Initially the study tapered Epag rapidly but then changed to slow tapering over up to 2 years. Patients whose platelet counts were >50,000/uL were tapered at 4 week intervals in 10-20% dose increments. Tapering could be postponed for clinical reasons ie impending procedure or trip, infection skewing count, sports or other physical activity, etc. Analysis was descriptive and t test comparisons used to assess variables associated with successful tapering. Results: Patients were divided into 3 groups: 10 responders (those able to discontinue eltrombopag completely within 2 years, fig 1A), 10 tapering (those still tapering who have reduced their medication but not discontinued it, fig 1B), and 12 non-responders (those who tried and failed to discontinue within 2 years). To complete being a responder required >12 weeks without any ITP treatment, platelet count > 30,000/uL and 20,000/uL more than baseline after the last dose of eltrombopag. Eight of the 10 responders have remained off therapy for more than 1 year with platelet counts consistently > 50,000/uL. No medication was provided in the study. No serious AEs occurred and no serious bleeding events were seen. Fig 1a illustrates the discontinuation of eltrombopag treatment in responders: 4 discontinued within 8 weeks while the longest discontinuation required a full 2 years. Fig 1b shows patients who are tapering eltrombopag but have not reached 2 years by indicating how many are on <70% and <40% of their starting doses; it shows that tapering is typically a slow process but that at least dose reduction can be achieved in many patients even if they do not discontinue their eltrombopag. Table 1 compares means and medians of the 3 groups for a number of clinical variables. While the numbers are small and the results preliminary, it surprisingly shows that patients who have been on eltrombopag longer prior to tapering and those who have received more treatments are more likely to successfully discontinue eltrombopag. In contrast, non-responders failed splenectomy and rituximab more often than did those tapering and responders. Finally AIPF at initiation of study did not predict a successful taper. Summary: A substantial fraction of patients with chronic ITP will be able to successfully taper off eltrombopag; the exact number (somewhere between 10 and 20 of the 32 patients) depends upon the group still tapering. The tapering schedule selected is slow and requires regular monitoring and individualization/flexibility. Even if patients do not fully taper off eltrombopag, they may be able to substantially reduce their dose. We speculate that tapering eltrombopag as outlined here may reduce the toxicity and costs of long-term treatment without diminishing hemostatic efficacy. Table 1. Comparison Table (Responders, Tapering, Non-Responders) Responders (n=10) Tapering (n=10) Non-Responders (n=12) Age (years) (median/average) 29/37.4 11/25.70 21/30.58 Gender (m/f) 3/7 6/4 5/7 Duration ITP (years) (median/average) 8.75/11.95 5.5/17.45 7/8.25 Duration of TPO-RA Therapy (years) (median/average) 5/4.2 5.5/7.45 2.5/3.38 # of prior ITP treatments (median/average) 4.5/5.5 2/2.14 3.5/3.83 # of patients with previous splenectomy 4 0 6 patients with previous Rituximab treatments 5 4 9 Baseline AIPF (tapering counts) (*10E2/uL) (median/average) 81.75/75.5 63/57.43 75/69 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Bussel: Immunomedics: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; BiologicTx: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Momenta: Membership on an entity's Board of Directors or advisory committees; Symphogen: Membership on an entity's Board of Directors or advisory committees; Protalex: Membership on an entity's Board of Directors or advisory committees.
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Safety and Efficacy of PRTX-100, a Highly Purified Form of Staphylococcal Protein A, in Patients with Immune Thrombocytopenia (ITP)
Article
  • Dec 2016
Background: ITP is a rare autoimmune hematologic disorder characterized by isolated thrombocytopenia caused by antibody-dependent platelet destruction and impaired platelet production. Several therapeutic options (eg glucocorticoids, intravenous immunoglobulin and thrombopoietin receptor agonists) are available to treat patients with ITP, although inadequate efficacy, side effects and/or cost can make them undesirable. PRTX-100 is a highly purified form of Staphylococcal protein A (SpA), which binds to human B-lymphocytes and monocytes, and modulates immune processes. Preclinical data indicate that PRTX-100 may have the potential to treat ITP by reducing immune-mediated destruction of platelets. Here we present safety/efficacy data from the scheduled analysis for dose escalation from the initial dose cohorts of patients with ITP enrolled in two Phase 1/2 open-label studies, PRTX-100-202 and PRTX-100-203. Methods: Adult patients with persistent/chronic ITP and either a platelet count <30,000/µL (if not receiving any ITP therapy) or a platelet count of <50,000/µL (if receiving a constant dose of permitted ITP treatment) were eligible for inclusion. Study 202 requires prior treatment with a thrombopoietin receptor agonist (TPO-RA) plus one additional standard ITP treatment, while Study 203 only requires prior treatment with one standard ITP treatment. In both studies, PRTX-100 was administered via a 30-min infusion (60 min if total dose >500 µg) on Days 1, 8, 15 and 22 in a standard 3 + 3 dose-escalation design. Starting dose was 1 µg/kg (Study 202) or 3 µg/kg (Study 203) with subsequent dose increases planned up to a maximum of 24 µg/kg. Platelet counts were monitored on Days 1, 3, 8, 15, 22, 29, 36, 43, 50, 78 and 106. Safety analyses included consideration of adverse events (AEs), serious AEs, infusion reactions, clinical laboratory tests, vital signs, physical findings and electrocardiograms. The key efficacy endpoint was platelet response defined as: a platelet count ≥30,000/µL and at least a doubling of baseline platelet count in patients with a baseline platelet count <30,000/µL; or, in patients receiving permitted treatments for ITP with a baseline platelet count ≥30,000/µL and <50,000/µL, an increase in platelet count to ≥50,000/µL and at least a doubling of baseline platelet count or an increase to >100,000/µL. Results:Data are available from 6 patients (Study 202 n=3; Study 203 n=3) enrolled in the lowest-dose cohorts of the PRTX-100 ITP studies. There were 3 women and 3 men who were all Caucasian and ranged in age from 49 to 78 years; four patients had a splenectomy. Concomitant ITP medications were prednisone (n=4), dapsone (n=1), and TPO-RAs (n=2). Two patients in Study 202 received four doses of PRTX-100 (1 µg/kg); three patients in Study 203 received four doses of PRTX-100 (3 µg/kg). One patient receiving a dose of 1 µg/kg (Study 202) experienced a grade 3 vasculitis allergic reaction and discontinued from the study after 2 doses. This patient had a history of milder allergic reactions to other therapies. No additional serious or grade >3 AEs or immediately reportable events have been reported for any patient. Three grade 3 laboratory abnormalities have been reported: one patient (1 µg/kg; Study 202) experienced decreased hemoglobin and hyperkalemia, and one patient (1 µg/kg; Study 202) experienced high white blood cell count. One grade 1 infusion reaction occurred (itching rash at the infusion site in one patient receiving 3 µg/kg [Study 203]). No other infusion reactions were reported. Baseline platelet counts ranged from 6,000 - 30,000/µL. One patient in Study 203 (3 µg/kg) had a platelet response with a peak platelet count of 105,000/µL following the initiation of treatment. Platelet count elevation was observed as early as Day 3 and remained elevated for 2-3 weeks following the initiation of treatment (Figure 1). Conclusions:Data from initial cohorts in two dose escalation trials of patients treated with PRTX-100 at a dose of 1 µg/kg or 3 µg/kg have demonstrated an acceptable safety profile to support continued enrollment into higher-dose cohorts in both trials. A platelet response was observed in one patient treated at the lowest dose in one of the trials. Enrollment into higher-dose cohorts is ongoing and updated data from patients treated in those cohorts will be included in any presentation. Figure 1 Figure 1. Disclosures Bussel: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Immunomedics: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; UpToDate: Patents & Royalties; Sysmex: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; BiologicTx: Research Funding. Kuter:Syntimmune: Consultancy; MedImmune: Consultancy; Eisai: Consultancy; Genzyme: Consultancy; 3SBios: Consultancy; Shire: Consultancy; Amgen: Consultancy, Paid expert testimony; Pfizer: Consultancy; Shionogi: Consultancy; ONO: Consultancy; GlaxoSmithKline: Consultancy; Bristol-Myers Squibb: Research Funding; Protalex: Research Funding; CRICO: Other: Paid expert testimony; Rigel: Consultancy, Research Funding. Francovitch:Protalex, Inc.: Employment. Michel:Amgen: Honoraria; Novartis: Honoraria.
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Thrombopoietin receptor agonist (TPO-RA) treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia (ITP)
Article
  • May 2019
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which autoantibodies and/or autoreactive T cells destroy platelets and megakaryocytes in the spleen and bone marrow, respectively. Thrombopoietin receptor agonists (TPO-RA e.g. Romiplostim and Eltrombopag) have made a substantial contribution to the treatment of patients with ITP, which are refractory to first-line treatments and approximately 30% demonstrate sustained elevated platelet counts after drug tapering. How TPO-RA induce these sustained responses is not known. We analyzed the efficacy of a murine TPO-RA in a well-established murine model of active ITP. Treatment with TPO-RA (10 ug/ kg, based on pilot dose escalation experiments) significantly raised the platelet counts in ITP-mice. Immunomodulation was assessed by measuring serum IgG anti-platelet antibody levels; TPO-RA-treated mice had significantly reduced IgG anti-platelet antibodies despite the increasing platelet counts. These results suggest that TPO-RA is not only an efficacious therapy but also reduces anti-platelet humoral immunity in ITP.
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SAFETY AND EFFICACY OF AN ANTI-FCRN ANTIBODY, ROZANOLIXIZUMAB, IN PATIENTS WITH PRIMARY IMMUNE THROMBOCYTOPENIA: INTERIM RESULTS OF A PHASE II, MULTIPLE-DOSE STUDY: S850
Article
  • Jun 2019
Background Rozanolixizumab, a subcutaneous (SC) monoclonal antibody specific for the human neonatal Fc receptor (FcRn), is being developed with the aim of improving the lives of people with immunoglobulin G (IgG)‐mediated autoimmune diseases, by reducing pathogenic IgG autoantibodies. Aims To report a planned interim analysis (13 th Data Monitoring Committee review; data cut‐off: 02‐Aug‐2018) of an ongoing Phase II, open‐label study of rozanolixizumab in patients with primary immune thrombocytopenia (ITP) (NCT02718716). Methods Eligibility criteria included: ≥18 years of age; diagnosis of primary ITP for ≥3 months prior to screening; platelet count <30x10 ⁹ /L at screening and <35x10 ⁹ /L at baseline; current/history of peripheral blood smear consistent with ITP. Eligible patients received 4 mg/kg (5 doses), 7 mg/kg (3 doses), 10 mg/kg (2 doses) or 15 mg/kg (1 dose) rozanolixizumab SC weekly; the study is ongoing with 20 mg/kg (1 dose). An 8‐week observation period followed dosing. Primary objective: evaluate safety and tolerability of rozanolixizumab by occurrence of treatment‐emergent adverse events (TEAEs); secondary objective: assess clinical efficacy through assessment of platelet count. Results Median number of prior ITP therapies was 3.5–7.0, suggesting a difficult‐to‐treat population. 39/54 (72%) patients reported ≥1 TEAE (104 TEAEs total). There were four serious TEAEs overall (none deemed treatment‐related by the investigator): bleeding from genital tract (4 mg/kg group), thrombocytopenia (10 mg/kg group), thrombocytopenia, platelet count decrease (both 15 mg/kg group). The most frequently reported TEAE was headache (17/31 overall; all mild or moderate in severity). 1 patient in each of the 4 mg/kg, 7 mg/kg and 10 mg/kg groups and 8 patients in the 15 mg/kg group reported TEAEs deemed treatment‐related by the investigator, of which headache was the most frequent (0/15, 4 mg/kg; 1/15 (7%), 7 mg/kg; 1/12 (8%), 10 mg/kg; 5/12 (42%), 15 mg/kg). No deaths or treatment discontinuations due to TEAEs were reported. No clinically relevant changes were observed in all other routine safety parameters. No unexpected changes in total protein were observed. Clinically relevant improvements in platelet count (≥50x10 ⁹ /L) were observed across all dose groups; 4 mg/kg group: 5/15 (33%), 7 mg/kg group: 5/15 (33%), 10 mg/kg group: 6/12 (50%), and 15 mg/kg group: 8/12 (67%). Of those with a platelet count ≥50x10 ⁹ /L, a response was seen ≤8 days after first rozanolixizumab dose for 1/5 (4 mg/kg), 2/5 (7 mg/kg), 3/6 (10 mg/kg), and 7/8 (15 mg/kg) patients. Maximum mean (range) decreases in total IgG concentration were observed at Day 29, after 4 doses, for the 4 mg/kg group (43.6%, 21.9–68.6); at Day 22, after 3 doses, for the 7 mg/kg group (49.9%, 29.5–65.5); at Day 15, after 2 doses, for the 10 mg/kg group (63.8%, 38.4–75.0) and at Day 8, after a single dose, for the 15 mg/kg group (52.3%, 30.1–68.0) (Figure). Summary/Conclusion Rozanolixizumab demonstrated a well‐tolerated safety profile across all reported dose groups. Clinically meaningful platelet responses were observed for all doses; response rate increased in line with dose, maximum response was seen after the single 15 mg/kg SC dose. For patients achieving a platelet response, the time to response reduced with increasing dose. Rapid decreases in IgG concentration were observed. Data support the rationale that targeting the natural IgG recycling mechanism could offer a new treatment paradigm for people with IgG‐driven autoimmune diseases. image
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