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How I treat refractory immune thrombocytopenia
Abstract
This article summarizes our approach to the management of children and adults with primary immune thrombocytopenia (ITP) who do not respond to, cannot tolerate, or are unwilling to undergo splenectomy. We begin with a critical reassessment of the diagnosis and a deliberate attempt to exclude non-autoimmune causes of thrombocytopenia and secondary ITP. For patients in whom the diagnosis is affirmed, we consider observation without treatment. Observation is appropriate for most asymptomatic patients with a platelet count of ≥ 20-30 × 10(9)/L. We use a tiered approach to treatment for patients who require platelet-raising therapy. Tier 1 options (rituximab, thrombopoietin receptor agonists, low-dose corticosteroids) have a relatively favorable therapeutic index. We exhaust all Tier 1 options before proceeding to Tier 2, which comprises a host of immunosuppressive agents with relatively lower response rates and/or greater toxicity. We often prescribe Tier 2 drugs not alone but in combination with a Tier 1 or a second Tier 2 drug with a different mechanism of action. We reserve Tier 3 strategies, which are of uncertain benefit and/or high toxicity with little supporting evidence, for the rare patient with serious bleeding who does not respond to Tier 1 and Tier 2 therapies.
... 4,5 Refractory ITP refers to patients who have failed multiple therapies (including TPO-RA and rituximab) and/or have not responded or relapsed after splenectomy. 6,7 These patients often have aggravated bleeding symptoms, a severe decline in quality of life, and increased mortality. 6,7 However, the regimens recommended by the current guidelines have limited effectiveness in alleviating the situation, and patients with refractory ITP are in urgent need of novel therapies to overcome this dilemma. ...
... 6,7 These patients often have aggravated bleeding symptoms, a severe decline in quality of life, and increased mortality. 6,7 However, the regimens recommended by the current guidelines have limited effectiveness in alleviating the situation, and patients with refractory ITP are in urgent need of novel therapies to overcome this dilemma. 8,9 Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, are pluripotent progenitor cells with regenerative and immunomodulatory properties. ...
... Patients diagnosed with refractory ITP according to the international consensus on the identifying and treating of refractory immune thrombocytopenia were screened for the study. 7,29 The major inclusion criteria included age 18 to 60 years, ITP duration lasting for more than 6 months, platelet count <30 × 10 9 /L and concomitant bleeding manifestations at enrollment. Patients were allowed to have concomitant treatments (TPO-RAs, glucocorticoids, danazol), but the doses must have been stable at the time of enrollment. ...
Patients with refractory immune thrombocytopenia (ITP) frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) present a promising alternative, capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders. This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP. The research design included administering UC-MSCs at escalating doses of 0.5 × 106 cells/kg, 1.0 × 106 cells/kg, and 2.0 × 106 cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase, followed by a dose of 2.0 × 106 cells/kg weekly for the dose-expansion phase. Adverse events, platelet counts, and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period. Ultimately, 12 (with an addition of three patients in the 2.0 × 106 cells/kg group due to dose-limiting toxicity) and six patients were enrolled in the dose-escalation and dose-expansion phase, respectively. Thirteen patients (13/18, 72.2%) experienced one or more treatment emergent adverse events. Serious adverse events occurred in four patients (4/18, 22.2%), including gastrointestinal hemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). The response rates were 41.7% in the dose-escalation phase (5/12, two received 1.0 × 106 cells/kg per week, and three received 2.0 × 106 cells/kg per week) and 50.0% (3/6) in the dose-expansion phase. The overall response rate was 44.4% (8/18) among all enrolled patients. To sum up, UC-MSCs are effective and well tolerated in treating refractory ITP (ClinicalTrials.gov ID: NCT04014166).
... When treating ITP, as in the current case, it should be noted that the disease may be resistant to treatment or persistent/chronic. Although thrombopoietin receptor agonist (TPO-RA) treatment is an option, it was not approved for pediatric patients by the Korean Health Insurance Review and Assessment Service at the time of treatment [11,12]. Thus, according to the ASH 2019 guidelines, rituximab is the recommended secondline treatment option [11,12]. ...
... Although thrombopoietin receptor agonist (TPO-RA) treatment is an option, it was not approved for pediatric patients by the Korean Health Insurance Review and Assessment Service at the time of treatment [11,12]. Thus, according to the ASH 2019 guidelines, rituximab is the recommended secondline treatment option [11,12]. In the current case, rituximab was administered to the patient for treatment [11][12][13][14]. ...
... Thus, according to the ASH 2019 guidelines, rituximab is the recommended secondline treatment option [11,12]. In the current case, rituximab was administered to the patient for treatment [11][12][13][14]. ...
... 12 El rituximab también constituye un tratamiento de segunda línea y su respuesta es de 40 a 60%, pero la respuesta sostenida de tres a cinco años solo es de 15-20%, de acuerdo con diferentes reportes. 2,3,9,13,14,15,16,17 En un estudio en el que se compararon adultos y niños con TIP > seis meses de evolución, los cuales recibieron dosis de 375 mg/m 2 de rituximab, se observó una respuesta de 57% en ambos grupos y la respuesta libre de tratamiento, estimada a cinco años fue de 21 y 26%, respectivamente, sin mayor toxicidad. 18 Una revisión sistemática que incluyó a 313 pacientes con TIP que fueron tratados con rituximab reportó una tasa de respuesta global (plaquetas > 50 x 10 9 /L) de 62.5% y una respuesta completa (plaquetas > 150 x 10 9 /L) de 46%. ...
... La limitación de este informe fue la falta de estudios controlados. 9,19 Este tratamiento también se aplicó a 26 pacientes con TIP que se encontraban en recaída o refractarios, y se reportó RC en 54% y RP en 15%; el 35% mantuvo la respuesta con una mediana de seguimiento de 57 meses, con un buen perfil de seguri-dad. 10 Otro metaanálisis señaló que la RC fue más probable en pacientes que recibieron rituximab, comparado con el tratamiento de TIP estándar; en 376 pacientes adultos, 38% lograron RC y 19% RP, y mantuvieron la remisión por un año el 38% y por cinco años solo 21%. ...
... Entre los factores predictivos de respuesta a rituximab, se ha informado que hay mejor respuesta en pacientes jóvenes, 10 en especial en mujeres menores de 40 años, con una evolución de la enfermedad entre 12 y 24 meses. 4,9,15,22,25,26 En este estudio, la mediana de la edad de nuestros pacientes con respuesta global, fuera que se encontraran en fase crónica o persistente, fue de 51 años y es probable que en nuestros pacientes la edad no fuera una limitante para obtener respuesta con este tratamiento. ...
Background:
Primary immune thrombocytopenia (ITP) is an autoimmune disease that could cause different grades of bleeding, which could even threat the patients' life or make them experience poor quality of life. ITP can be treated with rituximab either as a first or second-line therapy option, resulting in an overall response of 60%. The best results have been observed on young women with a short time of disease evolution.
Objective:
To report the response and clinical evolution by providing therapy with rituximab, which was used as a rescue in adult patients with either persistent or chronical ITP.
Material and methods:
4 weekly doses of rituximab were administered to 31 adult patients and it was made a follow-up with them for a year.
Results:
Out of the 31 patients, a complete response was observed (CR, platelets ≥ 100 x 109 /L) in 22 patients (71%), and a partial response (PR, platelets ≥ 30 and ≤ 99 x 109 /L) in 5 patients (16%); the global response was of 87%. 3 patients relapsed during follow-up and sustained response after rituximab (≥ 12 months) was held in 24 patients, 21 (67%) with CR and 3 (10%) with PR. Side effects were from low to moderate in 13% of patients.
Conclusions:
Rituximab showed its effectiveness in patients with ITP as a rescue therapy in both chronical and persistent phases. Sustained response ≥ 12 months was of 77%, with good tolerance and acceptable toxicity.
... As a result, in 2016, Cuker et al. extended the definition of refractory ITP to patients who require treatment but are unable or unwilling to undergo splenectomy [16]. The exclusion of splenectomy from the definition of refractory ITP has opened a debate about which and how many lines of medical therapy must fail before refractory disease is declared and whether or not an active bleeding syndrome should be present. ...
... The exclusion of splenectomy from the definition of refractory ITP has opened a debate about which and how many lines of medical therapy must fail before refractory disease is declared and whether or not an active bleeding syndrome should be present. In 2020, refractory ITP was defined as a total lack of response to one or more single-agent therapies (including rituximab and TPO-RA) [16]. Shortly thereafter, Miltiadous et al. reserved the description of "refractory" for patients whose platelet counts do not respond to ≥ 2 treatments, there is no single medication to which they respond, and their platelet counts are very low and accompanied by bleeding. ...
... First-line therapeutic options include corticosteroids (prednisone or high-dose dexamethasone), clinically used to rapidly increase platelets counts and to reduce or resolve bleedings [16,17]. Intravenous high-dose immunoglobulins (IVIg) can be also employed up-front, especially to treat patients at high hemorrhagic risk. ...
Chronic primary immune thrombocytopenia (ITP) can today benefit from multiple therapeutic approaches with proven clinical efficacy, including rituximab, thrombopoietin receptor agonists (TPO-RA), and splenectomy. However, some ITP patients are unresponsive to multiple lines of therapy with prolonged and severe thrombocytopenia. The diagnosis of refractory ITP is mainly performed by exclusion of other disorders and is based on the clinician’s expertise. However, it significantly increases the risk of drug-related toxicity and of bleedings, including life-threatening events. The management of refractory ITP remains a major clinical challenge. Here, we provide an overview of the currently available treatment options, and we discuss the emerging rationale of new therapeutic approaches and their strategic combination. Particularly, combination strategies may target multiple pathogenetic mechanisms and trigger additive or synergistic effects. A series of best practices arising both from published studies and from real-life clinical experience is also included, aiming to optimize the management of refractory ITP.
... An International Working Group (IWG) defined refractory ITP as disease that does not remit with splenectomy or relapses after splenectomy. 13 The American Society of Hematology 2019 guidelines recommend thrombopoietin receptor agonists (romiplostim, eltrombopag), immunotherapy with rituximab, antimetabolites (azathioprine, mycophenolate mofetil) and if all else fails, splenectomy as second line therapies. 14 It is however, a category C drug and its safety for use in pregnancy requires further studies. ...
... 15 The initial response occurs within 7-14 days and the remission is varied with studies pointing toward as short as 1 year to 4-5 years. 13,15,16 Romiplostim can cross the placenta and possible adverse effects include fetal thrombocytosis thus warranting caution. 17 Response rates to romiplostim in adults go as high as 95% outside pregnancy. ...
... The systematic review of Yi Liang et al., which summarized the published data regarding rituximab use in pediatrics, concluded that the pooled complete response rate of rituximab was 39% [90]. The response rate of rituximab was also evaluated in more recent studies [37,91,92]. ...
... For both eltrombopag and romiplostim, it is necessary to monitor for side effect development. At the same time, their efficacy and safety have been described in various studies [92,[95][96][97]. ...
Immune thrombocytopenia (ITP) in pediatric patients is a common cause of isolated thrombocytopenia. Various pathophysiological mechanisms are implicated in ITP pathogenesis, including the production of autoantibodies against components of platelets (PLTs) by B-cells, the activation of the complement system, phagocytosis by macrophages mediated by Fcγ receptors, the dysregulation of T cells, and reduced bone marrow megakaryopoiesis. ITP is commonly manifested with skin and mucosal bleeding, and it is a diagnosis of exclusion. In some ITP cases, the disease is self-limiting, and treatment is not required, but chronic-persistent disease can also be developed. In these cases, anti-CD20 monoclonal antibodies, such as rituximab and thrombopoietin (TPO) receptor agonists, can be used. TPO agonists have become standard of care today. It has been reported in the published literature that the efficacy of TPO-RAs can be up to 80% in the achievement of several end goals, such as PLT counts. In the current literature review, the data regarding the impact of TPO agonists in the pathogenesis of ITP and treatment outcomes of the patients are examined. In the era of precision medicine, targeted and individualized therapies are crucial to achieving better outcomes for pediatric patients with ITP, especially when chronic refractory disease is developed.
... The term "refractoriness" has been controversial. It has been recently defined as the total loss of response to one or more treatments, including rituximab and TPO-RA [36]. In these cases, reconsidering primary ITP diagnosis is advisable, and bone marrow examination is indicated. ...
... Patient rescues subsequent to administration of steroids concomitantly with rituximab or TPO-RA have been described [38][39][40]. The use of immunosuppressants such as azathioprine, cyclosporine or mycophenolate mofetil, immunomodulators such as danazol or dapsone, or cytostatic agents such as cyclophosphamide or vinca alkaloids (vincristine, vinblastine) can also be envisaged [36,[41][42][43][44][45][46]. Nevertheless, these agents may induce side effects that should prompt a careful examination of the benefit:risk ratio. ...
Primary immune thrombocytopenia (ITP) is a complex autoimmune disease whose hallmark is a deregulation of cellular and humoral immunity leading to an increased destruction and a reduced production of platelets. The heterogeneity of presentation and clinical course hampers personalized approaches for diagnosis and management. In 2021, the Spanish ITP Group (GEPTI) of the Spanish Society of Hematology and Hemotherapy (SEHH) updated a consensus document which had been launched in 2011. The updated guidelines have been the reference for diagnosis and management of primary ITP in Spain ever since. Nevertheless, the emergence of new tools and strategies makes it advisable to review them again. For this reason, we have properly updated the main recommendations. Our aim is to provide a practical tool to enable the integral management of all the aspects concerning primary ITP management.
... There is no clear agreement on which second-line treatment should be used in patients with ITP who do not respond to first-line therapy [5]. Splenectomy, thrombopoietin receptor agonist (TPO-RAs), and rituximab are the currently used second-line options [6]. ...
... TPO-RAs have been approved for the treatment of patients with chronic ITP who failed to respond to a first-line treatment or splenectomy [8]. In patients not responding to TPO-RA, a combination with an immunosuppressive agent may allow for synergistic outcomes [6]. ...
Introduction
The treatment options for patients with refractory splenectomized chronic immune thrombocytopenic purpura (ITP) are often unsatisfactory despite different lines of treatment, especially after thrombopoietin receptor agonist (TPO-RA) failure.
Objective
This study was done to assess the efficacy of vincristine in the treatment of patients with splenectomized chronic ITP who failed TPO-RA therapy as well as their 8-month follow-up following vincristine discontinuation.
Patients and methods
A total of 12 patients with splenectomized chronic ITP who failed to respond to TPO-RA were treated with vincristine 1–2 mg weekly for 6 weeks.
Results
The platelet count was evaluated during the treatment, and every 2 months for 8-month follow-up. The mean platelet count was significantly increased at the third, fourth, fifth, and sixth weeks during the treatment and persistently elevated during the second, fourth, and sixth months of follow-up when compared with the baseline platelet count, while decreasing at the 8-month follow-up, with no significant difference at their baseline.
Conclusion
Vincristine could be an effective treatment in patients with splenectomized ITP who failed to respond to TPO-RAs and in patients requiring a short-term increase in the platelet count.
... First-line treatments for ITP include corticosteroids (prednisone, dexamethasone), intravenous immunoglobulin (IVIg), and anti-D (Rh0) immunoglobulin. While corticosteroids and immunoglobulins produce an initial response in most patients (60%-70% and 90%, respectively), the response is usually transient (<6 months and 2-4 weeks, respectively), and the medications must be readministered if the patient's platelet count does not stabilize Repeated or prolonged administration of first-line therapies is typically not suitable due to significant adverse effects with corticosteroids and high cost, inconvenience of frequent infusions, and debilitating post-infusion headache with immunoglobulins [6][7][8][9][10] . ...
... Other agents, including mycophenolate mofetil, azathioprine, danazol, dapsone, vinca alkaloids, sirolimus, cyclosporine, and cyclophosphamide have been used in ITP as alternative treatments since they are less expensive compared with rituximab and the TPO-RAs. These agents may play an important role in the secondline treatment of ITP in countries where access to standard second-line therapies is limited 2,6,8 . ...
BACKGROUND AND OBJECTIVES: We have studied the clinical profile of adult patients with chronic immune thrombocytopenia (ITP) and treatment response to different therapies, focusing mainly on second-line therapy. METHODOLOGY: 42 patients with chronic ITP were included in the study over 2 years (1 st April 2020 to 31 st March 2022) from Chettinad Hospital And Research Institute, Kelambakkam, Tamilnadu. Patients were interviewed for detailed history, including active complaints, past medical information, current therapy, and blood counts. A complete clinical examination included documentation of bleeding areas and examination of other systems to rule out underlying problems. These patients were further followed, and responses to the respective treatments were noted. RESULTS: Out of 42 patients included in the study, most patients (40.5%) were <30 years old, whereas 88.1% were female and 11.9% were male. In the case of comorbidity, we have seen that most patients (88.1%) do not have any comorbid condition. In comparison, 2.4%, 4.8%, 4.8%, and 2.4% of patients have DM, HTN, or thyroid disorders, and 2.4% of patients have other comorbid conditions, respectively. Further, 42.9%, 31.0%, 16.7%, 16.7%, and 2.4% of patients presented with menorrhagia symptoms, mucosal symptoms, asymptomatic condition, skin symptoms, and ich, respectively. However, 52.4%, 38.1%, and 9.5% of patients had platelet count <10000, 10000-30000, and >30000 at presentation, respectively. There was a significant difference between the third and fourth therapy response. The duration of therapy response with and without treatment showed that azathioprine and dapsone response was similar to other standard second-line therapies. CONCLUSION: Our study shows a response of azathioprine and dapsone similar to other standard second-line therapies.
... Given the patient's refusal of red blood cell transfusions and the presence of severe ongoing anemia, we determined that traditional cytotoxic regimens for refractory ITP-including high-dose cyclophosphamide, 6-mercaptopurine, azathioprine, and vinca alkaloids-were not suitable options due to the risk of worsening anemia [29]. We next turned to other newer and off-label medications for refractory ITP. ...
In patients with severe refractory immune thrombocytopenia (ITP), especially those unable to receive blood transfusions due to religious beliefs, alternative non‐cytotoxic therapies are important to avoid worsening cytopenias. Immunomodulatory agents such as mycophenolate mofetil and daratumumab should be used alongside traditional therapies including steroids, IVIG and rituximab.
... Rituximab is also approved in pemphigus vulgaris, when clinical remission is not achieved with systemic corticosteroids or other immunosuppressive drugs (rituximab 2 × 1,000 mg 2 weeks apart or 375 mg/m 2 weekly x4) (8)(9)(10). Moreover, rituximab is frequently used "off-label" in other autoimmune diseases such as autoimmune hemolytic anemia (AIHA) (11), thrombotic thrombocytopenic purpura (12), immune thrombocytopenia (13), or multiple sclerosis, typically with four doses of 375 mg/m 2 per week (14). Although, the approval for rituximab dates back decades (1) and the pharmacokinetics (PK) of rituximab have been analyzed in numerous studies, only a single dose finding study was performed in 15 patients with relapsed low-grade B cell lymphoma (15,16). ...
Introduction
Although rituximab is approved for several autoimmune diseases, no formal dose finding studies have been conducted. The amount of CD20+ cells differs significantly between autoimmune diseases and B-cell malignancies. Hence, dose requirements of anti-CD20 therapies may differ accordingly.
Methods
We conducted a phase II pilot trial investigating the effects and safety of very low doses of rituximab, i.e., 5 mg/m² every 3 weeks, 20 mg every 4 weeks, 50 mg every 3 months (n = 3 each) and 100 mg every 3 months (n = 1) in patients with autoimmune hemolytic anemia (AIHA) to effectively suppress CD20⁺ cell counts. Doses were increased if circulating CD20⁺ cell depletion was insufficient (i.e., <95% reduction from baseline) in a dose group. Plasma rituximab concentrations were quantified by enzyme-linked immunosorbent assay, CD20⁺ cell counts were determined by flow cytometry.
Results
Ten patients were included in the final analysis (7 with cold agglutinin disease, 2 with warm AIHA, 1 with mixed-type AIHA). The first infusion depleted ≥95% of CD20⁺ cells in all but one of the included patients. However, the dosing regimens were found ineffective, because a sustained CD20⁺ cell depletion was not achieved, and CD20⁺ cells recovered with a high interindividual variability. CD20⁺ lymphocytes were below the detection limit if rituximab plasma concentrations exceeded 0.4 μg/mL. One endokarditis occured.
Conclusion
Rituximab doses as low as 5 mg/m² transiently depleted CD20⁺ cells in almost all patients, but the tested low-dose regimens failed to permanently suppress CD20⁺ cells. The empirically identified EC95% of 0.4 μg/mL rituximab may guide future studies using low-doses of rituximab.
Clinical trial registration
https://clinicaltrials.gov/, identifier [EudraCT 2016-002478-11].
... Currently, the treatment for patients with ITP focuses on inducing an early increase in platelet count through the administration of steroids, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin [13,14]. Alternatively, long-term maintenance of platelet levels can be achieved through splenectomy or the use of drugs, such as rituximab, danazol, azathioprine, or even long-term corticosteroid therapy [15,16]. These treatments have been effective for a large number of patients, but they are associated with issues related to the duration of treatment response and the occurrence of side effects. ...
Introduction: Idiopathic thrombocytopenic purpura (ITP) is a chronic autoimmune disease that manifests as persistent thrombocytopenia and mucocutaneous bleeding. The aim of this study was to evaluate the effects and side effects of two drugs, Rituximab and Romiplostim, in children with ITP. Materials and methods: This prospective cohort study included children with ITP who were prescribed Romiplostim and Rituximab. The study followed the children for six months to monitor the medication's effectiveness and side effects, with the treatment response defined as an increase in platelet count to over 30,000 per cubic millimeter of blood. The patients were evaluated monthly for possible side effects such as fever, rash, respiratory infections, and peripheral edema. The data obtained from the patients were then analyzed using SPSS version 26 software. Results: In the current study, 140 children were included, with 70 children in each of the Rituximab and Romiplostim groups. The average age of the children participating in the study was between 8-9 years. There was no significant difference between the two study groups in terms of age. Changes in the average platelet count during 9 measurements were significantly higher in the Romiplostim group compared to Rituximab (P<0.001). Additionally, the treatment response rate was significantly higher in the Romiplostim group than in the Rituximab group (71.4% vs. 48.6% and P=0.006). In the present study, none of the children taking either drug experienced peripheral edema. When examining other side effects related to the use of these two drugs, it should be mentioned that the rates of fever, skin rashes, and respiratory infections, although not significantly different between the two study groups during the nine repeated measurements (P>0.05), were generally lower in the Romiplostim group than in the Rituximab group during the second to fourth weeks of the study. Conclusions: Romiplostim demonstrates superior efficacy compared to rituximab in raising peripheral blood platelet counts in pediatric patients with immune thrombocytopenia purpura. Furthermore, the treatment response rate is higher with Romiplostim and it is also associated with fewer complications when compared to rituximab.
... Following an ITP diagnosis, initial management typically involves first-line therapy with either prednisone or a high-dose dexamethasone regimen. Given our patient's history of excessive bleeding, severely low platelet count, and prior steroid treatment, we initiated high-dose dexamethasone (10 mg IV every 6 h) [10]. While intravenous immunoglobulins (IVIg) were unavailable in our setting, they represent an alternative first-line treatment option, either alone or in combination with steroids, for the rapid, albeit transient, control of life-threatening hemorrhage and platelet recovery [11]. ...
Introduction and importance
Refractory immune thrombocytopenic purpura (ITP) is a rare but serious condition causing significant morbidity and mortality due to inadequate response to standard treatments, resulting in persistent thrombocytopenia and increased bleeding risk.
Case presentation
An 18-year-old female patient, diagnosed with ITP two years prior following excessive vaginal bleeding and fatigue, was initially treated with oral prednisolone for two months and discharged in improved condition. Eighteen months after treatment cessation, she presented with recurrent excessive vaginal bleeding, intermittent bilateral nasal bleeding, skin rash, blurred vision, fatigue, tinnitus, vertigo, and intermittent headaches (one-month duration). Following a one-month admission during which she proved unresponsive to steroids, she received rituximab 500 mg IV weekly for four weeks, along with supportive care.
Clinical discussion
Refractory ITP in conjunction with COVID-19 is a rare and serious condition associated with significant morbidity and mortality, and a low survival rate. Effective, coordinated medical and surgical management, along with comprehensive rehabilitation from COVID-19, are crucial for improving outcomes in this severe condition.
Conclusion
Refractory ITP is a challenging and rare condition that can result in significant health complications, economic burdens, and a reduced quality of life for those affected.
... Despite extensive research, the precise pathogenesis of ITP remains incompletely understood 34,35 . In this study, we have delineated the role and impact of AgB on the suppressive function of Treg cells within the context of ITP. ...
Dysregulation of T cell homeostasis is a pivotal factor in the pathogenesis of Immune Thrombocytopenia (ITP), a condition hallmarked by a decrease in platelet counts. Antigen B (AgB), a predominant immunodominant protein found in the cyst fluid of Echinococcus granulosus, has demonstrated the capacity to modulate T cell differentiation, thereby dampening inflammatory responses. However, the potential of AgB to modulate immune responses in ITP remains unexplored. In this study, we investigated the capacity of AgB to regulate T cell functions within the context of ITP. Our findings reveal that AgB fosters the generation and differentiation of regulatory T (Treg) cells, enhancing their immunosuppressive capabilities. AgB treatment ameliorated thrombocytopenia and rebalanced the equilibrium between Treg and T helper cells (Th) in a passive ITP murine model. The therapeutic effects of AgB on CD4 + T cell subpopulations were negated by Treg depletion, indicating their necessity for AgB's action. Furthermore, AgB curtailed the production of proinflammatory cytokines and suppressed the activation of Signal Transducer and Activator of Transcription 3 (STAT3) in ITP. The inhibition of STAT3 was shown to abrogate the regulatory function of AgB on Treg cells. Subsequent investigations demonstrated that AgB enhanced the degradation of STAT3 through the promotion of TRAF6-mediated ubiquitination. In summary, AgB rectifies T cell homeostasis and bolsters the immunosuppressive function of Treg cells by facilitating TRAF6-mediated STAT3 ubiquitination, thereby offering relief from ITP.
... Ранее рефрактерными было принято считать пациентов с неэффективностью спленэктомии [16]. В 2016 г. содержание данного термина расширилось, и сегодня оно включает пациентов с необходимостью проведения терапии после нескольких линий терапии без привязки к спленэктомии при невозможности ее проведения [17]. ...
Background. Primary immune thrombocytopenia (ITP) is an orphan disease characterized by decreased platelet count in the peripheral blood which in some cases can cause bleeding of varying severity. Currently, the use of thrombopoietin receptor agonists (TPO-RAs) is recommended as the second line therapy for ITP as it allows to achieve high platelet response (PR), including complete, in 73 % of cases of chronic ITP and in 87 % of cases of newly diagnosed disease. The mechanism of action differs for different TPO-RAs. Given this fact, in cases of resistance or intolerance to therapy with one TPO-RA, attempts are made to switch to another. The effectiveness of this approach for overcoming ITP resistance varies from 50 to 93 % according to various publications.
Aim. To assess the ability to achieve and maintain PR by switching from one TPO-RA to another in cases of resistance to the previous TPO-RA used in the second or subsequent lines of therapy.
Materials and methods. The analysis included 59 patients who were resistant (in 2 cases intolerance was also noted) to TPO-RA therapy (received after standard therapy) who were prescribed TPO-RA treatment with a different mechanism of action: switch from romiplostim to eltrombopag (25 patients) or vice versa (34 patients). Both groups were comparable in terms of demographic characteristics and median platelet level at the time of TPO-RA switching.
Results. PR was obtained in 76 % of cases, including complete response in 54 %, as a result of switching from one TPO-RA to another in 59 patients. Among 34 patients switched from eltrombopag to romiplostim, PR was achieved in 31 (91 %) patients, including complete response in 22 (65 %). Romiplostim was switched to eltrombopag in 25 patients, PR was achieved in 14 (56 %) with complete response in 10 (40 %).
Conclusion. The study showed that PR can be achieved and maintained through switching from one TPO-RA to an alternative.
... In cases where treatment is necessary, intravenous immunoglobulin (IVIG) and corticosteroids are commonly used, with anti-D immunoglobulin reserved for specific cases [15]. The differential diagnosis in this age group is crucial, as other causes of thrombocytopenia, such as congenital platelet disorders or infections, must be excluded [36]. ...
Immune thrombocytopenia (ITP) in paediatric patients is a complex and heterogeneous disorder characterized by isolated thrombocytopenia and an increased risk of bleeding. The diagnosis of ITP involves a careful exclusion of other causes of thrombocytopenia, supported by clinical evaluation and laboratory findings. Management strategies have evolved significantly, emphasizing individualized treatment approaches based on disease severity, bleeding risk, and patient-specific factors. This comprehensive review provides an in-depth analysis of the current diagnostic criteria, including the role of novel biomarkers and genetic testing in distinguishing ITP from other haematological disorders. We also explore the latest therapeutic options, ranging from observation and first-line treatments such as corticosteroids and intravenous immunoglobulin (IVIG) to second-line therapies, including thrombopoietin receptor agonists and immunosuppressive agents. The review addresses the challenges of managing chronic ITP in pediatric patients, focusing on balancing treatment efficacy with the potential side effects and long-term outcomes. Additionally, we discuss the emerging role of personalized medicine in optimizing care for children with ITP, highlighting recent advances in targeted therapies and the potential for future research to refine diagnostic and treatment paradigms to refine diagnostic and treatment paradigms further.
... 1,2 The limitations of this definition have been acknowledged and the IWG has reported an inability to reach consensus on the definition of pediatric refractory ITP. 1,3 Furthermore, the increased availability and use of novel pharmacotherapy options has greatly decreased the role for splenectomy in the standard care of pediatric ITP. 4 Updated IWG and American Society of Hematology ITP guidelines published in 2019 acknowledged that defining refractory ITP in regard to splenectomy response was no longer applicable, and declined to comment further on a more relevant use of the term. 5,6 In 2023, the Pediatric ITP Consortium of North America (ICON) published a systematic literature review to better understand previous and current use of the term "refractory" as it applies to pediatric ITP. ...
There are no agreed upon terminology to define "refractory" pediatric Immune Thrombocytopenia (ITP). Guidelines are therefore limited to arbitrary and outdated definitions. The Pediatric ITP Consortium of North America held a meeting in 2023 to define this entity. With 100% agreement, the faculty established that pediatric ITP that is refractory to emergent therapy could be defined as no platelet response after treatment with all eligible emergent pharmacotherapies. With 100% agreement, the working group established that pediatric patients with ITP that continue to demonstrate high disease burden and/or no platelet response despite treatment with multiple classes of disease modifying therapies represent a challenging subset of ITP. These patients are at higher risk of ongoing disease burden and merit additional investigation as well as consideration for clinical trials or novel therapies. Future efforts to define disease burden and disease response will be completed in collaboration with the ITP International Working Group.
... In 2020, refractory ITP was defined as a total lack of response to two or more single-agent therapies (including Rituximab and TPO-RA), which displayed a high disease burden with lower platelet counts, a higher proportion of reported bleeding with more internal bleeding and intracerebral haemorrhage and a higher need for treatment. 2,3 Recently, encouraging ITP therapies emerged, including different targeted antibody drugs, monoclonal anti-CD20 antibodies (Rituximab) and monoclonal anti-CD38 antibodies (Dara). 4,5 The use of rituximab for selective depletion of CD20-positive B cells has emerged as one of the important second-line treatments to elevate and maintain the platelet count for children who have no response or relapse to firstline treatment. ...
Chronic refractory primary immune thrombocytopenia (CRITP) is currently defined as refractory to multiple therapeutic of second‐line agents with or without splenectomy, faced with the threat of severe bleeding and challenging to obtain effective treatment. Although stable and effective drug therapy is needed, it is tough to find one. Daratumumab (Dara), an anti‐CD38 monoclonal antibody presented the target cloned plasma cells in multiple myeloma, has also been reported to be effective in refractory autoimmune cytopenia in some case or series reports and ongoing clinical trials for adult patients with CRITP. Here, we report the early and durable response of Dara combination with avatrombopag in three CRITP patients (2 male and 1 female aged 12, 5 and 7 years, respectively) in our centre, with a follow‐up period of more than 25 weeks. Before Dara, the duration of immune thrombocytopenia was 9, 1.4 and 4 years, respectively, a baseline platelet count of 4, 6, 9 × 10⁹/L, the bleeding score was all above level 2 and the number of previous drugs was >3. The time to response (R: Plt ≥30 × 10⁹/L with at least a twofold increase in the baseline count) of Dara was on Day 45, 6 and 4 and achieved complete response (CR: Plt ≥100 × 10⁹/L) on Day 51, 6 and 8, the sustained response (SR: Plt >30 × 10⁹/L following Dara at ≥75% of the platelet count assessment at follow‐up end‐point since the patient achieved response) was 48, 175 and 204 days with the follow‐up time of 39.1, 25.9 and 29.7 weeks. The bleeding score decreased from grade 3 to grade 0 during follow‐up. No significant treatment‐related adverse events were found during follow‐up. Dara combination with avatrombopag may be a safe and efficacious therapy for children with CRITP, but it needs to be further explored.
... 1 Although the exact pathophysiology of ITP is still not well known, the dysregulation of the immune system due to various reasons such as autoimmune conditions, infections, inflammations, and vaccinations as well as genetic background are involved in the occurrence of ITP. 2 The immune reaction to platelet autoantigens causes the spleen to destroy premature platelets and the bone marrow megakaryocytes to produce fewer platelets. 3 Autoantibodies that specifically target platelet glycoproteins (GPs), including GPIIb/IIIa and GPIb/IX, are regarded to be the main reason of platelet destruction and underproduction. In damaged blood vessels, the GP complexes operate as physiological receptors to mediate interactions between platelets and vascular subendothelium. ...
Background and Aims
Inflammation is one of the immune thrombocytopenic purpura (ITP)'s aggravating elements due to inflammatory cells' function. This study aims to identify and evaluate hematological inflammatory parameters, including neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and hemoglobin‐to‐platelet ratio (HPR), in patients with ITP compared to the control group.
Methods
We retrospectively analyzed the profile of 190 ITP patients from August 2019 to January 2021 at Imam Reza Hospital of Mashhad, Iran, along with 100 healthy individuals who had no ITP‐related clinical or laboratory symptoms. Immune cell counts, NLR, PLR, and HPR were calculated using the complete blood count at the time of diagnosis and after the treatment. The results were analyzed through MedCalc, SPSS software, and the receiver operating characteristic curve.
Results
The result showed that white blood cell (WBC) and neutrophil counts were higher in ITP patients (WBC: p: 0.001, neutrophil: p: 0.001), and conversely, platelet and lymphocyte counts were higher in the control group compared to ITP patients (platelets: p: 0.001, lymphocytes: p: 0.001). The indices analysis between the two groups revealed that NLR was significantly increased in ITP patients (p: 0.001), but PLR was significantly reduced in ITP patients (with the mean platelet count of 23.44 ± 35.26 × 10⁹/L) compared to the control group (with the mean platelet count of 234.04 ± 55.88 × 10⁹/L). The HPR index also significantly increased in ITP patients (p: 0.001).
Conclusion
An increase in NLR, PLR, and a decrease in HPR can be considered a valuable diagnostic algorithm in patients with ITP.
... Cuker etal. expand the description of refractory ITP to encompass cases who need treatment however are unable or unwilling to have a splenectomy (154), even as an entire loss of reaction to one or further single-agent remedies, similar as rituximab and TPO-RA, turned into the description of refractory ITP in 2020 (66). shortly later, Miltiadous et al., defined "refractory" cases as those whose platelet counts don't reply to, in addition than two treatments, and whose platelet counts are extremely low and are accompanied by haemorrhage (155). ...
Primary immune thrombocytopenia is an autoimmune disorder associated with a decreased prephiral blood platelet count. The phenotype is variable with a few instances struggling no bleeding while others have extreme bleeding which may be deadly. Variability in clinical behaviour and remedy responses reflects its complicated pathophysiology. Traditionally the management has relied heavily on immune suppression. latest studies have shown that the older empirical immune suppressants fail to adjust the natural history of the complaint and are associated with a bad exceptional life for patients. More recent remedies, the thrombopoietin receptor agonists, have converted ITP care. they've excessive efficacy, are nicely tolerated and ameliorate cases ' high-quality of lifestyles. An extra expertise of the underpinning pathophysiology of this criticism has helped development more recent targeted curatives. These consist of inhibitors of the neonatal Fc receptor inhibitors, Bruton tyrosine kinase and supplement pathway. Then we bandy the mechanisms underlying ITP and the new method to ITP care.
... For details see Table S1. 6,8 Guidelines also recommend that ITP treatments should have minimal toxicity and optimise, instead of impair, patients' health-related quality of life (HRQoL). 5,6 A shared decision-making approach to treatment is recommended here, whereby a patient and their healthcare professionals (HCPs) work together to make collaborative decisions about care. ...
Although bleeding is one of the main symptoms of primary immune thrombocytopenia (ITP), risk factors for bleeding have yet to be fully established. Low platelet count (PC; <20–30 × 10⁹/L) is generally indicative of increased risk of bleeding. However, PC and bleeding events cannot be fully correlated; many other patient‐ and disease‐related factors are thought to contribute to increased bleeding risk. Furthermore, even though ITP patients have thrombocytopenia and are at increased risk of bleeding, ITP also carries higher risk of thrombotic events. Factors like older age and certain ITP treatments are associated with increased thrombotic risk. Women's health in ITP requires particular attention concerning haemorrhagic and thrombotic complications. Management of bleeding/thrombotic risk, and eventually antithrombotic therapies in ITP patients, should be based on individual risk profiles, using a tailored, patient‐centric approach. Currently, evidence‐based recommendations and validated tools are lacking to support decision‐making and help clinicians weigh risk of bleeding against thrombosis. Moreover, evidence is lacking about optimal PC for achieving haemostasis in invasive procedures settings. Further research is needed to fully define risk factors for each event, enabling development of comprehensive risk stratification approaches. This review discusses risk‐based and individualised management of bleeding and thrombosis risk in adults with primary ITP.
... It is no longer feasible, with a menagerie of a dozen available therapies, to need to fail them all. In a well-reasoned article discussing refractory ITP management, 51 the authors propose a framework of 'Tier 1 agents' including low-dose prednisone, rituximab and approved TPO agents, versus 'Tier 2 agents', 6-mercaptopurine/azathioprine, ciclosporin A, danazol, dapsone, mycophenolate mofetil and vincristine. Newer therapies 52 might fall into either tier because some (e.g. ...
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti‐CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in‐depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health‐related quality of life as an indispensable clinical trial end‐point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life‐threatening bleeding.
... 1 In 2009, the International Working Group (IWG) defined refractory ITP as a disease that does not respond to or relapses after splenectomy and that requires treatment to reduce the risk of bleeding. 2,3 There are several underlying causes that may lead to refractoriness in ITP and these may include, for example, inadequate dose or duration of treatment, non-compliance, underlying medical conditions, genetic factors and/or persistence of autoantibodies. In addition, very little is known about the immunopathophysiology of refractory ITP or whether it may be different or altered which leads to refractoriness. ...
Immune thrombocytopenia (ITP) is characterized by a dysregulated immune response against platelets, affecting both their destruction and production. A role for an abnormal T‐cell compartment has been established in ITP pathogenesis and treatments that increase platelet counts in patients with ITP have shown improvements in T‐cell profiles. On the other hand, patients who were refractory to treatment appear to retain the T‐cell abnormalities as before. Myeloid‐derived suppressive cells (MDSCs) are also emerging as key contributors to the immune pathology of ITP and response to treatment. In this review, we will discuss how various treatments affect the T‐cell and MDSC compartments in ITP. The review will focus on studies that have examined the underlying mechanisms and/or genetic basis responsible for refractoriness to a given treatment and highlight remaining challenges in identifying factors and mechanisms to predict response to treatment.
... Para esta condición se recurre a otros agentes inmunosupresores o manejo combinado, aunque con limitada evidencia para reducir el riesgo de hemorragia clínicamente significativa (6,7). Por lo cual presentamos nuestra experiencia con el uso de terapia combinada en una paciente con PTI refractaria al manejo convencional con adecuada respuesta. ...
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.
... However, none of these therapies have been universally accepted as the most effective for all ITP patients [15]. Relapsed ITP refers to patients who relapsed following the initial response to first-line corticosteroid therapy and conventional therapies [16]. ...
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder caused by antigen-specific T cells and antiplatelet autoantibodies that inhibit platelet production in the bone marrow or destroy platelets in the spleen. ITP is a form of autoimmunity and is closely associated with inflammation. Corticosteroids are the first-line therapy for ITP, with a total response rate of 53–80%. However, corticosteroid therapy is associated with significant side effects and is often ineffective in patients with corticosteroid-resistant or -intolerant disease. Eltrombopag has been validated as a second-line option in ITP therapy. Despite several studies demonstrating the efficacy and safety of Eltrombopag in immune thrombocytopenia patients, the prevalence of Eltrombopag-induced acute kidney injury has been observed. This case report describes a patient who experienced acute kidney injury during Eltrombopag therapy. A sudden increase in serum creatinine to 6.7 mg/dL and metabolic acidosis occurred after eight weeks of Eltrombopag. The patient’s renal failure had worsened, proteinuria was detected, and emergency hemodialysis was initiated. With vigilant kidney function screening and prompt treatment, the patient’s renal function improved remarkably following cessation of Eltrombopag and initiation of hemodialysis. This case highlights the importance of comprehensive medication history-taking and vigilant kidney function screening in patients receiving Eltrombopag.
... 2 Some authors have delineated the need in clinical practice to define refractory ITP as refractoriness to a given treatment. 3 In this article, we review the clinical and biological factors associated with refractoriness to 'second-line' treatments, that is those used after a treatment with corticosteroids, intravenous immunoglobulin (IVIg) or anti-D immunoglobulin. Apart splenectomy, we restricted to the treatments that have been evaluated with a high level of evidence (i.e. ...
Refractory immune thrombocytopenia (ITP) is a challenging disease that can be defined by refractoriness to second‐line treatments. In this review, we list and comment available evidence about clinical and biological factors associated with refractoriness to splenectomy, thrombopoietin receptor agonists (TPO‐RAs), rituximab and fostamatinib, as well as those associated with multirefractory ITP (active disease with failure of rituximab, TPO‐RAs and splenectomy).
... Moreover, we described the refractory ITP who relapsed after splenectomy and initial response to conventional therapies (including rituximab and thrombopoietin Receptor Agonists [13][14][15]. The relapsed ITP patients who relapsed after normalization of platelets while patients were both on and off-label treatment, with the greatest response to that line recorded before relapse and subsequent requiring re-therapy [16,46]. ...
Background:
Primary immune thrombocytopenia (ITP) is an inflammatory autoimmune disease that can be managed with several treatment options. However, there is a lack of comparative data on the efficacy of these options in different phases of the disease.
Aim of the study:
This study aimed to evaluate the efficacy of high-dose Dexamethasone (HD-DXM), Prednisolone + Azathioprine, Rituximab, Eltrombopag, and Romiplostim schedules in persistent, chronic refractory or relapsed Egyptian ITP patients with a platelet count ≤30 × 109/L. The primary outcome measure was a sustained increase in platelet counts over 50 × 109/L for an additional 12 months without additional ITP regimens. The study also aimed to identify a suitable treatment regimen with a long remission duration for each phase of ITP.
Results:
Prednisolone + Azathioprine was significantly more effective in achieving an overall response in persistent patients than Romiplostim, high-dose Dexamethasone, and Rituximab. (90.9% vs. 66.6, [Odds ratio, OR: 5; confidence interval, CI 95% (0.866-28.86)], 45%, [OR: 0.082, CI 95% (0.015-0.448)] and, 25%, [OR: 30, CI 95% (4.24-211.8)], respectively, p-value < 0.01). Eltrombopag was significantly more effective in achieving a durable response in refractory ITP than HD-DXM, Rituximab, and Prednisolone; (80% compared to 32.2% [OR: 0.119, CI 95% (0.035-0.410)], 22.2% [OR:0.071, CI 95% (0.011-0.455)], and 18.1% [OR: 0.056, CI 95% (0.009-0.342)], respectively, p-value < 0.01).
Conclusions:
Finally, Eltrombopag following HD-DXM showed the highest percentage of patients with complete treatment-free survival times of at least 330 days. These findings could help clinicians choose the most appropriate treatment for their patients with ITP based on the phase of the disease. This trial is registered in clinicaltrials.gov with registration number NCT05861297.
... 9 With the declining rate of splenectomy, a subsequent definition of refractory ITP from 2016 removed the requirement for splenectomy from the definition. 10 More recently, the 2019 international consensus report on the investigation and management of primary ITP de-emphasized the term 'refractory', reasoning that many patients eventually obtain a haemostatically safe platelet count. 7 In 2020, Miltiadous et al. proposed a definition of refractory as a lack of response to at least two treatments, specifically TPO-RAs and rituximab, in patients with severe thrombocytopenia and bleeding, without any effective treatment identified. ...
Immune thrombocytopenia (ITP) is an autoimmune haematological disorder characterized by immune‐mediated thrombocytopenia and a variable risk of bleeding. Despite the availability of multiple treatment options, some patients are considered refractory since they do not achieve a platelet count response to multiple treatments and are at risk of bleeding. The term ‘refractory’ has been used to identify this patient group; however, with the advent of multiple lines of treatment, its meaning has become ambiguous. To address this issue, we reviewed previous definitions of refractory ITP, solicited the views of ITP experts and collected data from registries to inform a definition. Twenty ITP experts who attended the 7th Expert Meeting of the Intercontinental Cooperative ITP Study Group in September 2022 answered a web‐based survey: 95% felt that there was a need for a new definition of refractory ITP for clinical and research purposes. The use of the term refractory, accompanied by a clear indication of the type and timing of failed treatments, was supported by 85% of respondents. Preliminary data on the frequency of refractory patients from the McMaster and Norwegian ITP Registries demonstrated that the proportion of adult ITP patients who had failed first‐line therapy, rituximab, thrombopoietin receptor agonists, any immune suppressant medication and splenectomy ranged from 0.4% to 3.8%. We propose a definition of refractory ITP that could be evaluated in future studies.
... Rituximab and/or mycophenolate mofetil (MMF) (14) were the first medications tested for thrombocytopenia, with the former being particularly helpful for thrombocytopenia but not usually advised due to a persistent increase in the risk of serious infections. MMF, on the other hand, has been shown to Frontiers in Pediatrics be an efficient steroid-sparing medication with no notable toxicities or infections (15). Sirolimus is the only treatment shown to significantly reduce lymphoproliferation, consistent with the description of an overactive the mammalian target of rapamycin (mTOR) pathway in ALPS, which may be regarded as a targeted treatment for ALPS (16), commensurate with the high degree of remission attained and the large reduction of ALPS biomarkers after 6 months of medication. ...
Background
Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease characterized by defective FAS signaling, which results in chronic, nonmalignant lymphoproliferation and autoimmunity accompanied by increased numbers of “double-negative” T-cells (DNTs) (T-cell receptor αβ+ CD4−CD8−) and an increased risk of developing malignancies later in life.Case presentationWe herein report a case of a newborn boy with a novel germline homozygous variant identified in the FAS gene, exon 9, c.775del, which was considered pathogenic. The consequence of this sequence change was the creation of a premature translational stop signal p.(lle259*), associated with a severe clinical phenotype of ALPS-FAS. The elder brother of the proband was also affected by ALPS and has been found to have the same FAS homozygous variant associated with a severe clinical phenotype of ALPS-FAS, whereas the unaffected parents are heterozygous carriers of this variant. This new variant has not previously been described in population databases (gnomAD and ExAC) or in patients with FAS-related conditions. Treatment with sirolimus effectively improved the patient clinical manifestations with obvious reduction in the percentage of DNTs.Conclusion
We described a new ALPS-FAS clinical phenotype-associated germline FAS homozygous pathogenic variant, exon 9, c.775del, that produces a premature translational stop signal p.(lle259*). Sirolimus significantly reduced DNTs and substantially relieved the patient's clinical symptoms.
... Additionally, its pediatric indication is poor [110]. Cuker et al. expanded the definition of refractory ITP to include patients who need treatment but are unable or unwilling to have a splenectomy [111], while a complete lack of response to one or more single-agent treatments, such as rituximab and TPO-RA, was the definition of refractory ITP in 2020 [20]. Shortly after, Miltiadous et al. defined "refractory" patients as those whose platelet counts do not respond to more than two treatments, and whose platelet counts are extremely low and are accompanied by haemorrhage [112]. ...
Lower-than-normal platelet counts are a hallmark of the acquired autoimmune illness known as immune thrombocytopenia, which can affect both adults and children. Immune thrombocytopenia patients’ care has evolved significantly in recent years, but the disease’s diagnosis has not, and it is still only clinically achievable with the elimination of other causes of thrombocytopenia. The lack of a valid biomarker or gold-standard diagnostic test, despite ongoing efforts to find one, adds to the high rate of disease misdiagnosis. However, in recent years, several studies have helped to elucidate a number of features of the disease’s etiology, highlighting how the platelet loss is not only caused by an increase in peripheral platelet destruction but also involves a number of humoral and cellular immune system effectors. This made it possible to identify the role of immune-activating substances such cytokines and chemokines, complement, non-coding genetic material, the microbiome, and gene mutations. Furthermore, platelet and megakaryocyte immaturity indices have been emphasized as new disease markers, and prognostic signs and responses to particular types of therapy have been suggested. Our review’s goal was to compile information from the literature on novel immune thrombocytopenia biomarkers, markers that will help us improve the management of these patients.
... At study entry, three (60%) subjects in the sTCC-high group received concomitant ITP drugs as compared to three (30%) subjects in the sTCC-normal group (p = .33). Third-line therapy [24] was only utilized in the sTCC-high group with two (40%) subjects treated with cyclosporine. Types of TPO-RA (romiplostim vs. eltrombopag) were equally distributed between the study groups (p = 1.0). ...
Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before and two, six and 12 weeks after the initiation of TPO-RA therapy. Plasma levels of complement degradation product C4d and soluble terminal complement complexes were assessed. Patients with significantly elevated baseline levels of terminal complement complexes exhibited more often an inadequate platelet response (p = .04), were exclusively subjected to rescue therapy with intravenous immunoglobulin (p = .02), and did not respond with a significant platelet count increase during the study period. C4d showed a significant (p = .01) ability to distinguish samples with significant terminal complement activation, implying engagement of the classical complement pathway. In conclusion, elevated levels of complement biomarkers were associated with a worse TPO-RA treatment response. Larger studies are needed to confirm these results. Biomarkers of complement activation may prove valuable as a prognostic tool to predict which patients that potentially could benefit from complement-inhibiting therapy in the future.
... Even a few years ago, the same dose of AA was still mentioned. 65 Actually, with the current pharmacokinetic concept, HDIVC should now be used for any therapeutic purposes. Moreover, it is also well known that the blood level of AA may drastically be reduced especially with chronic illness. ...
Background
Immune thrombocytopenia (ITP) is a rare disorder involving excessive peripheral destruction of platelets and inadequate bone marrow platelet production due to autoimmune reactions against megakaryocytes. Diagnosis is usually by the exclusion of primary causes; its rarity would only permit trial and error therapy experience.
Historically, for ITP, oral ascorbic acid (AA) gave inconsistent results. However, unlike other nutrients, AA is found to have an exceptionally tight intestinal absorption restriction mandating intravenous delivery for any therapeutic purposes. Recently, as there is more pre‐clinical evidence of AA restoring regulatory T cells (Tregs) by robust demethylation, the historical oral route was likely to be the “bottle neck” restricting effective blood levels. During this era of thrombopoietin receptor agonists (TPO‐RAs), planned tapering is often required upon discontinuation but unplanned discontinuations, for example, due to side effects, are more problematic. Moreover, combinations with TPO‐RAs are currently being tried using steroids and rituximab except rituximab is inappropriate during pandemics. Notably, with the indirect (but prognostically relevant) action of TPO‐RAs on Tregs, boosting Treg functions by adding other Treg active agents, for example, steroids or AA, seems appropriate, especially if without added toxicity upon combining.
Conclusions
With updated pharmacokinetic concepts, it is timely to repeat AA clinical trials for ITP but using intravenous administration. Initially, this may be on compassionate grounds for its probable role as an adjunct to TPO‐RAs for unsuccessful tapering and, especially, for all unplanned discontinuations of TPO‐RAs. Such off‐label usage of AA is justified because of AA's robust pre‐clinical evidence on demethylation and initial clinical experience (despite the inappropriate administrative route). Moreover, moderate intravenous AA dosages have one of the best safety profiles, let alone its eminent affordability. Admittedly, after the initial clinical experience, more systematic trials on AA are required, especially for the most appropriate dosage range and its efficacy as monotherapy.
... "Refractory" was initially defined as failure or recurrence after splenectomy (1). In 2016, the definition expanded to include not only those splenectomy nonresponders but also those intolerant or unwilling to undergo splenectomy (4). In another study, authors defined those not responding to splenectomy, rituximab, romiplostim and eltrombopag as refractory ITP patients (5). ...
Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder featured by increased platelet destruction and deficient megakaryocyte maturation. First-line treatments include corticosteroids, intravenous immunoglobulin and intravenous anti-D immunoglobulin. Second-line treatments consist of rituximab, thrombopoietin receptor agonists and splenectomy. Although most patients benefit from these treatments, an individualized treatment approach is warranted due to the large heterogeneity among ITP patients. In addition, ITP patients may relapse and there remains a subset of patients who become refractory to treatments. The management of these refractory patients is still a challenge. This review aims to summarize emerging therapeutic approaches for refractory ITP in several categories according to their different targets, including macrophages, platelets/megakaryocytes, T cells, B cells, and endothelial cells. Moreover, current management strategies and combination regimens of refractory ITP are also discussed.
... For example, in primary immune thrombocytopenia, decreased Treg cell levels are the main cause of refractory/ recurrent ITP, which provides a theoretical basis for sirolimus treatment of ITP. After a randomized group trial by Li (Cuker and Neunert, 2016) et al. showed that sirolimus significantly improved remission rates as well as platelet counts in patients with ITP . Jasinski et al. included 12 patients with ITP and switched to sirolimus combined with hormone therapy after conventional treatment failed and found that the patients' cure rate was greatly improved and no significant adverse effects were observed during the use of the drug (Jasinski et al., 2017), further establishing the possibility of sirolimus for the treatment of immune thrombocytopenia. ...
Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.
... Unfortunately, the patient's kidney function did not normalize and his counts dropped. He was started on dapsone 100 mg once daily followed by danazol 200 mg BID (Figure 2), which are both used for the management of refractory immune thrombocytopenia [14]. Dapsone and danazol were used as immunosuppressive therapies to target his immune cytopenias. ...
We report a case of pure white cell aplasia (PWCA) postthymoma resection in a 74-year-old male presenting with a 2-week history of fevers, night sweats, and severe febrile neutropenia. His pure white cell aplasia was treated with intravenous immunoglobulin (IVIg), granulocyte colony-stimulating factor (G-CSF), prednisone, and cyclosporine with a mixed response. He also developed immune thrombocytopenia, which responded well to a short course of eltrombopag. With continued cyclosporine treatment, his platelet counts were stable after stopping eltrombopag. The patient's cyclosporine treatment was complicated by renal failure, resulting in cessation of cyclosporine. His PWCA and immune thrombocytopenia significantly worsened after stopping cyclosporine, and unfortunately, he died from multiorgan failure and sepsis.
... LPDs. When ITP is found refractory to standard therapies, the diagnosis should be reassessed [7]. In our patient, serum IgM level and protein electrophoresis helped diagnose IgM-MGUS. ...
When immune thrombocytopenia (ITP) is secondary to malignant diseases, chemotherapy is expected to improve the platelet count (PC) as well. Herein, we report a case of a 72‐year‐old man with ITP refractory to standard therapies. IgM monoclonal gammopathy of undetermined significance (MGUS) was determined as an underlying disease. After bendamustine and rituximab (BR) therapy was found inadequately effective, tirabrutinib, a novel Bruton's tyrosine kinase inhibitor, was initiated, and the PC normalised subsequently. Surveillance of underlying diseases with which effective therapies are available may help manage refractory ITP, and IgM‐MGUS is potentially a targetable underlying disease with this newly available drug.
... For TRAs, we utilized an initial overall response rate of 80% and assumed a best case scenario where this response is sustained in all patients throughout the duration of the Markov model, despite rates of persistent response reported as low as 40%-50%. 29 We further increased the response rate to TRA therapy by 20%, to 96% in our sensitivity analyses. We did not model adverse effects such as thrombosis, assuming perfectly tolerated TRA therapy. ...
Major options for second‐line therapy in adults with chronic immune thrombocytopenia (ITP) include splenectomy, rituximab, and thrombopoietin receptor agonists (TRAs). The American Society of Hematology guidelines recommend rituximab over splenectomy, TRAs over rituximab, and splenectomy or TRAs while noting a lack of evidence on the cost‐effectiveness of these therapies. Using prospective, observational, and meta‐analytic data, we performed the first cost‐effectiveness analysis of second‐line therapies in chronic ITP, from the perspective of the U.S. health system. Over a 20‐year time‐horizon, our six‐strategy Markov model shows that a strategy incorporating early splenectomy, an approach at odds with current guidelines and clinical practice, is the cost‐effective strategy. All four strategies utilizing TRAs in the first or second position cost over $1 million per quality‐adjusted life‐year, as compared to strategies involving early use of splenectomy and rituximab. In a probabilistic sensitivity analysis, early use of splenectomy and rituximab in either order was favored in 100% of 10 000 iterations. The annual cost of TRAs would have to decrease over 80% to begin to become cost‐effective in any early TRA strategy. Our data indicate that effectiveness of early TRA and late TRA strategies is similar with the cost significantly greater with early TRA strategies. Contrary to current practice trends and guidelines, early use of splenectomy and rituximab, rather than TRAs, constitutes cost‐effective treatment in adults with chronic ITP.
Rationale
Immune thrombocytopenia (ITP) is an autoimmune-mediated disorder caused by antibody-mediated platelet destruction and impaired platelet production by megakaryocytes. Treating refractory ITP remains a significant challenge.
Patient Concerns and Diagnoses
We report 2 patients with refractory ITP.
Interventions and Outcomes
Two patients received low-dose decitabine combined with recombinant human thrombopoietin or eltrombopag. Platelet counts in both patients increased to within the normal range.
Lessons
Low-dose decitabine combined with recombinant human thrombopoietin or eltrombopag may exert a synergistic effect in the treatment of refractory ITP.
Objectives:
To describe and compare real-world treatment patterns and clinical outcomes among individuals with immune thrombocytopenia (ITP) receiving second-line therapies (rituximab, romiplostim, or eltrombopag).
Methods:
A retrospective cohort study was conducted using a large administrative claims database (January 2013-May 2020) among continuously enrolled patients ≥18 years prescribed second-line ITP therapies. The index date was the date of the first claim of the study medications. Treatment patterns and outcomes were measured during the 12-month follow-up period. Inverse probability of treatment weighting (IPTW) was used to balance covariates across treatment groups. Multivariable logistic regression was used to compare treatment patterns and bleeding risk outcomes.
Results:
A total of 695 patients were included (rituximab, N = 285; romiplostim, N = 212; eltrombopag, N = 198). After IPTW, all baseline covariates were balanced. Compared to eltrombopag, patients in the rituximab cohort were 57% more likely to receive other ITP therapies (systematic corticosteroids or third-line therapies) during the follow-up period (odds ratio [OR] = 1.571, p = .030). There was no significant difference in the odds of receiving a different second-line therapy or experiencing a bleeding-related episode among three groups (p > .050). Patients in the romiplostim cohort were 69% more likely to receive rescue therapy compared to those in the rituximab cohort (OR = 1.688, p = .025).
Conclusion:
Patients with ITP receiving rituximab were more likely to need other ITP therapies but did not experience higher risk of bleeding compared to those receiving eltrombopag or romiplostim. Benefits, risks, cost-effectiveness, and patient preference should all be considered in optimizing second-line therapy for ITP.
目的
评估地西他滨（DAC）在糖皮质激素治疗失败原发免疫性血小板减少症（ITP）中的疗效及影响因素。
方法
纳入2015年11月至2021年6月在山东大学齐鲁医院血液科接受DAC治疗（5 mg·m⁻²·d⁻¹×3 d静脉滴注，至少应用3个疗程，每疗程间隔3～4周）的61例糖皮质激素治疗失败ITP患者，对其临床资料进行回顾性分析。
结果
61例患者中，男20例，女41例。中位年龄45（15～81）岁。糖皮质激素依赖43例，无效18例。DAC治疗后，12例（19.67％）患者获得完全反应（CR），16例（26.23％）有效（R），总有效（OR）率为45.90％（28/61）。DAC治疗OR组（28例）与无效组（NR，33例）比较，糖皮质激素的反应性（依赖或无效）、治疗前血小板计数差异具有统计学意义（χ²＝8.789，P＝0.003；z＝−2.416，P＝0.016）。糖皮质激素依赖组与糖皮质激素无效组比较，DAC治疗2、3疗程后血小板计数较高（P＝0.032、0.024）；DAC治疗1、2、3疗程OR率比较，糖皮质激素依赖组均高于糖皮质激素无效组（P＝0.042，P＝0.012，P＝0.029）。糖皮质激素依赖与DAC疗效具有明显相关性（OR＝9.213，95％ CI 1.937～43.820，P＝0.005）。
结论
DAC对于部分糖皮质激素治疗失败的ITP患者具有确切的疗效且不良反应轻微。糖皮质激素依赖、治疗前血小板计数高的患者DAC疗效较好。
Primary immune thrombocytopenia (ITP) is a complex autoimmune disease whose hallmark is a deregulation of cellular and humoral immunity leading to increased destruction and reduced production of platelets. The heterogeneity of presentation and clinical course hampers personalized approaches for diagnosis and management. In 2021, the Spanish ITP Group (GEPTI) of the Spanish Society of Hematology and Hemotherapy (SEHH) updated a consensus document that had been launched in 2011. The updated guidelines have been the reference for the diagnosis and management of primary ITP in Spain ever since. Nevertheless, the emergence of new tools and strategies makes it advisable to review them again. For this reason, we have updated the main recommendations appropriately. Our aim is to provide a practical tool to facilitate the integral management of all aspects of primary ITP management.
We present a case of a 30-year-old man suffering from chronic refractory immune thrombocytopenia (ITP) from early childhood. The patient was treated with all the therapeutic methods available in Poland, without platelet response: corticosteroids, intravenous immunoglobulins, splenectomy, cyclophosphamide, vinblastine, azathioprine, mycophenolate mofetil, rituximab, ciclosporin A, romiplostim, and eltrombopag. He continued to function persistently with deep thrombocytopenia, symptoms of hemorrhagic diathesis, and one episode of spontaneous subarachnoid bleeding. In April 2022, at the age of 29, the patient received avatrombopag. Within 4 weeks of starting avatrombopag 20 mg daily for 2 weeks and then 40 mg daily, he reached a platelet (PLT) count of 67 x 109/l. In the next month, platelets fell below 30 x 109/l, but subsequently the count increased to 47 x 109/l, then to 52 x 109/l, and remained stable. The symptoms of cutaneous hemorrhage diathesis have resolved completely since avatrombopag was introduced and did not reappear despite the decrease in PLT count.
There are not many publications that provide a holistic view of the management of primary and secondary ITP as a whole, reflecting the similarities and differences between the two. Given the lack of major clinical trials, we believe that comprehensive reviews are much needed to guide the diagnosis and treatment of ITP today. Therefore, our review addresses the contemporary diagnosis and treatment of ITP in adult patients. With respect to primary ITP we especially focus on establishing the management of ITP based on the different and successive lines of treatment. Life-threatening situations, "bridge therapy" to surgery or invasive procedures and refractory ITP are also comprehensively reviewed here. Secondary ITP is studied according to its pathogenesis by establishing three major differential groups: Immune Thrombocytopenia due to Central Defects, Immune Thrombocytopenia due to Blocked Differentiation and Immune Thrombocytopenia due to Defective Peripheral Immune Response. Here we provide an up-to-date snapshot of the current diagnosis and treatment of ITP, including a special interest in addressing rare causes of this disease in our daily clinical practice. The target population of this review is adult patients only and the target audience is medical professionals.
The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. In the Ninth Edition, the JCA Special Issue Writing Committee has incorporated systematic review and evidence-based approaches in the grading of evidence and categorization of apheresis indications to make recommendations on the use of apheresis in a wide variety of diseases and conditions. This edition has largely maintained the general layout and concept of a fact sheet introduced in the Fourth Edition (2007). Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease or medical condition. The Ninth Edition of the JCA Special Issue comprises 91 fact sheets and 166 graded and categorized indications. This includes seven new fact sheets, nine new indications on existing fact sheets, and eight changes in the category for existing indications. The Ninth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.
Many patients worldwide receive platelet components (PCs) through the transfusion of diverse types of blood components. PC transfusions are essential for the treatment of central thrombocytopenia of diverse causes, and such treatment is beneficial in patients at risk of severe bleeding. PC transfusions account for almost 10% of all the blood components supplied by blood services, but they are associated with about 3.25 times as many severe reactions (attributable to transfusion) than red blood cell transfusions after stringent in-process leukoreduction to less than 10⁶ residual cells per blood component. PCs are not homogeneous, due to the considerable differences between donors. Furthermore, the modes of PC collection and preparation, the safety precautions taken to limit either the most common (allergic-type reactions and febrile non-hemolytic reactions) or the most severe (bacterial contamination, pulmonary lesions) adverse reactions, and storage and conservation methods can all result in so-called PC “storage lesions”. Some storage lesions affect PC quality, with implications for patient outcome. Good transfusion practices should result in higher levels of platelet recovery and efficacy, and lower complication rates. These practices include a matching of tissue ABH antigens whenever possible, and of platelet HLA (and, to a lesser extent, HPA) antigens in immunization situations. This review provides an overview of all the available information relating to platelet transfusion, from donor and donation to bedside transfusion, and considers the impact of the measures applied to increase transfusion efficacy while improving safety and preventing transfusion inefficacy and refractoriness. It also considers alternatives to platelet component (PC) transfusion.
Introduction:
Primary immune thrombocytopenia (ITP) is an acquired bleeding disorder. Conventionally, first-line ITP therapy aims to obtain a rapid response and stop or decrease the risk of bleeding by increasing the platelet count. At this point, the duration of the response, the tolerability, and the long-term safety of pharmacologic interventions are considered less of a priority. Combination treatments that simultaneously address multiple disease mechanisms are an attractive strategy to increase efficacy in acute ITP therapy. In this review, we discuss the treatment of newly diagnosed ITP patients, emphasizing the use of new combinations to benefit from their synergy.
Areas covered:
This article summarizes conventional treatment, recent and novel combinations, and COVID-19 management recommendations of newly diagnosed ITP patients.
Expert opinion:
The key areas for improvement consider the long-term effects of conventional first-line therapy, reducing relapse rates, and extending responses to achieve long-term remission. Although corticosteroids remain first-line therapy, restricting their use to avoid toxicity and the increasing use of rituximab and TPO-RAs in the first three months after diagnosis open the landscape for future interventions in frontline therapy for ITP. First-line therapy intensification or synergistic drug combination offers a potential and realistic shift in future treatment guidelines.
Introduction
Refractory or recurrent immune thrombocytopenia (ITP) patients suffer from the dual threat of high mortality and drug toxicity in addition to a very poor quality of life. Previous studies have shown that high mobility group box 1 (HMGB1) can promote the development of rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune diseases. However, there is still a lack of research on the role of HMGB1 in the pathogenesis of ITP and whether it can be used as a predictor of efficacy and prognosis.
Methods
20 patients of adult ITP with splenectomy were chosen as the experimental group, while 19 adults underwent splenectomy for traumatic splenic rupture without other diseases as the control group. We measured the expression of HMGB1, RORγt and Foxp3 in spleen tissues by immunohistochemistry. Another 50 patients, of which 20 were newly diagnosed without treatment and 30 were refractory ITP, and 25 healthy controls were enrolled to analyse the expression levels and mRNA levels of HMGB1, RORγt and Foxp3 in peripheral blood by Western blot and RT-qPCR. The expression of HMGB1, IL-17 and IL-10 in serum was assayed by ELISA. PBMCs from newly diagnosed ITP patients were cultured in vitro which stimulated with recombinant humanHMGB1 (rHMGB1) and its inhibitors, in which the expressions of RORγt and Foxp3 were measured.
Results
The expression of HMGB1 in the spleen with refractory ITP was significantly higher, while Foxp3 was decreased. A significant negative correlation was found between HMGB1 and Foxp3, and the overexpression of HMGB1 was significantly correlated with poor efficacy after splenectomy. The expression of HMGB1 and IL-17 increased and showed a positive correlation in serum, while IL-10 decreased and was negatively correlated with HMGB1. In PBMCs, the expression of HMGB1 and RORγt increased, while Foxp3 decreased, and the differences were more obvious in the refractory chronic ITP group. In a coculture system with PBMCs of untreated ITP patients, rHMGB1 increased RORγt expression and decreased Foxp3 expression, while an antiHMGB1 antibody partially corrected the above changes.
Conclusion
Our results suggest that HMGB1 is associated with the imbalance of Treg/Th17 cells and is involved in the pathogenesis of ITP.
La trombocitopenia inmune primaria (TIP) es un trastorno autoinmune común que afecta de forma variable a pacientes de todas las edades, géneros y razas. Su diagnóstico excluye todas aquellas trombocitopenias secundarias a otras enfermedades autoinmunes, infecciones o por medicamentos, de manera que no se evidencia alteración alguna en las restantes líneas celulares. Más del 80 % de las trombocitopenias autoinmunes responden de forma favorable a tratamientos de primera línea y, del 20 % restante, hasta un 60 % resolverá con medidas de segunda línea. Solo de un 35 a un 8 % no responderá al manejo convencional, configurando así una trombocitopenia inmune refractaria, de modo que se convierte, en sí misma, en un reto terapéutico. La incidencia de la trombocitopenia inmune refractaria se desconoce durante el embarazo y se limita a reportes de pocos casos en la literatura. Se presenta el caso de una gestante con antecedente de TIP que se torna refractaria durante la gestación con recuentos plaquetarios persistentemente bajos, síntomas de sangrado y limitaciones terapéuticas por su condición gestante.
Romiplostim was effective, safe, and well-tolerated over 6–12 months of continuous treatment in Phase 3 trials in patients with immune thrombocytopenia (ITP). This report describes up to 5 years of weekly treatment with romiplostim in 292 adult ITP patients in a long-term, single-arm, open-label study. Outcome measures included adverse events (including bleeding, thrombosis, malignancy, and reticulin / fibrosis), platelet response (platelet count >50 × 109 per litre), and the proportion of patients requiring rescue treatments. Treatment – related serious adverse events were infrequent and did not increase with longer treatment. No new classes of adverse events emerged. Thrombotic events occurred in 6.5 % of patients and were not associated with platelet count. Median platelet counts of 50–200 × 109 per litre were maintainedwith stable doses of romiplostim (mean 5–8 μg / kg; generally self-administered at home) throughout the study. A platelet response was achieved at least once by 95 % of patients, with a platelet response maintained by all patients on a median 92 % of study visits. There was a low rate of bleeding and infrequent need for rescue treatments. In conclusion, this study demonstrated that romiplostim was safe and welltolerated over 614 patient-years of exposure in ITP patients, and that efficacy was maintained with stable dosing for up to 5 years of continuous treatment.
Background
Treatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12–16-week study, 15/17 romiplostim-treated patients achieved platelet counts ≥50 × 109/L, and romiplostim treatment was well tolerated. In a subsequent open-label extension (≤109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 × 109/L. Twelve patients continued in a second extension (≤127 weeks). Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP.ProcedurePatients received weekly subcutaneous romiplostim, adjusted by 1 µg/kg/week to maintain platelet counts (50–200 × 109/L, maximum dose 10 µg/kg). Bone marrow examinations were not required.ResultsAt baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 × 109/L; 73% were male; and 36% had prior splenectomy. Median romiplostim treatment duration was 167 weeks (Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 µg/kg (Q1, Q3: 4.3, 8.0 µg/kg). Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy. None withdrew because of adverse events (AEs). After the first 12 weeks, median platelet counts remained >50 × 109/L. Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy. Seven patients (31.8%) reported serious AEs, and two (9.1%) reported life-threatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities.Conclusions
Long-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Pediatr Blood Cancer © 2014. The Authors. Pediatr Blood & Cancer published by Wiley Periodicals, Inc.
Glucocorticosteroids (GCs) have been employed extensively for the treatment of rheumatoid arthritis (RA) and other autoimmune and systemic inflammatory disorders. Their use is supported by extensive literature and their utility is reflected in their incorporation into current treatment guidelines for RA and other conditions. Nevertheless, there is still some concern regarding the long-term use of GCs because of their potential for clinically important adverse events, particularly with an extended duration of treatment and the use of high doses. This article systematically reviews the efficacy for radiological and clinical outcomes for low-dose GCs (defined as ≤10 mg/day prednisone equivalent) in the treatment of RA. Results reviewed indicated that low-dose GCs, usually administered in combination with synthetic DMARDs, most often MTX, significantly improve structural outcomes and decrease symptom severity in patients with RA. Safety data indicate that GC-associated adverse events are dose related, but still occur in patients receiving low doses of these agents. Concerns about side effects associated with GCs have prompted the development of new strategies aimed at improving safety without compromising efficacy. These include altering the structure of existing GCs and the development of delayed-release GC formulations so that drug delivery is timed to match greatest symptom severity. Optimal use of low-dose GCs has the potential to improve long-term outcomes for patients with RA.
B-cell depletion may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). We investigated the effects of rituximab on antibody and cellular responses to Streptococcus pneumoniae polysaccharide and Haemophilus influenzae type b (Hib) vaccines in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n = 17) or placebo (n = 7). Among 20 evaluable patients, 3 of 14 (21%) in the rituximab group and 4 of 6 (67%) in the placebo group achieved a fourfold increase in anti-pneumococcal antibodies (P = .12). For anti-Hib antibodies, 4 of 14 (29%) and 5 of 6 (83%), respectively, achieved a fourfold increase (P < .05). Fewer patients in the rituximab group demonstrated Hib killing (2 of 14 [14%], 5 of 6 [83%], P < .05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, preplasma cell blasts and interferon-γ-secreting T cells were reduced in rituximab-treated patients. Antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with depleted B-cell pools. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in ITP patients.
Key Points
Severe thrombocytopenia is rare and major hemorrhage is uncommon in children with persistent and chronic ITP. In children with persistent or chronic ITP, there is a trend toward reserving drug therapy for those experiencing significant bleeding.
Romiplostim was effective, safe, and well-tolerated over 6-12 months of continuous treatment in Phase 3 trials in patients with immune thrombocytopenia (ITP). This report describes up to 5 years of weekly treatment with romiplostim in 292 adult ITP patients in a long-term, single-arm, open-label study. Outcome measures included adverse events (including bleeding, thrombosis, malignancy, and reticulin/fibrosis), platelet response (platelet count >50 × 10(9) per litre), and the proportion of patients requiring rescue treatments. Treatment-related serious adverse events were infrequent and did not increase with longer treatment. No new classes of adverse events emerged. Thrombotic events occurred in 6·5% of patients and were not associated with platelet count. Median platelet counts of 50-200 × 10(9) per litre were maintained with stable doses of romiplostim (mean 5-8 μg/kg; generally self-administered at home) throughout the study. A platelet response was achieved at least once by 95% of patients, with a platelet response maintained by all patients on a median 92% of study visits. There was a low rate of bleeding and infrequent need for rescue treatments. In conclusion, this study demonstrated that romiplostim was safe and well-tolerated over 614 patient-years of exposure in ITP patients, and that efficacy was maintained with stable dosing for up to 5 years of continuous treatment.
Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 10(9)/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 10(9)/L (interquartile range, 75-167 × 10(9)/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 10(9)/L (interquartile range, 35-44 × 10(9)/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.
Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality--interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of "front-line" therapy for ITP, the management of serious bleeding in patients with ITP, and studies that will provide guidance about which therapy should be used as salvage therapy for patients after failure of a first-line intervention.
Previously published guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) require updating largely due to the introduction of new classes of therapeutic agents, and a greater understanding of the disease pathophysiology. However, treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than high-quality clinical trial evidence. This consensus document aims to report on new data and provide consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. The inclusion of summary tables within this document, supported by information tables in the online appendices, is intended to aid in clinical decision making.
Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.
Extracorporeal immunoadsorption of plasma to remove IgG and circulating immune complexes (CIC) was evaluated as a therapy for adults with treatment-resistant immune thrombocytopenic purpura (ITP). Seventy-two patients with initial platelet counts less than 50,000/microL who had failed at least two other therapies were studied. They received an average of six treatments of 0.25 to 2.0 L plasma per procedure over a 2- to 3-week period using columns of staphylococcal protein A-silica (PROSORBA immunoadsorption treatment columns; IMRE Corp, Seattle, WA). The treatments caused an acute increase in the platelet count to greater than 100,000/microL in 18 patients and to 50,000 to 100,000/microL in 15 patients. The median time to response was 2 weeks. Responses were transient (less than 1 month duration) in seven of those patients (10%), but no additional relapses were reported over a follow- up period of up to 26 months (mean of 8 months). Clinical responses were associated with significant decreases in specific serum platelet autoantibodies (including anti-glycoprotein IIb/IIIa), platelet- associated Ig, and CIC. Thirty percent of treatments were associated with transient mild to moderate side effects usually presenting as a hypersensitivity-type reaction. Continued administration of failed therapies for ITP, which always included low-dose corticosteroids (less than or equal to 30 mg/d), had no demonstrable influence on the effectiveness of immunoadsorption treatment but did depress the incidence and severity of side effects. The degree of effectiveness of protein A immunoadsorption therapy in patients with treatment-resistant ITP is promising and further controlled studies in this patient population are warranted.
Introduction:
Immune thrombocytopenia (ITP) is a common hematologic disorder characterized by isolated thrombocytopenia. In adults, ITP is more likely to be chronic, requiring individualised treatment and management. Corticosteroids and splenectomy are the most common therapy for ITP. However, these routine approaches failed in these patients with chronic ITP. The aim of this study was to evaluate the efficacy of immunomodulatory therapy with all-trans retinoid acid (ATRA) in adult patients with chronic ITP.
Materials and methods:
ATRA therapy was applied in a total of 35 patients with chronic ITP who failed with standard dose corticosteroids and/or splenectomy. The response ratio and the change of the T cell subsets including Th1, Th2, Th17 and Treg, were evaluated.
Results:
Complete response and overall response were observed in 10 (28.6%) and 19 patients (54.3%), respectively. Compared with the control group, a significant decreased level of Treg cells, IL-10 and Foxp3 expression were found in ITP patients. ATRA therapy could significantly increase the percentage of Treg cell, IL-10 level and Foxp3 expression.
Conclusions:
Our findings indicate that ATRA therapy could induce significant changes of Treg cells to induce response in patients with chronic ITP.
• Fourteen patients with Idiopathic thrombocytopenic purpura (ITP) refractory to splenectomy and corticosteroids (prednisone, 1 to 2 mg/kg of body weight per day) received at least 1.2 mg of oral colchicine daily for a minimum of two weeks. Three patients had complete responses and one had a partial response (response rate, 29%). Responses were evident within two weeks of commencing therapy. Only the patient with a partial response was receiving concomitant therapy, a stable dose of prednisone. Responsiveness to colchicine did not seem to correlate with responsiveness to vincristine sulfate. Side effects of colchicine therapy were mild and complications did not occur. A possible mechanism of action for colchicine in ITP is decreased clearance of opsonized platelets secondary to inhibition of microtubule-dependent events In macrophages. Colchicine Is useful in the treatment of ITP resistant to standard treatment.
(Arch Intern Med 1984;144:2198-2200)
Owing to the sensitive equilibrium between the hepatitis B virus (HBV) and the host’s immune system in infected and exposed individuals, the immunosuppression caused by biologic treatment has been strongly linked to HBV reactivation (HBVr). HBVr in the setting of biologic therapy is a cause of considerable morbidity, hospitalization, interruption of treatment and mortality. However, recent literature has established that this is a largely preventable problem. Thus, it is essential for clinicians using biologic agents to be aware of HBVr potential and screen all susceptible patients. The risk for HBVr may vary depending on the host’s HBV infection status and the potency of immunosuppression. The appropriate pre-emptive antiviral prophylaxis or monitoring for individuals at risk is emphasized in the latest evidence-based guidelines, but a number of unanswered questions remain.
Background:
Eltrombopag is effective and safe in chronic immune thrombocytopenia (ITP). However, clinical trials may not accurately reflect what happens in clinical practice. We evaluated the efficacy and safety of eltrombopag in primary chronic ITP in a real-world setting.
Methods:
164 primary chronic ITP patients from 40 Spanish centers, who had been treated with eltrombopag, were retrospectively evaluated.
Results:
The median age of our cohort (72% women) was 63 years (interquartile range, IQR, 45-75 years). The median time with ITP diagnosis was 81 months (IQR, 30-192 months). The median number of therapies prior to eltrombopag was 3 (IQR, 2-4). At the time of eltrombopag start, 45 patients (30%) were receiving concomitant treatment for ITP. Forty-six patients (30%) had bleeding signs/symptoms the month before treatment start. The median platelet count at eltrombopag initiation was 22 x 10(9) /L (IQR, 8-39 x 10(9) /L). 135 patients (88.8%) achieved a platelet response. The median time to platelet response was 12 days (95% CI, 9-13 days). Maintained platelet response rate during the 15-month period under examination was 75.2%. 28 patients (18.4%) experienced adverse events, mainly grades 1-2.
Conclusion:
Eltrombopag is highly effective and well tolerated in unselected patients with primary chronic ITP. This article is protected by copyright. All rights reserved.
Summary
Background
The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia.
Methods
PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1–17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 109 per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12–17, 6–11, and 1–5 years. We established patients' starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6–17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing <27 kg) and patients aged 1–5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1–5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12–17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6–11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1–5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 109 per L or more at least once from weeks 1–6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037.
Findings
Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12–17 years, 19 aged 6–11 years, and ten aged 1–5 years) and 22 to receive placebo (eight children aged 12–17 years, nine aged 6–11 years, and five aged 1–5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 109 per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39–13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase.
Interpretation
Our results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults.
Severe immune thrombocytopenia purpura (ITP) presents a clinical challenge. Second-line treatment options are variable without a precise protocol. We present 46 severe ITP patients treated with mycophenolate mofetil (MMF), retrospectively identified from three London teaching hospitals. Data was collected on patient demographics, co-morbidities and previous treatment strategies. Our key interest was whether there was a sustained response in platelet count to MMF. Patients included 27 males and 19 females whose ages ranged from 19 to 93 years old (median 52·5 years). Twenty-nine had primary ITP and 17 had secondary ITP, a third of whom had viral-associated disease. The standard dose of MMF was 1 g/day. Twenty-four patients (52%) responded with 15 (33%) achieving a complete response. No active viral-associated ITP patients demonstrated a response to MMF, although numbers were small (n = 4). We were not able to demonstrate a difference between responders and non-responders based on gender, age, previous therapies or time since diagnosis of ITP. Three of four previously splenectomized patients responded, two achieving complete response. We conclude that MMF is a useful steroid-sparing immunosuppressant to be considered in the second-line or later treatment of ITP.
© 2015 John Wiley & Sons Ltd.
The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia.
PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1-5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909.
Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3-140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial.
Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events.
GlaxoSmithKline.
Copyright © 2015 Elsevier Ltd. All rights reserved.
A safety analysis of pooled data from clinical studies of romiplostim, a thrombopoietin (TPO) receptor agonist, in which patients with immune thrombocytopaenia (ITP) received romiplostim, placebo, or medical standard of care (SOC) Rodeghiero et al. (Eur J Haematol 91:423-436, 2013), has been updated. Included are data from 14 trials spanning 2002-2011; placebo- and SOC-arm data are pooled. Most patients (n = 1059) were female (61 %) and Caucasian (85 %); 38 % had undergone splenectomy; 23 were children. Mean (SD) baseline platelet count was 20.6 (16.5) × 10(9)/L. Mean (SD) weekly dose of romiplostim was 4.2 (2.8) µg/kg; total exposure was 1520 patient-years. Overall, 921 patients received romiplostim only, 65 received placebo/SOC only, and 73 received placebo/SOC followed by romiplostim. Rates of haemorrhage (romiplostim, 205/100 patient-years; placebo/SOC, 263/100), thrombosis (both, 5.5/100 patient-years), haematological malignancy/myelodysplastic syndrome (romiplostim, 0.5/100 patient-years; placebo/SOC, 2.7/100), and non-haematological tumours (romiplostim, 2.2/100 patient-years; placebo/SOC, 3.6/100) were comparable among groups. Bone marrow reticulin was reported in 17 patients and collagen in one patient receiving romiplostim; one patient receiving placebo/SOC had reticulin reported. Three patients developed neutralizing antibodies to romiplostim, but not to endogenous TPO. This integrated analysis of the safety profile of romiplostim in patients with ITP is consistent with previously reported studies; no new safety concerns emerged.
This work aims to observe the efficacy and safety of low-dose rituximab in combination with recombinant human thrombopoietin in treating immune thrombocytopenia (ITP).
Fourteen ITP patients were treated four times with 100 mg qw of rituximab in combination with 300 µg/kg/d ih recombinant human thrombopoietin (rhTPO) for 14 d. Platelet count in peripheral blood, serum immunoglobulin, and lymphocyte subgroups by flow cytometry were detected regularly both pre- and post-treatment.
Among the 14 patients, seven complete responses, six responses, and one no response were obtained, with an overall response of 93%.
Low-dose rituximab in combination with rhTPO is effective in treating ITP.
Promising reports of combination immunosuppression with high dose dexamethasone and rituximab for the treatment of primary immune thrombocytopenia (ITP) have recently emerged. They suggest a potential to further optimize the efficacy of therapy. We investigate the use of a novel combination of conventional therapies in ITP given over 4 weeks. From 2011 to 2014, 20 patients were prospectively enrolled onto a single-arm phase IIb study to describe the safety, efficacy and tolerability of oral dexamethasone 40mg Day 1-4, oral cyclosporine 2.5-3mg/kg/daily Day 1-28 and intravenous low-dose rituximab 100mg Day 7, 14, 21 and 28. There were no therapy-related serious adverse side effects, 6 month response rate was 60% and treatment was well tolerated. Responders enjoyed relapse free survival of 92% and 76% respectively at 12 and 24 months. This study highlights the possibility of achieving an enduring remission from 4 weeks of therapy. This study is registered at www.anzctr.org.au (ANZCTRN12611000015943).
Copyright © 2015 American Society of Hematology.
Although vincristine is sometimes prescribed for newly diagnosed immune thrombocytopenia (ITP), it efficacy in refractory ITP and sustained efficacy has yet to be demonstrated. We describe our clinical experience and recommend vincristine's correct place in ITP management. This retrospective study analysed data from 35 patients with newly diagnosed (ND), persistent (P) or chronic (C) ITP treated with vincristine. The initial response rate, defined as > 30 × 10(9) platelets/L, reached 83% after a median of 7 [IQR 6-13] days. In ND and P ITP, even when previous therapies were inefficient, initial response was 87.5%, suggesting that this treatment could be used particularly in rescue. Median survival time, without failure or relapse, was 15 months (Kaplan-Meier curve). Predictive Factors (univariate analysis) of an initial and long-term response was a small number of prior treatments received. However, at 2 years, only 7 patients had sustained response. Eight (23%) patients experienced adverse events: neuropathy for 7 and bowel obstruction for one. Vincristine efficacy in ITP was confirmed and it could be a good strategy for treating resistant ITP, especially in emergencies. In this era of new therapeutics, vincristine deserves to remain on the list of ITP treatments because of its initial efficacy, safety and low cost. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Thrombopoietin receptor agonists, which raise platelet counts in patients with chronic immune thrombocytopenia, may be associated with increases in bone marrow reticulin. Patients with chronic immune thrombocytopenia participating in the Eltrombopag Extended Dosing (EXTEND) study underwent bone marrow biopsies to identify clinically relevant bone marrow fibrosis-related increases. Specimens were centrally reviewed by 2 hematopathologists. Two hundred thirty-two biopsy specimens were collected from 117 patients treated for ≤5.5 years. Moderate to marked reticulin fibrosis was found in 2 patients. After withdrawing from the study, the biopsy of 1 patient reverted to normal. There were no other pathologic changes identified among on-treatment specimens, and no pattern of abnormal reticulin deposition associated with eltrombopag treatment was evident. This article is protected by copyright. All rights reserved.
© 2015 Wiley Periodicals, Inc.
Primary immune thrombocytopenia (ITP) in adults often assumes a chronic course that requires persistent monitoring and treatment. Medical therapy has traditionally been viewed as a means of temporarily raising the platelet count with little or no potential to induce long-term platelet responses off treatment. However, several recent studies have tested the hypothesis that intensive medical therapy administered early in the disease course may ameliorate or even cure ITP. In this review, we propose a biological rationale for medical intervention that simultaneously targets the innate and adaptive immune responses administered early in the course of disease. We also critically examine data on long-term outcomes after single-agent and multi-agent medical therapy. Intensive regimens that target inflammation and adaptive immunity (e.g., combination high-dose dexamethasone and rituximab) appear to improve response rates at 6 to 12 months compared with standard first-line therapy (e.g., prednisone, high-dose dexamethasone alone) in newly diagnosed patients. Controlled trials with extended follow-up are needed to determine whether these intensive regimens induce more cures compared with standard treatment or merely delay relapse at the expense of potentially greater toxicity.
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Dear Editor,Dapsone has been recommended at a second-line therapy for immune thrombocytopenia (ITP) [1] although only one study reported its use immediately after failure of first-line therapy [2]. We therefore highlight our experience of treating a sequential series of adult patients with dapsone after failure of first-line therapy, finding a worse response rate (RR) than anticipated.During the 28-month study period (March 2009 to June 2011), we offered dapsone to all adult patients with primary ITP requiring second-line treatment (n = 11), although therapeutic decisions were still individualised. Outcomes were audited retrospectively. Patients were identified systematically from an electronic patient record. ITP was diagnosed as per international consensus guidelines [1], and outcome criteria were defined as per international working group guidelines [3].All 11 patients received 75–100 mg oral dapsone daily (9 started at 100 mg, 2 at 50 mg, titrated up to 100 mg as tolerated), all re ...
Adults with newly-diagnosed or persistent Immunothrombocytopenia frequently relapse upon tapering steroids; adults and children with chronic disease have an even lower likelihood of lasting response. In adults with newly-diagnosed Immunothrombocytopenia, 2 studies showed that dexamethasone 40mg/dayx4days and 4 rituximab infusions were superior to dexamethasone alone. Studies have also shown 3 cycles of dexamethasone are better than one and patients with persistent/chronic Immunothrombocytopenia respond less well to either dexamethasone or rituximab. Therefore 375mg/m2x4 rituximab was combined with three 4-day cycles of 28mg/m2 (maximum40mg) dexamethasone at 2-week intervals and explored in 67 ITP patients. Best long-term response was assessed as complete (platelet count≥100x109/L) or partial (50-99x109/L). Only 5 patients had not been previously treated. Fifty achieved complete (43, 64%) or partial (7, 10%) responses. Thirty-five/50 responders maintained treatment-free platelet counts >50x109/L at median 17 months (range4-67) projecting 44% event-free survival. Duration of Immunothrombocytopenia <24 months, achieving complete responses, and being female were associated with better long-term response (p-values <0.01). Adverse events were generally mild-moderate, but 3 patients developed serum sickness and 2 colitis; there were no sequelae. Dexamethasone could be difficult to tolerate. Fourteen patients became hypogammaglobulinemic and half had increased frequency of minor infections; 9/12 evaluable recovered their IgG levels. Rituximab combined with 3 cycles of dexamethasone provides apparently better results to reported findings with rituximab alone, dexamethasone alone, or the combination with 1 cycle of dexamethasone. The results suggest medical cure may be achievable in immunothrombocytopenia, especially in women with and in patients within 2 years of diagnosis. ClinicalTrials.gov #NCT02050581.
Abstract Dapsone is one of the second line treatments of immune thrombocytopenic purpura (ITP). Dapsone is cheap and has response rates comparable to other second line treatment options like azathioprine, danazol, cyclophosphamide, cyclosporine, and vincristine. This retrospective analysis includes 38 patients (out of total 313 patients) of ITP treated with dapsone from 2004 to 2012. All male patients were screened for G6PD deficiency before starting dapsone. Out of 38 patients (12 children and 26 adults), one was newly diagnosed ITP, seven were persistent ITP, and 30 were chronic ITP. Five patients had side effects of dapsone; two required discontinuation due to skin rashes. The average dose of dapsone was 1.57 mg/kg/day and time to response was 57 days (19-108 days). The response was irrespective of previous treatments and response to them. The response rate was 48.6% (complete response = 40.5%). Only two adult patients had sustained response (> 6 months) after dapsone discontinuation. There were no predictors identified for dapsone response. Dapsone is a safe and cheap second-line therapy for ITP with a response rate of about 50% (majority being CR). A response to dapsone is slow, sustained, and relapses are uncommon on therapy. Dapsone withdrawal leads to relapse in most of the patients.
The management of patients with refractory immune thrombocytopenia (ITP) is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin (rhTPO) in combination with cyclosporin A (CsA) for the management of patients with corticosteroid-resistant primary ITP.
Thirty-six patients with corticosteroid-resistant ITP were randomly divided into an observation group and control group. In the observation group, 19 patients received subcutaneous injection of rhTPO at a dose of 1 µg/kg (300 U/kg) once daily up to day 14. Simultaneously they also received oral CsA at a dose of 1.5-2.0 mg/kg twice daily for three months. In the control group, rhTPO alone was administered subcutaneously at 1 µg/kg once daily in the other 17 ITP patients for 14 consecutive days and then the treatment was withdrawn.
There was no significant difference in the response rate at the end of the first week after treatment initiation between the observation group and the control group (63.2% vs. 58.8%, P > 0.05), neither was there at the end of the second week (89.5% vs. 94.1%, P > 0.05). However, the relapse rate in the observation group was significantly lower than that in control group at the end of the first (17.7% vs. 50.0%, P < 0.05), second (29.4% vs. 68.8%, P < 0.05) and the third month (29.4% vs. 87.5%, P < 0.01). In addition, rhTPO plus CsA were well tolerated and adverse events recorded were mild.
Combination therapy with rhTPO and CsA was effective in the management of patients with corticosteroidresistant ITP, with a relatively short time to response and low recurrence rate. It might be considered as a potential secondline treatment regimen for ITP.
Objective
To review the influence of age on the response of patients with idiopathic thrombocytopenic purpura (ITP) to corticosteroids, splenectomy and danazol.
Methods
We retrospectively reviewed a cohort of 139 consecutively treated patients with ITP diagnosed between 1985 and 1994. In particular, we analysed the therapies used, their response rates, prognostic indicators of response and adverse effects. Furthermore, we compared the efficacy and tolerability of the various therapies between younger and older patients (<60 and ≥60 years old).
Results
Corticosteroids were used as first-line treatment in 118 patients with an initial response rate of 83%. Age did not affect the outcome of corticosteroid therapy, but all the patients aged ≥60 years reported adverse effects. A splenectomy was performed in 55 patients with an initial response rate of 87%. Older patients had significantly poorer outcomes from splenectomy with higher postoperative morbidity. Finally, danazol was given in 33 patients with a favourable response in 72% of cases. Compared with younger patients, older patients had a significantly better outcome with danazol.
Conclusions
Age may have significant effects on the response to and adverse effects of therapy in ITP, and this should be considered when choosing the treatment modality for the elderly.
Primary immune thrombocytopenia is a potential life threatening condition. About two thirds of adult patients do not have a sustained response to steroids (first line therapy). For these patients, a number of other treatment options exist such as rituximab, splenectomy, immunosuppressants and thrombopoietin receptor agonists but they are costly and have side effects. Dapsone is an inexpensive drug with a well established safety profile. Unfortunately, this option of treatment has not been explored adequately. This review aims at analyzing the currently available evidence for use of dapsone as second or third line therapy in primary immune thrombocytopenia. This article is protected by copyright. All rights reserved.
Patients with chronic immune thrombocytopenia may have bleeding resulting from low platelet counts. Eltrombopag increases and maintains hemostatic platelet counts; however, to date, outcome has been reported only for treatment ≤6 months. This interim analysis of the ongoing open-label EXTEND study evaluates safety and efficacy of eltrombopag in 299 patients treated up to 3 years. Splenectomized and non-splenectomized patients achieved platelets ≥50,000/µL at least once (80% and 88%, respectively). Platelets ≥50,000/µL and 2x baseline were maintained for a median of 73 of 104 and 109 of 156 cumulative study weeks. Bleeding symptoms (WHO Grades 1-4) decreased from 56% of patients at baseline to 20% at 2 years and 11% at 3 years. One hundred (33%) patients were receiving concomitant treatments at study entry, 69 of whom attempted to reduce them; 65% (45/69) had a sustained reduction or permanently stopped ≥1 concomitant treatment. Thirty-eight patients (13%) experienced ≥1 adverse events leading to study withdrawal, including patients meeting protocol-defined withdrawal criteria (11 [4%] thromboembolic events, 5 [2%] exceeding liver enzyme thresholds). No new or increased incidence of safety issues was identified. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts in the desired range. Registered at clinicaltrials.gov: NCT00351468.
Immune thrombocytopenia (ITP) comprises a syndrome of diverse disorders that have in common immune-mediated thrombocytopenia, but that differ with respect to pathogenesis, natural history and response to therapy. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or as a sequela of a growing list of associated conditions (secondary ITP). Primary ITP remains a diagnosis of exclusion and must be differentiated from non-autoimmune etiologies of thrombocytopenia and secondary causes of ITP. The traditional objective of management is to provide a hemostatic platelet count (> 20-30 × 10(9) L(-1) in most cases) while minimizing treatment-related toxicity, although treatment goals should be tailored to the individual patient and clinical setting. Corticosteroids, supplemented with either intravenous immune globulin G or anti-Rh(D) as needed, are used as upfront therapy to stop bleeding and raise the platelet count acutely in patients with newly diagnosed or newly relapsed disease. Although most adults with primary ITP respond to first-line therapy, the majority relapse after treatment is tapered and require a second-line approach to maintain a hemostatic platelet count. Standard second-line options include splenectomy, rituximab and the thrombopoietin receptor agonists, romiplostim and eltrombopag. Studies that directly compare the efficacy, safety and cost-effectiveness of these approaches are lacking. In the absence of such data, we do not favor a single second-line approach for all patients. Rather, we consider the pros and cons of each option with our patients and engage them in the decision-making process.
The efficacy of recombinant human interferon α-2b (rh IFNα-2b) in the treatment of steroid resistant idiopathic thrombocytopenic purpura (ITP) was studied in 50 cases.
Forty-one patients treated with rh IFNα-2b three times a week, six of 18 (33.3%) in the low dose group (150 × 104IU: 3 MIU) and four of 20 (20.0%) in the high dose group (300 × 1010IU: 3 MIU) responded with platelet counts increasing to above 50 × 109/L. Because of the exacerbation of thrombocytopenia and nasal bleeding, treatment was discontinued within 2 weeks in three patients out of 41 cases. On the other hand, six of nine patients (66.7%) treated with 3 MIU of IFNα-2b once a week for 8 weeks showed satisfactory response.
Treatment with either administration schedule did not result in sustaining platelet counts above 50 × 109/L for a long time after treatment. The results indicate that once a week administration schedule of rh IFNα-2b is more efficacious for platelet counts increasing for short period in patients who failed to respond to steroid and other medications than other schedules. The maintenance of this treatment schedule will allow sustained increased platelet levels, resulting in relief of bleeding tendency, while also being cost effective in comparison with other IFN treatment schedules and achieving better patient compliance without flu-like symptoms.
Cyclophosphamide, an immunosuppressive agent, was administered as an additional mode of therapy to 30 patients with idiopathic thrombocytopenic purpura (ITP) refractory to conventional management. Of 22 previously tested by splenectomy an excellent response was achieved in 12, who remained in complete hematologic remission for 14–96 months after therapy was discontinued; a fair response in 3, with definite increase in platelets, but not to normal levels; and a poor response in 7 who failed to improve. Of 8 nonsplenectomized patients who failed to respond to steroids or maintain a response after steroids were discontinued, 4 were considered excellent, 1 required continued therapy to remain in remission (good response), 2 were fair, and 1 was poor. Remission was observed in 2–10 weeks in both groups and appeared to be related to duration of disease; presence of disease for less than 1 year was associated with a much better response to treatment (11 of 15) when compared with disorders lasting over 2 years (6 of 15). Cyclophosphamide therapy offers additional means of treating patients with ITP who fail to respond to conventional therapy and may serve as an alternative to splenectomy when surgery is contraindicated.
Forty-three adult patients with idiopathic thrombocytopenic purpura (ITP) were treated by slow intravenous infusions of vinblastine. Nineteen had ITP of recent onset (i.e. of less than 6 months duration) and had contraindication to steroids (3 patients), refractoriness to steroids (6 patients) or to steroids and high dose intravenous immunoglobulins (IVIg, 10 patients). Of the 19 patients, 10 achieved complete response (CR), 2 achieved partial response (PR), 2 had minor response (MR) and the remaining 5 patients had no response (NR). Six of the complete responders remained in CR after 12 to 48 months, whereas all other responders relapsed within 3 months, in spite of maintenance therapy. Twenty-four patients had chronic ITP (i.e. of 6 months duration or more) and had showed no or only transient response to steroids and/or splenectomy, and in many of them, to other therapeutic approaches. Four achieved CR, 4 PR, 6 MR and 10 NR. All but 2 responses were shorter than 3 months, in spite of maintenance therapy. Most responses to slow infusions of vinblastine began after the first infusion. Main side effects included leukopenia in 9 patients (but with absolute neutropenia in only one) and peripheral neuropathy in 2 patients. Interval from diagnosis was the only prognostic factor of response to treatment. We conclude that slow infusions of vinblastine may be a useful approach in ITP of recent onset, when contraindication or refractoriness to steroids and/or IVIg exists. In our experience, this treatment has limited benefit in chronic ITP. In addition, it remains to be demonstrated that slow infusions of vinca alkaloids have any superiority over intravenous bolus injections of the same drugs.
Treatments for immune thrombocytopenic purpura (ITP) providing durable platelet responses without continued dosing are limited. Whereas complete responses (CRs) to B-cell depletion in ITP usually last for 1 year in adults, partial responses (PRs) are less durable. Comparable data do not exist for children and 5-year outcomes are unavailable. Patients with ITP treated with rituximab who achieved CRs and PRs (platelets > 150 × 10(9)/L or 50-150 × 10(9)/L, respectively) were selected to be assessed for duration of their response; 72 adults whose response lasted at least 1 year and 66 children with response of any duration were included. Patients had baseline platelet counts < 30 × 10(9)/L; 95% had ITP of > 6 months in duration. Adults and children each had initial overall response rates of 57% and similar 5-year estimates of persisting response (21% and 26%, respectively). Children did not relapse after 2 years from initial treatment whereas adults did. Initial CR and prolonged B-cell depletion predicted sustained responses whereas prior splenectomy, age, sex, and duration of ITP did not. No novel or substantial long-term clinical toxicity was observed. In summary, 21% to 26% of adults and children with chronic ITP treated with standard-dose rituximab maintained a treatment-free response for at least 5 years without major toxicity. These results can inform clinical decision-making.
The effect of plasma exchange (PE) for the treatment of acute immune thrombocytopenic purpura (ITP) was assessed both through an analysis of the use of PE for ITP in Canada from 1980 to 1997, and in a study of 23 patients with acute ITP. Thirteen of these 23 patients were treated by PE (10 were exchanged with albumin and three with FFP) plus prednisone and 10 were treated with prednisone alone. At the 6 month follow-up, 11 of 19 patients were considered complete responders and six were considered partial responders. The difference in response rates between the PE and prednisone groups was not statistically significant. All patients had platelet specific antibodies at the time of entry into the study. Antibody concentration was reduced following PE in 10 of the 12 patients tested, and a response to PE was seen in all 10 patients who had a reduction in the level of platelet antibody. In contrast, antibody levels did not change in the patients who received steroid treatment only. This observation suggests that antibody removal may be of direct benefit in patients with ITP. Analysis of our results indicated that PE increased the length of time before splenectomy but did not alter the need for splenectomy. Short term benefits of PE were accomplished with no increase in morbidity or mortality which confirms that PE is a safe procedure in patients with ITP.
Romiplostim, a thrombopoietin-mimetic peptibody, increases and maintains platelet counts in adults with immune thrombocytopenia (ITP). In this first study of a thrombopoietic agent in children, patients with ITP of ≥ 6 months' duration were stratified by age 1:2:2 (12 months-< 3 years; 3-< 12 years; 12-< 18 years). Children received subcutaneous injections of romiplostim (n = 17) or placebo (n = 5) weekly for 12 weeks, with dose adjustments to maintain platelet counts between 50 × 109/L and 250 × 109/L. A platelet count ≥ 50 × 109/L for 2 consecutive weeks was achieved by 15/17 (88%) patients in the romiplostim group and no patients in the placebo group (P = .0008). Platelet counts ≥ 50 × 109/L were maintained for a median of 7 (range, 0-11) weeks in romiplostim patients and 0 (0-0) weeks in placebo patients (P = .0019). The median weekly dose of romiplostim at 12 weeks was 5 μg/kg. Fourteen responders received romiplostim for 4 additional weeks for assessment of pharmacokinetics. No patients discontinued the study. There were no treatment-related, serious adverse events. The most commonly reported adverse events in children, as in adults, were headache and epistaxis. In this short-term study, romiplostim increased platelet counts in 88% of children with ITP and was well-tolerated and apparently safe.
The trial was registered with http://www.clinicaltrials.gov as NCT00515203.
Treatment options are limited in patients with chronic immune thrombocytopenic purpura (ITP) which has been unresponsive to corticosteroids and/or splenectomy. Mycophenolate mophetil (MMF) is effective in many autoimmune disorders including severe and refractory ITP through its targeting of T-cell and B-cell lymphocytes. We report on the efficacy of MMF (1.5-2 g/day) in 16 adults with severe steroid-resistant ITP. MMF was administered for at least 12 weeks (median 37 weeks, range 14-64 weeks). Patients comprised of 10 females and six males, with median pre-treatment platelet counts of 8 × 10(9)/L, median age of 55 years, median ITP duration of 58 months and a median of four prior treatments (range 3-8); nine had been previously splenectomized. Eleven patients (69%) responded after 12 weeks of MMF: 6 (55%) achieving complete remission (CR) and five (45%) achieved partial remission (PR). MMF therapeutic responses were better in those patients who had had fewer prior treatments (p<0.05), and were independent of patient age, sex, disease duration, and splenectomy status (p>0.05). Five of the 11 responders (45%; 3CR/2PR) had sustained remissions; however, six responders (55%; 3CR/3PR) relapsed after median of 14 weeks (range 9-20). Three of the six relapsing patients responded to MMF reinstitution achieving stabile PRs; three were left untreated as none had further bleeding and their platelets remained at "safe" levels (median 30 × 10(9)/L). The MMF treatment was well tolerated; one heavily pretreated patient developed a bronchopneumonia and a second had an episode of diarrhea. MMF used as a second-line agent can produce a sustained response in severe ITP which has been unresponsive to steroid and/or splenectomy without major toxicity.
Treatment of autoimmune cytopenias remains unsatisfactory for patients refractory to first-line management. We evaluated the safety and efficacy of low-dose rituximab plus alemtuzumab in patients with steroid-refractory autoimmune hemolytic anemia and immune thrombocytopenic purpura. Nineteen of 21 included patients were assessable for response (11 with immune thrombocytopenic purpura, 8 with autoimmune hemolytic anemia). Treatment with 10 mg of alemtuzumab subcutaneously on days 1 to 3, plus 100 mg of rituximab intravenously weekly in 4 doses, was administered. The overall response rate was 100%, with complete response in 58%. The median response duration was 46 weeks (range, 16-89 weeks). Median follow-up was 70 weeks (range, 37-104 weeks). Most toxicity was grade 1 fever related to the first dose. Six patients developed infections. The combination of rituximab and alemtuzumab is feasible and has an acceptable safety profile and remarkable clinical activity in this group of patients. This study is registered at www.clinicaltrials.gov as #NCT00749112.
Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period.
We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months' duration who had baseline platelet counts lower than 30,000 per μL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤ 15,000 per μL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50,000-400,000 per μL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331.
Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59-18·73; p<0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (<1%) patient treated with eltrombopag.
Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatment.
GlaxoSmithKline.
Rituximab 375 mg/m(2) weekly for 4 wks has significant activity in adults with primary immune thrombocytopenia (ITP). In this setting, several evidences support the possible use of lower doses of rituximab. Objectives: To investigate the activity of low-dose rituximab as salvage therapy in previously treated symptomatic ITP.
Forty-eight adult patients were treated prospectively with rituximab 100 mg weekly for 4 wks.
Overall and complete responses (CR) (platelet level ≥ 50 and 100 × 10(9) /L) were 60.5% and 39.5%, respectively. In responders, the median time to response was 35 d (range: 7-112 d). The median time of observation was 18 months (range 3-49 months). Sixteen of 29 responding patients (55%) relapsed and 14 needed further treatments. The 12- and 24-month cumulative relapse-free survival was 61% and 45%, respectively. In univariate analysis, CR rate was in inverse relation with weight OR=0.95, CI(95%) [0.91; 0.99] (P=0.019) and age OR=0.96, CI(95%) [0.93; 0.99] (P=0.047). Cox regression model showed that relapse probability increases as weight (HR=1.06, CI(95%) [1.0031; 1.111]) and period between diagnosis and rituximab therapy (HR=1.01, CI(95%) [1.002; 1.017]) increase. One patient developed an interstitial pneumonia 1 month after the end of rituximab treatment. No other infectious, hematologic or extra-hematologic complications were documented during follow-up.
Low-dose rituximab is active in ITP but has moderate long-term effect. A comparative study with standard dose is warranted.
Treatment options for patients with chronic refractory immune thrombocytopenic purpura (ITP) are limited. Because combination immunosuppressant therapy appeared to be effective in ITP and other disorders, we used this approach in patients with particularly severe and refractory ITP. In this retrospective, observational study, we determined the response (platelet count above 30 x 10(9)/L and doubling of baseline) among 19 refractory ITP patients. Treatment consisted of azathioprine, mycophenolate mofetil, and cyclosporine. The patients had failed a median of 6 prior treatments, including splenectomy (in all except 1). Of 19 patients, 14 (73.7%) achieved a response lasting a median of 24 months, after which time 8 (57.1%) relapsed. Of the 8 relapsing patients, 6 responded to additional treatments. Of the 14 patients who achieved an initial response, 2 (14.3%) remained in remission after eventually stopping all medications. Severe adverse events did not occur. Combination immunosuppressant therapy can produce a rise in the platelet count that is sometimes sustained in refractory ITP patients.
Splenectomy is a common therapy for adults with chronic idiopathic thrombocytopenic purpura (ITP). Thisstudy was designed to estimate both the short-term surgical non-response rate and the long-term relapse rate after laparoscopic splenectomy. A systematic review was conducted of articles published between January 1, 1991 and January 1, 2008. Selection criteria included: chronic ITP, study enrollment in 1990 or later, > or =12 months of follow-up, > or =15 patients with ITP, > or =75% of patients at least 14 years of age, not HIV positive, not undergoing a second splenectomy, and type of performed splenectomy clearly reported. Data were pooled across studies to estimate rates. We identified 170 articles, of which 23 met our inclusion criteria (all observational studies). These studies represent 1,223 laparoscopic splenectomies (71 or 5.6% were converted to open splenectomy during surgery). The pooled short-term surgical non-response rate among the 18 studies reporting data was 8.2% (95% CI 5.4-11.0). The pooled long-term relapse rate across all 23 studies was 43.6 per 1,000 patient years (95% CI 28.2-67.2). This translates to an approximate failure rate of 28% at 5 years for all patients undergoing splenectomy. Studies with shorter durations of follow-up had significantly higher pooled relapse rates than studies with longer follow-up (P = 0.04). Laparoscopicsplenectomy is effective for most patients. Splenectomy may have higher initial relapse rates, particularly, in the first 2 years after surgery, and the rate may decline over time. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.
Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.
Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that stimulates thrombopoiesis, leading to increased platelet production. This study assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg.
In this phase III, randomised, double-blind, placebo-controlled study, adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura (ITP), platelet counts less than 30 000 per muL of blood, and one or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n=76) or placebo (n=38) for up to 6 weeks. Patients were randomly assigned in a 2:1 ratio of eltrombopag:placebo by a validated randomisation system. After 3 weeks, patients with platelet counts less than 50 000 per microL could increase study drug to 75 mg. The primary endpoint was the proportion of patients achieving platelet counts 50 000 per microL or more at day 43. All participants who received at least one dose of their allocated treatment were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00102739.
73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses. 43 (59%) eltrombopag patients and six (16%) placebo patients responded (ie, achieved platelet counts >/=50 000 per microL; odds ratio [OR] 9.61 [95% CI 3.31-27.86]; p<0.0001). Response to eltrombopag compared with placebo was not affected by predefined study stratification variables (baseline platelet counts, concomitant ITP drugs, and splenectomy status) or by the number of previous ITP treatments. Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, ten (29%) responded. Platelet counts generally returned to baseline values within 2 weeks after the end of treatment. Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo (OR 0.49 [95% CI 0.26-0.89]; p=0.021). The frequency of grade 3-4 adverse events during treatment (eltrombopag, two [3%]; placebo, one [3%]) and adverse events leading to study discontinuation (eltrombopag, three [4%]; placebo, two [5%]), were similar in both groups.
Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP.