Efficacy and safety of dapsone as a second-line treatment in non-splenectomized adults with immune thrombocytopenic purpura

In adults with immune thrombocytopenic purpura (ITP), steroids are usually proposed as first-line therapy, but long-term complete responses are obtained in no more than 20% of patients. For the remaining patients, splenectomy is considered the treatment of choice, with reported "cure" rates from 60-70%. However, the inherent risks of surgery and sepsis after splenectomy without a guarantee of success justify the search for strategies aimed to avoid splenectomy. Here we retrospectively evaluated the results of dapsone treatment in ITP patients that failed first-line therapy with steroids. These patients received dapsone 100 mg/day for a minimum of 30 days before splenectomy was considered. Efficacy was defined as a sustained rise in platelet counts (>50 x 10(9)/l) clearly attributed to dapsone treatment. Among 52 steroid-dependent or refractory patients, dapsone resulted in sustained increases in platelet counts in 44.2% of patients, after a median follow-up of 21.10 months after treatment initiation. The long-term efficacy of dapsone in this setting is further corroborated by the observation that none of the "responding" patients required splenectomy in the follow-up, compared to 69.0% of the "non-responding" patients. Dapsone-related adverse events were mild and promptly reversed by treatment withdrawal. The results of our retrospective analysis suggest that dapsone is a safe and effective second-line agent for steroid-dependent or refractory ITP patients. Because of its well-known safety profile and low cost compared to other potential second-line treatments for ITP, a trial course of dapsone should be viewed as an attractive option before splenectomy in steroid-dependent of refractory adult ITP patients.     

Chronic refractory idiopathic thrombocytopenic purpura (ITP) and anti-CD20 monoclonal antibody: a case report.

Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disorder characterized by accelerated and premature destruction of platelets by reticuloendothelial system. CD20, a trans-membrane B-cell-specific antigen, is a potential target for treatment of certain malignant and nonmalignant plasma cell disorders including refractory ITP. Rituximab is a genetically engineered human anti-CD20 monoclonal antibody, which is approved for the treatment of low-grade non-Hodgkin's lymphoma. Recent clinical reports suggest that rituximab may be useful in treating certain patients with chronic refractory ITP. A 59-year-old woman with refractory ITP was placed on rituximab (four weekly doses of 375 mg/m(2)) and her condition and platelet count were observed for 18 months. There was a gradual increase in platelet count and she was symptom free in this period and no side effects of the drug were reported. Anti-CD20 antibodies are likely to be used in the treatment of refractory ITP cases, but further studies about treatment schedule and criteria for patient selection should be done.     

The efficacy of rituximab in patients with splenectomized refractory chronic idiopathic thrombocythopenic purpura

The most difficult problem a physician encounters is the management of patients with idiopathic thrombocytopenic purpura (ITP), who has persistent severe thrombocytopenia after failure of initial treatment with glucocorticoids and splenectomy. Most of the patients refractory to corticosteroids and splenectomy will become refractory to other available agents, such as intravenous immunoglobulin (IVIg), danazol or chemotherapy. In this study, we investigated the effect of rituximab on 17 splenectomized refractory chronic ITP patients. Here, we showed that the anti-CD20 antibody, rituximab, induces a clinically significant response in severe chronic ITP patients, who are unresponsive to other therapeutic options. After sixth month, 10 out of 14 responders were still maintaining their durable and significant platelet responses (platelet counts >50 × 10⁹/l), without requirement to any other ITP medication. Therefore, we suggest that, rituximab is an effective treatment option in splenectomized refractory or relapsed ITP patients. Rituximab was well tolerated without severe side effects.     

Splenectomy results in patients with idiopathic thrombocytopenic purpura: 10 years of experience in Turgut Ozal Medical Center

The standard treatment for immune thrombocytopenic purpura (ITP) is corticosteroid therapy. In patients who are refractory to this treatment, splenectomy is the most usual therapy. Between 1993 and 2003, 125 patients were diagnosed with ITP in the Inonu University School of Medicine, Department of Haematology. Twenty-one of these patients who did not respond to steroids, underwent splenectomy. Of these 21 patients, 12 achieved complete and three achieved partial haematological responses, while the remaining six did not respond. Four of these six patients responded to drugs such as azathioprine and danazol, while the others were totally refractory. Only one of our patients showed fatal complications either during or after the surgery. Our results after 10 years experience demonstrate that splenectomy is an effective and safe treatment for ITP patients who are refractory to steroids.     

Successful treatment of severe refractory idiopathic thrombocytopenic purpura with liposomal doxorubicin

Idiopathic thrombocytopenic purpura (ITP) is refractory to initial treatment (steroids and splenectomy) in 25 to 30% of patients. These patients have a significant risk of fatal hemorrhage. Two patients with ITP refractory to multiple interventions and severe depression of platelet counts responded to treatment with liposomal doxorubicin with a return of platelet counts to normal. The drug is easily administered and was well tolerated. Use of this drug in refractory ITP merits further study. Am. J. Hematol. 57:85–86, 1998. © 1998 Wiley-Liss, Inc.     

Splenectomy results in patients with idiopathic thrombocytopenic purpura: 10 years of experience in Turgut Ozal Medical Center

The standard treatment for immune thrombocytopenic purpura (ITP) is corticosteroid therapy. In patients who are refractory to this treatment, splenectomy is the most usual therapy. Between 1993 and 2003, 125 patients were diagnosed with ITP in the Inonu University School of Medicine, Department of Haematology. Twenty‐one of these patients who did not respond to steroids, underwent splenectomy. Of these 21 patients, 12 achieved complete and three achieved partial haematological responses, while the remaining six did not respond. Four of these six patients responded to drugs such as azathioprine and danazol, while the others were totally refractory. Only one of our patients showed fatal complications either during or after the surgery. Our results after 10 years experience demonstrate that splenectomy is an effective and safe treatment for ITP patients who are refractory to steroids.     

Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy

Patients with chronic immune thrombocytopenic purpura (ITP) who are unresponsive to corticosteroids require splenectomy, but if this fails, treatment is difficult. We tried to induce durable remissions in ITP patients refractory to corticosteroids before or after splenectomy by applying strong immunosuppression with the combination of cyclosporin A (CyA 5 mg/kg/d) and prednisone (0.4 mg/kg/d). Patients were assigned to one of two groups. Group 1, 10 patients refractory to prednisone; and group 2, 10 patients refractory to at least prednisone and splenectomy. Overall response rate was 55% (50% in group 1 and 60% in group 2 patients). Nine of the 10 patients in group 1 finally had a splenectomy because of relapse, insufficient response or toxicity of CyA. Thirty percent of the patients discontinued CyA because of side-effects; hypertension, severe headache and muscle pain being the most frequent encountered. It is concluded that CyA treatment does not avoid, but only postpones, splenectomy in chronic ITP patients who are refractory to corticosteroids. However, CyA can be useful in a subgroup of patients with corticosteroid- and splenectomy-refractory ITP, but treatment toxicity is high.     

Interferon treatment of refractory idiopathic thrombocytopenic purpura (ITP)

Abstract: Up to 30% of patients with idiopathic thrombocytopenic purpura (ITP) are refractory to standard therapy with corticosteroids and splenectomy. The treatment of refractory ITP is barely effective, but promising results of interferon therapy were reported recently. In a prospective study 21 refractory ITP patients were treated with interferon alpha 2B at 3 million Units three times a week for a period of 4 weeks. Ten out of 21 patients had a response, of whom 2 had a complete response of 3.5 and 7 months duration, after which both relapsed. One other patient retreated after relapse has a complete response of 24 + months. The characteristics of the responding patients were not different from the non-responding patients. Adverse effects were minimal. Short treatment with interferon in refractory ITP patients may be justified and the results reported here challenge us to elucidate the mechanism of action of interferon.     

Chronic refractory immune thrombocytopenia in adolescents and young adults

Defining immune thrombocytopenia (ITP) in two age groups—children and adults—overlooks the specific clinical features and needs of adolescents and young adults (AYAS). We previously reported a high risk of chronic disease at 12 months (50%); however, data on the course of chronic ITP, the risk of refractoriness and treatment strategies in AYAS are limited. Data from patients aged 12–25 years with chronic primary ITP at 12 months were extracted from three large registries between 2004 and 2021. Clinical and laboratory data were evaluated until 48 months of follow-up (FU). Refractory ITP was defined as the administration of ≥3 different lines of therapy. A total of 427 AYAS (64% female) with chronic ITP were included. Overall, 7% and 14% were classified as ‘refractory’ at 12 and 48 months of FU respectively. The proportion of males was greater in the refractory group than in the non-refractory group (43% vs. 35%). AYAS with refractory disease displayed lower median platelet counts, more bleeding and a higher need for treatment at initial diagnosis and FU than non-refractory patients. This study reveals that refractory ITP is uncommon in AYAS; however, AYAS with refractory ITP display a high disease burden at all time points, including at initial diagnosis.     

Complement in immune thrombocytopenia (ITP): The role of complement in refractory ITP

Immune thrombocytopenia (ITP) is a disorder characterized by low platelets due to increased clearance and decreased platelet production. While ITP has been characterized as an acquired disorder of the adaptive immune system, the resulting platelet autoantibodies provide ancillary links to the innate immune system via antibody interaction with the complement system. Most autoantibodies in patients with ITP are of the IgG1 subclass, which can be potent activators of the classical complement pathway. Antibody-coated platelets can initiate complement activation via the classical pathway leading to both direct platelet destruction and enhanced clearance of C3b-coated platelets by complement receptors. Similar autoantibody interactions with bone marrow megakaryocytes can also result in complement injury and ineffective thrombopoiesis. The development of novel therapeutic complement inhibitors has revived interest in the role of complement in autoantibody-mediated disorders, such as ITP. A recent early-phase clinical trial of a classical complement pathway inhibitor has demonstrated efficacy in a subset of ITP patients refractory to conventional immune modulation. In this review, we will analyse the role of complement in refractory ITP.     

Efficacy of mycophenolate mofetil as single-agent therapy for refractory immune thrombocytopenic purpura

Refractory disease occurs in 25% or more of adults with idiopathic (immune) thrombocytopenic purpura (ITP). Therapy to elevate the platelet count may be required in a proportion of these patients. Immunosuppressive agents such as prednisone, azathioprine, cyclophosphamide, and cyclosporin have been shown to be effective treatments in a proportion of patients with refractory ITP. A newer immunosuppressive medication, mycophenolate mofetil (MMF), has been used successfully with acceptable toxicity in solid organ transplant patients to reduce the risk of organ rejection. The goal of this study was to determine whether MMF is an effective treatment for refractory ITP. Efficacy, defined as a sustained platelet increase to a level greater than 50 x 10(9)/L, was seen in 7 of 18 patients with refractory ITP. Three of these 7 patients have had intermittent thrombocytopenic episodes while continuing the medication. No severe toxicity was seen, although two of the 18 patients discontinued MMF within the first month of treatment because of side effects, i.e., headache. In summary, MMF may be a useful component of a combination protocol but does not appear to be highly effective as sole therapy in patients with refractory ITP. The data suggests that response rates to MMF may be higher in patients who have had a shorter duration of their ITP.     

Experiences with recombinant FVIIa in the emergency treatment of patients with autoimmune thrombocytopenia: a review of the literature

Patients with severe and refractory autoimmune thrombocytopenia (ITP) have significant morbidity and mortality rates. Currently, high-dose methylprednisolone and/or high-dose IVIgG are recommended for the emergency treatment of such patients with uncontrolled bleeding. However, some patients do not immediately respond to these therapeutic regimes and may require additional treatment. Recombinant activated FVIIa (rFVIIa) is a prothrombotic agent that appears to be useful in the treatment of patients with life-threatening bleeding. It has also been used in the treatment of several patients with thrombocytopenia. We administered rFVIIa into a patient with refractory ITP and performed a systemic review of all published reports to assess the available evidence on the efficacy and safety of this drug in patients with ITP. The results indicate that rFVIIa may help in the emergency treatment of patients with ITP who do not respond to other therapies.     

特发性血小板减少性紫癜与幽门螺杆菌感染的相关性研究

目的研究特发性血小板减少性紫癜(ITP)与幽门螺杆菌(Hp)感染的相关性,观察抗Hp治疗对难治性ITP的疗效。方法对中国医科大学附属第一医院血液科2002年11月至2005年5月收治的48例ITP患者进行研究,正常对照组52例,因消化系统症状行胃镜和其他相关检查但未见明显异常的门诊患者。采用13C-尿素呼气试验及Hp血清抗体联合诊断Hp感染。对11例Hp感染阳性的难治性ITP患者抗Hp治疗,采用经典的三联药物,具体为奥美拉唑20mg口服,每日2次;克拉霉素500mg口服,每日2次;阿莫西林1g口服,每日2次,连用7d,4~8周后复查13C-尿素呼气试验、Hp血清抗体、血小板计数和血小板抗体。结果ITP组和正常对照组的Hp感染阳性率分别为68.18%(33/48),46.12%(24/52),ITP组Hp阳性率显著升高(P<0.05);11例常规治疗无效或复发患者并伴有Hp感染,有8例经上述治疗Hp感染转为阴性,该8例4~8周后血小板计数显著升高,其中6例血小板自身抗体消失,而Hp检测阴性患者和Hp感染未得以根治的患者随访时血小板抗体和血小板计数均无变化。结论ITP患者Hp感染阳性率高于正常人;对于Hp感染阳性的难治性ITP患者,根除Hp的方法治疗ITP是行之有效的。     

Management of patients with chronic, refractory idiopathic thrombocytopenic purpura

Chronic refractory idiopathic thrombocytopenic purpura (ITP) is defined as ITP with persistent thrombocytopenia despite conventional initial management with prednisone and splenectomy. Rare in children, It may occur in as many as one third of adults with ITP. The goal of treatment is not cure of the ITP, but only to achieve a safe platelet count, which is arbitrarily assumed to be greater than 30,000 to 50,000/microL. The risk for major bleeding seems great only when the platelet count is less than 10,000/microL. Treatment of patients with moderate thrombocytopenia and no clinically important bleeding symptoms should be avoided. There is no accepted algorithm for management of patients with chronic refractory ITP. Observation without specific treatment must be considered a cornerstone of management. Combination regimens of Immunosuppressive agents may be required for patients with severe and symptomatic thrombocytopenia. Additional supportive care measures are also important.     

Rituximab treatment for chronic refractory idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) is characterized by mucocutaneous bleeding and a low platelet count caused by increased autoantibodies against self-antigens and T-cell mediated cytotoxicity. About 10-30% patients with ITP will become refractory ITP. Most of them will become refractory to corticosteroids and splenectomy, as well as other available agents such as intravenous immunoglobulins, danazol, or chemotherapy. B cells not only are the passive producers of immunoglobulins, but also play an important immunoregulatory role in pathophysiology of ITP. Rituximab, a chimeric anti-CD20 monoclonal antibody that specifically targets the CD20 molecule on the B-cell surface, is useful in the treatment of ITP through B cells depletion. Rituximab has multiple mechanisms of inducing cytotoxicity in vivo, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), direct apoptosis signaling, and possible vaccine effects. In most clinical reports, rituximab was given as an intravenous infusion at a dose of 375 mg/m(2) weekly for four doses. A total complete response (CR) of 33.2% and a total response of 52.9% were reported. Most results found that no clinical or laboratory parameters could predict treatment outcome. Though the infusion-related side effects of rituximab were common in ITP, it was well tolerated with rare severe side effects. In general, rituximab appears to be a promising immunotherapeutic agent for the treatment of refractory ITP. More controlled clinical trials are necessary to evaluate both the efficacy and long-term safety of the drug.     

A pilot study of rhuIL-11 treatment of refractory ITP

The objective of this research was to determine whether rhuIL-11 is an effective treatment in patients with refractory immune thrombocytopenic purpura (ITP). Platelet production is decreased in certain cases of refractory ITP. IL-11 stimulates megakaryocytopoiesis in vitro and was licensed for its clinical effects to ameliorate chemotherapy-induced thrombocytopenia. A pilot study was initiated, intending to enroll 12 patients with ITP. These patients were to receive rhuIL-11 (Neumega) at a dose of 50 microg/kg subcutaneously daily for 21 consecutive days and be observed afterward for 21 additional days. CBC with platelets were obtained twice weekly with visits and physical examinations weekly. The study was terminated after 7 patients were enrolled because of toxicity and lack of efficacy. All 7 patients had had ITP for >9 years and had failed splenectomy, intravenous gammaglobulin, corticosteroids, and a variety of other treatments. The patients at entry all had platelet counts <20,000/microl; 5 of 7 had counts <10,000/microl. The maximal median increase for any day of the study was 6,000/microl. No patient achieved a count of 30,000/microl, and only 3 patients achieved (once each) a platelet count >20,000/microl. Substantial toxicity was seen. The nadir hemoglobin decrease was a mean of 2 g/dl. rhuIL-11 was not effective at increasing the platelet count in any of these patients with refractory ITP. Toxicity was substantial. The lack of platelet response to rhuIL-11 in this study does not exclude the possibility of better effects at other doses and/or in less refractory patients.     

Diagnosis and therapy of idiopathic thrombocytopenic purpura (ITP) in adults

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder resulting from the binding of antibodies directed toward platelet surface glycoproteins GP IIb/IIIa and GP Ib/IX leading to their clearance by reticuloendothelial system. The diagnosis of ITP is made clinically by exclusion of other causes of thrombocytopenia. The treatment of chronic ITP is palliative, not curative and is directed toward inactivation and removal of a major site of platelet destruction and antibody production represented by the spleen. Spontaneous remission of ITP in adults are very rare. The goal of treatment for ITP is to prevent serious bleeding. About 30% of the affected patients show a long term response to steroid therapy. Splenectomy is the treatment of choice in the remaining patients. The treatment of patients refractory to corticosteroid therapy and splenectomy remains largely empirical and to date a generally accepted therapy has not been established. The newest approch to the treatment involves the use of monoclonal antibodies. In intracranial bleeding and in severe bleeding in refractory ITP use of rVIIa has been shown to might be useful. ITP in pregnancy represent a special situation. There is the trend toward treating these patients in a more conservative fashion.     

Efficacy and safety of dapsone as a second-line treatment in non-splenectomized adults with immune thrombocytopenic purpura

In adults with immune thrombocytopenic purpura (ITP), steroids are usually proposed as first-line therapy, but long-term complete responses are obtained in no more than 20% of patients. For the remaining patients, splenectomy is considered the treatment of choice, with reported “cure” rates from 60–70%. However, the inherent risks of surgery and sepsis after splenectomy without a guarantee of success justify the search for strategies aimed to avoid splenectomy. Here we retrospectively evaluated the results of dapsone treatment in ITP patients that failed first-line therapy with steroids. These patients received dapsone 100 mg/day for a minimum of 30 days before splenectomy was considered. Efficacy was defined as a sustained rise in platelet counts (>50 × 10⁹/l) clearly attributed to dapsone treatment. Among 52 steroid-dependent or refractory patients, dapsone resulted in sustained increases in platelet counts in 44.2% of patients, after a median follow-up of 21.10 months after treatment initiation. The long-term efficacy of dapsone in this setting is further corroborated by the observation that none of the “responding” patients required splenectomy in the follow-up, compared to 69.0% of the “non-responding” patients. Dapsone-related adverse events were mild and promptly reversed by treatment withdrawal. The results of our retrospective analysis suggest that dapsone is a safe and effective second-line agent for steroid-dependent or refractory ITP patients. Because of its well-known safety profile and low cost compared to other potential second-line treatments for ITP, a trial course of dapsone should be viewed as an attractive option before splenectomy in steroid-dependent of refractory adult ITP patients.     

Refractory idiopathic thrombocytopenic purpura which responded to protein A column

Currently, there is no satisfactory therapy available for patients with chronic idiopathic thrombocytopenic purpura (ITP) who are unresponsive to conventional therapeutic modalities. In this report, we describe a patient with chronic refractory ITP treated with immobilized protein A in an extracorporeal system. The patient was a 74 years old male diagnosed as ITP in 1980. Despite steroid therapy, the disease progressed and the patient exhibited ecchymosis and gum bleeding which was unresponsive to intravenous gammaglobulin therapy. Severe gastrointestinal bleeding was evident and administration of danazol was discontinued due to liver dysfunction. The patient was treated with extracorporeal protein A immunoabsorption. The patient's whole blood (200-300 ml per treatment) was separated into plasma and cellular components and the plasma was passed through an immunoabsorption column containing 200 mg of covalently bound protein A. The treated plasma and cellular components were returned to the patient. After 4 immunoabsorption treatments, the platelet counts elevated and there was evidence of improvement in gastrointestinal bleeding. This report indicates that protein A immunoabsorption therapy should be considered in patients with chronic refractory ITP.     

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

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet destruction and reduced platelet production resulting in decreased platelet level and an increased risk of bleeding. Based on the immunologic mechanism of ITP, front‐line standard therapy consists of corticosteroids and intravenous immunoglobulins (IVIG). If patients do not respond to the first‐line treatment, or if continuous therapy is required, the disorder is called refractory ITP, and second‐line therapy is indicated. This treatment may consist of rituximab, thrombopoietin receptor agonists, splenectomy, or cytotoxic drugs. Despite significant advances, many patients do not respond to any the treatments listed below, and new treatment options need to be developed for this relapsed and refractory group. Recent clinical studies have indicated promising outcomes for novel drugs, either as single agents or in combination with traditional drugs. This review discusses the latest and the most promising novel drugs for ITP in adults.