Chronic Refractory Immune Thrombocytopenic Purpura Research Articles

Efficacy and safety of rituximab as second-line therapy in immune thrombocytopenic purpura based on ethnicity: A descriptive study among the Arabic population.

Background: Rituximab is used as second-line therapy in patients with immune thrombocytopenic purpura (ITP) who do not respond to first-line management. The response rate for Rituximab is variable in different populations ranging from 30% to 90%. The adverse effects of rituximab in patients with ITP range from infusion site reactions to the reactivation of hepatitis B virus and progressive multifocal leukoencephalopathy and interpopulation variation.Methods: We conducted a single-center, retrospective study in Qatar's National Center for Cancer Care & Research. The study included patients with chronic refractory ITP who received rituximab as second-line therapy. Descriptive and summary statistics were used to describe the sociodemographic parameters of the study cohort.Results: Of the 41 patients with chronic ITP, 26 were Arabs, 12 were Asians, and 3 were of other ethnicities. Rituximab was associated with an overall response rate of 80.4%. Arabic patients had the highest clinical response (84.6%) among the ethnicities with the lowest adverse effects (11.5%). Asians had a response rate of 66.6%, and adverse effects were seen in 16.7% of the patients.Conclusions: In chronic refractory ITP, rituximab appears to have a better clinical response in the Arabic population with minimal toxicity than in other ethnicities.

Avatrombopag, a Novel Oral Thrombopoietin Receptor Agonist, Demonstrates Superiority to Placebo for the Treatment of Chronic Immune Thrombocytopenic Purpura in a Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Background: Avatrombopag (AVA) is an oral, 2nd generation thrombopoietin receptor agonist (TPO-RA) currently in development for the treatment of thrombocytopenia. Two other TPO-RAs have been approved for the treatment of chronic immune thrombocytopenic purpura (ITP) refractory to corticosteroids, immunoglobulins, or splenectomy, to maintain platelet counts and reduce the incidence of bleeding. Given the need for chronic administration, it is important to minimize treatment-related toxicities in patients with ITP. This trial investigated the efficacy and safety of AVA versus placebo (PBO) for the treatment of patients with chronic ITP in a multicenter, multinational, randomized, parallel group, PBO-controlled Phase 3 trial (NCT01438840). The once daily oral dosing of AVA, which can be taken with food, has no signal for hepatotoxicity, and a reliable pharmacokinetic-pharmacodynamic response profile due to limited metabolism of the parent molecule may provide advantages for its use in patients with ITP.Methods: Adult patients (age ≥18 years) with chronic ITP (Baseline platelet count <30 X 109/L) were recruited from 27 study sites and randomized 2:1 to 20 mg/day AVA or PBO over the 6-month study period. Dose titration of AVA and PBO were permitted based on individual responses (final dose range: 5-40 mg/day). Patients and investigators were blinded to treatment which was given in addition to standard of care. The primary efficacy endpoint was the number of cumulative weeks with a platelet response defined as a platelet count ≥50 x 109/L, in the absence of rescue therapy. Secondary endpoints included platelet response at Day 8, and the proportion of patients with a reduction in concomitant ITP medications from Baseline. Safety analyses included the monitoring of adverse events (AE) and clinical laboratory results.Results: In total, 49 patients met eligibility criteria and were included in the full analysis set and safety analysis sets. The majority of patients were White (93.9%) and female (63.3%) with a mean age of 44.6 years. At Baseline, 67.3% had not been splenectomized, 55.1% did not use concomitant ITP medication, and ~30% had received >5 previous ITP medications. The AVA treatment group included 32 patients; 22 (68.8%) completed the study. In the PBO group, which included 17 patients, only one (5.9%) completed the study. The most common reason for study discontinuation was inadequate therapeutic effect, which was lower in the AVA treatment group (21.9%) compared with the PBO group (88.2%).AVA was superior to PBO in the mean cumulative number of weeks with a platelet count ≥50 x 109/L during the 6-month treatment period, the primary study endpoint (12.4 weeks vs 0 weeks; P<0.0001). Day 8 platelet responses were also significantly higher for patients who received AVA treatment, 65.6% compared with 0% for PBO (P<0.0001). The proportion of AVA-treated patients with reduced concomitant ITP medication use from Baseline was 33.3% compared with 0% in PBO-treated subjects, although this treatment difference was not significant (P=0.1348). A durable platelet response, defined as the proportion of subjects who had at least 6 out of 8 weekly platelet responses during the last 8 weeks of treatment in the absence of rescue therapy, was observed in significantly more AVA-treated patients (34.3%) compared with PBO-treated patients (0%; P=0.009).Treatment emergent AEs (TEAEs) were reported by 31 patients (96.9%) in the AVA-treated group compared with 10 patients (58.5%) in the PBO-treated group; the incidence of TEAEs, Grade 3/4 TEAEs, and serious AEs were similar in the two treatment groups when adjusted for treatment exposure. The most commonly reported TEAEs included headache, contusion, upper respiratory tract infection, arthralgia, and epistaxis. Five patients had TEAEs leading to study drug dose adjustment in the AVA group, which led to study drug withdrawal for 3 patients. No patients in the PBO treatment group required study drug dose adjustment.Conclusions: AVA is novel 2nd generation TPO-RA that has been shown to be well tolerated and superior to PBO in patients with chronic ITP, as measured by the cumulative number of weeks with a platelet response, platelet response at Day 8, and durability of platelet response. The overall safety profile of AVA was similar to PBO when adjusted for treatment exposure. AVA may potentially provide an additional treatment option for patients with refractory chronic ITP. DisclosuresJurczak:Jagiellonian University: Employment; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Merck: Research Funding; Celtrion: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Pfizer: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Chojnowski:Novo Nordisk: Honoraria; Baxalte: Honoraria. Mayer:Novartis: Research Funding; Eisai: Research Funding. Bibbiani:Eisai, Inc.: Employment.

Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of a Romiplostim Biosimilar in Chronic Refractory Immune Thrombocytopenic Purpura (ITP) Patients.

The online version contains supplementary material available at 10.1007/s12288-021-01431-y.

Treatments for Primary Immune Thrombocytopenia: A Review.

Immune thrombocytopenic purpura (ITP) is an autoimmune condition that affects nearly 1:10,000 people in the world. It is traditionally defined by a platelet count of less than 100 x 109L, but treatment typically depends on symptomology rather than on the platelet count itself. For primary idiopathic ITP, corticosteroids have been the standard first-line of treatment for symptomatic patients, with the addition of intravenous immune globulin (IVIG) or Rho(D) immune globulin (anti-RhD) for steroid-resistant cases. In cases of refractory or non-responsive ITP, second-line therapy includes splenectomy or rituximab, a monoclonal antibody against the CD20 antigen (anti-CD20). In patients who continue to have severe thrombocytopenia and symptomatic bleeding despite first- and second-line treatments, the diagnosis of “chronic refractory ITP” is appropriate, and third-line treatments are evaluated. This manuscript describes the efficacy of different treatment options for primary ITP and introduces the reader to various third-line options that are emerging as a means of treating chronic refractory ITP.

Intravenous infusion umbilical cord-derived mesenchymal stem cell in primary immune thrombocytopenia: A two-year follow-up.

Four patients with chronic refractory immune thrombocytopenic purpura (ITP) received human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The hUC-MSC dose was 5×107 to 1×108. Complete remission (CR) was achieved in three patients in 12 months and one patient in 24 months. Three patients received the second hUC-MSC transplantation with the same dose. The median time between hUC-MSC transplantation and response was 12.5 days (range, 7–16). There were no severe adverse events during and post hUC-MSC transplantation. During follow-up (median, 17 months; range, 13–24) no other immunosuppressive drugs were used post-first hUC-MSCs transplantation. In conclusion, hUC-MSC transplantation is a reasonable salvage treatment in chronic refractory ITP. Prospective randomized large-scale clinical trials are needed to further elucidate the efficacy of hUC-MSCs transplantation therapy on ITP.

Eltrombopag enhances platelet adhesion by upregulating the expression of glycoprotein VI in patients with chronic immune thrombocytopenic purpura

Eltrombopag, a thrombopoietin receptor agonist, has been approved for the treatment of patients with immune thrombocytopenia because of its abilities to enhance platelet production and reduce hemorrhage. Both platelet count and platelet adhesion are crucial to stop bleeding. Although eltrombopag is known to improve platelet counts, its effects on platelet adhesion are not yet known. This study aimed to assess the efficacy of eltrombopag on platelet production and platelet adhesive affinity. To evaluate the efficacy of low-dose eltrombopag (25 mg) for patients with chronic refractory immune thrombocytopenic purpura (ITP) and to determine the ex vivo platelet adhesion ability before and after treatment with eltrombopag, we conducted an open-label, multicenter study in which 25 Taiwanese patients with chronic ITP were enrolled. During the 6-month evaluation, the starting and maximum doses of eltrombopag were 25 and 50 mg, respectively, to maintain the platelet count of ≥50,000 per μL. Flow-based adhesion assay was used to detect the percentage of platelets adhering to immobilized von Willebrand factor-collagen on microslides. Of the enrolled patients, 48% achieved a platelet count of ≥50,000 per μL. Interestingly, 83% of all responders required 25 mg of eltrombopag daily to achieve the target platelet count. In addition, the percentage of bleeding patients was significantly reduced in both responders and nonresponders by 50% from the baseline level throughout the treatment period. The ex vivo platelet adhesion capacity was elevated after the 6-month eltrombopag treatment in both responders and nonresponders. Furthermore, glycoprotein VI (GPVI) expression was significantly upregulated after treatment with eltrombopag. Low-to-intermediate dose of eltrombopag showed good efficacy to expedite platelet production and augment platelet adhesion. These 2 factors might explain the efficacy of eltrombopag in ameliorating hemorrhage in patients with ITP.

High Dose Methylprednisolone: Effective in Pregnancy Associated Post-splenectomy Refractory Chronic Immune Thrombocytopenic Purpura

We present a case of 23 years multigravid woman (G2P0+1) with chronic idiopathic thrombocytopenic purpura (ITP), refractory to treatment in forms of oral steroid, dapsone, azathioprine and splenectomy. She presented to the hospital in third trimester of pregnancy, with reduced platelet counts and purpuric rashes over abdomen and both upper extremeties. There was a past history of spontaneous abortion at 18 weeks. The patient responded to intravenous high dose methylprednisolone (HDMP) infusion leading to delivery of full term male baby. The baby also required treatment for thrombocytopenia with intravenous immunoglobulin (IVIG). This case lays down the importance of HDMP in form of using it effectively in managing acute crisis of low platelet counts in pregnant patients with ITP refractory to splenectomy. DOI: http://dx.doi.org/10.3126/njog.v9i1.11192 NJOG 2014 Jan-Jun; 2(1):64-66

Is Splenectomy Necessary for Immune Thrombocytopenic Purpura? The Role of Rituximab in Patients With Corticosteroid Resistance in a Single-Center Experience

BackgroundCorticosteroid therapy followed by splenectomy for immune thrombocytopenic purpura (ITP) is the standard practice. Rituximab is mostly used in patients with chronic refractory ITP who have failed multiple previous treatments, including splenectomy. ObjectiveWe explored the potential role of rituximab as an early therapeutic option for patients with corticosteroid-resistant ITP who preferred to avoid splenectomy in favor of other treatment. MethodsTwenty-five patients with corticosteroid-resistant ITP were treated with rituximab between May 1, 2009, and June 30, 2012, at a single center. Rituximab was administered at 100 mg/m2 on days 7, 14, 21, and 28. The response to rituximab therapy and adverse effects were observed. ResultsComplete remission was achieved in 19 patients (76%), partial remission in 3 patients (12%), and minimal response in none of the patients; 1 patient was considered a treatment failure (4%). Two patients (8%) were lost to follow-up. Twenty-two patients (88%) achieved a platelet count >50×109/L. The median time from administration of the first rituximab dose to partial remission was 2 months (range, 0.7–3 months) for all the patients. Response classified as sustained was achieved in 21 patients (84%). No serious adverse effects were observed during rituximab therapy. ConclusionsRituximab therapy is effective and safe for patients with corticosteroid-resistant ITP before splenectomy, resulting in high complete remission and overall response rates. A multicenter study with a larger sample should be performed to further explore the role of rituximab therapy.

The Paradoxical Beneficial Effect on Thrombocytopenia in Refractory Immune Thrombocytopaenic Purpura by Leishmaniasis

The phenomenon of platelet recovery in untreated patients with severe chronic refractory immune thrombocytopenic purpura (ITP) has never been described. A 44 year old lady presented with pyrexia. The blood count was Hb 9.8 g/l WBC 6.5 × 109/l Platelets 125 × 109/l. A bone marrow aspirate revealed macrophage hyperplasia with heavy infiltration by Leishman Donovani. The patient had a twenty year history of severe ITP responsive only to high doses of prednisolone. She had undergone two splenectomies and failed to respond to the sequential administration of dapsone, azathiaprine and cyclosporine. The minimum daily dose of prednisolone required to maintain the platelet count was 30 mg and she was on this maintenance dose for most of the duration of the disease. Intensive treatment with liposomal amphotericin and sodium stibogluconate failed to clear the parasites and for the rest of her life (14 months) she remained a carrier of leishmania requiring maintainance monthly doses of Leishmaniacides. During this period the platelet count remained normal even though the steroids were tapered to zero. The normalisation of the platelet count without steroids was unexpected and had never been observed before in her case. It was noted that she maintained a normal platelet count spontaneously even though she had developed transfusion dependent anaemia. Moreover, by then she had developed severe neutropenia partially corrected with granulocyte colony stimulating factor. Both cytopenic effects were a consequence of the ongoing sepsis. The patient eventually succumbed to renal failure secondary to a diabetic nephropathy. Kala-azar in normal subjects characteristically causes thrombocytopenia partly because of hypersplenism and partly because of consumption by the diffuse macrophage hyperplasia within the reticuloendothelial system. Also, in HIV infection where ITP is common, visceral leishmaniasis has been shown to worsen the thrombocytopenia. The main reason for thrombocytopenia in ITP is macrophage mediated phagocytosis of the antibody coated platelets. Two highly effective therapeutic agents are directed against this macrophage activity. Intravenous immunoglobulin saturates the macrophage receptor sites, thereby sparing the sensitised platelets by competitive inhibition [1]. Anti–D transiently diverts macrophages from destruction of platelets by focusing their activity against the sensitised erythrocytes [2]. Using the similar paradigm of these immunemodulatory agents, I postulate that the continual saturation of macrophages with the Leishmania parasites likewise had a platelet sparing effect. This observation may be of interest for pharmaceutical companies in their drug development research.

Combination therapy of rituximab and corticosteroids for patients with refractory chronic immune thrombocytopenic purpura: Report on two cases

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder, for which rituximab has been proven to be an effective treatment. The response rate was reported to be approximately 60% in refractory ITP patients. However, the response time is slower than expected, and the mechanism of action of rituximab in ITP is still unclear. Thus, sometimes, the use of a combination therapy with rituximab according to different patient conditions is necessary. We report two refractory chronic ITP cases. The two patients were administered a low dose of dexamethasone (10 mg, weekly) combined with rituximab and a smaller dose of prednisone (10 mg, daily) as maintenance therapy. Although their peripheral B cells were almost eliminated, no complete reaction was observed. The maintenance therapy with prednisone was helpful in the prevention of bleeding. The patients’ responses to rituximab treatment suggest that multiple immunological mechanisms are involved in ITP pathogenesis and that the use of a combination therapy with rituximab according to the different patient conditions is necessary.

A Case of Cerebral Venous Thrombosis in the Setting of Romiplostim Use (P02.226)

Objective: To describe a case of CVT in the setting of Romiplostim (Nplate®) use. Background Thrombopoietin receptor agonists are currently recommended in patients with chronic refractory immune thrombocytopenic purpura (ITP). Thromboembolic events have been reported in less than 5% of individuals treated with romiplostim, and usually in the presence of known risk factors for thrombosis. Cerebral venous thrombosis (CVT) has been rarely reported in association with romiplostim use. Design/Methods: We report the case of a 40-year-old Caucasian woman with refractory ITP who had failed medical therapy as well as splenectomy and presented with headache and visual blurring. She was transferred to our institution due to concerns for idiopathic intracranial hypertension. Romiplostim was first administered in 2007 as part of a clinical trial and then weekly upon FDA approval in late 2008. Results: Her course while on therapy was complicated by wide fluctuations in her platelet count ranging from severe thrombocytopenia to thrombocytosis and was associated with clinically-significant bleeding and thromboembolic phenomena. A hypercoagulable work up had been unrevealing. On admission, magnetic resonance venogram (MRV) revealed extensive sagittal sinus and bilateral transverse sinus thrombosis. Her platelet count was 165 x109/L. She was initially managed with intravenous heparin, but given subsequent clinical worsening, mechanical thrombectomy and local alteplase administration was undertaken. Unfortunately, she developed refractory cerebral edema and elevated intracranial pressure. Conclusions: The association between romiplostim use and CVT is not well understood. Headache is the most commonly reported side-effect to romiplostim therapy, a fact that can mask the presence of CVT. We hypothesize that significant fluctuation in platelet count with rebound thrombocytosis while receiving thrombopoietin receptor agonists can increase the risk of thromboembolic events. Disclosure: Dr. George has nothing to disclose. Dr. Ahrens has nothing to disclose. Dr. Gomes has nothing to disclose.

Favorable Response of Chronic Refractory Immune Thrombocytopenic Purpura to Mesenchymal Stem Cells

Seven patients with chronic refractory immune thrombocytopenic purpura (ITP) received adipose tissue-derived mesenchymal stem cells (AMSC) from haplo-identical family donors. The AMSC dose was 2.0×10(6)/kg. No side effects were noted after the AMSC infusions. Overall responses were reached in all patients and sustained response rate was 57.1% (4/7). The serum levels of transforming growth factor β1 (TGF-β1), interleukin (IL)-4, and IL-10 were significantly elevated, whereas those of interferon-γ (IFN-γ) and IL-2 were significantly decreased after AMSC administration, compared with those in the patients with active ITP. During follow-up, the cytokine profiles in patients maintaining sustained response remained stable compared with the post-treatment level, but IFN-γ and IL-2 levels were significantly increased, and those of TGF-β1, IL-4, and IL-10 were significantly reduced again in relapsed patients. AMSC therapy seems to represent reasonable salvage treatment in severe, chronic refractory ITP by causing a shift in the Th1/Th2 cytokine balance to the same levels as normal controls.

Rituximab-induced serum sickness in a patient with refractory chronic immune thrombocytopenic purpura: a case report and review of the literature

Ates, titreme ve kasilma gibi yan etkiler ilk kez yapilan rituksimab infuzyonu sirasinda sikca gorulmesine karsilik, serum hastaligi ve Steven-Johnson sendromu gibi gecikmis yan etkiler nadir olarak bildirilmistir. Steroide direncli ve splenektomize kronik immun trombositopenili bir hasta, ucuncu rituksimab infuzyonundan iki gun sonra ates, artralji, astim benzeri solunum sistemi semptomlari, makulopapuler ras ve palpabl purpurik lezyonlar ile basvurdu. Rituksimabin kesilmesi, sonrasinda intravenoz steroid ve antihistaminik tedavi uygulanmasi ile hastanin klinigi ve fiziki bulgulari duzeldi. Bu gibi vakalarda rituksimabin kesilmesi ve sistemik steroid tedavi uygulanmasi ile tam ve hizli bir duzelme saglanabilecegini dusunmekteyiz

Successful Treatment of An Elderly Patient with Refractory Chronic Immune Thrombocytopenic Purpura with Combination Therapy of Rituximab and Corticosteroids: A Case Report

AbstractAbstract 4686Immune thrombocytopenic purpura (ITP) is an autoimmune disorder. A corticosteroid, usually prednisone is often the first line treatment for ITP. However, the problem is that about 70 percent of adult patients experience a relapse after discontinuation of corticosteroids. And approximately 20–30% of patients with chronic ITP do not respond to corticosteroids therapy. Rituximab has been proven effective in refractory chronic ITP, but the timing of response is slower than expected, at least three months might be necessary to observe an effect. And the response duration to rituximab remains relatively short in some patients. So, sometimes it is necessary to use combination therapy including rituximab, according to different patient conditions. Here, we report an 82-year-old man with chronic ITP who had thrombocytopenia (platelet count <10 × 109/L) for more than 6 months and relapsed on a prednisone taper. He presented sustaining blood-tinged sputum, bleeding in skin and steroid-induced diabetes, the result of short-term prednisone. He didn't want splenectomy and other immune suppressive drugs. His blood glucose got control after insulin therapy. We gave the patient intravenous infusions of rituximab 375 mg/m2 weekly for 4 weeks combined with dexamethasone (10 mg intravenously weekly for 4 weeks). After first dose of dexamethasone followed by rituximab, within 24 hours his platelet count had increased to 65 × 109/L and bleeding symptoms were significantly improved. During the next 3-week period of treatment, his platelet counts fluctuated between 30 × 109/L and 60 × 109/L. And then the platelet count dropped back to a minimum of 19 × 109/L. Consider the slow responses to rituximab and prevention of bleeding, we still gave the patient maintenance therapy with 15mg prednisone daily and he had been no bleeding. Two months after starting rituximab and dexamethasone, his platelet counts began to gradually recover to normal. Although we need to further observe the patients's duration of response, this case suggests that combination therapy of rituximab and corticosteroids may be a promising treatment for refractory chronic ITP. Disclosures:No relevant conflicts of interest to declare.

Romiplostim (N-Plate) In Children with Chronic Refractory ITP.

AbstractAbstract 1443▪ Background:Chronic immune thrombocytopenic purpura (ITP) is characterized by platelet deficiency due to platelet destruction and/or inadequate production. Romiplostim stimulates thrombopoietin receptor to increase platelet production in chronic ITP. This study aimed to evaluate the safety and short term efficacy of Romiplostim (N-Plate) in children with chronic refractory ITP. Design and Methods:Eighteen patients less than 16 years old suffering from refractory chronic ITP for more than a year who failed to maintain response on more than two therapeutic modalities (steroids, IVIG, Anti-D and/or immunosuppressive therapy) were enrolled. Written informed consent was taken from all parents and consent or ascent form from patients when applicable. Patients were randomized (2:1) to receive Romiplostim or placebo for 12 weeks, initiated at 1μg/kg/week escalated weekly to 5μg/kg/week; then tapered based on weekly platelet count and were followed up to week fifteen. Results:The median age of the studied group was 8.5 years, median duration of thrombocytopenia was 3.5 years and the median baseline platelet count (PC) was 10.5 × 109/L. The median weekly dose of Romiplostim was 2μg/kg. Fifty percent of patients in both the Romiplostim and placebo arms had at least one AE with no serious AEs. Ten patients (83.3%) on Romiplostim achieved efficacy endpoint (platelet count of > 50 × 109/L for 2 consecutive weeks without rescue therapy at any point during the treatment period) and 6 patients (50%) maintained that response 3 weeks after treatment discontinuation in contrast to non in the placebo group. Four of the patients on Romiplostim reached the targeted range (>50 × 109/L) after the 2nd week and 11 patients reached the targeted range after the 5th week. None of our patients experienced thrombocytosis or rebound thrombocytopenia. The peak PC was reached in the Romiplostim arm by the 5th week of treatment at a dose of 5ug/kg with median PC of 73.50 ×109/L; compared to 18.50 ×109/L for the placebo group. Rescue medication was administered to 1/12 (8.3%) patient on Romiplostim due to accidental head trauma compared to 2/6 (33.3%) patients on placebo. Number of patients in the Romiplostim arm with grade 3 bleeding severity decreased from 33.3% (prior to study) to 0% (during the study and then after) and from 50% to 16.6% for grade 2. Conclusion:Romiplostim is well tolerated in children with refractory chronic ITP with no serious AEs. It was efficient in treating most of them with minimal bleeding during the study period while using lower doses of N-Plate compared to previous published data. Abbreviations:ITP; immune thrombocytopenia. PC; platelet count. AE; adverse event. Disclosures:No relevant conflicts of interest to declare.

Efficacy of Early Use of Rituximab In Steroid Refractory Severe Immune Thrombocytopenic Purpura In Adult Patients: Single Institution Experience From Saudi Arabia

AbstractAbstract 4681 Background:Immune thrombocytopenic purpura (ITP) is characterized by mucocutaneous purpura and thrombocytopenia. Majority of patients swiftly respond to intravenous immunoglobulin (IVIg) and or steroids therapy but approximately 25% to 30% of adult patients develop a chronic disease that will become refractory to corticosteroids and splenectomy, leading to substantial morbidity and mortality. Guidelines recommend glucocorticoids and splenectomy as standard 1st and 2nd line treatments for chronic ITP but there is considerable variation in 2nd and 3rd line therapies worldwide. In addition to variable response rates immunosuppressive therapies for ITP are associated with substantial side effects, limiting their use for long-term treatment. Management of adults with severe ITP (platelet count less than 10 × 10^9/L) is costly, with IVIg use being a major cost driver. From a budget payer's perspective, the availability of therapeutic agents that could reduce the need for IVIg and emergency hospitalizations could mitigate the costs of current treatments of ITP. Rituximab, a monoclonal antibody to CD-20, has shown promising results in patients with chronic refractory ITP and many patients have this as “off-label” therapy. The rationale for its use in ITP rests on the attempt to eliminate autoreactive B-cell clones. Severe ITP that does not respond to IVIg and steroid therapy is worrisome for both physician and patient due to fears of Intracranial hemorrhage. In this study we evaluated the efficacy of relatively early use of Rituximab for steroid refractory severe ITP. Methods:The data for the reported patients with severe ITP was retrospectively reviewed from medical records. All patients had typical clinical findings of ITP and bone marrow biopsy findings were consistent with peripheral destruction. Six patients who failed to achieve a platelet of > 10 × 10^9/L after IVIG and steroids; or who relapsed after 3 lines of treatment (including IVIG, Prednisone and Dexamathasone pulse) were treated with Rituximab at a dose of 375mg/m^2 weekly for total of four doses (except one patient who underwent splenectomy after 3 doses due to very poor response). Platelet counts were frequently monitored during the follow-up. Complete response (CR) was defined as platelet count >150 × 10^9/L; and partial response (PR) as platelets 50–149×10^9/L. Duration of disease prior to Rituximab and follow up time after Rituximab were recorded. Results:Median age of patients was 50 years (range 17–59 years). Median duration of ITP prior to Rituximab was 4.5 weeks (range 3–14 weeks). Median of baseline platelet count was 4.5 ×109/L (range 1.2–9 ×109/L) prior to Rituximab. All patients had received 3 lines of prior ITP therapies for at least some time. Severity of thrombocytopenia was the main reason for change to rituximab. Patients had a median follow up of 28 weeks (range 6 to 72 weeks).No short term (except mild headaches and chills) or long term adverse events were documented among patient who received Rituximab. Complete response was observed in 83.3 % (5/6). This response was sustained without a rescue therapy in all patients except one (80 %). One of the six patients (case #4) who had no response to first 3 doses of rituximab underwent splenectomy (16.6 %). After splenectomy her platelets count remain very low with two episodes of rescue therapy but she reported clinical benefit (no bleeding manifestations) on last follow up. Conclusion:Although this study is limited by small number but data supports the effectiveness and safety of relatively early use of rituximab in severe steroid refractory ITP patients. Disclosures:Off Label Use: Rituximab (monoclonal anti-CD20 antibody) has been used in chronic ITP but in USA it is used as off-label drug.

New advances in the treatment of adult chronic immune thrombocytopenic purpura: role of thrombopoietin receptor-stimulating agents

New advances in the treatment of adult chronic immune thrombocytopenic purpura: role of thrombopoietin receptor-stimulating agents Ara Metjian1, Charles S Abrams21Department of Medicine, Duke University Medical Center, Durham, NC, USA; 2Department of Medicine, University of Pennsylvania, Philadelphia, PA, USAAbstract: Decades of basic science and clinical research have led to an increased understanding of the pathophysiology of immune thrombocytopenic purpura (ITP), the processes underlying thrombopoiesis, and the treatment of chronic ITP. Now, new agents are available to treat ITP in a nonimmunosuppressive fashion. Lessons learned from the clinical trials of recombinant human thrombopoietin (TPO) have led to the development of a novel class of compounds: nonimmunogenic agonists of the thrombopoietin receptor. Representing the first nonimmunosuppressive agents to treat chronic refractory ITP in decades, medications such as romiplostim and eltrombopag were recently approved by the US Food and Drug Administration. These new agents offer physicians a new tool for treating difficult cases of ITP in their medical armamentarium. Additional TPO mimetics are also being developed that show promise in vitro, and await future development.Keywords: thrombocytopenia, immune-mediated thrombocytopenia, eltrombopag, romiplostim, thrombopoietin, thrombopoietin receptor

New advances in the treatment of adult chronic immune thrombocytopenic purpura: role of thrombopoietin receptor-stimulating agents

Decades of basic science and clinical research have led to an increased understanding of the pathophysiology of immune thrombocytopenic purpura (ITP), the processes underlying thrombopoiesis, and the treatment of chronic ITP. Now, new agents are available to treat ITP in a nonimmunosuppressive fashion. Lessons learned from the clinical trials of recombinant human thrombopoietin (TPO) have led to the development of a novel class of compounds: nonimmunogenic agonists of the thrombopoietin receptor. Representing the first nonimmunosuppressive agents to treat chronic refractory ITP in decades, medications such as romiplostim and eltrombopag were recently approved by the US Food and Drug Administration. These new agents offer physicians a new tool for treating difficult cases of ITP in their medical armamentarium. Additional TPO mimetics are also being developed that show promise in vitro, and await future development.

Time to Splenectomy Failure in Patients with Recurrent or Refractory Chronic Immune Thrombocytopenic Purpura.

Abstract 3522Poster Board III-459 INTRODUCTIONSplenectomy has been perceived as a potentially curative treatment for patients with chronic immune thrombocytopenic purpura (ITP). Historical data demonstrate that the risk of relapse is between 33% and 50% in patients with long-term follow-up (Fabris, Br J Haematol, 2001; Schwartz, Am J Hematol, 2003). No clear pattern of time to relapse after splenectomy has been described which complicates the decision making process for physicians who are considering this irreversible therapeutic option. Splenectomized patients are at risk for: early and late surgical complications (Kojouri, Blood, 2004; Portielje, Blood, 2001); infections secondary to impaired immunity (BCSH 1996; Moffett, JAAPA, 2009; Oren 2008); thrombotic and/or cardiovascular disease (Schilling, J Thromb Haemost, 2008; Fontana, Thromb Res, 2008); and pulmonary hypertension (Schilling, J Thromb Haemost, 2008; Bonderman, Circulation, 2007). Splenectomy requires preoperative vaccinations, general anesthesia with antibiotic prophylaxis, and subsequent long-term vigilance with early antibiotic treatments. These factors not only impact the utilization of medical resources but also, due to clinically problematic outcomes, may lead to a requirement for additional treatments. OBJECTIVE: To describe the time from splenectomy to splenectomy failure among patients with chronic ITP enrolled in the eltrombopag clinical program. METHODS: Date of splenectomy and prior medications for ITP were reviewed in patients enrolled in 5 clinical trials using eltrombopag. Splenectomy was considered to have failed upon administration of the first treatment for ITP after surgery or when patients were not able to taper or interrupt concomitant ITP treatments in the 30 days following splenectomy. Of the 495 patients enrolled in the ITP program, 192 (39%) were splenectomized and 185 patients were evaluable for this analysis. The analysis does not describe overall effectiveness of splenectomy as the patient population is limited to splenectomy failure patients who required additional treatment for their ITP. RESULTS: Fifty-one percent of patients required ITP medications within 1 year of splenectomy (Figure 1). Five years after splenectomy, 27% of patients still had a response; this percentage decreased to 18% after 10 years. CONCLUSION: This retrospective analysis demonstrates that success of splenectomy appears to diminish over time. In patients requiring further ITP treatment, most splenectomized patients who relapse do so within 5 years. The treatment of chronic ITP has advanced as more data on the safety and efficacy of new medications like the thrombopoietin receptor agonists have become available. As physicians and patients become more familiar with the risks and benefits of all treatments, options other than splenectomy may be preferred for certain patients. [Display omitted] Disclosures:Cheng:GlaxoSmithKline: Research Funding. Gernsheimer:GlaxoSmithKline: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Olney:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bussel:Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Shah:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment. Grotzinger:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment.

Six Month Treatment of Low Dose Eltrombopag Is Efficacious in Japanese Patients with Refractory Chronic Immune Thrombocytopenic Purpura (ITP).

Abstract 1324Poster Board I-346 INTRODUCTIONEltrombopag (PROMACTA®, GlaxoSmithKline) is the first non peptide, oral thrombopoietin receptor agonist which promotes the differentiation and proliferation of megakaryocytes and increases platelet counts. This study is a randomized study comprising a double-blind (DB), placebo (PBO)-controlled phase, followed by an open-label (OL) phase in previously treated Japanese patients with chronic ITP and platelet counts <30Gi/L. Since eltrombopag exposure has been reported to be 70% higher in East Asian patients with ITP as compared to Caucasian patients and given the chronic nature of the disease state, the lower initial dose of 12.5mg/day was used in this study. METHODSIn the DB phase, patients were randomized into one of two treatment groups to receive either an initial dose of 12.5mg of eltrombopag or matching PBO once daily. A dose increase was allowed at Day 22 based on individual platelet count. For each patient, primary data up to Week 6 were frozen and the treatment assignment was unblinded at Week 7 before entering into the OL phase. The primary endpoint of the DB phase was to compare the proportion of patients achieving a platelet count of ≥50Gi/L and ≤400Gi/L after 6 weeks of eltrombopag or PBO. All patients completing the DB phase progressed to the OL phase. In the OL phase, patients who had received eltrombopag during the DB phase continued to receive eltrombopag for up to 26 weeks with dosage (12.5, 25 or 50mg/day) based on the individual platelet count. Patients who had received PBO during the DB phase initiated treatment with 12.5mg of eltrombopag and received eltrombopag for 26 weeks with dosage (12.5, 25 or 50mg/day) based on the individual platelet count. The primary efficacy endpoint of the long-term OL phase was to assess the ability of eltrombopag to elevate and maintain platelet counts in a target range (50-400Gi/L) during 6 months of treatment. Bleeding symptoms were also assessed subjectively and objectively at each visit. Blood samples were collected to describe the PK profile of eltrombopag. RESULTSOf 23 patients randomized, 16 had undergone splenectomy, 17 had received H. pylori eradication and 19 were receiving concomitant ITP medication at baseline. DB Phase: 23 patients were randomized to receive 6 weeks of once daily eltrombopag (n=15) or matching PBO (n=8). By Week 3, 5 of 15 (33.3%) patients receiving 12.5mg eltrombopag achieved platelet counts >50Gi/L. Three of the responders had platelet counts ≥100Gi/L at Week 3. At the end of the Week 6, 9 of the 15 patients (60.0%) receiving eltrombopag were responders (platelet count 50-400Gi/L). Three of these patients were receiving 12.5mg and the remaining 6 were receiving 25mg. All PBO patients failed to achieve a response at any point during the 6 weeks. Long-term OL Phase: During the first 3 weeks when all patients received 12.5mg of eltrombopag, 21.7% of patients achieved a platelet response of ≥50Gi/L. From Day 22 onwards a greater proportion of patients (47.8-69.6%) achieved platelet counts within the target range of 50-400Gi/L. Over the initial 3 week period a gradual rise in median platelet counts was observed and a marked increase in the median platelet count was observed from Day 22. From Day 36 until Week 26 the median platelet count was consistently within the target range of 50-400Gi/L. Eltrombopag therapy was associated with a consistent reduction in the proportion of patients with bleeding. 36.8% (7/19) had a reduction in concomitant ITP medication (corticosteroids) during the 6 months.Adverse events (AE) were reported in 22 out of 23 patients throughout the study. Nasopharyngitis was the most common AE (43%). One patient receiving eltrombopag developed a serious AE (transient ischemic attack of mild severity, considered related to study medication by the investigator) on day 10 and was withdrawn from the study. The AEs were mostly mild to moderate. There was a linear relationship between eltrombopag dose and exposure. CONCLUSIONSix month treatment of low dose eltrombopag with an initial dose of 12.5mg up to a maximum dose of 50mg increased platelet counts and reduced bleeding and the use of concomitant ITP medication in Japanese patients with refractory ITP. The higher eltrombopag exposure in Japanese patients than in Caucasian patients may explain the equivalent efficacy at lower dosages of eltrombopag. Eltrombopag was well-tolerated and is an important new treatment option for patients with chronic ITP. DisclosuresMiyakawa:GlaxoSmithKline: Consultancy; Nissan Chemical Industries: Research Funding; Shionogi: Honoraria; Ono Pharmaceutical: Honoraria. Ikeda:Daiichi-Sankyo: Research Funding; Tanabe-Mitsubishi: Research Funding; Chugai: Research Funding; Bayer: Research Funding; Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi-Aventis: Honoraria; Takeda: Honoraria; GlaxoSmithKline: Honoraria; Kaken: Honoraria; Sumitomo: Honoraria; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Boehringer: Membership on an entity's Board of Directors or advisory committees. Koh:GlaxoSmithKline: Employment. Katsura:GlaxoSmithKline: Employment. Kanakura:GlaxoSmithKline: Consultancy; Kyowa Hakko Kirin: Research Funding; GlaxoSmithKline: Research Funding.