Refractory Chronic Immune Thrombocytopenia Research Articles

Primary immune thrombocytopenia (ITP) treated with romiplostim in routine clinical practice: retrospective study from the United Kingdom ITP Registry.

BackgroundRomiplostim is a thrombopoietin‐mimetic peptibody for adult refractory chronic immune thrombocytopenia (ITP). We aimed to describe ITP patients receiving romiplostim, platelet counts and romiplostim usage in UK clinical practice.MethodsThis was a retrospective cohort study of patients in the UKITP Registry who received romiplostim between October 2009 and January 2015, including data up to 6 months before romiplostim initiation through follow‐up.ResultsOf 1440 patients in the UKITP Registry, 118 adults with primary ITP were eligible. Before romiplostim, 22% had splenectomy, 12% received platelet transfusion, 97% received ≥ 1 different ITP medication and 77% received ≥ 3. Most patients (73%) initiated romiplostim ≥ 1 year after ITP diagnosis (chronic phase). The mean duration of romiplostim treatment was 5.7 (SE 0.9) months, and the median was 1.4 months (IQR: 0.2, 6.5). Mean platelet count before romiplostim was 38 × 109/L, rising to 103 × 109/L within 1 month, and remaining 50‐150 × 109/L through up to 3 years of follow‐up. After romiplostim, 4% of patients had splenectomy, 6% received platelet transfusion, and 57% received just one ITP medication other than romiplostim.ConclusionThe study provides valuable insights into the real‐world use of romiplostim in primary ITP in routine practice and highlighted the timing of romiplostim initiation at different ITP disease phases.

Expression of HMGB1 in Spleen of Adult Patients with Chronic and Refractory Immune Thrombocytopenia and Its Significance

To investigate the expression and clinical significance of high mobility group box 1(HMGB1) in spleen of adult patients with chronic and refractory immune thrombocytopenia(ITP). Twenty chronic and refactory ITP patients received splenectomy were enrolled in ITP group and 20 cases of traumatic spleen rupture were enrolled in control group. The splenectomy efficacy in ITP patients was analyzed retrospectively. The HMGB1 expression in spleen tissue was detected by immunohistochemistry, and the correlation between different expression levels of HMGB1 and splenectomy efficacy were analysed. Meanwhile, the protein expression levels of HMGB1 in peripheral blood serum and mononuclear cells(PBMNC) of 25 patients with chronic and refractory ITP were detected by ELISA and Western blot. The median platelet count before splenectomy was 7.5 (0-20) ×109/L; all the patients showed that the initial response to splenectomy within the first month after operation was 100%, the median time of response was 1 day (1-6 days). The median peak platelet count post splenectomy was 448.5 (161-1272)×109/L. In the median time of 10(3-30) months, the platelets count in 8 patients was reduced to varying degrees. After a median follow-up of 69.5 months (22-195), complete response was found in 12 patients, 4 cases showed response and 4 did not. The HMGB1 expression positive rate in spleen of ITP patients was significantly higher than that in control group (85.0% vs 15.0%)(P<0.001). There were a negative correlation between the HMGB1 expression in ITP and therapeutic outcome after splenectomy (r=-0.791, P<0.01). In addition, HMGB1 expression levels in serum and PBMNC of the patients with chronic refractory ITP were also significantly higher than that in healthy controls (P<0.01). The splenectomy has been found to be effective therapeutic method for patients with ITP, the HMGB1 highly express in the spleen of the patients with chronic refractory ITP, but negatively correlats with the therapeutic outcome after splenectomy.

Treatment strategy of childhood immune thrombocytopenia

Immune thrombocytopenia (ITP) of childhood is the most common hemorrhagic disease which is characterized by isolated thrombocytopenia.Depending on individual patient characteristics, appropriate initial management for newly diagnosed ITP may be either watchful waiting or pharmacologic intervention.The main options for initial pharmacologic intervention include a single dose of intravenous immune globulin(IVIG)and/or a short course of glucocorticoids.For ITP children with severe or life-threatening bleeding, it is recommended that both platelet transfusions and the combination of pharmacotherapy.Approximately 20 percent of children who present with ITP will progress to chronic ITP(CITP). Children who develop CITP should have an additional evaluation to exclude other disorders.The pharmacologic options for CITP include Rituximab, and thrombopoietin (TPO)/TPO receptor agonist (Romiplostim or Eltrombopag). Combination therapy and novel immunological targeting drugs become more effective treatment options.Splenectomy is only suit for a small number of children with chronic refractory ITP patients who present significant and persistent hemorrhagic symptoms requiring repeated pharmacologic interventions. Key words: Immune thrombocytopenia; Treatment; Child

Splenectomy in Egyptian Children with Immune Thrombocytopenia: A 10-Year Retrospective Single Center Study

Splenectomy represents a second-line treatment of patients with chronic refractory immune thrombocytopenia (ITP),that is recommended to be postponed for at least 12 months after the initial diagnosis. Post-splenectomy long-term remission is achieved in more than two thirds of children with low risk of short- and long-term severe adverse events. Indication for splenectomy in pediatrics is individually based and remains on expert opinion, local practice and availability of resources. Aim of the study is to assess short- and long-term response to splenectomy in Egyptian children diagnosed with ITP.Methods: All children were diagnosed with chronic refractory ITP in Cairo University Pediatric Hospital and were candidates for a splenectomy( steroids and other immunosuppressive therapy fail to control mucous membrane bleeds and /or accomplish a hemostatic platelet count and patient usually ≥ 5 years of age ) over the past 10 years were included in the study .Their records were reviewed and they were further assessed clinically and by platelet counts. Chronic ITP children were divided into 2 groups; those who conducted a splenectomy(Group 1) and those who did not(Group2) .All patients’data was analysed. Descriptive statistics were used to describe results by percentages, means, and standard deviations and Chi square test was used to compare two of more than two qualitative groups and P ≤ 0.05 was considered the cut-off value for significance.Results: The study included 31 children diagnosed with chronic ITP and a teenage girl with newly diagnosed ITP having persistent severe menorrhagia and who was not responding to standard therapy. There were 51.6% males and 48.4% females. Their mean initial and current age was 5.1±2.8 and 10.2±4.8 years, respectively. 16.1% of patients were of consanguineous marriage and one patient had a similarly affected sibling. The mean initial platelet count was 19+/-14x109/L whilst pre- and post-splenectomy platelet counts were 24+/-19x109/L and 183+/-221x109/L, respectively. Splenectomy was conducted after a mean period of 2.9 years of follow-up. All children exhibited subcutaneous bleedings at the time of initial presentation, 24 of 32 children had mucous membrane bleeds with a mean initial hemoglobin (Hb) of 11.1+/-1.3g/L, 2 of 32 children experienced an intracranial hemorrhage and 6 of 9 teenage girls had menorrhagia. After the splenectomy 16 of 32 children had subcutaneous bleeds and 10 of 32 had mucous membrane bleeds. Treatment was administered in all children due to frequent and/or severe mucous membrane bleeds and consisted in newly diagnosed ITP of methylprednisolone (HDMP) in 61.3%, anti-D in 16.1%, immunoglobulines in 25.8%.Second line therapies in chronic ITP consisted of azathioprine in 48.4% and triple therapy (prednisolone 0.8mg/kg/d, azathioprine 2mg/kg/d, and cyclosporine 2.5mg/kg/d) in 22.6% of children . These treatments were also used to boost platelet counts pre-splenectomy. 25 of 32 children (78.1%, half requiring HDMP initially) achieved a complete remission after 2 year of follow-up. 7 of 32 children (18.9%) required post-splenectomy treatment. One patient had post-operative hernia and another died unexplained on her way to hospital with a history suggestive of ICH, although doing well before and on no treatment for 2 years. In children with chronic ITP without splenectomy(Group2), the mean initial platelet count was lower with more frequent mucous membrane bleeds (p=0.001) as compared to those who underwent splenectomy(Group1Conclusion: Splenectomy can be considered an appropriate second-line therapy for children with chronic refractory ITP especially in countries with resource constraint. DisclosuresNo relevant conflicts of interest to declare.

Thrombopoietin receptor agonists for preparing adult patients with immune thrombocytopenia to splenectomy: results of a retrospective, observational GIMEMA study.

In patients with immune thrombocytopenia (ITP) refractory to corticosteroids and intravenous immunoglobulins (IVIG), splenectomy may result at higher risk of peri-operative complications and, for this reason, potentially contraindicated. The thrombopoietin receptor agonists (TPO-RAs) romiplostim and eltrombopag have shown high therapeutic activity in primary ITP, but data of efficacy and safety regarding their use in preparation for splenectomy are missing. Thirty-one adult patients, median age 50 years, with corticosteroids and/or IVIG refractory persistent and chronic ITP who were treated with TPO-RAs (romiplostim= 24; eltrombopag= 7) with the aim to increase platelet count and allow a safer execution of splenectomy were retrospectively evaluated. Twenty-four patients (77%) responded to the use of TPO-RAs with a median platelet count that increased from 11 × 10(9) /L before starting TPO-RAs to 114 × 10(9) /L pre-splenectomy, but a concomitant treatment with corticosteroids and/or IVIG was required in 19 patients. Twenty-nine patients underwent splenectomy while two patients who responded to TPO-RAs subsequently refused surgery. Post-splenectomy complications were characterized by two Grade 3 thrombotic events (1 portal vein thrombosis in the patient with previous history of HCV hepatitis and 1 pulmonary embolism), with a platelet count at the time of thrombosis of 260 and 167 × 10(9) /L, respectively and one Grade 3 infectious event. TPO-RAs may represent a therapeutic option to improve platelet count and reduce the risk of peri-operative complications in ITP candidates to splenectomy. An increased risk of post-splenectomy thromboembolic events cannot be ruled out and thromboprophylaxis with low-molecular weight heparin is generally recommended.

Persistent Thrombopoietin Mimetic Induced Myelofibrosis in a Woman with Chronic Refractory Immune Thrombocytopenia

BackgroundImmune thrombocytopenia (ITP) is a disease caused by autoimmune destruction and impaired production of platelets. It can be primary or secondary in origin. It manifests as isolated thrombocytopenia with platelet counts less than 100 x109/L. Therapy is typically initiated when the platelet counts fall to less than 20 to 30 x 109/L in asymptomatic patients to reduce the risk of bleeding. ITP that persists for greater than 12 months is classified as chronic and ITP that endures despite splenectomy is defined as refractory. Most therapeutic approaches, such as corticosteroids, target the pathologic platelet destruction. Thrombopoietin (Tpo) mimetics, on the other hand, enhance platelet production via stimulation of the Tpo receptor on megakaryocytes. Studies suggest that Tpo mimetics increase reticulin deposition in the bone marrow. Tpo mimetics are postulated to promote reticulin deposition through stimulation of cytokine production by megakaryocytes, including transforming growth factor beta. There are reports of myelofibrosis, with abnormal deposition of collagen and reticulin in bone marrow trephine biopsies of ITP patients treated with these agents. Tpo mimetic induced myelofibrosis however, is described as reversible upon cessation of Tpo based therapy in most reports. Here we present a case of myelofibrosis induced by sequential therapy with two high dose TPO mimetics, which was not reversed six months after discontinuation of the medications.Case ReportAn 87-year-old woman with chronic ITP resistant to multiple lines of therapy (prednisone, dexamethasone, rituximab, dapsone, mycofenylate mofetil, and splenectomy) was treated consecutively with two thrombopoietin (Tpo) mimetics, romiplostim and then eltrombopag. Bone marrow evaluation at diagnosis, prior to treatment with Tpo mimetics, showed megakaryocyte hyperplasia without evidence of fibrosis. There was no definitive evidence of an underlying clonal hematologic disorder.. The patient's course was complicated by gastrointestinal and intracranial hemorrhage. Tpo mimetics were introduced as fourth line therapy. ITP response to romiplostim and then to eltrombopag was initially encouraging but rapidly fleeting.The peak dose of romiplostim used was 10 mcg/kg/week and eltrombopag was used at a dose of 75 mg per day. While on eltrombopag and within six months of romiplostim, therapy, she developed persistent left-shifted leukocytosis and a peripheral blood film showing leukoerythroblastosis and dacrocytic erythrocytes. This prompted a bone marrow evaluation that confirmed myelofibrosis, with a dense and diffuse increase in reticulin content and focal bundles of collagen (MF 2 of 3). There was associated marrow hypercellularity, increased numbers of enlarged megakaryocytes, clustered megakaryocyte topography and extensive bone resorption and remodelling Eltrombopag was promptly discontinued and peripheral blood leukoerythroblastic picture improved. Repeat bone marrow evaluation 6 months after stopping therapy showed partial reversal of the abnormalities seen in the previous marrow, including a reduction in the extent of reticulin fibrosis without any evidence of collagen fibrosis (MF 1-2 of 3). These changes are shown in Figure 1.DiscussionChronic, refractory ITP is a challenging syndrome to treat, and the Tpo mimetics have emerged as an important therapeutic option for patients who have failed traditional therapies. Clinical experience with the relatively novel Tpo mimetic drug class is maturing as we obtain longitudinal data and reports about adverse effects like myelofibrosis. While the myelofibrosis in our patient improved upon cessation of Tpo mimetic therapy, it did not resolve entirely and persisted 6 months after stopping therapy. We hypothesize that the sequential use of high dose Tpo mimetic therapy may have contributed to the development and persistence of myelofibrosis in this patient. This report adds to the body of evidence suggesting that myelofibrosis is a serious and, potentially chronic, adverse effect of treatment with Tpo mimetics.TPO mimetic treatment and B) Grade 1-2 of 3 Myelofibrosis after cessation of TPO mimetic.Semiquantitative grading is based on the 2008 WHO classification.Images from left to right represent hematoxylin andeosin, reticulin, and trichrome stains. [Display omitted] DisclosuresSholzberg:CSL Behring: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding; Amgen: Honoraria.

Successful switching from eltrombopag to romiplostim in a pediatric patient with refractory chronic ITP.

Herein, we report a successful treatment experience with romiplostim in a child with immune thrombocytopenia (ITP) refractory to eltrombopag. A 9-year-old female developed chronic ITP, which was refractory to standard treatments, including intravenous immunoglobulin, cepharanthine and splenectomy, and she thus became dependent on prednisolone (PSL). At age 12 years, eltrombopag was started, but failed to increase her platelet count. Another thrombopoietin receptor agonist (TPO-RA), romiplostim, possibly having a different mechanism of action, was then administered. Platelet counts increased and PSL could thus be terminated. Our case suggests TPO-RA alteration to potentially be effective for chronic refractory ITP.

Advances in pathogenesis of children with chronic refractory immune thrombocytopenia

Chronic refractory autoimmune thrombocytopenia (C/RITP) comprises complex and heterogeneous pathogenesis.Beyond the classic immune disorders such as platelet autoantibodies and cellular immune imbalance, other important considerations that can cause acquired C/RITP include infection, drug, vaccines, autoimmune diseases, tumor, or platelet function disorder.In addition, advances in the molecular mechanism and genetic correlations of C/RITP for children are also discussed. Key words: Chronic refractory autoimmune thrombocytopenia; Pathogenesis; Acquired; Genetic

Novel Management of Immune Thrombocytopenia in Gaucher Disease Patients

Type I Gaucher disease (GD) the is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and infiltration of bone marrow by lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in GD patients. In GD ERT treated patients, manifesting persistent low platelet counts, immune thrombocytopenia (ITP) should be considered.Treatment of GD with concomitant ITP is a challenge. Splenectomy may worsen bone manifestations in GD patients and is controversial. Steroids should be used with caution because of possible induction of osteopenia and joints avascular necrosis. Thrombopoietin receptor analogues (TPO-RA) are therapeutic option in GD patients with ITP. Beneficial use of TPO-RA is reported in 2 cases.Patient 1: 39 YO male with new onset of purpura and low platelet count failed treatment with 1 mg/kg of Prednisone. Bone marrow biopsy (BM) showed Gaucher cells infiltration, numerous atypical megakaryocytes, normal erythropoiesis and myelopoiesis with no fibrosis. Low level of ß-glucocerebrosidase activity with compound heterozygosity for 84GG /R495H mutations, established the diagnosis of Type I GD. Low C4 and detection of IgG platelet antibodies added to the diagnosis of concomitant immune thrombocytopenia. ERT with taliglucerase alfa (ElelysoTM) 60 Units/kg/month was given with Prednisone for six weeks. Occurrence of retinal bleeding and purpura, with decrease of platelet count necessitated addition of high-dose IVIG with no response regarding platelet counts. Splenectomy was not considered due to known bony complication risk in splenectomised GD patients. Rituximab was given to prevent wet purpura recurrence with short response regarding platelet count. Romiplostim was initiated raising platelet count from 29,000/µL to 60,000/µL after 3 wks. and to 90,000/µL after 8 wks. enabling corticosteroids withdrawal. Same dose Romiplostim is maintained for the last 30 months with platelet counts of 90,000 - 110,000/µL with no bleeding events. Repeated BMB showed no increase in collagen fibrosis.Patient 2: 63 YO female patient diagnosed with Gaucher at age 33 with a history of purpura, ecchymosis, and occasional vaginal bleeding episodes. At age 53 the platelet count dropped to < 20,000/µL with presence of Anti Platelets Ab (IgG). BMB revealed megakaryocytic hyperplasia with atypical forms, focal infiltration by Gaucher cells and no fibrosis. Combined therapy by ERT (Imiglucerase® followed by Velaglucerase Alfa®), Prednisone (1mg/kg/d for 2 months) and one course of IVIG yielded no increase in platelet count. The patient refused Rituximab®. Romiplostim was initiated increasing platelet count to100,000/µL maintained throughout a year of follow up. Repeated BMB showed slight increase of fibrosis and marked hyperplasia of atypical megakaryocytes.Discussion: Thrombocytopenia is often present in GD and may be severe in approximately 15% of the patients. Persistent cytopenias may be caused by other underlying pathologies such as autoimmune disorders and are important to be recognized and addressed. Before ERT era GD patients with hypersplenism and severe cytopenia were splenectomised. Risks of splenectomy include serious bacterial infection and vascular complications limiting its use in chronic refractory ITP. Splenectomy is avoided in Gaucher patients, due to risk of exacerbating skeletal complications (bone infarcts, avascular necrosis). Stable bone marrow results regarding fibrosis in our patients are consistent with data from a recent 2-year follow-up of 100 ITP patients receiving Romiplostim treatment with no evidence of BM fibrosis.Conclusion: In patients with type I Gaucher disease and concomitant ITP, adjunctive treatment with Romiplostim was successful in maintaining haemostatic platelet counts with no adverse effects. Traditional treatment regimens of corticosteroids and splenectomy should be used with caution or avoided in GD patients due to possible aggravation of Gaucher skeletal disease and the risk of osteopenia and avascular necrosis resulting in increased morbidity in this cohort of patients. Use of TPO-RA should be considered in GD patients with ITP. DisclosuresOff Label Use: Romiplostim in gaucher patients.

PSY47 - Romiplostim Cost Per Response In Itp Treatment In the Brazilian Health Care System

Immune thrombocytopenia (ITP) is characterized by isolated thrombocytopenia with no underlying cause. It manifests clinically as mucocutaneous bleeding caused by decreased platelets. Recently, two thrombopoietin receptor-agonists have emerged as an important therapeutic options: romiplostim and eltrombopag. Since these medications have different mode of administration, safety and efficacy profiles, the present study was carried out in an attempt to investigate which drug would be more cost-effective in the Brazilian setting. The objective was to perform an economic analysis evaluating the cost per response of romiplostim versus eltrombopag in adult patients with chronic ITP and refractory to other treatments as corticosteroids and immunoglobulins in Brazil health care private system. Two economic analyses were performed in order to study the use of romiplostim and eltrombopag for the treatment of adults with chronic refractory ITP, based on annual treatment costs and cost per response. The average body weight adopted was 74,6 kg. Efficacy data were obtained from the product inserts, as well as from scientific publications. In cost per response, it was considered a 6-month analysis, which corresponds to the overall platelet response in clinical trials. The outcome of these trials was the global response to treatment. The cost of each drug presentation were based on ex-factory price (VAT 18%) and obtained from the official price list (CMED; April, 2014). The cost of treatment with romiplostim showed an annual saving of R$7,724 over eltrombopag within the payer perspective, which may be further improved if we assume that drug-food interactions of eltrombopag in some patients lead to reduced medication adherence and loss of response. The cost per response with romiplostim was 26% lower than with eltrombopag. Romiplostim was more cost-effective than eltrombopag for the treatment of chronic refractory ITP in adult patients and may represent savings to the Brazilian health system.

High response rate but short‐term effect of romiplostim in paediatric refractory chronic immune thrombocytopenia

High response rate but short‐term effect of romiplostim in paediatric refractory chronic immune thrombocytopenia

Efficacy and Safety Of Eltrombopag In Korean Adult Patients With Refractory Chronic Immune Thrombocytopenia

Introduction Eltrombopag is a synthetic non-peptide thrombopoietin receptor agonist (TPO-RA), which shows an excellent treatment outcome in immune thrombocytopenia (ITP) patients. For East Asians, starting dose of eltrombopag is generally recommended as a 25 mg/day and maximal dose is restricted as a 50 mg/day because of higher plasma eltrombopag AUC values. Furthermore, sensitivity to TPO-RA may increase or decrease over time. Here, we attempted to analyze the effective eltrombopag doses to achieve and maintain safe platelet counts in Korean ITP patients. Methods A total of twelve adult chronic ITP patients were enrolled, which showed insufficient response to previous ITP treatments (platelet counts less than or equal to 30,000/uL). All patients were allowed to take concomitant low dose prednisolone or danazol. Ten patients started eltromobopag at a dose of 25 mg/day and two patients started 25 mg every other day (EOD) because of previously detected hepatic problem. The doses increased every two weeks to achieve a target platelet count (equal to or more than 50,000/uL). For patients achieving platelet count within the range of 50,000 to 200,000/uL, firstly, we reduced concomitant ITP medications and then reduced eltrombopag doses to find the lowest effective dose of eltrombopag to maintain platelet counts more than 50,000/uL (maintenance dose). Results Before starting eltrombopag treatment, patients received median 4 (ranges; 3-9) ITP treatments including 1 case of splenectomy (Table 1). Bone marrow (BM) examinations including reticulin / Masson-trichrome staining were performed and all patients confirmed not to have BM fibrosis before eltrombopag treatment. Follow-up BM examinations were performed at 1 and 2 year of eltrombopag medication. Of total 12 patients, 10 (83.3%) achieved platelet counts more than 100,000/uL, 1 (8.3%) achieved platelet between 50,000-100,000/uL and 1 (8.3%) failed to increase platelet counts. One failed patient was diagnosed as ITP 114 months ago and received eight ITP treatments before starting eltrombopag. Eleven (91.7%) patients who achieved the target platelet counts (equal to or more than 50,000/uL) could quit or reduce the dose of concomitant ITP medications and median time to achieve the target platelet counts was 21 days (6-151 days). Most common initially required dose to achieve the target platelet counts was 25 mg/day (63.6%). Others were 25 mg EOD (9.1%), 50 mg/day (18.2%) and 75 mg/day (9.1%). After achieving the target platelet counts, most common adjusted maintenance dose was 25 mg/day (63.6%). Others were 25 mg twice a week (27.3%) and 50 mg/day (9.1%). There was no more than gr. 2 bleeding episode during eltrombopag treatment. One patient who required 75 mg/day to achieve the target platelet was diagnosed as ITP 91 months ago and received nine ITP treatments before starting eltrombopag. In 11 responded patients, 9 discontinued eltrombopag medication. Among them, 6 (66.7%) were relapsed and median relapse-free survival (RFS) was 11 days (6-574 days). In an aspect of adverse events, seven (58.3%) showed hepatobiliary laboratory abnormalities (HBLA, two gr. 3), however, all HBLA resolved after reduction or short-term discontinuation of eltrombopag. Eight patients underwent follow-up BM assessment. In 2 year BM, one patient revealed gr. 1 BM fibrosis during eltrombopag medication, however, there was no significant hematologic abnormality or lactate dehydrogenase (LDH) elevation in peripheral blood and no definitive abnormal immature cell clusters in his BM specimen. Conclusions Eltrombopag was generally well tolerated and showed an excellent treatment outcome in refractory chronic ITP patients in Korea. Low doses eltrombopag (25 mg/day or 25 mg twice a week) were effective to maintain safe platelet counts in most Korean patients. However, some of the patients needed longer time and higher doses (50 or 75 mg/day) to initially achieve and to maintain the target platelet counts, especially in heavily pre-treated patients with longer time from diagnosis to starting eltrombopag treatment. Disclosures: No relevant conflicts of interest to declare.

Thrombopoietin Analogs In ITP Patients Daily Practice: Treatment Profile, Efficacy and Safety

Rationale and Objectives Thrombopoietin analogues (TPOa) are an effective alternative of treatment in patients with refractary primary immune thrombocytopenia (ITP) or chronic ITP patients with esplenectomy contraindication. Although this is their ITP indication, there are other clinical situations in day by day ITP patients clinical management in where these drugs are being used off label. We describe the treatment profile, efficacy and safety of TPOa in ITP patients in ours centers. Material and Methods ITP patients diagnosed and treated with TPOa between March 2009 and May 2013 in five centers. The study variables were: age, sex, ITP status and bleeding profile, treatment lines before TPOa, reason to use them, baseline platelet and hemoglobin, response rate, time to response, treatment duration, bleeding and adverse events. Results We analyze 62 patients (35 women), median age 51.5 years-old (10-88 years old). 32.5% of patients present refractory chronic ITP, 51% non splenectomized chronic ITP, 10% persistent and 7.5% recently diagnosed ITP. 50% receive 3 or more treatment lines before TPOa. 8 patients receive treatment because of surgery, chemotherapy or radiotherapy (1 newly diagnosed, 1 persistent and 6 chronic non splenectomized ITP). The rest are treated because of bleeding and/or thrombocytopenia severity. Reasons to non splenectomize patients are comorbidities (52.8%), patient refusal (24.5%) or non chronic ITP criteria. Median follow-up of TPOa treatment is 75 weeks (range 3-215 weeks), 91%. response rate. Median time to reach platelet count higher than 30x10e9/L is 2 weeks (1-22 weeks). Mean stable dose: eltrombopag 48.5+/-17mg/day and Romiplostin 3.4 +/-2.64mcg/kg/week with no difference between splenectomized and non splenectomized patients. 67% of chronic ITP patients present an stable response. 37% of patients require resque treatment during the follow-up. 6 (12%) patients with chronic ITP have discontinued TPOa after 6 to 24 months and they stay in response. 24 patients received only romiplostin, 22 only eltrombopag and 16 patients have been treated with the two available TPOa. One patient did not respond to any of them, another responded to romiplostin and not to eltrombopag, two to eltrombopag and not to romiplostin and the remaining 12 respond to both. 82% of patients present no bleeding event during TPOa treatment. 6 patients receive secondary prophylaxis with anticoagulants drugs and other 6 ones with antiplatelet during TPOa treatment with no haemorragic problems. In the 40 romiplostin treatments, the most common side effect was headache. We find only one case of transient elevation of transaminases among the 38 eltrombopag treatments. In 57 patients bone marrow aspirate was performed before TPOa indication, only 26 bone marrow biopsy were done. In two of these patients are described reticulin fibrosis grade 1 before treatment. No information on subsequent tests. We describe three thromboembolic events. One pulmonary embolism (PE) in a woman with vascular risk factors and history of lung cancer. The other two events were lower limbs venous thrombosis in young subjects with no risk factors or abnormally high platelet counts. Diagnosis of 1 aplastic anemia and 1 myeloma during treatment with TPOa. Four exitus, 2 intracranial bleedings, 1 PE and 1 of unknown cause. 24% of patients treated with romiplostin are on out-hospital treatmen, in most cases for reasons not related to patient autoself-treatment capacity. Conclusions New thrombopoietic agents are indicated in refractory chronic ITP or chronic ITP patients with splenectomy contraindications. There are other situations in ITP evolution where they could be useful. These off label situations can become even more prevalent than so far established indication. In our experience, these drugs are effective and safe in these others conditions but treatment should be individualized based on patient needs and comorbidities. Lack of response to one TPOa agent does not mean the other one inefficiency. Disclosures: No relevant conflicts of interest to declare.

Romiplostim in children with chronic immune thrombocytopenia (ITP): the French Experience

A minority of children with chronic immune thrombocytopenia (ITP) require therapeutic intervention to prevent haemorrhagic risk. This retrospective national study evaluated romiplostim in childhood non-responsive or refractory chronic ITP. Between 2009 and 2012, 10 patients whose Buchanan score was 3-4 were treated with romiplostim. The median duration of thrombocytopenia was 1·9years (0·8-15). The median duration of romiplostim treatment was 9months (3-36). A response was observed in 5/10 patients (one complete, four partial). No serious adverse effect was noticed. The long-term benefit/risk balance of this innovative treatment is currently recorded by Centre de Référence National des Cytopénies Auto-immunes de l'Enfant.

Multiple Cycles of Rituximab Therapy in Chronic Refractory Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated low platelet counts often leading to mucocutaneous bleeding. Administration of rituximab was shown to increase platelet counts in patients relapsing chronic ITP. However, duration of response with rituximab and the long-term benefit remains unknown. Herein, the authors presented a case of a 36-year-old splenectomised man with a relapsing ITP who received a total of 10 cycles of rituximab over the last decade with the concomitant assessments of circulating B cells. The data show that rituximab can be an effective therapy over 10 years, and monitoring B cells may help to herald ITP recurrence.

Absence of bi‐directional cross‐resistance of thrombopoietin receptor agonists in chronic refractory immune thrombocytopenia: possible role of MPL polymorphisms

Absence of bi‐directional cross‐resistance of thrombopoietin receptor agonists in chronic refractory immune thrombocytopenia: possible role of <i><scp>MPL</scp></i> polymorphisms

Long-Term Use of Open-Label Romiplostim in Children with Chronic/Refractory Immune Thrombocytopenia (ITP)

Abstract 621 Background:Treatment options for children with chronic/refractory ITP are not well characterized. In a phase 1/2 16-week randomized double-blind placebo-controlled study of 22 patients (romiplostim n = 17, placebo n = 5), the thrombopoietin (TPO) receptor agonist romiplostim was well tolerated and 15 of 17 romiplostim-treated patients achieved platelet counts ≥50×109/L (Bussel et al, Blood 2011). Twenty-one of 22 patients from this phase 1/2 study subsequently entered an open-label extension study; 1/21 patients discontinued the extension study before receiving romiplostim. For the 20 patients who received romiplostim in the first extension study, the mean duration of treatment was 1.6 years (range, 0.1 to 2.1 years); all 20 achieved platelet counts >50×109/L (Nugent et al, 2011 ASPHO abstracts). Of the 17 patients who completed this extension study, 12 rolled over into a second open-label extension study for up to 2.5 years of further romiplostim treatment. Results from those 12 patients are described here. Objective:To investigate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods:During the second extension study, patients received weekly subcutaneous injections of romiplostim with the initial dose being the same as the last dose in the prior study. Dose adjustment was allowed to maintain platelet counts in the target range of 50–200×109/L. The maximum allowed romiplostim dose was 10 μg/kg. The primary endpoint of this study was incidence of adverse events; platelet response was a secondary endpoint. The protocol did not require bone marrow biopsies to be conducted at pre-defined intervals, but any bone marrow biopsies performed as clinically indicated were to be analyzed. As deemed appropriate by investigators, patients or their caregivers had the option to administer romiplostim at home during this study; those patients who administered romiplostim at home used diary cards to record dosing date, time, volume administered, and any dosing errors. Patients who turned 18 years of age during this study were permitted to remain on study. Results:Baseline demographics for this second extension study included a median age of 12 years (range 3, 16 years), 67% male, and 33% with a prior splenectomy. Median romiplostim treatment duration in this second extension study was 118.9 weeks (range 100.1, 125.9 weeks); median average weekly romiplostim dose was 5.2 μg/kg (range 1, 10 μg/kg). Of the 3 patients who discontinued the study, 2 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 9 continued on study. Median platelet counts for all 12 patients were above 50×109/L throughout, and were in the target range of 50–200×109/L for all visits but Weeks 3 and 76 (Figure). Interestingly, the median dose decreased over time from a median (Q1, Q3) of 8.0 (5.5, 9.0) μg/kg at Week 1 to 1.0 (0.0, 6.0) μg/kg at Week 116 (last timepoint for which data are available) (Figure). Two patients received rescue medications (defined as medications used for platelet counts <10×109/L, bleeding/wet purpura, or investigator decision); one patient received platelet transfusions and another prednisone. Four patients (33.3%) had serious adverse events (asthma, epistaxis, hemangioma, hypotension, pyrexia, thrombocytopenia, and transfusion reaction) and one had a life-threatening adverse event (thrombocytopenia). None of the adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Eight patients had bleeding adverse events; one of which (gingival bleeding) was deemed treatment-related. These bleeding adverse events included epistaxis (4 patients), petechiae (3 patients), gingival bleeding (2 patients), and (in 1 patient each) bleeding from the anus, injection site, lip, and mouth; 1 patient also had unspecified bleeding. No bone marrow biopsies were reported to have been performed. Conclusion:In this open-label extension study, romiplostim increased platelet counts in pediatric patients with chronic ITP without significant toxicity. Thus, romiplostim has been well tolerated and shown to be of clinical benefit to pediatric patients with refractory severe chronic ITP. As this study is ongoing, future results will provide additional data regarding even longer-term use of TPO receptor agonists in this patient population. [Display omitted] Disclosures:Bussel:Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy; Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: The use of romiplostim in pediatric patients was examined in this study. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

Successful Management of Chronic Refractory Immune Thrombocytopenia with Laparoscopic Splenectomy in a Patient with Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a particular type of acute myeloid leukemia with characteristic biological and clinical features, the frequent association at diagnosis of a severe hemorrhagic diathesis. Immune thrombocytopenia (ITP) is a common autoimmune disease characterized by low platelet counts and an increased risk of bleeding. Here we present a patient with the diagnosis of APL who achieved and maintained a remission with an induction consisting of idarubicin and ATRA, and then developed corticosteroid refractory ITP which is successfully treated with laparoscopic splenectomy.

Bone mass and biochemical markers of bone turnover in children and adolescents with chronic immune thrombocytopenia: Relation to corticosteroid therapy and vitamin D receptor gene polymorphisms

Optional drug therapy in refractory chronic immune thrombocytopenia (ITP) includes standard oral, pulsed high-dose steroid therapy, intravenous gamma globulin, anti-D, and immunosuppressive therapy or thrombopoietin receptor agonists. This work aimed to study the bone mass in children and adolescents with chronic ITP in relation to biochemical markers of bone turnover, cumulative steroid therapy, and the possible modulating effect of vitamin D receptor (VDR) gene polymorphisms. Thirty-six children and adolescents with chronic ITP were recruited from the Hematology Clinic, Children's Hospital, Ain Shams University and the Hematology Clinic of the National Research Centre in Egypt and compared with 43 healthy age- and sex-matched controls. The total cumulative dose of steroids was calculated. Bone markers (serum osteocalcin (OC) and propeptide I precollagen (PICP) and urinary deoxypyridinoline (DPD) excretion), analysis of VDR gene distribution, and dual energy X-ray absorptiometry at lumbar and hip regions were performed for patients and controls. Compared to controls, chronic ITP patients had higher body mass index (BMI) and lower height for age standard deviation score (SDS). Chronic ITP patients had lower levels of OC and C-terminal propeptide of type I procollagen (PICP) and higher urinary DPD excretion, and bone mineral density (BMD) was significantly lower for both spine and hip z-score (<0.001). BMD was inversely correlated with urinary DPD excretion, age, BMI, and cumulative steroid dose. There was significant negative correlation between cumulative oral steroid dose and BMD (r = −0.4, P = 0.01 and r = −0.45, p = 0.001 for spine and hip z-scores, respectively), but the correlation was non-significant in relation to cumulative pulsed steroid therapy. FokI polymorphism was significantly related to BMD for both spine and hip z-score (p = 0.015 and p = 0.008, respectively), but there was no relation between BMD and Bsm1 polymorphism. FokI gene polymorphism may be one of the contributing factors in bone loss in patients on chronic steroid therapy. High cumulative doses of corticosteroids increased bone resorption in young chronic ITP patients. Longitudinal studies are needed to confirm the effect of different steroid protocols on bone turnover. Protocols of therapy of chronic ITP should restrict corticosteroid use in growing children and favor alternative less harmful therapies.

Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia

Romiplostim, a thrombopoiesis-stimulating peptibody, represents a new therapeutic option in adult refractory chronic immune thrombocytopenia (ITP). This study aimed to assess the short-term efficacy and safety of romiplostim in children with chronic ITP. Eight non-splenectomized patients with chronic ITP refractory to standard lines of medical therapy were recruited from the Pediatric Hematology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt. One patient was initially excluded because of increased bone marrow reticulin (grade 3). Therapy was initiated in seven patients, aged 3.4–15.2 years (median 5.5 years), and the disease duration ranged from 13 months to 7.3 years (median 2.4 years); none were splenectomized. Romiplostim dose was started as 1 µgm/kg/week and the dose escalated by 1 µgm/kg/week according to platelet count. The duration of therapy varied between 1 and 22 weeks (median 12 weeks). Results revealed that four out of the seven patients achieved variable response. Four patients demonstrated rapid increase in platelet count when pulse steroid therapy was added. Most reported adverse events were mild and transient. This case series study reveals variable response rate in children with chronic ITP to romiplostim therapy; addition of steroids especially in emergency bleeding situations could potentiate romiplostim thrombopoietic effect even in patients initially refractory to steroids. Romiplostim safety and efficacy in pediatric ITP needs further long-term studies.