Chronic Immune Thrombocytopenia Purpura Research Articles

Fostamatinib or Thrombopoietin for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients: A Real-World Assessment of Safety, Effectiveness and Cost

Introduction: Chronic immune thrombocytopenia purpura (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment starts with corticosteroids. In patients who become resistant or intolerant to corticosteroids, the thrombopoietic agents (TPOs), consisting of romiplostim (ROM), eltrombopag (ELT), and avatrombopag (AVA), or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety, effectiveness, and cost of care between fostamatinib and the TPOs were evaluated in a real-world setting. Methods: A retrospective analysis of 17 community hematology practices across the USA was conducted to identify adult ITP patients who received one of the four agents. Data collection consisted of patient demographics, disease characteristics, as well as number and type of prior treatments. From the first day until the end of treatment, data were also collected on platelet (PLT) counts, adverse events, the use of rescue IVIG, platelet transfusions, and corticosteroids. Multivariable logistic regression analysis was used to compare PLT-related endpoints between agents. Results: A sample of 179 ITP patients who had received at least one of the four agents was identified. This resulted in a final sample of 51, 87, 127, and 44 patients who received FOS, ELT, ROM, or AVA, respectively. At month six, there were no significant differences between FOS and the TPOs in terms of the proportion of patients with the PLT count being ≥30 × 103/μL, ≥50 × 103/μL as well as the proportion of patients whose PLT levels doubled relative to baseline. The frequency of thromboembolic events (TEs) was 3.9% in FOS patients compared to 9.2%, 4.7%, and 11.4% in the ELT, ROM, and AVA groups. The mean cost per patient with FOS was $99,209 (95% CI: $59,595–$115,074), compared to $92,426 (95% CI: $68,331–$115,519), $108,482 (95% CI: $84,782–$132,182), and $131,050 (95% CI: $83,327–$179,897) for ELT, ROM, or AVA, respectively. Conclusions: In this real-world analysis, FOS was comparable to the TPOs in maintaining PLTs at clinically beneficial levels. Given these findings, the choice of therapy should be based on overall patient safety, preexisting risk factors for TEs, and cost effectiveness.

RWD137 A Real-World Comparative Effectiveness Analysis of Fostamatinib Vs. Thrombopoietic Receptor Agonists (TPOS) for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients

Chronic immune thrombocytopenia purpura (ITP) is an acquired autoimmune disease characterized by antibody-induced platelet (PLT) destruction, leading to a reduction in the number of circulating PLTs. Initial treatment is with corticosteroids. In patients who become resistant to corticosteroids, the TPOs, consisting of romiplostim (ROM), eltrombopag (ELT) and avatrombopag (AVA) or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety and effectiveness between fostamatinib vs. the TPOs was evaluated in a real-world setting.

Immune Thrombocytopenia Purpura in Children in Lebanon: Prevalence, Treatment Modalities, and Clinical Outcomes in a Retrospective Study

Background: Immune thrombocytopenia purpura (ITP) is one of the most common autoimmune diseases in children characterized by a decreased number of circulating platelets combined with impaired platelet production. There is limited literature data on the prevalence and treatment modalities, and outcome of ITP in children from Lebanon. Methods: We retrospectively reviewed the demographic and clinical data of 59 patients aged 0–18 years diagnosed with ITP between January 2007 and April 2016 in different hospitals in Beirut and the south of Lebanon. Results: ITP patients represented 2.5% of the total number of children admitted to these hospitals during this period. Among the ITP children, 55.93% were male and 44.07% were female. The greatest number of ITP children were in the 1–4 year group, followed by the 5–9 year group. As for the clinical course of the disease, 40.68% of the ITP children presented acute ITP, whereas 59.32% presented chronic ITP. Among the different therapeutic approaches adopted to treat these ITP children, intravenous immunoglobulin was the most commonly used, followed by steroids, a combination of these both agents, cyclosporine, and splenectomy. Interestingly, these therapeutic modalities induced a statistically significant increase in the patients’ platelet count. In addition, the clinical course of ITP was not significantly associated with each of the age group, the platelet count at diagnosis, and gender of patients. Conclusion:This study showed the prevalence of ITP among children from Lebanon, where more than half of ITP children presented a chronic disease. Further studies are needed to evaluate additional predictors of chronic ITP among children from Lebanon and help medical providers make informed decisions about treating childhood ITP. Doi: 10.28991/SciMedJ-2022-04-04-02 Full Text: PDF

Does Chronic Immune Thrombocytopenia Lead to Hearing Loss?

Objective: We aimed to investigate the incidence of hearing loss in patients followed up for Chronic Immune Thrombocytopenia Purpura (ITP). Material and Methods: All patients over the age of 18 who referred to the hematology outpatient clinic between January and June 2020 and followed up with the diagnosis of Chronic ITP were included in the study. Hearing tests of patients diagnosed with Chronic ITP and received first-line treatment (IVIG and corticosteroid) for any reason other than ear diseases during their treatment were evaluated retrospectively. Patients with a history of hearing loss, perforation of the tympanic membrane or who had any squeal due to a previous chronic ear infection and patients who had a previous ear operation were excluded from the study. In addition, patients' age, gender, time of ITP diagnosis, platelet values at the time of diagnosis, platelet values during audiological evaluation, concomitant disease, history of splenectomy, additional drug use and ISTH-SSC Bleeding Evaluation Score data were also recorded. Results: Of the 34 cases, 58.8% (n=20) were female and 41.2% (n=14) were male. The mean age was 49.06±18.26. Similarly, when compared, usage of IVIG/Methylprednisolone, IVIG/ Methylprednisolone /Eltrombopag, and IVIG/Methylprednisolone /Rituximab/Eltrombopag was not found to be a factor that would cause hearing loss (p>0.05). No statistical correlation was found between ISTH-SSC and time of diagnosis (months) and hearing loss (p>0.05). Conclusion: Parameters such as various drugs used in the course of Chronic ITP disease, age, gender, time of diagnosis, and presence of concomitant disease do not cause hearing loss.

NEUTROPHIL COUNTS RELATED TO PRESENTATION OF COVID IN AUTOIMMUNE NEUTROPENIA?

To describe 2 cases of autoimmune neutropenia (AIN) patients infected with Sars-Cov-2. Two subjects case report. Case report 1: A girl with primary AIN since 1 year and 10 months old, maintaining severe neutropenia and mild recurrent infections. Presented to the emergency department in June/2020, at 3 years and 8 months old, with flu-like symptoms, afebrile, in good general condition. Physical examination was normal. The absolute neutrophil count (ANC) was 0.279 × 10 9 /L. At hospital admission, Sars-Cov-2 (RT-PCR) tested positive and filgrastim (G-CSF) 5 μg/kg/day was initiated. Chest X-ray was also normal and blood culture resulted negative. She remained in great general condition, afebrile, and was discharged on the 2nd day of hospitalization, with clarithromycin (15 mg/kg/day). After G-CSF, ANC: 0.494 × 10 9 /L (1 st dose), 1.431 × 10 9 /L (2 nd dose). On outpatient follow-up, she had no long-term complications from Covid-19. Case Report 2: A man with chronic immune thrombocytopenia purpura (ITP) since 2008, autoimmune hemolytic anemia since 2013, evolved with AIN on May/2020, at 42 years old, with ANC lower than 0.5 × 10 9 /L. On 6/1/2020, he had ANC 0.170 × 10 9 /L. On 6/25/2020, he started flu-like symptoms, had ANC of 5.118 × 10 9 /L, and tested positive for Sars-Cov-2 (RT-PCR). He kept high fever (102,2°F) and was hospitalized for 10 days without use of G-CSF. After discharge, on outpatient follow-up, he had no long-term complications from Covid-19, and presented ANC 0.338 × 10 9 /L (Aug/2020). At beginning of Covid-19 pandemic, severity infection in children was unknown. Today is known that most of them have milder clinical course, regardless of chronic diseases. In adults, in contrast, the inflammatory response tends to exacerbation, with more severe clinical conditions. Furthermore, many case reports of patients infected by SARS-CoV-2 with comorbidities literature are published. However, to date there are no reports on the impact of COVID-19 in AIN patients. Increased neutrophil counts during infectious episodes are common in AIN, which appears to be related to the benign course of most infections. We reported 2 cases of AIN patients diagnosed with Covid-19, both with favorable clinical outcomes despite heterogenic clinical course. On the first case, she presented few symptoms and ANC increased only after using G-CSF. On the second reported patient, there was a spontaneous increase of ANC and greater inflammatory response than the first case. It could suggest a correlation between inflammatory response to COVID-19 and ANC in cases of autoimmune neutropenia. In the reported cases, clinical course of disease and neutrophil count were different between adult and pediatric patients. It is not possible to state whether this difference is due to age group, individual response to infection or other variables. It is important to assess other cases of AIN infected by COVID 19 to better understand correlation between severity of infection and neutrophil count response.

Management of pregnant women with Refractory Immune Thrombocytopenia Purpura (ITP) receiving eltrombopag therapy at Sanjiwani Hospital, Gianyar, Indonesia

Background: Immune Thrombocytopenia Purpura (ITP) is an autoimmune disease characterized by a low level of platelets in the blood caused by accelerated platelet destruction or disruption of the thrombopoiesis due to antibodies to platelets. Drugs with similar functions to thrombopoietins (TPO) such as eltrombopag and romiplostim have been widely used and have been shown to be quite successful in treating ITP in nonpregnant patients. This case study aims to evaluate eltrombopag therapy's role in managing the refractory ITP in pregnant women.Case Presentation: A 25-year-old patient, a housewife, presented to the obstetrics clinic at Sanjiwani Hospital for the first time at a gestational age of 13 weeks for her third pregnancy, with a history of two abortions. ITP was diagnosed in 2017 during the second abortion treatment. The platelet examination results were between 32,000-66,000/?l, with platelet count during delivery planning at 34 weeks of 41,000/?l. The patient was diagnosed with chronic refractory ITP and was considered for second-line drug administration. Intravenous Immunoglobulin Therapy (IVIG) and anti-D administration as second-line drugs were not possible due to cost. The patient was given 50 mg eltrombopag per day for a week. The platelet counts increased to 202,000/?l a week after therapy. The patient then underwent vaginal delivery with a baby weight of 2,850 gram, Apgar Score of 8-10. The baby was exclusively breastfed and subjected to clinical monitoring and laboratory tests. The patient's clinical condition was favorable and the platelets fell to 20,000/?l nineteen days after delivery.Conclusion: In this case, the patient with chronic ITP refractory to steroid therapy showed an immediate response to eltrombopag. However, the platelet level decreased two weeks after the treatment cessation. More studies are needed on the use of eltrombopag in pregnant women.

Dengue hemorrhagic fever as a rare cause of chronic immune thrombocytopenic purpura\u2014a pediatric case report

BackgroundDengue is a common mosquito-borne infection in tropical countries. Dengue incidence in Sri Lanka is generally showing a rising trend. Both chronic immune thrombocytopenia purpura (ITP) children and chronic ITP triggered by dengue fever in the pediatric age group are rarely reported. This unusual presentation is a diagnostic challenge to clinicians. The authors have reported a pediatric patient who presented with chronic ITP following recovery from dengue hemorrhagic fever.Case presentationA 14-year-old previously healthy boy was initially managed as for dengue hemorrhagic fever. Following initial detection of persistent thrombocytopenia at 2 weeks post-discharge, his parents defaulted follow-up for 1 year as he remained asymptomatic. However, 1 year after initial admission, the child re-presented with ecchymotic patches and a platelet count of 30 × 103/cumm. Review of serial blood counts performed during previous hospital admission and by his parents themselves revealed persistent thrombocytopenia over preceding 12 months. Subsequently, the child had an in-depth evaluation. The diagnosis of ITP was confirmed by ruling out differential diagnosis and he was managed as for chronic ITP. His platelet counts showed good response to oral corticosteroids and he is currently being followed up at the pediatric hematology clinic.ConclusionWhile reporting, a 14-year-old boy who developed chronic ITP following dengue hemorrhagic fever, this report highlights importance of frequent monitoring of blood counts to accurately detect and manage critical phase of dengue fever. The report also highlights the value of monitoring platelet counts in post-recovery phase to ensure they have normalized.

Thrombopoietin Receptor Agonists: Eltrombopag and Romiplostim for the Treatment of Chronic Immune Thrombocytopenia Purpura.

The thrombopoietin receptor agonists, eltrombopag and romiplostim, are second-line agents used to treat chronic immune thrombocytopenia purpura (ITP) in adults and children. ITP is a rare autoimmune disease and hematologic disorder characterized by reduced platelet counts that can result in significant symptoms, such as bleeding, bruising, epistaxis, petechiae, wet purpura, or blood in the urine or stool. This article reviews ITP treatment for adult and pediatric patients, including the use of the oral agent eltrombopag and the injectible agent romiplostim, nursing considerations, and patient education.

Initial lymphocyte count's predictive value in immune thrombocytopenic purpura

ObjectiveThe objective of this study was to examine whether absolute lymphocyte count (ALC) at diagnosis correlates with the course of immune thrombocytopenia purpura (ITP) and could be considered as a prognostic factor in adults and children.Patients and methodsA retrospective study of 250 patients diagnosed as having primary ITP, including 150 adult patients and 100 children, was conducted between July 2013 and July 2018 at Hematology Department and outpatient clinic.ResultsA highly significant decrease in mean ALC was noted in chronic ITP adult cases (1.55 ± 0.69) compared with newly diagnosed ITP cases (2.99 ± 1.23) (P = 0.000). Moreover, ALC less than 2.050/mm3 was associated with a significant risk for developing chronic ITP (P = 0.000), as only eight (26.7%) cases with ALC less than 2050/mm3 developed newly diagnosed ITP, whereas 97 cases with ALC less than 2050/mm3 (80.8%) developed chronic ITP. Thus ALC less than 2050/mm3 is considered a significant risk factor for developing chronic ITP in adults. In contrast, mean ALC in pediatric cases showed a significant decrease in chronic ITP cases (2.55 ± 1.01) compared with newly diagnosed cases (3.68 ± 1.34) (P = 0.000). Moreover, ALC less than 2050/mm3 was associated with a significant risk for developing chronic ITP (P = 0.001), as only one case less than 2050/mm3 (2.5%) developed newly diagnosed ITP, whereas 17 cases less than 2050/mm3 (28.3%) developed chronic ITP.ConclusionALCs at diagnosis is statistically a strong predictor of the development of chronic ITP in adult and pediatric patients. ALC at cutoff less than 2050/mm3 is considered a significant risk factor for developing chronic ITP in adults and pediatric cases (P = 0.000 and 0.001, respectively).

Routine clinical care for chronic immune thrombocytopenia purpura in Denmark, 2009–2015

ABSTRACTObjectives: To describe routine treatment and clinical characteristics of patients with chronic ITP (cITP).Methods: We used data from Danish nationwide registers and medical records to examine routine clinical care, including splenectomy and medical treatment, of Danish patients with chronic immune thrombocytopenia (cITP, defined as two or more ITP diagnoses at least 6 months apart), i.e. treatment initiation before cITP diagnosis and treatment initiation within one year post-diagnosis for treatment-naïve patients.Results: Nearly half of all 964 cITP patients diagnosed during 2009–2015 initiated treatment between initial ITP diagnosis and chronic onset; 43% received glucocorticoids, 12% received IVIG and 18% received rituximab. Within one year post-diagnosis, 9.2% of previously untreated patients commenced therapy, most often corticosteroids and rituximab.Discussion: Our results are in line with findings of recent studies from other countries.Conclusion: We found that corticosteroids, IVIG, and rituximab are common first- choice of ITP drugs. Bleeding events occurred in nearly one third of treated patients in the year before cITP diagnosis and in 5% of the treatment-naïve patients. A substantial number of patients do not need treatment during the first 6–12 months. However, some of these patients will subsequently need treatment as the disease may worsen, indicating the need for continuous follow-up of these patients.

Zastosowanie eltrombopagu w leczeniu przewlekłej małopłytkowości immunologicznej u dziecka – doświadczenia własne

Immune thrombocytopenia purpura (ITP) is a rare autoimmune disorder but it is one of the most common bleeding disorder in childhood. Most children with this disease have acute form of ITP with self-limiting thrombocytopenia. A small subset of children with ITP has clinically significant disease with severe thrombocytopenia. We presented the case of a boy with a severe form of chronic immune thrombocytopenia who was treated for the first time six years before presented. At first autoimmunohemolytic anaemia was recognized. Next in therapeutic procedure, multi-drug treatment, including intravenous corticosteroids, intravenous immunoglobulins, and cyclosporine were used to achieve permanent improvement. Due to a chronic ITP and significant decrease platelets counts and severe symptoms of nose bleeding and anaemia, eltrombopag, thrombopoiesis stimulating factor, was used. After 16 weeks of treatment, as a result of triple therapy consisting of eltrombopag, prednisone and azathioprine, the platelets counts were normalized and the symptoms of bleeding resolved.

Improvements in Patient Health-Related Quality of Life (HRQoL) with Clinical Efficacy in Patients Treated with Eltrombopag: Final Results from the Long-Term, Open-Label Extend Study

Background:EXTEND (June 2006 to July 2015) was an open-label, dose-adjustment extension study to evaluate the safety and efficacy of eltrombopag for the treatment of patients with chronic immune thrombocytopenia purpura (cITP) who had previously been enrolled in a pivotal eltrombopag trial. CITP may lead to fatigue and interference with daily activities, and affect patient functioning and experience i.e., health-related quality of life (HRQoL).Objective:To investigate the association between platelet response and HRQoL reported by patients in the EXTEND study, employing widely used and well-validated measures.Methods:Four standard HRQoL instruments were used in this study: SF-36v2 including Physical Component Summary (PCS) and Mental Component Summary (MCS) to measure general physical and mental health status; Motivation and Energy Inventory Short Form (MEI-SF) to measure motivation and energy; Fatigue Subscale of FACIT (FACIT-F) to measure symptoms of fatigue; and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6) to measure concerns related to bleeding and bruising and their impact on usual activities. The four instruments were used at baseline (BL) and at a frequency of every 3 months until last on-treatment assessment. Patients were blinded to their current platelet count results before completing the questionnaires. HRQoL scores and mean platelet count based on clinical assessments were calculated during time periods post-baseline (BL) to <3 months, ≥3 to <6 months, and at 6-month periods thereafter. Three definitions of response in the absence of rescue therapy (composite of new cITP medication, increased dose of cITP medication from BL, platelet transfusion, and splenectomy) were considered: 1) platelet count ≥30 Gi/L (109/Liter); 2) platelet count ≥50 Gi/L; and 3) platelet count ≥50 Gi/L and > 2 times BL. Generalized estimating equations were used to assess the association between HRQoL over time and clinical response, accounting for within-patient correlation. Covariates included demographic characteristics and BL clinical characteristics (BMI, BL use of cITP medication, prior splenectomy, prior eltrombopag use, and BL platelet count).Results:302 patients were enrolled in EXTEND. Between 273 and 292 (depending on instrument) had a BL, at least one on-treatment HRQoL assessment, and platelet count information. Baseline platelet count was <30 Gi/L for 69.9% of patients. Median treatment duration was 2.4 years. During treatment, 86.8% of the patients achieved platelet response of platelet count ≥30 Gi/L, 79.8% achieved ≥50 Gi/L, and 75.2% achieved ≥50 Gi/L and 2x BL at least once during the study. All HRQoL instruments had a positive best mean change from BL greater than a minimally important difference of at least half a standard deviation from BL score or an established threshold. All four HRQoL instruments had positive association with the three platelet response definitions. The adjusted mean score increase (signifying improvement) associated with platelet response compared to no response was 0.9-1.3 for SF-36v2 PCS, 0.8-1.3 for SF-36v2 MCS, 1.3-1.9 for MEI-SF, 1.6-2.0 for FACIT-F, and 1.8-2.3 for FACT-Th6 (most p <0.05; Table 1).Conclusion:These data show positive associations between platelet response and HRQoL measurements, especially with SF-36v2 PCS, FACIT-F, and FACT-Th6. Benefits from eltrombopag therapy in increasing platelet counts may carry forward into alleviating fatigue, concerns about bleeding and bruising, as well as enhancing motivation, energy, general physical and mental health status. [Display omitted] DisclosuresSaleh:GSK: Consultancy, Research Funding, Speakers Bureau. Bussel:Boehringer Ingelheim: Research Funding; Protalex: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Rigel Pharmaceuticals: 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; Prophylix Pharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Momenta Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Symphogen: Membership on an entity’s Board of Directors or advisory committees; Shionogi: Membership on an entity’s Board of Directors or advisory committees; Sysmex: Research Funding; Immunomedics: Research Funding; Genzyme: Research Funding; Cangene: Research Funding; BiologicTx: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Burgess:Novartis: Employment. El-Ali:Novartis: Employment. Roy:Novartis: Employment. Barghout:Novartis: Consultancy. Duh:Novartis: Research Funding; Abbvie: Consultancy; Allergan: Consultancy; GSK: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Medtronic: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Ariad: Research Funding.

Granulocyte colony-stimulating factor decreases the Th1/Th2 ratio in peripheral blood mononuclear cells from patients with chronic immune thrombocytopenic purpura in vitro

Chronic immune thrombocytopenia purpura (ITP) is an autoimmune disease that exhibits an abnormally high Th1/Th2 ratio. Granulocyte colony-stimulating factor (G-CSF) has been shown to decrease the Th1/Th2 ratio in healthy donors. In this study, we investigated the effects of G-CSF treatment on the Th1/Th2 cells and the underlying mechanisms in patients with ITP in vitro. Peripheral blood mononuclear cells (PBMCs) isolated from patients with ITP and healthy controls were treated with G-CSF. Expression levels of interferon (IFN)-γ, interleukin (IL)-2, IL-4, and IL-13 in supernatants were measured by enzyme-linked immunosorbent assays. The expression of IFN-γ, IL-4, and G-CSF receptor (G-CSFR) on Th1 and Th2 cells were examined by flow cytometry and confocal microscopy. The mRNA expression of IFN-γ, IL-2, IL-4, IL-13, and T-box expressed in T cells (T-bet) and GATA-binding protein 3 (GATA-3) in PBMCs was evaluated by reverse transcription polymerase chain reaction. The results showed that G-CSF could significantly reduce the Th1/Th2 ratio in PBMCs from patients with ITP in vitro. As the concentration of G-CSF increased, Th1/Th2 ([IFN-γ+IL-2]/[IL-4+IL-13]) cytokine ratios and T-bet/GATA-3 mRNA ratios decreased in a concentration-dependent manner. Th1 cells and Th2 cells both expressed G-CSFR. These results suggest that G-CSF could decrease the Th1/Th2 ratio in the context of ITP, and elucidate the direct and indirect immunomodulatory mechanisms underlying G-CSF functions in Th1/Th2 cells, thus supporting the therapeutic potential of G-CSF in the treatment of patients with ITP.

Thrombopoiesis-stimulating agents and myelodysplastic syndromes.

Thrombocytopenia in patients with myelodysplastic syndromes (MDS) is a frequent cause of haemorrhage-related morbidity and mortality, and is associated with increased risk of leukaemic transformation and reduced overall survival. In addition, thrombocytopenia in MDS limits the tolerability and therapeutic efficacy of disease-modifying therapies, such as azacitidine or lenalidomide. The recombinant human erythropoietin (rHuEPO) erythropoiesis-stimulating agents, epoetin and darbepoetin, are an established component of anaemia management in lower-risk MDS. Their success has, in turn, driven the development of haematopoietic growth factors targeting thrombocytopenia. While recombinant thrombopoietin (THPO) proved too immunogenic for clinical use, novel thrombopoiesis-stimulating agents (TSAs) have the potential to reduce bleeding events, decrease dependency on platelet transfusions and extend exposure to disease-modifying therapies. Two TSAs, eltrombopag and romiplostim, have demonstrated benefit in chronic immune thrombocytopenia purpura (ITP) and safety and efficacy data for use of these agents in MDS is growing. However, important safety concerns remain, such as the potential for stimulation of neoplastic myeloid clones by THPO agonists. In this narrative review, we discuss the rationale and biological mechanism for TSAs in MDS, describe the agents currently available and their mechanism of action, and present current clinical data relating to TSA safety and efficacy in the context of MDS.

An analysis of outcomes and treatment costs for children undergoing splenectomy for chronic immune thrombocytopenia purpura

PurposeIndications and timing for splenectomy in pediatric chronic immune thrombocytopenic purpura (cITP) are controversial because of high spontaneous remission rates and concern for overwhelming postsplenectomy infection. The objective of this study was to assess the risks, costs, and benefits of medical and surgical intervention for children with cITP. MethodsAfter receiving institutional review board approval, medical records for all children with cITP who underwent splenectomy from 2002 through 2009 were retrospectively reviewed (n = 22). Preoperative and postoperative data were collected. Medical and surgical costs were calculated based on pharmacy charges per dose and hospital charges, respectively. ResultsThe median age at diagnosis was 11 years (range, 3-16 years). Medical management included steroids (n = 21), intravenous gamma globulin (n = 19), anti-D antibody (n = 19), or a combination of these therapies (n = 22). Nineteen patients (86%) reported side effects from medical therapy. Median age at splenectomy was 13 years (range, 6-18 years), and time to surgery was 23 months from diagnosis (range, 6-104 months). Splenectomy increased platelet counts in all children from a median of 25,500 to 380,000 postoperatively (P < .0001). One child experienced overwhelming postsplenectomy infection after a dog bite (n = 1). At the last follow-up (15 months; range, 1-79 months), 19 patients (86%) were asymptomatic with platelet counts greater than 50,000. Of the 3 children with persistent thrombocytopenia, 2 were diagnosed with secondary cITP. Median cost of splenectomy was significantly less than the cost of medical therapy ($20,803 vs $146,284; P < .0002). ConclusionEarlier surgical consultation for children with cITP may be justified given the high success rate and low morbidity, particularly given the significant complication rate and cost of continued medical treatment.

A case of ITP that'll make you go blue in the face

Immune Thrombocytopenia Purpura (ITP) is a relatively common paediatric presentation (3-8 cases per 100,000). It is usually a benign condition with spontaneous resolution occurring in 80% of cases within 6 months. Chronic ITP is only rarely associated with severe symptoms and the mainstay of treatment remains supportive care. We describe an unusual case of chronic relapsing symptomatic ITP whose refractory nature challenged conventional treatment options and triggered reflection on ITP management. 3 year old AS presented acutely with fever and extensive petechiae, following a 6 month history of easy bruising. She was initially treated for meningococcaemia but a diagnosis of ITP was subsequently made based on the findings of an isolated thrombocytopenia (with an otherwise normal blood film) in the absence of hepatospenomegaly or lymphadenopathy. Initial management was conservative. However, symptomatic cutaneous and mucosal bleeding continued associated with thrombocytopenia (&lt;20−×10 9/L). Active management was therefore considered at this stage. Lymphoproliferative, autoimmune and post-viral causes were excluded and empirical treatments were given for symptom relief. Prednisolone was ineffective and intravenous immunoglobulin provided only short-lived improvement. As symptoms persisted, a second line agent rituximab was given, achieving 10 months of remission. Following further relapse, a second course of rituximab achieved remission prior to performing a laparoscopic splenectomy. Despite this she relapsed again 6 months later. Treatment options were again reviewed and oral dapsone was started. This was ineffective and stopped due to symptomatic methaemoglobinaemia (22.6%). It was subsequently restarted at a lower dose but she again developed methaemoglobinaemia and therefore dapsone was discontinued and a yellow card was completed to highlight this dramatic reaction. Following national discussions, she was enrolled for a trial of a TPO-receptor agonist. However, whilst awaiting entry into this trial, she developed spontaneous remission – 2.5 years following initial diagnosis. Chronic ITP is rarely associated with significant thrombocytopenia and symptomatology. Medical and surgical treatments can effect remission but therapeutic cure is unusual. It is therefore essential to weigh up the risk balance when considering treatment. This case clearly highlights this point and prompts consideration of the indications for medical treatment in chronic ITP and of where the risk-benefit balance lies in complex cases such as this.

C-Mpl Is Not Expressed or Functional At Detectable Levels on Primary Chronic Lymphocytic Leukemia (CLL) Tumor Samples

Abstract 2849The development of thrombocytopenia is associated with progression of CLL to a more advanced stage and is commonly used to classify CLL into the higher disease risk categories. It has been estimated that 5% of CLL patients will present with associated immune thrombocytopenia purpura (ITP) and immune mediated destruction can exacerbate thrombocytopenia related to bone marrow infiltration. Thromopoietin (TPO) mimetics stimulate platelet production though activation of the thrombopoietin receptor (c-Mpl) on megakaryocytes and are currently indicated for chronic ITP. In principle, this approach could be considered for treatment of ITP in CLL patients. In order to rule out the possibility that c-Mpl is functionally expressed in CLL tumor cells; we analyzed expression and TPO-dependent function in primary patient samples.We have developed assays for the analysis of c-Mpl expression on the surface of B-cells in CLL patient samples and to assess functional response to ex-vivo stimulation of theses primary samples with TPO. Peripheral blood was collected from CLL patients and mononuclear cells isolated by Ficoll separation. This cohort included treatment naïve CLL samples (n=57) and CLL samples collected from subjects undergoing active treatment (n=30). CLL cells were analyzed by flow cytometry and identified based upon viability and CD5+/CD19+ expression. c-Mpl expression was measured using a novel c-Mpl-specific monoclonal antibody that was shown to be specific for c-Mpl by flow cytometry. Residual platelets associated with individual PBMC aliquot served as an internal control for c-Mpl expression. To investigate c-Mpl function, CLL cells were stimulated with rhTPO (10 ng/mL for 10 min) and induction of pSTAT5 was measured to assess a functional response to ex-vivo stimulation of TPO. In addition c-Mpl mRNA expression was surveyed in CLL by using mRNA microarray analyses to correlate c-Mpl mRNA expression with protein and functional expression of c-Mpl.Robust c-Mpl protein expression was observed in platelets from normal and CLL patients (fold over control -normal: 31.90 ± 6.39, CLL: 26.76 ± 6.57; mean ± 95%CI), no significant expression of c-Mpl was observed on CD5+/CD19+ CLL cells (fold over control −1.06 ± 0.021; mean ± 95%CI). No induction of STAT5 phosphorylation was detected in B-cell CLL cells in any of the samples stimulated with TPO (fold over control - normal: 0.90 ± 0.02, CLL: 1.04 ± 0.034; mean ± 95%CI). Microarray analysis of the CLL samples demonstrated c-Mpl mRNA expression levels equivalent to background across all CLL samples analyzed (intensity score −10.3 ± 3.0; mean ± 95%CI). In conclusion, we demonstrated a lack of cell surface c-Mpl protein expression in CLL cells. The additional data suggesting the lack of evidence for significant expression of c-Mpl mRNA expression supports the hypothesis that CLL cells do not express c-Mpl and unlikely to be stimulated in patients treated with TPO mimetics. This hypothesis will need to be tested in an appropriate clinical trial to assess the potential benefits of TPO mimetics for the treatment of thrombocytopenia in CLL patients. Disclosures:Loberg:Amgen: Employment, Equity Ownership. Wang:Amgen: Employment, Equity Ownership. Patterson:Amgen: Employment, Equity Ownership. McCaffery:Amgen: Employment, Equity Ownership.

Investigation of thrombopoietin (TPO) function in primary chronic lymphocytic leukemia cells.

6613 Background: Immune thrombocytopenia purpura (ITP) is associated with poor prognosis of chronic lymphoid leukemia (CLL). TPO mimetics have been approved for the treatment of chronic ITP and have been suggested for the use in CLL-related ITP. Before testing this hypothesis in the clinic, the hypothesized role of TPO function in CLL cells was investigated. TPO mimetics stimulate platelet production via activation of the TPO receptor, c-Mpl, thus we analyzed c-Mpl cell surface expression and functional response to TPO in primary CLL cells in samples collected from early and late stage CLL patients. Methods: Peripheral blood was collected from CLL patients and mononuclear cells isolated by Ficoll separation. CLL cells were analyzed by flow cytometry and gated based upon viability and CD5+/CD19+ expression. c-Mpl expression was measured using a tested and validated novel c-Mpl-specific monoclonal antibody by flow cytometry. CLL samples were stimulated with TPO (10 ng/mL for 10 min) and induction of pSTAT5 was measured by intracellular flow cytometry. Platelets (CD41a+) provided internal controls for c-Mpl expression and response to TPO and phorbol myristate acetate was used as a control stimulation to demonstrate that CLL cells were responsive. Results: Analysis of expression and function of c-Mpl was performed on CLL samples (n=89) including 14 patients with thrombocytopenia. While robust c-Mpl expression was observed consistently in platelets from normal and CLL patients (normal: 31.90 ± 2.83, CLL: 26.76 ± 3.31; mean ± SEM), no significant expression of c-Mpl was observed on CD5+/CD19+ CLL cells (1.06 ± 0.01; mean ± SEM). No activation of downstream signaling (pSTAT5) was detected in CLL cells in any of the samples stimulated with TPO (normal: 0.90 ± 0.007, CLL: 1.04 ± 0.02; mean ± SEM), while robust pSTAT5 was detected in platelets (normal: 10.22 ± 0.29, CLL: 6.21 ± 0.23; mean ± SEM). Conclusions: A robust/sensitive platform was developed to profile biologically relevant c-Mpl expression and function in platelets. Using this platform we demonstrate a lack of c-Mpl expression and functional response to TPO challenge in CLL cells suggesting that CLL cells are unlikely to be activated in patients treated with TPO mimetics.

Improved Regulatory T Cell Activity in Patients with Chronic Immune Thrombocytopenia Purpura Treated with Thrombopoietic Agents.

Abstract 684Immune thrombocytopenic purpura (ITP) is an autoimmune, autoantibody-mediated disease with accelerated platelet destruction and impaired platelet production resulting in. thrombocytopenia and bleeding due to breakdown of immune tolerance. We and others have reported impaired regulatory CD4+CD25hi T cells (Treg) suppressive function in ITP patients. Clinical trials using thrombopoietic agents to stimulate platelet production have shown favorable outcomes in ITP patients with increased platelet counts and reduced bleeding. Two such agents, romiplostim (Nplate) and eltrombopag (Promacta), were recently licensed in the USA and elsewhere. Information on the immune responses of patients treated with these drugs pertaining to prognosis and response to treatment are lacking. We therefore studied the immunological profile of ITP patients with an average platelet counts of 21×109/L before treatment (n=6) and those who had been more than 3 months on treatment (total n=12, average platelet count 133 ×109/L) with either Nplate (n=5), eltrombopag (n=2) or an investigational thrombopoietic agent AKR-501 (n=5). We found no statistically significant differences in the Treg frequencies (Foxp3+CD25hi in the CD4+ population) of patients pre- and on-treatment (2.4± 0.6% versus 2.9± 0.5, p=0.5). However, the Treg activity as measured by suppression of proliferation of autologous CD4+CD25 cells at 1:1 and 1:4 ratios of Tregs : CD4+CD25 cells was significantly improved in patients on treatment compared to the pre-treatment group (at 1:1 ratio, 60% on-treatment versus 41% pre-treatment, p=0.001 and at 1:4 ratio, 44% versus 24%, p=0.04) and comparable to the overall Treg activity of controls (p=0.9). [Display omitted] Improved Treg function correlated with reduction in IL-2-producing Th cells (Pearsons r=0.6, p=0.01), and patients on treatment had a 30% reduced frequency single positive type 1 IFN-g-producing Th cells (p=0.04). Circulatory levels of pro-inflammatory sCD40L in platelet poor plasma (PPP) were decreased in patients on treatment versus pre-treatment (0.54 ± 0.05 ng/ml versus 0.89 ± 0.13ng/ml, p=0.02) and comparable to controls (p=0.9). TGF-b levels in PPP strongly correlated with improved platelet counts (Pearsons r=0.8, p<0.0001) and were increased in patients following treatment (2177 ± 258 ng/ml versus 1083 ± 127 ng/ml p=0.004). In summary, our data indicates that treatment with thrombopoietic agents results in improved immune regulation by Tregs which may be responsible for the observed dampening of the pro-inflammatory Th1-associated responses. The concomitant increase in TGF-b levels and decrease in sCD40L levels, both of which are platelet-derived, are consistent with a rise in platelet counts in patients on treatment. This raises the interesting possibility that platelets in patients on treatment may play a role in improving Treg function either directly through cell-cell interactions or indirectly by release of TGF-b. In conclusion, our findings suggest that thrombopoietic agents are not immunologically inert but rather have profound effects to restore immune tolerance. Disclosures: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.

Can Rituximab Replace Splenectomy in Immune Thrombocytopenic Purpura (ITP)?.

Introduction: Immune thrombocytopenia purpura (ITP) is an autoimmune disorder characterized by premature platelet destruction by the reticuloendothelial system, mediated by autoantobodies against platelet antigens. The main goal of treatment is to provide a safe platelet count to prevent major bleeding. Current practice is to initiate treatment with corticosteroids, followed by splenectomy as the traditional second-line. Relapses still occur in a third of these patients, and splenectomy is associated with approximately 1 percent operative mortality and lifelong increased risk of opportunistic infections. Rituximab, a monoclonal antibody targeting the CD20 surface antigen on the B-lymphocytes, has shown major responses (platelet counts >50,000/microL) in approximately 50 percent, with complete remissions (CR) (platelet counts >150,000/microL) in about one-third. Although clearly a useful agent in ITP, published data is sparse; available literature is in patients with chronic refractory ITP having failed multiple prior treatments, including splenectomy. While two systematic reviews of case series in patients with chronic refractory ITP, have documented a 30 to 43 percent CR rate, the median follow-up was only 9.5 months, thereby questioning the durability of these responses. We therefore attempted to analyze our ITP patients treated with rituximab prior to splenectomy.Study: A retrospective chart review of patients with ITP treated with rituximab between January 2001 and December 2006 was carried out. Data included age, sex, date of diagnosis, previous treatments including splenectomy, platelet counts before and after treatment with rituximab, type and duration of response, and date of relapse, last follow up or death. Rituximab was administered as a weekly infusion of 375 mg/m2 for 4 consecutive weeks. We defined CR as a platelet count greater than 150 x 10^9 cell/l and partial response (PR) as between 50 and 150x10^9 provided response was sustained for 12 months.Results: A total of 29 patients were treated with rituximab in the second line setting. Eighteen (62%) had a CR, 2 (7%) had a PR, with an overall response rate (ORR) of 69%, but 6 (21%) did not respond. The average time to response was 5 weeks. An additional 3 (10%) achieved a CR which was short lived, and they had to be treated with other modalities. Neither did age, race, sex or steroid responsiveness predict response to treatment. Of note, however, amongst those who responded, majority had received rituximab soon after their diagnosis, usually within a year.Conclusions: Our study demonstrated higher CR rates to those published, with longer duration of response. This could be due to the fact that our patients received rituximab earlier in the course of their disease. We believe it underscores such a use for the drug, and would support future clinical trials like the one in Norway, prospectively looking to determine whether early treatment with Rituximab can result in durable remissions, and lead to the avoidance of splenectomy in a significant number of patients. We conclude that rituximab is an effective second line option in ITP treatment, achieving higher long lasting response rates with minimal toxicity, thereby avoiding the need for splenectomy in a majority.