Hemostatic Platelet Counts Research Articles

A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adults Patients with Newly Diagnosed Primary ITP (XPAG-ITP)

A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adults Patients with Newly Diagnosed Primary ITP (XPAG-ITP)

Spotlight on eltrombopag in pediatric ITP in China: a long-term observational study in real-world practice

AbstractImmune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and risk of hemorrhage. Treatment with eltrombopag increases and maintains hemostatic platelet counts; however, to date, long-term data are lacking on the outcome of children with ITP who are treated with eltrombopag. This prospective, observational, longitudinal cohort study evaluated the efficacy and safety of eltrombopag in pediatric patients with persistent or chronic ITP. For the 116 pediatric patients enrolled, duration of eltrombopag treatment was at least 3 months. Median effective dose was 25 mg/day, 50 mg/day, and 50 mg/day, respectively, for children age 5 years or younger, 6 to 11 years, or 12 years or older. In all, 89 patients (76.7%) achieved overall response, 53 (45.7%) achieved complete response, and 36 (31.0%) achieved response. Median platelet counts increased by week 1 and were sustained throughout the treatment period. During treatment with eltrombopag, the proportion of patients with grade 1 to 4 bleeding symptoms decreased from 83.61% at baseline to 9.88% at 6 months when only grade 1 was reported. Forty-three patients (37.1%) reported using concomitant medications at study entry, which was reduced to 1 patient (2.5%) who needed concomitant medications at 12 months. All adverse events were grade 1 or 2 according to Common Terminology Criteria for Adverse Events. No serious adverse events, cataracts, malignancies, or thromboses were reported during the study. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts and reducing bleeding in most pediatric patients with persistent or chronic ITP. Combined with future studies, these findings will help establish how eltrombopag should best be used in the management of pediatric patients with East Asian ancestry.

Physiological Characteristics of Platelet Activity in Calves of the Dairy and Plant Nutrition of the Holstein Breed

The hemostatic properties of platelets to a large degree determine the activity of metabolic processes that have great biological significance especially in early ontogeny. This study was conducted on 43 calves of the Holstein breed during the phase of milk-vegetable diet. It was found during the observation period that the indicators were stable in the calves between 31 and 60 days of life, and the platelet aggregation weakened. In the blood of the calves of the Holstein breed there was a slight increase in the number of discocytes. The total number of active thrombocytes in calves observed after stability between 31-60 days of life decreased during the follow-up observation. The levels of circulating platelet aggregates of small and large sizes decreased between 60 and 90 days by 66.7% and 2.5 times, respectively. This contributed to a weakening of the calves’ platelet synthesis of thromboxane, a decrease in the content of adenosinfosfatom, and to inhibition of their secretion. During the observation period, the number of actin and myosin in the platelets of the animals also decreased, which reduced the overall platelet activity. In the second part of the phase of lacto-vegetarian nutrition, the synthesis of actin and myosin in the exposed aggregate platelets weakened in the calves. The stability of the hemostatic platelet counts of the Holstein calves at the age of 31-60 days was typical, which changed their physiologically acceptable weakening by the end of observation.
 Keywords: calves, dairy plant phase, Holstein breed, platelets, aggregation, secretion

Risk factors and predictors of treatment responses and complications in immune thrombocytopenia.

Management of adult patients with immune thrombocytopenia (ITP) is often unsatisfactory, due to variable efficacy of treatment, risk of life-threatening bleeding if disease control is poor, and side effects associated with treatment. Lack of data on the platelet count threshold associated with bleeding and infection risk associated with ITP treatment limits risk/benefit clinical decision making. We reviewed medical records of all ITP patients who were admitted to our hospital between 2012 and 2017 to evaluate the platelet count threshold for bleeding, infection burden associated with treatment, and real-world efficacy of second-line treatment. We demonstrated fair discrimination between platelet count and occurrence of bleeding, with 15 × 109/L being the optimal cut-off for predicting any bleeding while 20 × 109/L had the highest negative predictive value for severe bleeding. In multivariable analyses, patients who were treated with corticosteroids for at least 2 months were 5.3 times as likely to have an infection. In addition, rituximab response was strongly associated with response to frontline corticosteroids and infection was associated with older age ≥ 65 years and corticosteroid dependence. If corticosteroids are initiated, physicians should aim for the shortest duration of treatment before switching to effective second-line agents for hemostatic platelet counts.

Tapering thrombopoietin receptor agonists in primary immune thrombocytopenia: Expert consensus based on the RAND/UCLA modified Delphi panel method

BackgroundThrombopoietin receptor agonists (TPO‐RAs) are used to treat primary immune thrombocytopenia (ITP). Some patients have discontinued treatment while maintaining a hemostatic platelet count. ObjectivesTo develop expert consensus on when it is appropriate to consider tapering TPO‐RAs in ITP, how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy. MethodsWe used a RAND/UCLA modified Delphi panel method. Ratings were completed independently by each expert before and after a meeting. Second‐round ratings were used to develop the panel’s guidance. The panel was double‐blinded: The sponsor and nonchair experts did not know each other’s identities. ResultsGuidance on when it is appropriate to taper TPO‐RAs in children and adults was developed based on patient platelet count, history of bleeding, intensification of treatment, trauma risk, and use of anticoagulants/platelet inhibitors. For example, it is appropriate to taper TPO‐RAs in patients who have normal/above‐normal platelet counts, have no history of major bleeding, and have not required an intensification of treatment in the past 6 months; it is inappropriate to taper TPO‐RAs in patients with low platelet counts. Duration of ITP, months on TPO‐RA, or timing of platelet response to TPO‐RA did not have an impact on the panel’s guidance on appropriateness to taper. Guidance on how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy is also provided. ConclusionThis guidance could support clinical decision making and the development of clinical trials that prospectively test the safety of tapering TPO‐RAs.

A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adult Patients with Newly Diagnosed Primary ITP (XPAG-ITP)

A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adult Patients with Newly Diagnosed Primary ITP (XPAG-ITP)

Tapering Thrombopoietin Receptor Agonists in Primary Immune Thrombocytopenia: Recommendations Based on the RAND/UCLA Modified Delphi Panel Method

Tapering Thrombopoietin Receptor Agonists in Primary Immune Thrombocytopenia: Recommendations Based on the RAND/UCLA Modified Delphi Panel Method

Hepatic thrombopoietin gene silencing reduces platelet count and breast cancer progression in transgenic MMTV-PyMT mice

AbstractIn humans, platelet count within the normal range is required for physiological hemostasis, but, adversely, platelets also support pathological thrombosis. Moreover, by releasing growth factors, they may enhance neoplastic proliferation. We hypothesize that platelet count correlates with platelet-dependent pathologies, even within the range of hemostatic competence. Because platelet production is promoted by thrombopoietin signaling through the myeloproliferative leukemia virus oncogene (cMPL), a receptor expressed on megakaryocytes, we evaluated the feasibility of selective targeting of hepatic thrombopoietin production to test this hypothesis. We synthesized murine- and primate-specific antisense oligonucleotides (THPO-ASO) that silence hepatic thrombopoietin gene (THPO) expression without blocking extrahepatic THPO. Repeated doses of THPO-ASO were administered to mice and a baboon, causing a sustained 50% decline in plasma thrombopoietin levels and platelet count within 4 weeks in both species. To investigate whether reducing platelet count within the translationally relevant hemostatic range could alter a neoplastic process, we administered THPO-ASO to 6-week-old transgenic MMTV-PyMT mice that develop early ductal atypia that progresses into cMPL-negative fatal metastatic breast cancer within 2 to 3 months. THPO-ASO treatment increased the average time to euthanasia (primary humane endpoint) at 2 cm3 combined palpable tumor volume. Our results show that THPO-ASO reduced blood platelet count, plasma platelet factor 4, vascular endothelial growth factor, thrombopoietin levels, bone marrow megakaryocyte density, tumor growth rate, proliferation index, vascularization, platelet and macrophage content, and pulmonary metastases vs untreated controls. These findings confirm that sustained and moderate pharmacological platelet count reduction is feasible with THPO-ASO administration and can delay progression of certain platelet-dependent pathological processes within a safe hemostatic platelet count range.

Predictors of Remission in Adults with Immune Thrombocytopenia Treated with Romiplostim

Background: In adults with ITP, thrombopoietin receptor agonists (TPO-RA) are often assumed to be lifelong therapy. However, some patients achieve treatment-free remission (TFR) by maintaining hemostatic platelet counts after discontinuing TPO-RA, despite not replacing them with other ITP medications. Predictors of safely discontinuing romiplostim have varied across studies. In an analysis of 8 romiplostim studies, 27 patients achieved TFR; more remitters than nonremitters had ITP for Aim: This multivariate analysis integrated data across multiple romiplostim studies in adults with ITP to explore predictors of TFR. Methods: Data were pooled for 911 romiplostim-treated patients in 13 ITP studies conducted from 2002 to 2014. All patients failed first-line treatments before study enrollment. Secondary thrombocytopenia patients were excluded. Romiplostim treatment was discontinued per dosing rules; 1 study included a forced taper after 1 year of romiplostim. Typically, the romiplostim dose was reduced for platelet counts >200×109/L and withheld, then reduced, for platelet counts >400×109/L. Concomitant ITP medication could be reduced for platelet counts >50×109/L. TFR was defined as a ≥6-month treatment-free period with platelet counts consistently ≥50×109/L. Univariate analysis with logistic regression examined potential predictors of TFR, including age, sex, ITP duration, prior splenectomy, platelet count (baseline and first 4 weeks), bleeding in the first 6 months, and baseline concurrent therapy. Multivariate analysis with logistic regression evaluated significant predictors from the univariate analysis. Results: TFR was achieved by 61 ITP study patients who received romiplostim. For remitters vs nonremitters, median baseline age was 53 years in both cohorts; 57% vs 61% were female; and 93% vs 88% were Caucasian (Table 1). Median ITP duration at study baseline was 0.5 years among remitters and 3.5 years among nonremitters. Prior splenectomy occurred in 21% of remitters and 36% of nonremitters. The number of prior ITP treatments was ≤3 for 74% of remitters and 39% of nonremitters. Baseline platelet count was 12 months (chronic; odds ratio [OR], 4.275; P Conclusions: In this integrated analysis of 911 adult ITP patients across 13 studies, shorter ITP duration at baseline (≤12 months) was an independent predictor of TFR. Neither previous splenectomy (which predicted TFR in 1 study) nor bleeding were independent predictors of TFR in this much larger analysis. In total, these results imply that earlier use of romiplostim in adults with ITP could be associated with greater likelihood of achieving TFR. Future studies should also explore biologic variables as predictors of TFR. Disclosures Newland:Amgen Inc., Angle, Dova Pharmaceuticals, Argenx, Rigel, Shionogi, Novartis: Consultancy; Amgen Inc., GlaxoSmithKline, and Novartis: Research Funding; Novartis: Speakers Bureau. Bussel:Uptodate: Honoraria; Protalex: Consultancy; Momenta: Consultancy; Rigel: Consultancy, Research Funding; Prophylix: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding. Bird:Amgen, Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Arnold:Novartis: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Kessler:Novo Nordisk: Honoraria, Research Funding; Biomarin: Research Funding; Genentech: Research Funding; Dimension Advisory boards: Membership on an entity9s Board of Directors or advisory committees; DSMB: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Sangamo: Research Funding; Bayer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Mayer:Novartis: Research Funding; Amgen: Research Funding. Janssens:Roche: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Novartis: Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Wang:Amgen: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

Current and evolving treatment strategies in adult immune thrombocytopenia.

SummaryImmune thrombocytopenia (ITP) is an acquired autoimmune phenomenon resulting in low platelet count and increased bleeding risk. Goals of upfront management include prompt control of severe bleeding—which is rare—as well as induction and maintenance of a hemostatic platelet count. Thus, optimal management of ITP patients is often challenging and requires a highly individualized approach. Many patients may not suffer significant bleeding despite severe thrombocytopenia and the risk of toxicity associated with treatment may outweigh its benefit. Most patients treated with standard first-line regimen of glucocorticoids achieve an initial response. However, the rate of long-term remission remains low and multiple lines of therapy are often required. Current investigations aim at defining the subgroup of patients at risk of relapse and providing intensified risk-balanced induction regimens to improve long-term disease control.This short review summarizes current and emerging treatment strategies in adult ITP.

A Randomized, Double-Blinded, Placebo Controlled Study of IVIG Vs. IVIG with High Dose Methylprednisolone in Rapidly Augmenting Platelet Counts in Childhood ITP

The combination of intravenous (IV) methylprednisolone (IVMP) and IV immune globulin (IVIG) is often used in children with immune thrombocytopenia (ITP) to rapidly increase platelet counts (PCs) to a safe hemostatic level. However, there are no controlled data to support the use of combination therapy over IVIG alone in children with severe thrombocytopenia [PC <20 x109/L] and/or life-threatening bleeding.We conducted a randomized, double-blinded, placebo controlled, multicenter, prospective study to evaluate 2 regimens: IVMP (Solu-Medrol®, UpJohn) 30 mg/kg (max. 1 gram) over 1 hour (h) followed by IVIG 1 g/kg (Gammunex 10%, Bayer) given at a rapid infusion rate (over a maximum of 3 h), vs IV placebo over 1 h followed by IVIG 1 g/kg in children with primary ITP. The goal was to evaluate the rapidity of the PC increment and associated adverse events with both regimens.Eligible patients were children [ages: 1 to 17 years (y)] with acute (defined at the time of study initiation as <6 months (mo.) since diagnosis) or chronic primary ITP (>6 mo.), with PCs <20x109/L in whom it was decided to treat with IVIG. Exclusion criteria included: previous splenectomy, life/organ threatening hemorrhage, renal disease, diabetes, hypertension, sepsis, fever >38.5°C, disseminated intravascular coagulation, pregnancy or a previous documented lack of response to IVIG.Baseline studies included: a complete blood count (CBC), a reticulocyte count, Coombs test and renal and liver function tests. CBCs were repeated at the end of the IVIG infusion, at 8±1h, 24±2h, 72±4h, day 7±2 day (d) and day 21±3d following the start of the placebo/IVMP.The primary outcome measure was the PC increment over the first 24 h following the administration of therapy; the main secondary outcome measures were the attainment of a PC of ≥20x109/L and ≥50x109/L at times + 8, +24 and +72h.Sample size was estimated based on the assumption that patients treated with placebo + IVIG would attain a mean PC at +24h of 30x109/L vs. 50x109/L for those treated with IVMP + IVIG. For 80% power to show a difference in PC of 20x109/L (at +24h)with an a of 0.025 (two-sided) and a b of 0.2, 32 patients were required.Patients were stratified by block randomization according to type of ITP (acute vs. chronic) and according to center. The trial was registered in ClinicalTrials.gov. (NCT00376077).Thirty two patients were enrolled (ages: median 8 y; min. 1.2 y; max: 17.5 y; 22 male: 10 female; 16 acute: 16 chronic; 11 were blood type O; 14 blood type A and 7 blood type B). Fourteen patients were randomized to IVMP+IVIG while 18 were randomized to placebo+IVIG. Randomization was not equal as 1 patient was randomized and then immediately declined to participate and another patient was incorrectly assigned; both were assigned to the placebo group. PCs for the 2 groups of patients at the different time points are shown in table 1. The difference in PC was statistically significant at the 24 hr time point (p<0.0001). At this time the proportion of patients achieving a PC of ≥50x109/L was 77% in the IVMP+IVIG vs 50% in the placebo+IVIG.No patient experienced a severe bleed or an unexpected severe adverse event during the study. There was a statistically significant drop in mean Hb post-treatment among all patients (baseline 133.3 (13.6) g/L to 121.6 (14.2) g/L at time +8h) but there was no difference between O and non-O blood type patients or between treatment groups.This study showed that PCs increased rapidly following administration of IVIG with or without IVMP such that by 8h post initiation of therapy 55% (17/31) of all patients had achieved a PC ≥20x109/L. The mean PC was significantly different between the groups at time +24h. Our findings provide level 1 evidence to support the use of combination therapy (IVMP+IVIG) in life threatening situations where it is deemed to important to attain as rapidly as possible a hemostatic platelet count. [Display omitted] DisclosuresBlanchette:Shire: Consultancy, Other: Member of a Data Safety Monitoring Board, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL-Behring: Research Funding; Octapharna: Other: Member of a Data Safety Monitoring Board; Biogen Idec: Research Funding; Bayer Healthcare: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau.

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.

Successful Discontinuation of Eltrombopag after Complete Remission in Patients with Primary Immune Thrombocytopenia

Background: Eltrombopag is effective and safe for treating chronic immune thrombocytopenia (ITP) patients who have not responded to previous therapy. Interestingly, some patients in whom hemostatic platelet counts are achieved with eltrombopag may sustain the platelet response when eltrombopag ceases to be administered. However, the frequency of sustained responses after discontinuing eltrombopag without additional therapy for ITP is largely unknown.Methods: A total of 260 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry were retrospectively evaluated. The study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee.Results: The median age was 62 [range, 18–93] years. There were 165 women and 95 men. According to the standard definition, patients were allocated to newly diagnosed (n=29), persistent (n=36) and chronic (n=195) ITP groups. The median time from diagnosis to eltrombopag initiation was 24 [range, 1–480] months. The median number of previous therapies was 3 [range, 0–10], including splenectomy (22%), rituximab (23%) and romiplostim (19%). The initial response rate to eltrombopag was 231/260 (89%), including 77% (n=201) cases of complete remission (platelet count ≥100 x 109/L). The median duration of eltrombopag treatment was 6 [range, 1–54] months.Eltrombopag was discontinued in 80 out of 201 (39.8%) patients who achieved CR. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=33), platelet count >400x109/L (n=29), patient’s request (n=5), aspartate aminotransferase elevation (n=3), diarrhea (n=3), thrombosis (n=3) and other reasons (n=4). For analysis of discontinuation, patients with follow-up < 6 months (n=15), newly diagnosed ITP (n=11) or patients who received concomitant or previous (6 months before) treatments at the start of eltrombopag use (n=5) were excluded. Of the 49 evaluable patients, 22 (45%) had an immediate relapse after stopping eltrombopag. One patient with sustained response after stopping treatment relapsed at 10 months. A total of 26 patients (53%) showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 [range, 6–25] months. These patients were characterized by a median time since ITP diagnosis of 46.5±114.1 months, with 4/26 having ITP <1 year. Eleven patients (42%) were male and their median age was 59 [range, 18-88] years. They had received a median of four previous treatment lines [range: 0–9 lines] and 11 (42%) were splenectomized. The median platelet count before starting eltrombopag was 22 x 109/L and that before eltrombopag withdrawal was 269 x 109/L.The main characteristics (age, gender, duration of ITP, prior anti-ITP lines, prior splenectomy, prior rituximab, prior romiplostim, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 26 patients with sustained response after stopping eltrombopag were compared with those of the 23 patients relapsing after eltrombopag withdrawal. No predictive factors of sustained response after eltrombopag withdrawal could be identified.Conclusion: Platelet response following eltrombopag cessation may be sustained in nearly half of adult patients with primary ITP after CR with eltrombopag. However, reliable markers for predicting which patients will have this response are lacking. DisclosuresNo relevant conflicts of interest to declare.

Case Studies Of Remission In Adults With Immune Thrombocytopenia (ITP) Following Cessation Of Treatment With The TPO Receptor Agonist Romiplostim

▪ BackgroundIn adults, ITP (characterized by platelet counts <100x109/L) is typically chronic, with remission reported infrequently ≥3 y post-diagnosis (Sailer, Haematol 2006). The TPO-mimetic romiplostim increases platelet counts and reduces use of concomitant ITP medications in chronic ITP. While often perceived as a long-term treatment, dose adjustment rules allow romiplostim to be discontinued when hemostatic platelet counts are reached, as reported in Amgen trials (pivotal trials, 2011 EHA, 2011 ASH) and case reports. MethodsData from 8 romiplostim trials (4 phase 3, 2 single-arm, and 2 extension trials) were examined for cases in which patients receiving romiplostim subsequently had ≥26 consecutive wks of platelet counts ≥50x109/L without romiplostim or any other ITP medications. The number of evaluable patients could not be calculated as many trials had dosing rules that did not allow for the reduction of romiplostim in patients with platelet counts <400x109/L (making remission unlikely), treatment durations varied by study, and follow-up data were not always available. ResultsTwenty-seven patients had ≥26 wk of platelet counts ≥50x109/L without romiplostim or any other ITP medications (Table; data from 4 of these patients were presented at ASH 2011). These patients had characteristics of median (Q1, Q3) time since ITP diagnosis of 2.1 (0.5, 4.2) y, with 17/27 having ITP >1 y, mean (SD) baseline platelet count of 20.9 (15.41) x109/L, median (Q1, Q3) age of 49.0 (36.0, 67.0) y, and mean (SD) maximum dose prior to remission of 4.6 (3.6) µg/kg. Of the 27 patients, 12 (44%) were splenectomized at baseline and 15 (56%) were male. Patients had from 40 to 276 cumulative wks of romiplostim with doses ranging from 0.1 to 4.3 µg/kg. Prior to romiplostim treatment, minimum platelet counts ranged from 1-37x109/L and individual average platelet counts ranged from 1-152x109/L. On treatment, minimum (1-182x109/L) and average (121-654x109/L) platelet counts ranged widely. The median (Q1, Q3) time to remission was 7.1 (1.9, 12.7) months. Only 3 patients (3, 6, 15) had bleeding of grade 3; the remainder had either bleeding of grade 1 or 2 or none. [Display omitted] ConclusionsThe patient population who entered clinical remission (platelet counts ≥50x109/L for 26 wks) after treatment with romiplostim generally had: ITP of less than 5 y duration, a wide range of ages (23-78 y), about equal proportions of men and women, were as likely to be splenectomized as not, and no significant bleeding. Therefore, it is difficult to predict which patients would have this response. Reporting of these cases was not predefined, so a prospective assessment, such as the phase 2 single-arm study currently underway (NCT01143038), will provide a more comprehensive evaluation of remission with romiplostim. Potential mechanisms for the phenomenon of remission, both in early and late stages of ITP, may involve T-regulatory cell function, increased numbers/activity of natural killer T-cells, or increased B-regulatory cell activity. Disclosures:Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; GSK: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: 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. Wang:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study

AbstractPatients with chronic immune thrombocytopenia may have bleeding resulting from low platelet counts. Eltrombopag increases and maintains hemostatic platelet counts; however, to date, outcome has been reported only for treatment lasting ≤ 6 months. This interim analysis of the ongoing open-label EXTEND (Eltrombopag eXTENded Dosing) study evaluates the safety and efficacy of eltrombopag in 299 patients treated up to 3 years. Splenectomized and nonsplenectomized patients achieved platelets ≥ 50 000/μL at least once (80% and 88%, respectively). Platelets ≥ 50 000/μL and 2 × baseline were maintained for a median of 73 of 104 and 109 of 156 cumulative study weeks, respectively. Bleeding symptoms (World Health Organization Grades 1-4) decreased from 56% of patients at baseline to 20% at 2 years and 11% at 3 years. One hundred (33%) patients were receiving concomitant treatments at study entry, 69 of whom attempted to reduce them; 65% (45 of 69) had a sustained reduction or permanently stopped ≥ 1 concomitant treatment. Thirty-eight patients (13%) experienced ≥ 1 adverse events leading to study withdrawal, including patients meeting protocol-defined withdrawal criteria (11 [4%] thromboembolic events, 5 [2%] exceeding liver enzyme thresholds). No new or increased incidence of safety issues was identified. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts in the desired range. This study is registered at www.clinicaltrials.gov as NCT00351468.

Sustained Hemostatic Platelet Counts in Adults with Immune Thrombocytopenia (ITP) Following Cessation of Treatment with the TPO Receptor Agonist Romiplostim: Report of 9 Cases,

Abstract 3281▪▪This icon denotes a clinically relevant abstract Background:While romiplostim is often perceived as a long-term treatment for adults with chronic ITP, previous data suggest that some patients can maintain hemostatic platelet counts when romiplostim is permanently discontinued, as occurred in 7 of 83 romiplostim-treated patients in the pivotal trials (Kuter et al, Lancet 2008) and as presented at the 2011 EHA meeting (Newland et al, 2011). Methods:We describe 9 patients from an open-label extension study (N = 291, Bussel et al, Blood 2009) who had ITP of various durations unresponsive to treatments such as splenectomy, corticosteroids, IVIg, anti-D, danazol, azathioprine, and rituximab. Romiplostim was administered at the same dose as in the previous study or at 1 μg/kg (if patients had previously received placebo) and adjusted by no more than 1 μg/kg weekly to maintain platelet counts at 50–200×109/L. These patients were selected for this report because romiplostim was discontinued and hemostatic platelet counts maintained for at least 6 months. Results:In these cases, patients had ITP ranging in duration from 0.1 to 5.5 years and between 2 and 5 prior ITP therapies before entering romiplostim clinical trials (Table). The duration over which romiplostim was received in these cases (previous study and extension study combined) ranged from 37 to 139 weeks. No clinically significant bleeding (grade ≥3) was observed with romiplostim in these patients during the initial studies; during the open-label extension, epistaxis in Week 10 and gastrointestinal hemorrhage in Week 18 were reported for Case 6. Examination of these 9 cases indicates that there are no factors that appear to predict which patients, after discontinuing romiplostim, will achieve hemostatic platelet counts off treatment. Of note, as this was a post hoc analysis and not a prespecified endpoint, there may be other cases in which hemostatic platelet counts were maintained without romiplostim treatment. Summary/conclusions:Dose adjustment rules allow romiplostim to be discontinued when appropriate. These case reports indicate that some patients may not require romiplostim indefinitely. In the absence of other ITP treatments (e.g., immunosuppressive therapies), hemostatic platelet counts can be maintained in certain cases after cessation of romiplostim. We believe that more such cases will become known, allowing us to gain greater insights into which ITP patients are able to discontinue romiplostim and to the relationship to the natural history of ITP and possible remission. Potential mechanisms for this phenomenon should be explored, including what role is played by the improvement of T-regulatory cell function in the presence of hemostatic platelet counts (Bao et al, Blood 2010).Table Patient dataPatient123456789Age (yrs)435154467929505138SexMMFFFMFFFITP duration (years)10.11.30.60.63.35.54.2NA0.8Splenectomy–Yes–––YesYes–YesPrior ITP therapies2232543NA2Baseline plt count216132358951113424938Romiplostim starting dose1621215111Range romiplostim dose11–651–2511–452–155151–351–8Romiplostim over X weeks this study (parent study)3 (52)21 (16)23 (52)23 (52)41 (24)91 (24)105 (24)117 (6)139 (0)Plt range on romiplostim this study3161–25532–809134–63883–26711–7469–74930–43731–7364–849Plt count before last romiplostim dose233380272267313303437309471Weeks after romiplostim discontinued4772636411661258815347Plt range after romiplostim discontinued94–174148–511213–41176–48797–496262–61172–255225–467125–366Post–study follow–up6Plt stableNANANA18 m later required ITP Rx7Plt stablePlt stableNAPlt stablePlt, platelet, NA = not available. Plt counts, × 109/L; romiplostim dose, μg/kg/week.1At initial romiplostim trial2For the latter part of the extension, baseline platelet count could be of any level.3Platelet counts for the 4 weeks after IVIg (as occurred with patients 8 and 9) were excluded.4Platelet counts >50×109/L lasted until the end of the study for all patients.5Romiplostim treatment was not continuous in these patients.6Where follow-up was available718 months post-study, this patient developed epistaxis, bruising, and petechiae, for which she received prednisone for 1 week. Romiplostim was also restarted. [Display omitted] Disclosures:Bussel:Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Rodeghiero:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Suppremol: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kessler:Amgen: Consultancy; Eisai: Consultancy; GlaxoSmithKline: Consultancy; Griffols: Consultancy, Research Funding. Terriou:Amgen: Honoraria; GSK: Honoraria. Stasi:GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Suppremol: Consultancy, Honoraria; Nycomed: Honoraria; Bayer: Honoraria; Baxter: Honoraria. Chang:Amgen: Employment, Equity Ownership. Jun:Amgen: Employment, Equity Ownership.

Evidence-Based Mini-Review: Is Indium-Labeled Autologous Platelet Scanning Predictive of Response to Splenectomy in Patients With Chronic Immune Thrombocytopenia?

Clinical scenario: An otherwise healthy 25-year-old woman returns to your office for management of chronic primary immune thrombocytopenia. She was diagnosed 6 months earlier and continues to require prednisone 15 mg daily and periodic infusions of intravenous immunoglobulin to maintain a hemostatic platelet count. You discuss second-line treatment options, including splenectomy. The patient asks if there are any means by which to predict likelihood of response to splenectomy. You have heard about the use of indium-labeled autologous platelet scanning for this purpose and wonder what the evidence shows.

Immune Thrombocytopenia

AbstractImmune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or secondary to a growing list of associated conditions (secondary ITP), and must be differentiated from other causes of thrombocytopenia. This review focuses on primary ITP in adults. The traditional goal of therapy in this population is to achieve a hemostatic platelet count of 30 × 109/L or above for most patients while minimizing treatment-related morbidity. This approach has been called into question by the recent advent of well-tolerated and effective agents for the management of ITP, including pulse-dose dexamethasone, rituximab, and the thrombopoietin receptor agonists. Recent studies suggest the potential for aggressive therapy at the time of diagnosis to alter the natural history of ITP and point to the importance of quality-of-life considerations in therapeutic decision making.

Immune Thrombocytopenia

Immune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or secondary to a growing list of associated conditions (secondary ITP), and must be differentiated from other causes of thrombocytopenia. This review focuses on primary ITP in adults. The traditional goal of therapy in this population is to achieve a hemostatic platelet count of 30×10(9)/L or above for most patients while minimizing treatment-related morbidity. This approach has been called into question by the recent advent of well-tolerated and effective agents for the management of ITP, including pulse-dose dexamethasone, rituximab, and the thrombopoietin receptor agonists. Recent studies suggest the potential for aggressive therapy at the time of diagnosis to alter the natural history of ITP and point to the importance of quality-of-life considerations in therapeutic decision making.

Immune thrombocytopenic purpura in adults

A review of recent studies was conducted to determine if guidelines promulgated by the American Society of Hematology and the British Committee for Standards in Haematology need to be updated as these were based mainly on expert opinion rather than outcomes derived from clinical trials. Recent studies suggest that most patients with immune thrombocytopenic purpura have a disease that is generally well tolerated, with little morbidity. Splenectomy remains the best 'curative' treatment for adults with chronic disease (at least 6 months of follow up). Other treatments such as anti-D, rituximab or dexamethasone may allow the decision of splenectomy to be postponed, possibly indefinitely, if hemostatic platelet count is attained. Mortality from bleeding may be relevant only in patients refractory to splenectomy. Cytotoxic agents should be reserved for patients with bleeding refractory to other treatments. Patients with platelet counts less than 30 x 10(9)/l or bleeding have to be treated but management decisions should also be based on lifestyle, age, and other medical conditions that may contribute to the risk of serious bleeding. An aggressive therapeutic approach is justified only in patients with platelet counts below 20 x 10(9)/l and those refractory to splenectomy. Newer therapies may be more targeted in their action.