Response to Steroids Predicts Response to Rituximab In Pediatric Chronic Immune Thrombocytopenia.

Abstract Abstract 3681 Background: Pediatric Immune Thrombocytopenia (ITP) has an incidence of 4–6/100,000 with 1/3 of cases becoming chronic. Treatment choice is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies (Neunert CE, et al. Pediatr Blood Cancer 2008; 51(4):513). Previous studies in ITP have not examined predictors of response to rituximab or whether response to prior treatments predicts response. Objective: To evaluate univariate and multivariable predictors of platelet count response to rituximab. Methods: After local IRB approval, 550 patients with chronic ITP enrolled in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 16 weeks of rituximab and within 14 days of steroids. Steroids were prescribed as 1–4 mg/kg prednisone or adult equivalent over 4–14 days with or without taper. The NACIR captured treatment responses both retrospectively prior to enrollment and then prospectively, and both periods were included in this analysis. The multivariable logistic regression modeling process utilized SAS 9.1 using binary variables which were either significant in the univariate analysis or clinically important. A backwards elimination procedure was used to select the final model. Results: Seventy-six (13.8%) patients were treated with rituximab. Demographics of the patients treated with rituximab include: 42% male; 81% Caucasian, 17% Black, and 2% Asian. The mean age at diagnosis of ITP was 8.4 ± SD 5.1 years. The median platelet count at diagnosis of acute ITP was 10,000/uL (IQR 5,000-20,000/uL). 19 (25%) patients had secondary ITP or Evans syndrome. Treatment with rituximab had an overall response rate of 63.2% (48/76). Univariate predictors of response to rituximab are shown in Table I. The strongest univariate predictor of response to rituximab was response to steroids. Gender, ethnicity, and race were not predictive of response to rituximab. Furthermore, other variables which did not predict rituximab response include: history of a bleeding score ≥3 (Buchanan and Adix, J Pediatr 2002; 141: 683), symptoms ≥1 month prior to ITP diagnosis, older age (age >5 years), platelets ≥20,000/uL at acute ITP diagnosis, and a positive ANA. In multivariable analysis, response to steroids remained a strong predictor of response to rituximab with an OR 6.2 (95% CI 1.8–21.3, p=0.004). Secondary ITP also remained a strong a predictor of a positive response to rituximab with an OR 5.9 (95% CI 1.2–33.3, p=0.03). Conclusion: In the NACIR, response to steroids and secondary ITP were strong predictors of response to rituximab, a finding not previously reported in children or adults. Although this finding requires further validation, this result may provide evidence that rituximab should be most considered in patients previously responsive to steroids. Disclosures: Off Label Use: Rituximab for chronic ITP. Lambert:Cangene: Membership on an entity's Board of Directors or advisory committees. Klaassen:Novartis: Research Funding; Cangene: Research Funding. Neufeld:Novartis, Inc: Research Funding.

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The North American Chronic Immune Thrombocytopenia Registry (NACIR): Demographics and Treatment Responses

Blood ◽

10.1182/blood.v116.21.2509.2509 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2509-2509

Author(s):

Rachael F. Grace ◽

Ellis J. Neufeld ◽

A. Kim Ritchey ◽

Manjusha Kumar ◽

Michael R. Jeng ◽

...

Keyword(s):

Platelet Count ◽

North American ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Evans Syndrome ◽

Chronic Itp ◽

The North ◽

Acute Itp ◽

Positive Direct

Abstract Abstract 2509 Background: Chronic pediatric immune thrombocytopenia (ITP) has an incidence of 1–2/100,000. Due to its low incidence, large studies in pediatric chronic ITP are difficult. This registry includes patients from 16 sites in the US and Canada and represents one of the largest longitudinal datasets of children/adolescents with chronic ITP. Objective: To describe the North American Chronic ITP Registry (NACIR) study population and evaluate univariate predictors of platelet count response to therapies, including IVIG, anti-D globulin (anti-D), steroids (5–14 day course), and splenectomy. Registry methods and patient characteristics: After local IRB approval, 550 patients with chronic ITP enrolled in the NACIR between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 7 days of IVIG, 10 days of anti-D, 14 days of steroids, and 30 days of splenectomy. 365 subjects had at least one 6 month follow-up report after enrollment; median duration of follow-up was 2.1 yrs. Demographics of participants include: 46% male; 84% Caucasian, 7% Black, and 7% Asian; and 20% Hispanic. Mean age at diagnosis of acute ITP was 8.7 ± SD 5.2 years. At the time of enrollment in NACIR, subjects had received a median of 2 prior treatments (range 0–7). Results: The median platelet count at diagnosis of acute ITP was 11,000/uL (IQR 6,000–31,000/uL) and at chronic ITP was 35,000/uL (IQR 18,000–66,000/uL). 69 (12.5%) patients had secondary ITP or Evans syndrome. Of those tested, 25.6% (98/359) of patients had a positive ANA (titer > 1:40), and 75/337 (22.3%) had a positive direct anti-globulin test (DAT). 27.5% of patients had an antecedent viral illness. Of the 550 subjects, 2 (0.4%) experienced life-threatening bleeding. Patients were treated as follows: 259 (47.1%) with steroids, 253 (46%) with IVIG, 189 (34.4%) with anti-D, and 64 (11.6%) with splenectomy. Overall responses to therapy included: 69.1% response to steroids, 74.3% response to IVIG, 66.7% response to anti-D, and 85.9% response to splenectomy. Univariate predictors of response to treatments are shown in Table I. Higher platelet count at chronic ITP diagnosis and DAT positive predicted a platelet response to a short course of steroids in univariate analysis. This was confirmed in multivariable analysis of potential confounders, using logistic regression with a backwards elimination procedure. Response to one type of therapy was often strongly associated with a response to a second therapy. Gender, ethnicity, race, older age, and platelets ≥20,000/uL at acute ITP diagnosis were not associated with response to any single therapy. Conclusion: The demographics and laboratory findings of the large, well characterized NACIR population are consistent with other reports of young people with chronic ITP. The novel finding that DAT positivity predicts steroid response, even with multivariable adjustment for confounders, provides evidence that the NACIR is a robust and useful tool for trying to predict response to ITP treatment strategies. Disclosures: Klaassen: Novartis: Research Funding; Cangene: Research Funding. Lambert: Cangene: Membership on an entity's Board of Directors or advisory committees.

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Association Of Platelet Function Markers, Independent Of Platelet Count, With Bleeding Score In Patients With Immune Thrombocytopenia

Blood ◽

10.1182/blood.v122.21.3534.3534 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3534-3534

Author(s):

Andrew L. Frelinger ◽

Anja J Gerrits ◽

Michelle A. Berny-Lang ◽

Travis Brown ◽

Sabrina L. Carmichael ◽

...

Keyword(s):

Platelet Count ◽

Platelet Activation ◽

Platelet Function ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Univariate Analysis ◽

Blood Draw ◽

Platelet Surface ◽

Platelet Counts ◽

Bleeding Score

Abstract Background Immune thrombocytopenia (ITP) patients with similarly low platelet counts differ in their tendency to bleed. Aim To determine if differences in platelet function in ITP patients with similarly low platelet counts partly account for the variation in bleeding tendency. Methods The relationship between bleeding scores and platelet function markers was investigated in a single center cross-sectional study of pediatric patients with ITP. Following informed consent, blood was collected from ITP patients and bleeding was graded using the Buchanan and Adix Score (J Pediatr 2002) at routine clinic visits or while admitted to the hospital. Bleeding scores were obtained by one of three hematologists blinded to platelet function results, and investigators performing platelet function tests were blinded to clinical results. Platelet function was assessed by whole blood flow cytometric measurement of unstimulated, ADP- or TRAP-stimulated platelet surface activated GPIIb-IIIa (as measured by PAC1 binding), P-selectin, and GPIb and by unstimulated, convulxin-, or ADP plus TRAP-stimulated platelet surface phosphatidylserine expression (as determined by annexin V binding). Platelet count, immature platelet fraction (IPF) and mean platelet volume (MPV) were determined by a Sysmex XE-2100, and platelet forward angle light scatter (FSC) was measured by flow cytometry. Results Platelet function and bleeding scores were evaluated in 34 consecutive consenting pediatric ITP patients (16 female, 18 male, age 9.7 ± 5.7 years [mean ± SD]). ITP was newly diagnosed (< 3 months) in 10 patients, persistent (3 -- 12 months) in 7 patients, and chronic (>12 months) in 17 patients. Platelet count at the time of the blood draw was 47 ± 55 x 109/L. The median bleeding score on day of blood draw was 1 (range 0 to 4). By univariate analysis, higher IPF, and lower platelet count were significantly associated with a higher bleeding score (odds ratio [OR] >1, p<0.05) but MPV was not. Multiple measures of platelet function were associated with bleeding scores by univariate analysis: higher levels of platelet FSC (a measure affected by multiple variables including size) surface GPIb on unstimulated, ADP- or TRAP-stimulated platelets, surface P-selectin on unstimulated platelets, and platelet FSC were associated with increased odds for higher bleeding scores (ORs each >1, p<0.05), while higher ADP- and TRAP-stimulated platelet surface activated GPIIb-IIIa and P-selectin were associated with reduced odds of higher bleeding scores (ORs each <1, p<0.05). After adjustment for platelet count, higher levels of platelet surface P-selectin on unstimulated platelets, GPIb on TRAP-stimulated platelets, and FSC remained significantly associated with increased odds for higher bleeding scores (Figure), but IPF did not. Similarly, after adjustment for platelet count, higher TRAP-stimulated percentage of P-selectin and activated GPIIb-IIIa positive platelets remained significantly associated with reduced odds of higher bleeding scores (Figure). These findings were independent of recent ITP-related treatment. Conclusions In this study of pediatric ITP patients, we identified selected platelet function markers which, independent of platelet count, are associated with increased (platelet FSC, platelet surface P-selectin on unstimulated platelets, and GPIb on TRAP-stimulated platelets) or decreased (TRAP-stimulated percent P-selectin and GPIIb-IIIa positive platelets) odds of high bleeding scores. Possible hypotheses to explain these associations are as follows: 1) Increased P-selectin on unstimulated platelets demonstrates in vivo platelet activation, possibly as a consequence of the recent bleeding. 2) Because platelet activation results in a reduction in platelet surface GPIb and increases in platelet surface activated GPIIb-IIIa and P-selectin, the ORs associated with all of these markers could be explained by reduced ability of platelets in patients with higher bleeding scores to respond to agonists. 3) While platelet FSC is partly related to size, the finding that MPV and IPF, adjusted for platelet count, were not associated with bleeding score suggests that factors other than size account for the association of platelet FSC with higher bleeding scores. Further study is required to validate these findings and determine if differences in platelet function are associated with future risk for bleeding. Disclosures: Off Label Use: Eltrombopag was given to WAS/XLT patients for treatment of thrombocytopenia. Neufeld:Shire: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Apopharma: Consultancy. Michelson:Sysmex: Honoraria.

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PETIT and PETIT 2: Treatment with Eltrombopag in 171 Children with Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v124.21.1450.1450 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1450-1450 ◽

Cited By ~ 1

Author(s):

James B. Bussel ◽

John D. Grainger ◽

Purificacion Garcia de Miguel ◽

Jenny M. Despotovic ◽

Franco Locatelli ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Counts ◽

Chronic Itp ◽

Thrombopoietin Receptor ◽

Count Response ◽

Equity Ownership

Abstract Background: Eltrombopag (EPAG), an oral thrombopoietin receptor agonist, is approved for treating thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) with insufficient response to prior therapy. Pooled data from 2 similarly designed, randomized, double-blind, placebo (PBO)-controlled studies investigating safety and efficacy of EPAG in pediatric ITP are presented here. Methods: Subjects aged 1 to <18 years with a confirmed diagnosis of persistent or chronic ITP and a platelet count <30 Gi/L at day 1 were randomized 2:1 to EPAG or PBO and stratified by age: 12–17 years (Cohort 1), 6–11 years (Cohort 2), and 1–5 years (Cohort 3). Subjects could continue baseline ITP medications. After the PBO-controlled randomized phase, subjects were permitted to complete 17 or 24 weeks of treatment with open-label (OL) EPAG. Dose was adjusted based on platelet counts to a maximum of 75 mg daily. Results: A total of 174 subjects were enrolled in both studies; 171 received ≥1 dose of EPAG. 159 subjects were randomized (intent-to-treat population), and 157 received ≥1 dose of randomized study treatment (safety population). In the randomized period, 3 EPAG and 1 PBO subject discontinued study treatment, of which 2 EPAG and 1 PBO discontinued due to adverse events (AEs). In the OL-EPAG period, an additional 14 EPAG subjects discontinued study treatment, 6 due to AEs. Males comprised 47% of the EPAG and PBO groups and 20% and 24% were East Asians, respectively. Most subjects (93%) were diagnosed with ITP for ≥12 months, and 13% were receiving ITP medications at baseline. The majority of subjects (81%) received ≥2 prior ITP therapies. Most subjects (59%) had a baseline platelet count <15 Gi/L. All 9 (6%) splenectomized subjects were randomized to the EPAG group. Randomized Period A higher proportion of EPAG versus PBO subjects (62% vs 24%; P < 0.001) achieved a response with platelet counts ≥50 Gi/L at least once between weeks 1–6 (Cohort 1, 64% vs 11%; Cohort 2, 64% vs 27%; Cohort 3, 54% vs 36%, respectively). At each week, a higher proportion of EPAG subjects had a response versus PBO (Fig. 1). A lower proportion of EPAG subjects (13%) received rescue treatment compared with PBO subjects (31%; P = 0.009). The odds of having World Health Organization (WHO) bleeding grades 1–4 (0.19; P = 0.011) and clinically significant (WHO grades 2–4) bleeding (0.29; P = 0.007) were lower for EPAG versus PBO subjects. EPAG-Only Period Sustained reduction or discontinuation of baseline ITP medications, primarily corticosteroids, was achieved by 50% of subjects; 81% of subjects had a platelet count response at least once; 52% (n = 80/154) had a platelet count response for ≥50% of assessments; and 38% (n = 58/154) responded for ≥75% of assessments. For >13 of 24 weeks, 47% of subjects achieved responses (Fig. 2). The median average daily dose for EPAG-exposed patients in Cohorts 1, 2, and 3 were 64.0 mg (0.93 mg/kg), 57.6 mg (1.50 mg/kg), and 37.0 mg (2.02 mg/kg), respectively. AEs Similar proportions of subjects in the EPAG and PBO groups reported an AE during the randomization period. The most common AEs (≥10% of subjects) were headache, upper respiratory tract infection, and nasopharyngitis in the EPAG group, and headache, epistaxis, and vomiting in the PBO group. Serious AEs (SAEs) were reported in 8% of EPAG subjects versus 12% of PBO subjects. No SAEs were reported by >1 subject in either treatment group except epistaxis, which was reported by 2 subjects in the PBO group. No SAEs were common to both treatment groups. In the randomized period, an ALT elevation of ³3 x ULN occurred in 5 (4.7%) subjects in the EPAG group and no subjects in the PBO group. In the OL period, there were an additional 7 subjects with ALT ³3 x ULN. All elevations resolved either while still on treatment or after discontinuation of study treatment. Overall, the hepatobiliary laboratory findings were mostly mild, reversible, and not accompanied by impaired liver function. Fewer EPAG than PBO subjects reported bleeding AEs (17% vs 36%, respectively). No thromboembolic events were reported. Cataract events were experienced by 2 subjects who received EPAG; both had used corticosteroids and 1 had pre-existing cataracts. Conclusions: EPAG was safe and raised platelet counts in 62% of pediatric patients with persistent and chronic ITP during the randomized phase. Treatment with EPAG was well tolerated in both studies as evidenced by the low incidence of treatment discontinuations due to AEs. Disclosures Bussel: Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Honoraria; Novartis: Honoraria; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; GlaxoSmithKline: Equity Ownership, Honoraria, Research Funding; Genzyme: Research Funding; Eisai, Inc.: Research Funding; Cangene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding. Off Label Use: Eltrombopag is a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. Use in children and adolescents will be discussed.. Grainger:GlaxoSmithKline: Honoraria; Baxter: Honoraria, Research Funding; Amgen: Honoraria. Pongtanakul:GlaxoSmithKline: Research Funding. Komvilaisak:GlaxoSmithKline: I am an investigator on this study. Other. Sosothikul:CSL Behring: Research Funding; GlaxoSmithKline: Research Funding. Drelichman:GlaxoSmithKline: I am investigator on this study. Other. David:GlaxoSmithKline: Research Funding. Marcello:GlaxoSmithKline: Employment. Iyengar:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment. Chagin:GlaxoSmithKline: Employment. Theodore:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment, Equity Ownership.

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Differential Expression of Markers of Apoptosis in Platelets From Children with Acute Versus Chronic Immune Thrombocytopenia

Blood ◽

10.1182/blood.v120.21.1092.1092 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1092-1092

Author(s):

Markus Schmugge ◽

Jeanine Winkler ◽

Sabine Kroiss ◽

Margaret L. Rand ◽

Oliver Speer

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Caspase 3 ◽

Pediatric Patients ◽

Caspase 8 ◽

Caspase 9 ◽

Platelet Apoptosis ◽

Chronic Itp ◽

Acute Itp

Abstract Abstract 1092 Immune thrombocytopenia (ITP) is a common hematologic disorder in children that can lead to severe bleeding symptoms. In most children with ITP, platelet counts return to normal after weeks to months (acute ITP), however, in about 10–20% of patients, the low platelet counts persist for 12 months or longer (chronic ITP). No biological markers have been identified to predict the duration and/or severity of ITP. We have previously reported enhanced platelet apoptosis at the time of diagnosis of ITP in pediatric patients that was ameliorated after intravenous immunoglobulin (IVIg) (Winkler et al, Br J Haematol 2012;156:508–15). We have now investigated differences in the expression of markers of apoptosis in platelets from children with acute vs. chronic ITP. 23 pediatric patients with acute ITP were investigated and compared to 10 children with chronic ITP. In addition, from the initial group of acute ITP, 6 children developed chronic ITP and initial- and follow up results were compared. Markers of apoptosis, including activated caspase-3, caspase-8 and caspase-9, phosphatidylserine (PS) exposure, dissipation of the mitochondrial inner membrane potential (ΔYm), as well as microparticle formation, were analyzed by flow cytometry. At ITP diagnosis, the mean platelet count was 4×109/L (range: 1–14×109/L) and the proportions of platelets with activated caspase-3 (median, range) (20.4%, 1.4–64%, n=23), caspase-8 (16.7%, 1.0 – 42.7%, n=12) and caspase-9 (13.1%, 5 – 59.6%, n=12) were increased. While a higher mean platelet count was found in 10 children with chronic ITP (25×109/L, 4–60G/l), the proportions of platelets with activated caspase-3 (2.6%, 0.3–11.6%), caspase-8 (5.6%, 0.3–12.6%) and caspase-9 (4.3%, 0.3–15.6%) were significantly lower compared to children at diagnosis of acute ITP, but still higher compared to healthy controls (0.95%, 0 – 5.9%; 0.7%, 0.04 – 2.3% and 0.4%, 0.03 – 2.16%, respectively; n = 11) and children with thrombocytopenia due to chemotherapy (1.3%, 0.1 – 4.6%; 1.8%, 0.9 – 3.8%; and 1.8%, 0.6 – 2.9%, respectively; n = 11). Among the 6 children (26%) who developed chronic ITP from the initial cohort of 23 children, a mean platelet count of 29 (3–67×109/L) at >12 months after initial presentation was found. Except for one, none of the children with chronic ITP presented with bleeding symptoms; the median bleeding score was 2.5 (range: 1–3) at diagnosis and 1 (range: 0–2.5) at follow up during chronic ITP. In 5 of the children who developed chronic ITP, caspase activation was studied at diagnosis and at follow up >12 months after. In all of them, the proportions of platelets with activated caspase-3 (1.6%, 0.3–3.3%), caspase-8 (4.8%, 0.3–6.3%) and caspase-9 (4.1%, 0.3–7%) were found to be significantly lower at follow up compared to the time at diagnosis. In conclusion, although platelet apoptosis is enhanced at the time of diagnosis of pediatric ITP, this is not observed in platelets from patients with chronic ITP to the same degree. Further studies are needed to investigate other markers of apoptosis in platelets in the course of acute and chronic ITP. Disclosures: No relevant conflicts of interest to declare.

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A Comparative Prospective Observational Study of Children and Adults with Immune Thrombocytopenia: 2-Year Follow-up

Blood ◽

10.1182/blood.v128.22.3741.3741 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3741-3741 ◽

Cited By ~ 1

Author(s):

Thomas Kuehne ◽

Alexandra Schifferli

Keyword(s):

Platelet Count ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Initial Diagnosis ◽

Diagnostic Methods ◽

Newly Diagnosed ◽

Time Points ◽

Platelet Counts ◽

Chronic Itp

Abstract Introduction It is widely accepted that immune thrombocytopenia (ITP) of children differs from that of adults in the clinical course, such as the rate of spontaneous remission, the bleeding risk and the need of treatment. However, this assumption is limited by incongruity of study populations and divergences of collected information, definitions, study objectives and end-points. Surprisingly, data of the Pediatric and Adult Registry on Chronic ITP (PARC-ITP) at initial diagnosis demonstrated far less differences in clinical and laboratory findings between children and adults than expected (Kühne et al. Haematologica 2011). This suggests that newly diagnosed ITP may be driven by similar pathophysiological mechanisms. Differences may occur in the ability of restoring tolerance. We analyzed 6-, 12-, and 24-month follow-up data of children and adults recorded in the PARC-ITP Registry. Design and Methods PARC-ITP is an international multi-center registry designed to collect data prospectively of children and adults with newly diagnosed ITP, and was opened in May 2004. Demographic information, diagnostic methods, clinical data, and efficacy and safety of management are continuously registered at the time of diagnosis, 6 and 12months and then yearly. Patients younger than 3 months (n=167) and those with a platelet count of >100x109/l were excluded from the analysis. Patients with missing follow-up data at certain time-points were not excluded. Remission of ITP was defined as a platelet count of >100x109/l at any time point and regardless of therapy. Platelet counts of chronic ITP were defined as being <100x109/l at 12 or 24 months. The data were analyzed with descriptive statistics. Results A total of 3'780 evaluable patients with the initial diagnosis of primary ITP were recorded in the PARC-ITP database between 2004 and 2015. There were 3360 children (3 months - 16 years) and 420 adults (≥16 years). The pediatric female: male ratio was 1:1.09, and that of adults was 1:0.54. Follow-up information was available for 67% of children at the 6-month, 49% at the 12-month and 31 % at the 24-month evaluation and in adults in 77%, 64%, and 47%, respectively. In children remission was seen at 6, 12 and 24 months in 70%, 70%, and 71%, and in adults in 45%, 49%, and 56%, respectively. Of the patients with a platelet count of <100x109/l at 6 months, 212/590 children (36%) and 42/152 adults (28%) achieved again a remission at 12-months. The platelet counts of children and adults with chronic ITP at 12 months were 46±30x109/l and 51 ±26x109/l. Adults with a diagnosis of chronic ITP at 12 and 24 months reported having no bleeding in 69% and 65% for the last follow-up period, children in 37% at both time-points. Children with thrombocytopenia at 6, 12 and 24-months received platelet-enhancing drugs in 58%, 46% and 47% and adults in 58%, 52% and 40%, respectively. The diagnosis of secondary ITP and other causes of thrombocytopenia was reported for 123 children, i.e. 3.5%, 1.9% and 1.3% at 6, 12 and 24 months, respectively and 21 adults, i.e. 3.7%, 2.3% and 1.7% at 6, 12 and 24 months, respectively. The reported cause was an infectious disease in both children (49%) and adults (52%). Discussion The PARC-ITP Registry is the first cohort of ITP patients including a mixed pediatric and adult population. Limitations include the variety of participating centers (n=74), data registration on a voluntary basis, a high percentage of loss of follow-up and an unbalanced number of children and adults. Preliminary analyses of follow-up data demonstrate similarities between children and adults in much more areas, than previously assumed. Differences in remission rates where confirmed but in a smaller extent than expected. Treatment requirement in patients with active disease was very similar in both age groups. Surprisingly, adults with a diagnosis of chronic disease exhibited a greater number of a non-bleeding phenotype than children. Conclusion Understanding differences or similarities among children and adults with ITP may guide in finding immune modulatory strategies with the goal of achieving early sustained responses. Disclosures Kuehne: Amgen: Research Funding; UCB Biosciences GmbH: Consultancy. Schifferli:Amgen: Research Funding.

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Systematic Review and Meta-Analysis Of Rituximab For The Treatment Of Immune Thrombocytopenia In Adults

Blood ◽

10.1182/blood.v122.21.1681.1681 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1681-1681 ◽

Cited By ~ 1

Author(s):

Shaan Chugh ◽

Donald Arnold ◽

Wendy Lim ◽

Mark A. Crowther ◽

Saeed Darvish-Kazem

Keyword(s):

Systematic Review ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Meta Analysis ◽

Risk Of Infection ◽

Advisory Committees ◽

Count Response

Abstract Background Rituximab, a monoclonal anti-CD20 antibody is commonly used to treat immune thrombocytopenia (ITP). Results of randomized controlled trials (RCTs) evaluating the efficacy of rituximab are conflicting. We conducted a systematic review and meta-analysis of RCTs to determine a more precise estimate of the effect of rituximab on platelet count response in adults with ITP. Methods We searched MEDLINE (from 1946), EMBASE (from 1980), and the Cochrane database using the MeSH terms antibodies, monoclonal, and purpura thrombocytopenia idiopathic and the textwords rituximab, rituxan, mabthera, and immune thrombocytopenic purpura. In duplicate, two reviewers independently assessed study eligibility, abstracted data and assessed each study for methodological quality. Results We identified 4 RCTs (n=360) that met our eligibility criteria. Each trial compared rituximab to placebo combined with other ITP treatments, including dexamethasone, or standard of care. Each trial enrolled non-splenectomized patients only. The likelihood of achieving a platelet count >100 x109/L at 6 months was greater with rituximab than placebo (relative risk [RR] 1.38, 95% CI 1.08-1.76). More patients receiving rituximab achieved a platelet count greater than 50 x109/L at 6 months (RR 1.46, 95% CI 1.18-1.80) compared to placebo. Rituximab was not associated with a reduction in the risk of any bleeding (RR 1.49, 95% CI 0.55-4.04) or an increase in the risk of infection (RR 1.33, 95% CI 0.74-2.38). Conclusions Rituximab is associated with a modest increase in the likelihood of achieving a platelet count greater than >100 x109/L at 6 months compared to placebo. No significant reduction in bleeding or increased risk of infection was observed at 6 months. Randomized trials were generally small, with relatively short follow-up. Large pragmatic multicenter comparative trials are needed to examine durability of response over a longer period of follow-up. Disclosures: Arnold: Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hoffman-LaRoche: Research Funding. Lim:Leo Pharma: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Crowther:Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Consultancy; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees.

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Rituximab As Second-Line Treatment For Chronic Immune Thrombocytopenia: Investigator-Initiated Clinical Trial In Japan

Blood ◽

10.1182/blood.v122.21.3554.3554 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3554-3554

Author(s):

Yoshitaka Miyakawa ◽

Shinya Katsutani ◽

Takahiro Yano ◽

Shosaku Nomura ◽

Kaichi Nishiwaki ◽

...

Keyword(s):

Clinical Trial ◽

Platelet Count ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Pharmaceutical Research ◽

Japanese Patients ◽

Efficacy And Safety ◽

Platelet Counts ◽

Chronic Itp ◽

Chronic Immune Thrombocytopenia

Abstract The American Society of Hematology guidelines recommend rituximab as second-line treatment, as well as splenectomy and thrombopoietin receptor agonists (TPO-RAs), for chronic immune thrombocytopenia (ITP). However, rituximab has not been approved for the treatment of chronic ITP in Japan. To establish chronic ITP as a new indication for rituximab, we conducted an investigator-initiated clinical trial to clarify the efficacy and safety of rituximab for Japanese patients with ITP. This study was designed as a single-arm, multicenter phase III study. Patients diagnosed with chronic ITP who were previously treated with at least one therapy for ITP and whose platelet count was ≤ 30,000/μL were included. Patients with a past history or current hepatitis B virus, hepatitis C virus or HIV infection, who were treated with splenectomy within 12 weeks or with TPO-RA within 4 weeks were excluded. Rituximab at a dose of 375 mg/m2was intravenously infused once weekly for 4 weeks. Patients were premedicated with acetaminophen, restamin and hydrocortisone to prevent infusion reactions. Platelet counts, bleeding symptoms, and B lymphocyte counts were observed once monthly following the protocol. The primary endpoint was the proportion of patients whose platelet count was ≥ 50,000/μL 24 weeks after treatment with rituximab. Between October 2011 and January 2013, 26 patients were enrolled in this study from 10 hospitals in Japan. Median age of the patients was 40 years and 89% were female. Baseline platelet counts were 23,000/μL. Median interval from diagnosis of ITP to commencing rituximab therapy was 5.9 years. Previous treatment of ITP was corticosteroids (69%), splenectomy (15%), TPO-RA (27%) and intravenous immunoglobulins (39%). At baseline, 58% of patients had some bleeding symptoms. Median number of previous ITP treatments was two. All patients completed the study. At 24 weeks after treatment, 30.8% (95% CI: 14.3–51.8%) of patients achieved platelet counts > 50,000/μL. Seven of eight responders demonstrated improvement until 8 weeks. Platelet count was significantly increased compared with baseline (P<0.001). No unknown severe adverse events were observed. Subgroup analyses showed that ITP duration was numerically associated with the efficacy rate (46% vs 15% for duration< median vs ≥ median, respectively). Bleeding symptoms measured with the WHO bleeding scale were improved compared with baseline. We demonstrated the efficacy and safety of rituximab in Japanese patients with chronic ITP. The response rate was similar to that in previous reports in the US and Europe. We plan to propose that the Japanese government approve chronic ITP as a new indication for rituximab. Disclosures: Miyakawa: Fuji film: Consultancy; Alexion pharmaceuticals: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; KyowaHakkoKirin: Consultancy, Honoraria; Shire: Honoraria. Off Label Use: rituximab, clinical trial. Nishiwaki:Chugai pharmaceutical: Research Funding; Zenyaku Kogyo: Research Funding. Higashihara:Alexion: Honoraria; Asahi Kasei Pharma: Honoraria; Janssen pharma: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Shionogi: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; KyowaHakkoKirin: Honoraria, Research Funding; Boehringer-Ingeheim: Honoraria; Daiichi Sankyo: Honoraria; Yakurt: Honoraria; Astellas: Research Funding; Pfizer: Research Funding; Teijin: Research Funding; Meiji Seika pharma: Research Funding; Venesis: Research Funding; Baxter: Research Funding; Torii pharmaceutical: Research Funding; Bristol-Myers Squibb: Research Funding; Dainippon Sumitomo: Research Funding; Taiho: Research Funding; Taisho Tomiyama: Research Funding; MSD: Research Funding. Nishikawa:Daiichi-Sankyo: Research Funding. Ozaki:Chugai pharmaceutical: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria. Kanakura:Alexion Pharmaceuticals: Research Funding, Speakers Bureau. Okamoto:Novartis : Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; GlaxoSmithKlein: Honoraria, Research Funding; KyowaHakkoKirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding.

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A Phase 3 Study of Eltrombopag Vs. Standard First-Line Management for Newly Diagnosed Immune Thrombocytopenia in Children

Blood ◽

10.1182/blood-2019-125487 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2369-2369

Author(s):

Kristin A. Shimano ◽

Rachael F. Grace ◽

Carolyn M. Bennett ◽

Robert J Klaassen ◽

Cindy Neunert ◽

...

Keyword(s):

Platelet Count ◽

Treatment Failure ◽

Standard Therapy ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Newly Diagnosed ◽

Platelet Response ◽

First Line ◽

Chronic Itp ◽

Thrombopoietin Receptor

Background: Immune thrombocytopenia (ITP) is the most common autoimmune cytopenia diagnosed in children, typically causing a severely low platelet count, variable bleeding symptoms, and reductions in health-related quality of life (HRQoL). Eltrombopag is an established therapy for pediatric patients with chronic ITP. Favorable safety and efficacy were shown in the PETIT and PETIT2 trials leading to FDA-approval for children with chronic ITP in 2015. Off-label use of eltrombopag for adults with newly diagnosed ITP has been described in two small single-center trials. Gomez-Almaguer et al. reported 100% response (platelets >30 x 109/L) at completion of therapy and 66.7% relapse-free survival at 1 year in a single-arm study of dexamethasone in combination with 4 weeks of eltrombopag upfront in adult patients with newly diagnosed ITP, better outcomes than expected for comparable patients treated with steroids alone. In a second study, Tripathi et al. found 76% of steroid-nonresponsive patients had a durable response to eltrombopag after 3 months of therapy. Pediatric hematologists are already using thrombopoietin receptor agonists (TPO-RAs) in some cases of newly diagnosed ITP, according to a retrospective study by Neunert et al. TPO-RAs may be an efficacious first-line therapy for newly diagnosed ITP patients who require treatment. Study Design and Methods: The PINES (Pediatric ITP Newly diagnosed patients Eltrombopag vs Standard therapy) Study, NCT03939637, is an investigator-initiated prospective, open label, randomized, multi-center trial sponsored by the ITP Consortium of North America (ICON) and funded by Novartis. The primary objective is to determine if the proportion of patients with a platelet response, defined as ≥ 6 of 8 weeks with platelets >50 x109/L during weeks 5-12 of therapy without rescue treatment, is significantly greater in patients with newly diagnosed ITP treated with eltrombopag than in those treated with standard first-line treatments. This is a primary outcome used in a previous pediatric study of eltrombopag in chronic ITP (PETIT2) and is a clinically relevant outcome measuring a sustained, rather than transient, platelet response. Patients (n=156) from 20 ICON centers will be randomized 2:1 to receive the experimental treatment, eltrombopag, or investigator's choice of 3 standard front-line therapies: prednisone, intravenous immune globulin, or anti-D globulin at protocol-specified doses (Figure). Eligible patients are ages 1 to <18 with primary ITP, within 3 months of diagnosis, with platelet count <30 x109/L who require pharmacologic treatment from the perspective of the treating clinician. There are 2 treatment groups: 1) upfront treatment, defined as patients within 10 days of ITP diagnosis with no prior treatment, and 2) treatment failure, defined as patients previously managed with observation or a first-line standard agent. Patients are excluded if they have severe bleeding, defined by Buchanan Overall Grade 4 or 5 bleeding or bleeding requiring emergent treatment in the opinion of the provider. Patients will be followed for 1 year. Patients may receive prednisone, intravenous immune globulin, or anti-D globulin as rescue treatments beyond their study-assigned treatment in the first 12 weeks of the study. Patients randomized to the eltrombopag arm may continue this treatment throughout the 1-year duration of study participation if needed, with guidelines given for dose adjustments. Treatment after the first 12 weeks of study in the standard therapy arm or for patients originally assigned to eltrombopag who do not respond is at the discretion of the treating physician. Randomization is stratified by age and treatment status (upfront treatment vs. treatment failure). A one-sided z-test, at alpha=0.025, will be used to compare the proportion of patients who have a platelet response between the two arms. All randomized patients will be analyzed in the intention-to-treat analysis. Secondary objectives include comparison of bleeding scores (WHO Bleeding Scale and Modified Buchanan Score), changes in HRQoL (measured by the Kids ITP Tool, Hockenberry Fatigue Scale, PROMIS, and Global Change Scale), and changes in percentage of CD4+25+Foxp3+ regulatory T cells. Samples will be banked for optional future biology studies. Site activation and enrollment began in May 2019, and updated enrollment data will be presented at the meeting. Figure Disclosures Shimano: Novartis: Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bennett:Novartis: Research Funding. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored). London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Despotovic:Novartis: Research Funding; Amgen: Research Funding; Dova: Honoraria. OffLabel Disclosure: Eltrombopag is a thrombopoietin receptor agonist FDA-approved for use in chronic ITP.

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Immunomodulation with Romiplostim in Young Adult Primary Immune Thrombocytopenia (ITP) As Second-Line Strategy (iROM-study)

Blood ◽

10.1182/blood-2021-146648 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3149-3149

Author(s):

Alexandra Schifferli ◽

Axel Rüfer ◽

Alicia Rovo ◽

Nathan Cantoni ◽

Andreas Holbro ◽

...

Keyword(s):

Platelet Count ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Wilcoxon Test ◽

Second Line ◽

Newly Diagnosed ◽

Chronic Itp ◽

Primary Immune Thrombocytopenia ◽

Stopping Treatment ◽

Induction Of Tolerance

Abstract Introduction : To date most treatment strategies of primary immune thrombocytopenia (ITP) are symptomatic, preventing premature platelet destruction and increasing their production. New strategies should focus on targeting the immune dysregulation, rather than the platelet count. Rituximab and dexamethasone have the potential to induce tolerogenic mechanisms, however with moderate long-term results (<30%). Thrombopoietin-receptor agonists (TPO-RAs) obviously have the potential to affect the course of the disease with up to 30% treatment-free remission. Possible mechanisms could be exposure to high-dose antigen and/or the innate immune activity of platelets, especially the release of TGF-ß, which may stimulate or restore regulatory T cells (Tregs). Tregs play a fundamental role in the maintenance of immune tolerance. Previous studies have shown lower and impaired function of Tregs in the peripheral blood of ITP patients. Methods: The iROM study is a national multi-center, open label, single arm pilot study that aims to explore possible immunomodulatory effects of romiplostim administered as second line drug in young adults with ITP. Patients who failed, did not tolerate or relapsed after first-line treatment with steroids and/or intravenous immunoglobulin (IVIG) were included, irrespective of disease duration. Romiplostim was administered subcutaneously for 22 weeks and then stopped. The dose was adjusted every week depending on platelet response, following the product information (target platelet count 50-200x10 9/l). Follow-up was performed until week 52. Immunologic investigations were done at weeks 1, 6, 12, 22 and 52. Tregs (CD4 +, CD25 +, CD127 low) were investigated by flow cytometry and reported as percentage Tregs/CD3. Because of comedication at week 1 (IVIG, steroids), week 6 was defined as the initial immunological state. Confirmatory tests were performed using a paired samples Wilcoxon test at a two-sided alpha of 5%. The p-values are adjusted using the Holm method for all secondary analyses. Results: Between 2016 and 2020, 15 patients were enrolled, including two dropouts. Of the 13 patients analyzed, 9 had newly diagnosed ITP (<3 months), median age 31 years (IQR 8), and 4 chronic ITP (>12 months), median age 31.5 years (IQR 8.75), with a median platelet count at enrollment of 26x10 9/l (IQR 41) and 49.5x10 9/l (IQR 88.5), and at week 52, 168x10 9/l (IQR 88) and 96x10 9/l (IQR 23.5), respectively. All patients were on ITP treatment at enrollment (steroids and/or IVIG). In 6 out of 9 patients with newly diagnosed ITP, discontinuation of romiplostim was successful with sustained treatment-free complete remission (TFR) at 1 year, whereas all patients with chronic ITP relapsed and restarted various treatments. Interestingly, romiplostim dose titration was lower and platelet count response higher and more stable in patients achieving TFR (Fig 1). Platelet counts in patients with relapse showed a very jagged curve over the 22 weeks of treatment. Tregs increased between weeks 6 and 22 (end of treatment), so as between weeks 6 and 52 (end of study) in the whole group of patients with a median change of 0.62 (CI95 (0.14, 1.26)) (p=0.017) at end of study. Tregs variation for patients with sustained TFR versus no remission is shown in Fig 2a, and for the 9 patients with newly diagnosed ITP in Fig 2b. Conclusion : These results support the assumption that early treatment of ITP with TPO-RAs, e.g. romiplostim, could positively influence the natural course of ITP. Induction of tolerance may be more successful in the early stage of an autoimmune disorder because of autoimmune expansion and epitope spreading. We also assume that induction of tolerance may be more successful in younger patients because of potentially reduced immunosenescence. In this small trial only 3 out of 9 patients (33%) with newly diagnosed ITP relapsed after stopping treatment according to the iROM protocol. In contrast, all 4 patients with chronic ITP relapsed after stopping treatment. Our observation of a higher increase of platelets and a more stable increase of Tregs in patients with sustained TFR in comparison to those with relapse corroborate the hypothesis that the tolerogenic stimulus may be supported by the platelet mass. Limitations of the study were the small sample size, the heterogeneity of the patient population regarding ITP duration, and preceding medications overlapping the first study weeks. Figure 1 Figure 1. Disclosures Schifferli: Sobi: Honoraria; Novartis: Honoraria, Research Funding. Rovo: Novartis: Research Funding; AG Alexion: Honoraria; BMS: Honoraria; OrPhaSwiss GmbH: Honoraria; Swedish Orphan Biovitrum AG: Honoraria; Amgen: Other: Financial support for congresses and conference travel; AstraZeneca: Other; BMS: Other; Sanofi: Other; Roche: Other; AstraZeneca: Honoraria; Novartis: Honoraria; CSL Behring: Research Funding; AG Alexion: Research Funding. Kuehne: Novartis: Research Funding; UCB: Honoraria; SOBI: Honoraria; Amgen: Research Funding.

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A Case of Primary Refractory Immune Thrombocytopenia: Challenges in Choice of Therapies

Case Reports in Hematology ◽

10.1155/2018/8207017 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4

Author(s):

Hanyin Wang ◽

Hande Tuncer

Keyword(s):

Combination Therapy ◽

Standard Therapy ◽

Immune Thrombocytopenia ◽

Predictors Of Response ◽

Acute Itp ◽

Refractory Itp

The value of combination therapy for refractory ITP is not well defined. We present the case of a 29-year-old male with severe ITP refractory to initial standard therapy including steroids, IVIG, and subsequent splenectomy, who was treated with the combination therapy of rituximab, romiplostim, and mycophenolate and eventually developed thrombocytosis requiring plateletpheresis. Our case highlights the importance of the need to understand predictors of response to standard upfront treatment of acute ITP.

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