Pediatric Chronic Immune Thrombocytopenia Research Articles

Experience with Pediatric Chronic Immune Thrombocytopenia over 30 Years in the Era before Eltrombopag

Background: There is limited information on the natural course of chronic ITP in children. We aimed to evaluate the clinical and demographic characteristics of children with chronic ITP in the era before the availability of eltrombopag. Methods: A total of 86 children with chronic ITP between 1978–2014 were included. Demographic findings, laboratory results, clinical signs, bleeding scores, response time and time of complete remission were recorded. Results: The male/female ratio was 1.09, and median follow-up time was 3 years (range: 1.5–17 years). The median age at diagnosis of chronic ITP was 7 years (range: 2–17), and the median initial platelet count was 10 × 109/L (range: 1–66 × 109/L). Petechiae/ecchymoses were the most common clinical sign (86%) and followed by mucosal bleeding (39.5%). Severe bleeding was seen in 5% of the patients. None of them had intracranial hemorrhage. Twenty patients underwent splenectomy, and the rate of complete remission was 70%. Spontaneous complete remission was seen in 29% of the patients, and the median time to spontaneous complete remission was 3 years. Conclusions: Our study showed that almost one-third of patients with chronic ITP experienced spontaneous complete remission in an average of 3 years, and splenectomy provided satisfactory results in severe cases. This study demonstrates the natural history of chronic ITP in childhood before the era of eltrombopag.

Impact of age at diagnosis, sex, and immunopathological manifestations in 886 patients with pediatric chronic immune thrombocytopenia.

Pediatric chronic immune thrombocytopenia (cITP) is a heterogeneous condition in terms of bleeding severity, second-line treatment use, association with clinical and/or biological immunopathological manifestations (IMs), and progression to systemic lupus erythematosus (SLE). No risk factors for these outcomes are known. Specifically, whether age at ITP diagnosis, sex and IMs impact cITP outcomes is unknown. We report the outcomes of patients with pediatric cITP from the French nationwide prospective cohort OBS'CEREVANCE. We used multivariate analyses to investigate the effect of age at ITP diagnosis, sex and IMs on cITP outcomes. We included 886 patients with a median (min-max) follow-up duration of 5.3 (1.0-29.3) years. We identified an age cutoff that dichotomized the outcomes risk and defined two risk groups: patients with ITP diagnosed <10 years (children) and ≥ 10 years (adolescents). Adolescents had a two to four-fold higher risk of grade ≥3 bleeding, second-line treatment use, clinical and biological IMs, and SLE diagnosis. Moreover, female sex and biological IMs were independently associated with higher risks of biological IMs and SLE diagnosis, and second-line treatment use and SLE diagnosis, respectively. The combination of these three risk factors defined outcome-specific risk groups. Finally, we showed that patients clustered in mild and severe phenotypes, more frequent in children and adolescents, respectively. In conclusion, we identified that age at ITP diagnosis, sex, and biological IMs impacted the long-term outcomes of pediatric cITP. We defined risk groups for each outcome, that will help clinical management and further studies. This article is protected by copyright. All rights reserved.

Long-term efficacy and safety profile of splenectomy for pediatric chronic immune thrombocytopenia.

There are few reports of the long-term efficacy of splenectomy in children with immune thrombocytopenia (ITP). In a 33-year period, we performed splenectomies in 23 pediatric patients with ITP at a single institution in Japan. The age at surgery was 5-22years with a median of 10years. The follow-up period was 1-141months with a median of 48months. Before surgery, we confirmed the presence or absence of the accessory spleen by contrast-enhanced CT scan and we recommended vaccination with pneumococcal vaccine. Four patients underwent laparotomy before 1998, and 19 patients underwent laparoscopic surgery after 1999. Splenectomy showed high efficacy with a partial response rate of 83% and a complete response rate of 74%. Complete response was maintained in 70% of patients until the end of the observation period, and 91% were able to discontinue long-term management drugs such as steroids. No serious complications such as infectious diseases were observed. Although the number of cases here was small, the long-term efficacy and safety of splenectomy makes it a viable option in pediatric ITP despite the existence of newer therapeutic agents. Further research is necessary to compare the long-term efficacy and safety of splenectomy with new therapeutic agents.

Advances in management of pediatric chronic immune thrombocytopenia: a narrative review.

Immune thrombocytopenia (ITP) is a disease in which thrombocytopenia occurs because of immune-mediated platelet destruction and decreased platelet production. Although many pediatric patients with ITP experience spontaneous remission or reach remission within 12 months of first-line therapy, approximately 20% progress to chronic ITP. Patients who do not respond to first-line treatment or experience frequent relapses are of great concern to physicians. This review summarizes recent treatments for second-line treatment of pediatric chronic ITP.

Thrombopoietin receptor agonists (TPO-RAs) in pediatric chronic immune thrombocytopenia (ITP) - A 5 year experience from teriary care centre in India

Thrombopoietin receptor agonists (TPO-RAs) in pediatric chronic immune thrombocytopenia (ITP) - A 5 year experience from teriary care centre in India

Determinants of long-term outcomes of splenectomy in pediatric autoimmune cytopenias

AbstractSplenectomy is effective in ∼70% to 80% of pediatric chronic immune thrombocytopenia (cITP) cases, and few data exist about it in autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES). Because of the irreversibility of the procedure and the lack of predictions regarding long-term outcomes, the decision to undertake splenectomy is difficult in children. We report here factors associated with splenectomy outcomes from the OBS'CEREVANCE cohort, which prospectively includes French children with autoimmune cytopenia (AIC) since 2004. The primary outcome was failure-free survival (FFS), defined as the time from splenectomy to the initiation of a second-line treatment (other than steroids and intravenous immunoglobulins) or death. We included 161 patients (cITP, n = 120; AIHA, n = 19; ES, n = 22) with a median (minimum-maximum) follow-up of 6.8 years (1.0-33.3) after splenectomy. AIC subtype was not associated with FFS. We found that immunopathological manifestations (IMs) were strongly associated with unfavorable outcomes. Diagnosis of an IM before splenectomy was associated with a lower FFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.21-0.72, P = .003, adjusted for AIC subtype). Diagnosis of an IM at any timepoint during follow-up was associated with an even lower FFS (HR, 0.22; 95% CI, 0.12-0.39; P = 2.8 × 10−7, adjusted for AIC subtype) as well as with higher risk of recurrent or severe bacterial infections and thrombosis. In conclusion, our results support the search for associated IMs when considering a splenectomy to refine the risk-benefit ratio. After the procedure, monitoring IMs helps to identify patients with higher risk of unfavorable outcomes.

Increased proportion of Th17/Treg cells at the new diagnosed stage of chronic immune thrombocytopenia in pediatrics: the pilot study from a multi-center.

Chronic immune thrombocytopenia (CITP) is an autoimmune disease with many immune dysfunctions, including T helper type 17 cell (Th17)/regulatory T cells (Tregs) imbalance. Low quality of life and side effects of drugs are severe, especially in pediatrics. This study aimed to determine Th17/Treg polarization in pediatric CITP when first diagnosing ITP and evaluate its use as a predictive marker for pediatric CITP. This was a pilot study from a multi-center. Setting the effective data size to 100 patients, data entry ended in the 142nd patient who had completed a 1-year follow-up. The percentages of Treg cells and Th17 cells were quantified by flow cytometry when new diagnosed ITP patients first arrived. The association between the Th17/Treg ratio and CITP was analyzed statistically. The percentages of Treg cells and Th17 cells were lower (P = 0.0008) and higher (P = 0.0001), respectively, in the CITP-outcome group compared with the remission group. The receiver operating characteristic analysis showed that the area under the curve (AUC) of Treg and Th17 cells was 0.811 and 0.834, respectively. The ratio of Th17/Treg exhibited the largest AUC of 0.897 (cutoff value 0.076).Conclusions: Thus, the percentage of Th17 /Treg ratio of pediatric CITP is elevated at new diagnosed ITP stage. It is a promising predictive marker for the development of CITP to some extent.Trial registration: ChiCTR1900022419 (10th April 2019) What is Known: • The percentage of Th17 /Treg ratio of pediatric CITP is elevated. What is New: • This study shows that the percentage of Th17 /Treg ratio of pediatric CITP is elevated at new diagnosed ITP stage. This work may provide a new point for pediatric CITP's prediction. The imbalanced ratio of Th17/Treg was obvious when first diagnose ITP in pediatric CITP patients, rendering them as potential predictive tools for discriminating CITP to facilitate with the management of pediatric patient care. In addition, the combination of them may serve as a predictive marker in pediatric CITP.

Sirolimus versus cyclosporine for the treatment of pediatric chronic immune thrombocytopenia: A randomized blinded trial

IntroductionChronic immune thrombocytopenia (ITP) of childhood is still a problem. For treating ITP, several immunosuppressive medications can be considered with various response rates. Our goal was to compare effects of sirolimus and cyclosporine on children with chronic ITP. MethodsThis randomized and blinded trial was carried out on 67 children over 5 years old with chronic ITP. Patients were assigned 1:1 to cyclosporine and sirolimus for 6 months. Platelet count was assessed and compared between 2 study groups at different intervals. The clinical trial registry number was IRCT20180501039499N1. ResultsSixty-one children completed the 6-month treatment. Mean age was 9.3 years with an excess of females. Compared to baseline values, both drugs caused a significant increase in number of platelets over the course of treatment; sirolimus group: 15,800/mcL vs 96,566/mcL, (P < 0.001), cyclosporine group: 14,400/mcL vs 111,266/mcL, P < 0.001,). In addition, differences of platelet number were statistically significant at some treatment intervals (3rd and 6th month, P < 0.05). A quicker response was observed in children receiving cyclosporine. Both drugs had similar rate of response which occurred in 50% of included patients. Finally, sirolimus had a better safety profile. ConclusionsOur study showed that cyclosporine and sirolimus had an equal rate of response in treating chronic ITP of children. At the same time, the two medications showed significant differences in their side effects.

A Narrative Approach to Describe QoL in Children With Chronic ITP.

Objective: Primary immune thrombocytopenia (ITP) is a hemorrhagic disorder. Spontaneous recovery within 12 months occurs in the majority of pediatric patients. Nevertheless, in 20–30% of children the disease is chronic. The impact extends to the patients' families, whose everyday life, in terms of interpersonal relationships and financial status, is adversely affected. This study investigated the ability of a narrative instrument to improve the quality of life of pediatric chronic ITP patients and their families and quantified the familial burden imposed by the illness.Method: A quantitative survey and a narrative plot delivered through an online platform were adopted for the analysis.Results: Pediatricians of ten Italian Hematologic Centers explained the projects to patients and their family in the outpatient clinic. 70 caregivers of children with ITP filled the ad-hoc questionnaire. Data from 53 caregivers revealed the emotional impact of pediatric chronic ITP. The narrative approach highlighted the specific resources used by patients and their families to cope with the disease and its chronicity.Discussion: Caregivers underlined the need for “humaneness” in their interactions with clinical personnel. The majority of respondents provided positive feedback regarding the narrative project, defining the experience as “liberating” and improving their quality of life.

Cost-consequence model comparing eltrombopag and romiplostim in pediatric patients with chronic immune thrombocytopenia.

BackgroundImmune thrombocytopenia (ITP) is an auto-immune disorder characterized by enhanced platelet destruction and, subsequently, the potential for increased bleeding. Thrombopoietin receptor (TPO-R) agonists have recently emerged as promising therapies for ITP patients who are refractory to other treatments. While eltrombopag (EPAG) is the only TPO-R agonist US Food and Drug Administration approved for use in pediatric patients, romiplostin (ROMI) has been used in Phase III clinical studies.MethodsA cost-consequence model (CCM) was developed to evaluate the costs of EPAG, ROMI, and watch-and-rescue (W&R) in relation to their respective treatment outcomes in previously-treated pediatric chronic ITP (cITP) over a 26-week time horizon. The costs of drugs, administration, routine care, rescue medications, adverse events, and mortality were included. Data on platelet count response rate, bleeding events, and adverse events were derived from all relevant identified Phase III-registered clinical trials, health outcomes were compared via indirect treatment comparison.ResultsThe overall estimated cost of EPAG per patient was US$66,550, compared to US$101,056 for ROMI and US$32,720 for W&R. EPAG’s lower cost compared to ROMI was largely due to lower drug costs (US$62,202 vs US$84,396), administration costs (US$0 vs US$1,955), and significantly lower costs due to severe bleeding (US$354 vs US$10,191). When assessing cost per severe bleeding event avoided, EPAG was dominant over ROMI (less expensive and more effective). EPAG was again dominant over ROMI when assessing the cost per responder and per bleeding event (any grade). Sensitivity analysis was consistent with the base case findings.ConclusionEPAG was the preferred TPO-R agonist to treat cITP when indirectly compared to ROMI, largely driven by its favorable severe bleeding outcomes and lower drug and administration costs.

6-Mercaptopurine Fails to Improve Platelet Count in Pediatric Chronic Immune Thrombocytopenia.

6-Mercaptopurine Fails to Improve Platelet Count in Pediatric Chronic Immune Thrombocytopenia.

High-dose Cepharanthin for pediatric chronic immune thrombocytopenia in Japan.

A nationwide, multicenter and observational study was retrospectively conducted to evaluate the clinical utility of Cepharanthin (CEP) for pediatric patients with chronic immune thrombocytopenia (ITP). Clinical and laboratory data for 46 Japanese patients aged <16 years who were diagnosed as having chronic ITP in 14 hospitals during 2001-2011, and were treated with CEP for >12 months, were analyzed. Median daily CEP dose was 1 mg/kg (range, 0.12-2 mg/kg). Median platelet count prior to CEP was 20.5 × 109 /L (IQR, 8.3-53.0 × 109 /L), and then significantly increased to 58.5 × 109 /L (IQR, 22.8-115.0 × 109 /L) and 69.0 × 109 /L (IQR, 23.0-134.0 × 109 /L) at 12 and 24 months of treatment, respectively. No life-threatening bleeds or moderate-severe adverse events were reported. Of 38 patients who received both corticosteroids (CS) and CEP, 17 patients (45%) were weaned from CS, and 15 patients (39%) attained the reduced dose of CS. The duration from the start of CEP to the stopping of CS was a median of 413 days (range, 49-1734 days) in patients who were weaned from CS. CEP alone or combined with CS was useful for the management of pediatric chronic ITPs.

Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia

AbstractBecause Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) patients have microthrombocytopenia, hemorrhage is a major problem. We asked whether eltrombopag, a thrombopoietic agent, would increase platelet counts, improve platelet activation, and/or reduce bleeding in WAS/XLT patients. In 9 WAS/XLT patients and 8 age-matched healthy controls, platelet activation was assessed by whole blood flow cytometry. Agonist-induced platelet surface activated glycoprotein (GP) IIb-IIIa and P-selectin in WAS/XLT patients were proportional to platelet size and therefore decreased compared with controls. In contrast, annexin V binding showed no differences between WAS/XLT and controls. Eltrombopag treatment resulted in an increased platelet count in 5 out of 8 patients. Among responders to eltrombopag, immature platelet fraction in 3 WAS/XLT patients was significantly less increased compared with 7 pediatric chronic immune thrombocytopenia (ITP) patients. Platelet activation did not improve in 3 WAS/XLT patients whose platelet count improved on eltrombopag. In conclusion: (1) the reduced platelet activation observed in WAS/XLT is primarily due to the microthrombocytopenia; and (2) although the eltrombopag-induced increase in platelet production in WAS/XLT is less than in ITP, eltrombopag has beneficial effects on platelet count but not platelet activation in the majority of WAS/XLT patients. This trial was registered at www.clinicaltrials.gov as #NCT00909363.

Will thrombopoietin receptor agonists become a treatment option for pediatric chronic immune thrombocytopenia in the future?

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count and increased bleeding tendency. Most children with ITP spontaneously recover. However, children with severe bleeding may require treatment. Traditional treatments such as corticosteroids or splenectomy are often associated with increased risks of infections. Currently, there is evidence that platelet production is suboptimal in many chronic ITP patients and stimulation of platelet production by thrombopoietin receptor agonists (TpoR-As) is effective in raising the platelet counts. However, these clinical studies were conducted mainly in chronic ITP patients, age 18 or above, and TpoR-As are not yet licensed for use in children. Clinical trials are now being conducted to investigate the efficacy and safety of TpoR-As in pediatric ITP.

STAT1 single nucleotide polymorphisms and susceptibility to immune thrombocytopenia

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. One of the key mediators of IFN-γ signaling is the signal transducer and activator of transcription 1 protein (STAT1). We evaluated the relationship between STAT1 gene single nucleotide polymorphisms (SNPs) and the associated risk of ITP in a prospective case–control study. A total of 548 children were recruited: 328 children with ITP and 220 healthy children as sex- and age-matched normal controls. The Sequenom MassArray system (Sequenom, San Diego, CA) was used to detect three SNPs genotypes in the STAT1 gene: rs10208033, rs12693591, and rs1467199. There is a statistically significant difference in STAT1 rs1467199 allele frequencies with comparison of each of the four clinical subgroups of ITP patients to the normal controls (p = 0.0432). Also, newly diagnosed ITP patients and chronic ITP patients demonstrate significant different genotypes (χ2 = 8.511, p = 0.0142) and allelic frequency (p = 0.0055). Although a positive STAT1 rs1467199 genotype subgroups to the STAT1 mRNA expression level cannot be established, there is a weak correlation between STAT1 mRNA level and the activity ratio of Type 1 T helper lymphocyte and Type 2 T helper lymphocyte (Th1/Th2 ratio) (p = 0.0544); correlation with IFN-γ alone did not reach statistical significance (p = 0.1715). The findings in our study suggest that STAT1 rs1467199 SNP plays a potential role in the IFN-γ dependent development of autoimmunity in children with ITP. The important clinical implication of STAT1 SNPs testing as a predictor of pediatric chronic ITP will be validated in future molecular and protein functional analysis.

Effects Of Eltrombopag On Thrombocytopenia, Platelet Function and Bleeding In Patients With Wiskott-Aldrich Syndrome/X-Linked Thrombocytopenia

IntroductionPatients with Wiskott-Aldrich syndrome (WAS) including X-linked thrombocytopenia (XLT) have microthrombocytopenia, and hemorrhage is a major problem. Current management options in WAS/XLT patients include splenectomy, human stem cell transplant (HSCT) and gene therapy. In this study, we asked whether eltrombopag, a thrombopoietin mimetic, would increase platelet counts, improve platelet function, and/or reduce bleeding in WAS/XLT patients. MethodsIn 9 WAS/XLT patients and 8 age-matched healthy control subjects, flow cytometry was used to assess platelet function by surface expression of activated GPIIb-IIIa (reported by PAC1) and P-selectin in whole blood after stimulation with low and high concentrations of ADP or thrombin receptor activating peptide (TRAP), and by annexin V binding (a measure of surface phosphatidylserine) in platelet-rich plasma after stimulation with convulxin. Eltrombopag was administered to 5 WAS and 3 XLT patients (50 mg in 2 adults, and 1 mg/kg in 6 children up to 75 mg/day) with a goal platelet count ≥50k. ResultsHigh concentration ADP- or TRAP-induced PAC1 mean fluorescence intensity (MFI) was significantly reduced in WAS/XLT patients compared to healthy controls (Figure). Platelet surface P-selectin MFI in response to TRAP was also significantly reduced. In contrast, annexin V binding to platelets was not different between WAS/XLT and controls. As expected, platelet size of WAS/XLT patients was smaller than controls. WAS protein (which is deficient in WAS/XLT), is important for cytoskeletal movement and could therefore be involved in trafficking of surface proteins. However, surface expression of activated GPIIb-IIIa and P-selectin were no longer different in WAS/XLT patients vs. controls when corrected for size by platelet surface CD41 MFI. In 3 WAS/XLT patients whose platelet count improved on eltrombopag, platelet function did not improve. The table summarizes the results of eltrombopag treatment in 5 responders (2 WAS, 3 XLT patients) and 3 non-responders (3 WAS patients). Comparison of baseline, peak and change in immature platelet fraction in 5 WAS/XLT responders to eltrombopag vs. 7 pediatric chronic immune thrombocytopenia (ITP) patients responding to eltrombopag showed a significant decrease in all three measures, suggesting that platelet production in WAS/XLT patients is more difficult to increase than in ITP patients. Long term eltrombopag use in WAS/XLT patients showed no tachyphylaxis, transaminitis or induction of malignancy. [Display omitted] Conclusions1) Baseline platelet function in WAS/XLT is reduced compared to healthy age-matched controls, as measured by agonist-induced platelet surface activated GPIIb-IIIa and P-selectin. 2) This reduction is proportional to the reduced platelet size in WAS/XLT compared to controls. 3) In contrast, annexin V binding (a measure of platelet procoagulant activity) showed no differences between WAS/XLT and controls. 4) Eltrombopag has beneficial effects on the thrombocytopenia and bleeding, but not platelet function, in the majority of WAS/XLT patients. 5) This eltrombopag-induced reduction in bleeding is presumably primarily the result of the increased platelet count, but it was also observed in 2 eltrombopag “non-responders” (i.e. patients whose platelet counts did not increase after eltrombopag). 6) The production of new platelets with eltrombopag is less in WAS/XLT than in ITP. Disclosures:Off Label Use: Eltrombopag was given to WAS/XLT patients for treatment of thrombocytopenia. Michelson:Sysmex: Honoraria. Bussel:GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees.

Romiplostim for the treatment of primary immune thrombocytopenia

Romiplostim is a peptibody designed to evade the immune response to recombinant thrombopoietin and to stimulate the production of new platelets. The pathophysiology underlying primary immune thrombocytopenia (ITP) has shown that not only accelerated peripheral platelet destruction but also suppression of the production of new platelets can be responsible for the persistence of thrombocytopenia. Several prospective and well-designed trials have shown that weekly subcutaneous administration of romiplostim induces more durable platelet responses and less treatment failure compared with placebo or standard of care, not only in adult but also pediatric chronic ITP patients regardless of splenectomy status. Treatment with romiplostim also resulted in less use of rescue medication and permitted the majority of patients receiving concurrent ITP drugs to reduce or discontinue these therapies, avoiding further immunosuppression. Romiplostim has been shown to have overall a very favorable safety profile and to be well tolerated relative to other ITP treatments.

Response to steroids predicts response to rituximab in pediatric chronic immune thrombocytopenia

Treatment choice in pediatric immune thrombocytopenia (ITP) 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. The objective of this study was to evaluate univariate and multivariable predictors of platelet count response to rituximab. After local IRB approval, 565 patients with chronic ITP enrolled and met criteria for this study in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and October 2010. Treatment response was defined as a post-treatment platelet count ≥ 50,000/µl within 16 weeks of rituximab and 14 days of steroids. Treatment response data were captured both retrospectively at enrollment and then prospectively. Eighty (14.2%) patients were treated with rituximab with an overall response rate of 63.8% (51/80). Univariate correlates of response to rituximab included the presence of secondary ITP and a positive response to steroids. In multivariable analysis, response to steroids remained a strong correlate of response to rituximab, OR 6.8 (95% CI 2.0-23.0, P = 0.002). Secondary ITP also remained a strong predictor of response to rituximab, OR 5.6 (95% CI 1.1-28.6, P = 0.04). Although 87.5% of patients who responded to steroids responded to rituximab, 48% with a negative response to steroids did respond to rituximab. In the NACIR, response to steroids and presence of secondary ITP were strong correlates of response to rituximab, a finding not previously reported in children or adults.

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

AbstractAbstract 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.

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

AbstractAbstract 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.