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

Blood ◽  
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.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3741-3741 ◽  
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.

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

Blood ◽  
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.

scholarly journals Association between Megakaryocyte Abnormalities on Bone Marrow Smear and Response to Thrombopoietin Receptor Agonists in Adult Patients with Primary Immune Thrombocytopenia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3160-3160
Author(s):  
Ondine Walter ◽  
Agnès Ribes ◽  
Johanne Germain ◽  
Jean-Baptiste Rieu ◽  
Thibault Comont ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Adult Patients ◽  
Second Line ◽  
Bone Marrow Smear ◽  
Advisory Committees ◽  
Thrombopoietin Receptor

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease due to peripheral destruction but also impaired central production of platelets. Autoimmune reaction directed against megakaryocytes (MKs) has been described, and may explain morphological abnormalities of MKs observed in some patients with primary ITP. Thrombopoietin receptor agonists (TPO-RAs) are indicated as second-line treatments for ITP, but no predictive factors of response used in clinical routine practice has been demonstrated. The utility of systematic bone marrow smears (BMS) at ITP diagnosis is discussed. Howerer, it is usually recommended before second-line treatments. Two studies have suggested an association between MK abnormalities and response to corticosteroids in primary ITP, but none have investigated this association for TPO-RAs. This study aimed to investigate the association between MK abnormalities and response to TPO-RAs in adult patients with primary ITP. Methods: The source of population was the CARMEN registry. The CARMEN (Cytopénies Auto-immunes: Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) with incident ITP in routine visit or hospital stay. ITP was defined by international definition (platelet count &lt;100 x 10 9/L and exclusion of other causes of thrombocytopenia). The study population consisted in all patients included in the CARMEN registry between June 2013 and March 2018 with primary ITP, treated by TPO-RA and with a BMS before initiating TPO-RA. We excluded the patients with a number of MKs &lt;10 MK on the BMS. Morphological abnormalities were established based on literature and defined by consensus among 3 expert cytologists (AR, JBR and VDM). All MKs present on each smear were analyzed. MKs were categorized by the presence of dysplasia (monolobed MK and/or separated nuclei and/or microMKs), and according to their stage of maturation (basophilic, granular and thrombocytogenic). All patients' medical charts were reviewed by two experts in ITP (OW and GM) to determine the response to TPO-RAs. Response was defined by a platelet count between 30 and 100 G/L with at least a doubling of basal platelet count according to the international definition. In case of subsequent exposure to both TPORAs in a single patient, response was defined by response to at least one TPO-RA in the main analysis. We performed a subgroup analysis by TPORAs. Results: During the study period, 451 patients with incident ITP were included in CARMEN-registry. Among them, 105 had been treated by TPO-RAs, including 65 with BMS before the exposure to TPORA. We then excluded 20 patients with secondary ITP and 7 with less than 10 MKs on the BMS. We finally included 38 patients in the analysis. Median age at diagnosis was 71 years (interquartile range - IQR: 31 - 94) and 34.2% were women. Thirty-three patients were treated with eltrombopag, 17 with romiplostim including 13 who were exposed to both TPORAs. Thirty-four (89.4%) achieved response. The median number of MKs analyzed per patient was 137 (IQR: 50 - 265). All results are presented in Table 1. In the main analysis, there was no significant difference in the median percentage of dysplastic MKs in responders (4.0%, 95% confidence interval - CI: 2.3 - 6.4) and non-responders (4.5%, 95% CI: 0.7 - 7.1). There was a trend for a higher proportion of granular MKs (4.5%, 95% CI: 3 - 6) and basophilic MKs (30.1%, 95% CI: 21.9 - 39.1) in non-responders comparing to responders (granular: 2.0%, 95% CI: 0 - 4.1; basophilic: 21.3%, 95% CI: 11.4 - 40.7). Results were similar in the subgroup of patients treated with eltrombopag (data not shown; the low number of patients treated with romiplostim precluded any analysis). Conclusion: In this study, neither MK abnormalities nor the pattern of MK maturation stages were significantly associated with response to TPO-RAs. These results do not support a systematic bone marrow smear in patients with primary ITP to look for morphological predictive factors of response to TPO-RA. Figure 1 Figure 1. Disclosures Comont: AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees.

Results of the Russian Registry of Primary Immune Thrombocytopenia in Pediatric Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4643-4643
Author(s):  
Anastasia Shamardina ◽  
Inna Markova ◽  
Tatyana Sycheva ◽  
Elena Volodicheva ◽  
Alexander Rumyantsev ◽  
...  
Keyword(s):  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Disease Onset ◽  
Specific Treatment ◽  
Complete Response ◽  
Second Line ◽  
Second Line Therapy ◽  
Chronic Itp ◽  
Line Therapy ◽  
Clinically Significant

Abstract Study objectives We aim to evaluate disease characteristics and treatment practices of pediatric pts. with Immune thrombocytopenia (ITP) in Russia. Materials and methods The ITP Registry was a multicenter, prospective, observational cohort study. Inclusion criteria: diagnosis of primary ITP, informed consent of the patient/guardians. Exclusion criteria: secondary or congenital thrombocytopenia. Data from medical records were registered in the e-CRF in average every 3 months. Descriptive statistics were used. Patients were registered since June 2011 till June 2014. Results Ninety-three pediatric pts, 46 male (49.5%) and 47 female (50.5%) with a median age 8.4 yrs (range 0.5-17.8) from 5 centers in various regions of Russia were included. The mean observation period reached 17.1 ± 6.5 mo (range1.4 to 28.6 months). Seventy (75.3%) pts had acute and 24.7% pts had insidious disease onset. The presence of trigger factors for ITP development was found in more than half of the cases (in 61.3% of patients), they are listed in Table 1. Table 1. Triggers N % No triggers 36 38.7% Infection 46 49.5% Vaccination 8 8.6% Other 3 3.2% Total 93 100% Median disease duration at enrollment was 1.07 years (range 0 to 16.7 yrs). ITP duration shorter than 5 years at the enrollment was reported in 89.2% pts, up to 1 year - in 43 (46.2%), 1- 5 years - in 40 (43%), 5-10 years - in 8 (8.6%), >10 years - in 2 (2.2%) pts. Newly diagnosed ITP was reported in 35 (37.6 %) pts, persistent ITP - in 12 (12.9 %), chronic ITP - in 46 (49.5 %) pts.Median platelets count was 12,0 x 109/L (range 0.0 - 72.0 109/L). Ninety-two (98%) pts experienced hemorrhagic manifestations during the course of ITP: skin hemorrhages - in 98.9%, oral bleeding - in 15.1%, epistaxis - in 36.6%, gastrointestinal bleeding - in 1.1%, intracranial bleeding - in 1.1%, hematuria - in 1.1%, and other hemorrhages - in 9.7% of pts. Relationship between hemorrhagic syndrome and platelet count at the enrollment is provided in table 2. Table 2. Relationship between hemorrhagic syndrome and platelet count (at enrollment) Hemorrhage highest grade according to WHO Platelet count (visit 1) Total pts / % < 30,000 30,000 -50,000 >50,000 0 3 5.5% 3 5.5% 49 89.1% 55 100% 1 11 40.7% 5 18.5% 11 40.7% 27 100% 2 5 62.5% 0 0% 3 37.5% 8 100% 3 2 66.7% 1 33.3% 0 0% 3 100% Total 21 22,6% 9 9.7% 63 67.7% 93 100% Severe course of ITP after enrollment was observed in 12 (13%) pts (of whose 6 (6.5%) had clinically significant hemorrhage at the disease onset and 6 (6.5%) had new clinically significant hemorrhages during follow-up period. Refractory ITP at enrollment was reported in 9 (9.7%) pts and was associated with the resistance to the first-, second- and subsequent lines of therapy. At enrollment 42 (45.2%) pts received specific treatment for ITP. Before enrollment, splenectomy was reported in only 1 (1.1%) 14-years old patient who had a complete response. During the study, splenectomy was performed in 6 (6.6%) pts with chronic ITP; the duration of the disease at the time of splenectomy varied from 2 to 10 years, with average duration of 4.69 years (median - 4.5 years). Complete response to splenectomy was observed in 3 (50%) pts, a partial response - in 2 (33.3%), no response - in 1 (16.7%) patient. Loss of response to splenectomy was not reported. During the study, severe ITP was reported in 8 (8.7%) pts, 41 (44.6%) pt had various hemorrhagic manifestations of ITP at least at 1 visit, grade IV hemorrhagic syndrome was not reported. Thirty-eight (41%) pts received 1-st line treatment: glucocorticosteroids (GCS) - 23 (60.5%) pts, IVIG - 5 (13.2%), alfa-interferons -16 pts (42.1%). Twenty-three pts (24.7%) received second-line therapy: GCS - 1 (4.3%), IVIG -1 (4.3%), immunosupression - 1 (4.3%), rituximab - 2 (8.7%), romiplostim - 11 (47.8%), eltrombopag - 14 (60.9%). Conclusion For the first time new information on the features of the disease and patterns of management of pediatric pts with primary ITP in Russia was obtained in a prospective study. Interestingly, the preferred therapy for the 2nd or subsequent lines are TPO receptor agonists used outside the approved indications in research institutions, based on published clinical trial data. Splenectomy rate before and during the study was only 7.5% (7 pts) with chronic ITP; in 1 child (14.3%) splenectomy was ineffective. Low acceptance of splenectomy suggests TPO-mimetics as potential second-line therapy. In total, good disease control is achievable in the majority of pediatric pts with ITP. Disclosures Off Label Use: use of TPO-mimetics in children.

Romiplostim for Primary Immune Thrombocytopenia (ITP) in Routine Clinical Practice: Results from a Multicentre Observational Study in Germany

2021 ◽  
Author(s):  
Marcel Reiser ◽  
Klaus M. Josten ◽  
Hermann Dietzfelbinger ◽  
Anouchka Seesaghur ◽  
Markus Schill ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Observational Study ◽  
Immune Thrombocytopenia ◽  
Routine Clinical Practice ◽  
Newly Diagnosed ◽  
Platelet Response ◽  
Chronic Itp ◽  
Primary Immune Thrombocytopenia ◽  
Post Hoc

Introduction: The effectiveness and safety of romiplostim were evaluated by immune thrombocytopenia (ITP) phase (newly diagnosed/persistent/chronic) at romiplostim initiation. Methods: Post hoc analysis of a prospective, German, multicentre, observational study in adults with ITP who received ≥1 dose of romiplostim. Follow-up data were collected for ≤2 years. Outcomes included overall platelet response (≥1 platelet count ≥50 × 109/L at 2–24 weeks after romiplostim initiation) or durable platelet response (≥75% of measurements ≥50 x 109/L at 14–24 weeks), and adverse drug reactions (ADRs), evaluated by ITP phase. Results: Data from 96 patients were analysed (newly diagnosed, n=18; persistent, n=25; chronic, n=53). During the 2–24-week follow-up, overall platelet response was achieved in 100% (95% confidence interval [CI]: 81.5–100), 100% (86.3–100), and 96.2% (87.0–99.5) of patients with newly diagnosed, persistent, or chronic ITP, respectively; platelet responses were durable in 88.2% (63.6–98.5), 65.0% (40.8–84.6), and 69.4% (54.6–81.7) of patients. During the 2-year follow-up, ADRs occurred in 24.0–35.8% of patients across phases. Two patients with chronic ITP experienced bone marrow ADRs; no thrombotic ADRs occurred. Conclusion: Romiplostim was effective and well tolerated in patients with newly diagnosed, persistent, or chronic ITP in routine clinical practice.

Combination of Recombinant Factor VIIa and Fibrinogen Corrects Clot Formation in Primary Immune Thrombocytopenia At Very Low Platelet Counts

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4667-4667
Author(s):  
Ole Halfdan Larsen ◽  
Jesper Stentoft ◽  
Deepti Radia ◽  
J∅rgen Ingerslev ◽  
Benny S∅rensen
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Primary Immune Thrombocytopenia

Abstract Abstract 4667 Introduction: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. Hemostatic treatment modalities, bypassing the need for platelet transfusion, would be desirable for control of serious acute bleeds in patients with ITP. This study aimed at (i) performing a thorough characterization of the coagulopathy of ITP, (ii) investigate new ways to obtain acute correction of the coagulopathy performing in vitro experiments with recombinant factor VIIa (rFVIIa, NovoSeven®), fibrinogen (RiaSTAP®), and the combination of rFVIIa and fibrinogen, and finally (iii) investigate the correlation of the hemostatic response to the baseline platelet counts of the ITP patients. We challenged the hypothesis that rFVIIa combined with fibrinogen concentrate can correct whole blood (WB) clot formation in patients suffering from ITP even at very low platelet counts. Methods: Blood from 12 ITP patients and 15 healthy controls was drawn into 3.2% citrate containing corn trypsin inhibitor 18.3μg mL−1 to inhibit artificial contact activation. The WB (mean platelet count 22 × 109L−1 (range 0–42)) was spiked in vitro with buffer (control), fresh donor platelets (+40×109 L−1), rFVIIa (1 or 4μg mL−1), or fibrinogen (1 or 3mg mL−1) as well as the combination of rFVIIa and fibrinogen. Dynamic WB coagulation profiles were recorded by ROTEM® Thromboelastometry using activation with tissue factor (0.03pM) and re-calcification. Parameters of clot initiation (clotting time, CT), clot propagation (maximum velocity, MaxVel) as well as clot termination (maximum clot firmness, MCF) were evaluated. Thrombin generation in “platelet-rich” ITP plasma was evaluated using calibrated automated thrombography. Overall differences between groups were evaluated by paired and unpaired t-tests as appropriate. Simple linear regression analyses were performed using the differences observed after addition of the various interventions (intervention – baseline) as the dependent variable (y) and the platelet count as the independent variable (x). The slope was used to evaluate dependency of the hemostatic response on the platelet count, whereas the intercept was used to evaluate the hemostatic response at very low platelet counts. A p-value less than 0.05 was considered statistically significant. Results: Compared with healthy controls the WB coagulation profiles of the ITP patients were characterized by a prolonged CT (mean: 1490 vs. 941s, p<0.001) as well as a markedly reduced MaxVel (3.4 vs. 9.7mm×100s−1, p<0.001) and MCF (38.2 vs. 49.4mm, p=0.01). Fibrinogen showed no positive hemostatic effect. Recombinant FVIIa reduced the CT (744s, p<0.001) and increased the MaxVel (6.28mm×100s−1, p<0.001) whereas no change was observed in the MCF. Thrombin generation in “platelet-rich” plasma supported the findings in WB. The improvement in CT following addition of rFVIIa was independent of the platelet count (p-values > 0.45) and the intercept showed a significant improvement at very low platelet counts (1μg mL−1: −643s, p<0.001; 4μg mL−1: −811s, p<0.001). In contrast, the increase in MaxVel after addition of rFVIIa was highly dependent on the platelet count (1μg mL−1: R2 = 0.81, p < 0.001; 4μg mL−1: R2 = 0.86, p < 0.001) and the intercept was not significant (1μg mL−1: 0.05mm×100s−1 p=0.87; 4μg mL−1: 0.54 mm×100s−1 p=0.15). The combination of fibrinogen and rFVIIa revealed a synergistic effect also showing an increased MCF (50.7mm) in addition to a reduced CT (794s) and improved MaxVel (7.9 mm×100s−1) displaying larger effects than following fresh donor platelet substitution (CT 1164s; MaxVel 6.96mm×100s−1; MCF 49.6mm). Furthermore, rFVIIa together with fibrinogen also showed a significant response at very low platelet counts in all parameters (Intercept: CT −788s, MaxVel 3.3mm×100s−1, MCF 13.9mm, p-values<0.004) Conclusions: Data suggest that rFVIIa combined with fibrinogen can correct the coagulopathy of ITP even at very low platelet counts, and may be an alternative to platelet transfusion. Clinical trials are needed to further investigate if this new treatment modality holds the potential to serve as an effective acute treatment option in ITP. Disclosures: Off Label Use: Recombinant activated factor VII (NovoSeven) and fibrinogen concentrate (RiaSTAP). In vitro data suggesting a haemostatic effect in primary immune thrombocytopenia will be presented. S∅rensen:Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; SOBI: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pentapharm: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Grifols: Research Funding; LFB: Research Funding; Octapharma: Research Funding.

scholarly journals Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia: Italian Delphi-based consensus recommendations

2021 ◽  
Vol 12 ◽  
pp. 204062072110483
Author(s):  
Monica Carpenedo ◽  
Erminia Baldacci ◽  
Claudia Baratè ◽  
Alessandra Borchiellini ◽  
Francesco Buccisano ◽  
...  
Keyword(s):  
Platelet Count ◽  
Delphi Technique ◽  
Immune Thrombocytopenia ◽  
Daily Practice ◽  
Second Line ◽  
Thrombopoietin Receptor Agonists ◽  
Receptor Agonists ◽  
Line Therapy ◽  
Thrombopoietin Receptor ◽  
Primary Immune Thrombocytopenia

Introduction: In patients with primary immune thrombocytopenia (ITP), a short course of steroids is routinely given as first-line therapy. However, the response is often transient and additional therapy is usually needed. Thrombopoietin receptor agonists (TPO-RAs) are frequently used as second-line therapy, although there is little clinical guidance on the timing of their administration and on tapering/discontinuation of the drug. To provide clinical recommendations, we used the Delphi technique to obtain consensus for statements regarding administration and on tapering/discontinuation of second-line TPO-RAs among a group of Italian clinicians with expertise in management of ITP. Methods: The Delphi process was used to obtain agreement on five statements regarding initiation and on tapering/discontinuation of second-line TPO-RAs. Agreement was considered when 75% of participants approved the statement. Eleven experts participated in the voting. Results: Full consensus was reached for three of the five statements. The experts held that an early switch from corticosteroids to a TPO-RA has the dual advantage of sparing patients from corticosteroid abuse and improve long-term clinical outcomes. All felt that dose reduction of TPO-RAs can be considered in patients with a stable response and platelet count >100 × 109/L that is maintained for at least 6 months in the absence of concomitant treatments, although there was less agreement in patients with a platelet count >50 × 109/L. Near consensus was reached regarding the statement that early treatment with a TPO-RA is associated with an increase in clinically significant partial or complete response. The experts also agreed that optimization of tapering and discontinuation of TPO-RA therapy in selected patients can improve the quality of life. Conclusion: The present consensus can help to provide guidance on use of TPO-RAs in daily practice in patients with ITP. Plain language summary Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia There is little guidance on the timing of administration and tapering/discontinuation of thrombopoietin receptor agonists (TPO-RAs) in patients with primary immune thrombocytopenia (ITP). The Delphi technique was used to obtain consensus for five statements. The present consensus among Italian clinicians aims to provide guidance on second-line use of TPO-RAs for patients with ITP in daily practice.

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3681-3681
Author(s):  
Rachael F. Grace ◽  
Carolyn M. Bennett ◽  
A. Kim Ritchey ◽  
Michael R. Jeng ◽  
Courtney Thornburg ◽  
...  
Keyword(s):  
Platelet Count ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Evans Syndrome ◽  
Chronic Itp ◽  
Predictors Of Response ◽  
Count Response ◽  
Acute Itp

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.

scholarly journals Differential Expression of MiR-106b-5p and MiR-200c-3p in Newly Diagnosed Versus Chronic Primary Immune Thrombocytopenia Patients Based on Systematic Analysis

2018 ◽  
Vol 45 (1) ◽  
pp. 301-318 ◽  
Author(s):  
Cheng Qian ◽  
Wenying Yan ◽  
Tengda Li ◽  
Qingya Cui ◽  
Peng Liu ◽  
...  
Keyword(s):  
Immune Thrombocytopenia ◽  
Expression Profiles ◽  
Newly Diagnosed ◽  
Analysis Framework ◽  
Systematic Analysis ◽  
Microarray Experiments ◽  
Chronic Itp ◽  
Primary Immune Thrombocytopenia ◽  
Normal Controls ◽  
Potential Biomarkers

Background/Aims: MicroRNAs (miRNAs) have been described to have important roles in primary immune thrombocytopenia (ITP). To gain additional understanding, we have now further evaluated the involvement of miRNAs in ITP. Methods: Microarray experiments were performed to examine the expression profiles of miRNAs and mRNAs in samples from subjects with newly diagnosed ITP (G1), chronic ITP (G2), and normal controls. The systematic Pipeline of Outlier MicroRNA Analysis framework was applied to identify key miRNAs expressed in the G1 and G2 samples. Quantitative PCR and receiver operator characteristic curves were used to confirm the performance of key miRNAs. Results: Compared with normal controls, 14 miRNAs (12 over-expressed and 2 under-expressed) and 7 over-expressed miRNAs were identified as key in G1 and G2 samples, respectively. miR-106b-5p, miR-200c-3p, and miR-92a-3p exhibited significantly different expression profiles among the groups. In particular, miR-106b-5p and miR-200c-3p were expressed at higher levels in patients with ITP compared to the normal controls. Furthermore, these two miRNAs expressions were even higher in patients with chronic ITP. Conclusion: MiR-106b-5p and miR-200c-3p may represent valuable biomarkers of ITP, although further studies are needed to confirm and assess the value of these potential biomarkers at various stages of ITP.

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

Blood ◽  
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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