Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program

Abstract Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 109/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 109/L (interquartile range, 75-167 × 109/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 109/L (interquartile range, 35-44 × 109/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.

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Evaluating Clinical Outcomes and Potential Prognostic Factors Among 308 Children and Adolescents with Immune Thrombocytopenia (ITP): An 11-Year Retrospective Cohort Study

Blood ◽

10.1182/blood-2021-154344 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4053-4053

Author(s):

Xiaopei Lily Zeng ◽

Sherif M. Badawy

Keyword(s):

Platelet Count ◽

Prognostic Factors ◽

Clinical Outcomes ◽

Immune Thrombocytopenia ◽

Independent Predictor ◽

Patient Characteristics ◽

Early Response ◽

Abrupt Onset ◽

Chronic Itp ◽

Bleeding Score

Abstract Background: Immune thrombocytopenia (ITP) usually is a mild and self-limited disease; however, 25-30% of children develop chronic ITP. Nordic score is a validated clinical prediction tool, yet its use in children is limited and evidence for other prognostic factors is unclear. Purpose: To evaluate clinical outcomes among pediatric ITP patients, and examine their relationship to patient characteristics, including Nordic score. We hypothesized that Nordic score and patient characteristics will be predictive of ITP resolution or development of chronic ITP. Methods: We conducted a retrospective chart review of all children diagnosed with ITP at our institution between May 2008 to May 2019. Data extraction included patients' age, sex, presenting signs and symptoms, laboratory values, treatment decisions, and clinical outcomes. Nordic score calculated with 6 clinical features from diagnosis: abrupt onset <14 days, age < 10 years, preceding infection <1 month, platelet count < 5x10 9/L, wet purpura, and male sex. High scores (10-14) predict a brief disease course (<3 months), whereas low scores (0-4) predict a more prolonged course. Primary outcomes included complete response (CR) (platelets 100 x10 9/L on 2 occasions >7 days apart), recurrence (platelets < 100 after achieving CR), development of chronic ITP, and resolution (long term normal platelet count). Secondary outcomes included early response (platelets 30 x10 9/L in <1 week), time to CR, duration of CR (months between CR and recurrence), and time to resolution. Data presented as odds ratio (OR) with 95% confidence intervals. OR for Nordic score presented per 5-unit increase correlating with Nordic score categories (low 0-4, moderate 5-9, high 10-14). Results: A total of 308 patients were included (median age 5 years, IQR 2.0-10.8; 54.5% male) (Table 1). About 56% presented with platelets < 10 x10 9/L and 42% had bleeding at diagnosis (bleeding score 3 or higher), only 3% were severe. Median Nordic score was 10 (IQR 6-11). Overall, 64% of patients were treated upfront, majority (98%) receiving intravenous immunoglobulin (IVIG). Treatment at diagnosis was more likely for patients with platelets < 10 x10 9/L (OR 21, 10.4-42.5), bleeding score 3 or higher (OR 2.0, 1-4), and higher Nordic score (OR 6.2, 5.6-6.9) (Table 2). Treatment was predictive only of early response in multivariate analysis, not of CR, recurrence, development of chronic ITP, or disease resolution. Additionally, treatment at diagnosis was not associated with reduction in ITP-related complications, such as major bleeding episodes, need for platelet or red cell transfusions, or iron deficiency anemia. Overall rate of CR was 90% over a median of 1 month (IQR 0.3-4 months), while 13% had recurrence after median 19 months (IQR 8.3-26.0 months) and 32% developed chronic ITP. Overall, 80% of all study patients had resolution of ITP after median 1 month (IQR 0.3-5), with 86% achieving this before 12 months. About 36% of patients with chronic ITP had disease resolution over median 25 months (IQR 16.3-46.5 months). Univariate analysis showed significant variation across subgroups for age, viral symptoms, abrupt onset, Nordic score, hospital admission at diagnosis, platelet count, and treatment. Using multivariate regression analysis adjusted for the above variables, Nordic score was the only independent predictor of all primary outcomes. Higher Nordic score group had increased likelihood of CR (OR 6.2, 5.6-6.8) and disease resolution (OR 6.8, 5.1-8.9). Lower Nordic score group was associated with increased likelihood of recurrence (OR 6.5, 5.3-6.9) and development of chronic ITP (OR 8.6, 6.5-11.4). Additionally, higher Nordic score group was associated with increased time to recurrence and duration of response, decreased time to CR and resolution. Conclusions: In our cohort, low platelet count and bleeding symptoms were drivers of upfront treatment in pediatric ITP. Treatment initiation, associated with Nordic score, was predictive of faster increase in platelet count; however, it had no impact on overall disease trajectory or likelihood of complications. Our analysis demonstrate that Nordic score is an independent predictor of CR, resolution, recurrence, and development chronic ITP. Nordic score is a useful, simple prognostic tool that has the potential to help predict clinical course of pediatric ITP and identifying patients who may benefit from closer monitoring. Figure 1 Figure 1. Disclosures Badawy: Bluebird Bio Inc: Consultancy; Sanofi Genzyme: Consultancy; Vertex Pharmaceuticals Inc: Consultancy.

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

Acta Haematologica ◽

10.1159/000521689 ◽

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.

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Safety and Efficacy of Romiplostim in Immune Thrombocytopenia (ITP) in the “real-life” : Result of the French Experience in 72 Adults.

Blood ◽

10.1182/blood.v114.22.3519.3519 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3519-3519 ◽

Cited By ~ 1

Author(s):

Mehdi Khellaf ◽

Philippe Quittet ◽

Jean-Francois Viallard ◽

Magda Alexis ◽

Stéphane Cheze ◽

...

Keyword(s):

Platelet Count ◽

Rescue Medication ◽

Real Life ◽

Sustained Response ◽

Platelet Response ◽

Compassionate Use ◽

Safety And Efficacy ◽

Chronic Itp ◽

One Year

Abstract Abstract 3519 Poster Board III-456 Introduction Romiplostim is a thrombopoietic agent that has been unequivocaly demonstrated as highly effective in adult's ITP in prospective studies and has recently been licensed for adults with chronic ITP in USA, Europe, Canada, and Australia. France has been the only country where romiplostim could be given for a compassionate use outside clinical studies from January 2008. The official indication for obtaining romiplostim in this setting was: chronic ITP according to the international criteria and failure or relapse after at least one previous line of therapy regardless the status towards splenectomy. We report here the data on safety and efficacy of the first consecutive 80 ITP patients who have been registered by the French health authorities as receiving the treatment “off-label” and with at least one-year of follow up. Patients and methods The data were retrospectively reviewed using a standardized form. The protocol was approved by local ethical committee. Patients who did not fulfil official indication criteria of compassionate use were excluded (i.e. secondary-ITP). Platelet count was monitored at least monthly during the follow-up. Platelet response was defined as platelet count of 50×109/L or more and a doubling of the pre-treatment count in the absence of any rescue medication within the last 8 weeks. One-year sustained response was defined as a platelet response on at least 2 of the last 3 platelet determinations at month-10-11 and 12. Patients who received rescue medication at any time during the study could not be counted as having a one-year sustained response. Report of adverse events was captured using a standardized form. Results Among the 80 patients, 8 were actually excluded from the analysis (6 with secondary ITP and 2 have been misdiagnosed as having ITP). The analysis was then conducted on 72 patients (43 females) with a median age of 60 years (20 to 91). The median duration of ITP prior to romiplostim administration was 8.7 years (0.1 to 49) and the patients had received a median of 5 (2 to 12) treatment-lines before romiplostim including: corticosteroids (100%), rituximab (65/72, 90%) and splenectomy (39/72, 54%). Among the 33 non-splenectomized patients, 13 patients were reluctant to undergo splenectomy whereas splenectomy was considered as contra-indicated in 20 of them. At time of romiplostim first administration, median platelet count was 16×109/L (1 to 60) and 48 patients (66%) were receiving a concurrent treatment for ITP, including mainly steroids (n=29) ± immunosuppressive drugs (n=8). A platelet response was observed at least once in 76% (55/72) of the patients. On average, patients who responded at any point during the study had a platelet response during 64% of the time (range: 37 to 100%). Romiplostim was stopped in 28 % (20/72) of patients for either lack of efficacy (n=16), for intolerance (n=1) or because it was administered only transiently in preparation for surgery (n=3). Two patients had died respectively from a septic shock and from an ITP-related intracranial hemorrhage. At one-year of follow up, 52 patients were still receiving romiplostim at a median dose of 6.5 μg/kg per week. This dose remained relatively stable as after the first 12 weeks of treatment, romiplostim could be pursued at a stable dose ± 2 μg/kg in 82% of the cases. Twenty % (14/72) of patients received a rescue medication during the study and 50% (36/72) of the patients had a one-year sustained response. The percentage of one-year sustained response was similar in splenectomized and non splenectomized groups [respectively 54% (21/39) and 45% (15/33), NS)]. Among the 29 patients who responded to romiplostim and who were receiving a treatment at time of romiplostim initiation, 86 % (25/29) had discontinued this medication and a further 7% (2/29) had reduced the dose by at least 25%. Only one patient stopped romiplostim because of an adverse event (headache). The most frequent otherwise reported adverse events were: arthralgia (26%), fatigue (13%) and nausea (7%). A transient thrombocytosis > 400×109/L and > 1000×109/L has been observed in respectively 19% (14/72) and 4% (3/72) of patients. A transient stroke occurred in 2 elderly patients (age > 70 yrs). No deep vein thrombosis occurred. Myelofibrosis was not observed. Conclusion Our study confirms in “real-life” that romiplostim is definitely an effective and safe treatment for severe chronic ITP in both non-splenectomized and splenectomized adults. Disclosures: Godeau: AMGEN: Consultancy.

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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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Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽

10.1182/blood-2019-129274 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2352-2352

Author(s):

Tomas Jose Gonzalez-Lopez ◽

Fernando Fernandez-Fuertes ◽

Maria Cristina Pascual Izquierdo ◽

Isabel Caparros ◽

Silvia Bernat ◽

...

Keyword(s):

Platelet Count ◽

Median Time ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Previous Treatment ◽

Complete Response ◽

Platelet Response ◽

Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

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Association of Interleukin-18 Gene Polymorphism with Severity of Chronic Immune Thrombocytopenia (ITP).

Blood ◽

10.1182/blood.v116.21.3693.3693 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3693-3693

Author(s):

Takayuki Saitoh ◽

Norihiko Moriyama ◽

Tomonori Takani ◽

Takeki Mitsui ◽

Takumi Hoshino ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Initial Diagnosis ◽

Severe Thrombocytopenia ◽

Interleukin 18 ◽

Single Nucleotide ◽

Chronic Itp ◽

Significant Difference ◽

Haplotype Frequencies ◽

And Control

Abstract Abstract 3693 Introduction: Immune thrombocytopenia (ITP) is a chronic acquired organ-specific autoimmune disorder characterized by the production of antibodies against antigens on the membranes of platelets. Several cytokine studies have shown Th1 polarization in ITP patients. Interleukin-18 (IL-18) plays an important role in Th1 and Th2 immune response. Recent studies showed that single-nucleotide promoter polymorphisms influence the transcriptions of IL-18 mRNA. IL-18 polymorphism has been implicated in autoimmunity, including Crohn's disease, rheumatoid arthritis, and asthma. We examined the single nucleotide polymorphisms (SNPs) in the promoter regions of the IL-18 genes in patients with ITP, and analyzed the relationship between IL-18 SNPs and clinical features. Patients and Methods: One hundred patients (male/female; 22/78, median age; 54.5) diagnosed as chronic ITP and 151 healthy controls were included. Chronic ITP was defined as thrombocytopenia (platelet count < 100×109/L) persisting greater than 12 months, normal or increased marrow megakaryocytes, and no secondary immune or non-immune abnormality that could account for the thrombocytopenic state. ITP with severe thrombocytopenia was defined as thrombocytopenia (platelet count < 10×109/L) at presentation of ITP. The response criteria of the ITP International Working Group was used. A complete response (CR) is defined as any platelet count of at least 100×109/L, and a response (R) was defined as any platelet count between 30 and 100×109/L and at least doubling of the baseline count. Allparticipants gave written informed consent about the study. Genomic DNA was isolated from peripheral blood using the DNA Kit (QIAGEN, Hilden, Germany). An allele-specific polymerase chain reaction was used to analyze polymorphism in IL-18 –607A/C and -137G/C. Genotype and allele frequencies were compared between the study groups using Χ2-test. The characteristics and laboratory features of the ITP patients with each IL-10 promoter polymorphism were compared using X2-tests and student t-tests. Probability values <0.05 were considered statistically significant. Results: The platelet count was at an initial diagnosis ranged from 1×109/L to 98 ×109/L, with a median of platelet count of 15×109/L. Thirty-five patients (35%) had severe thrombocytopenia. Steroid treatment was given to 68 patients (68%), while splenectomy was used in 11 patients (11%).The frequencies of the genotypes were as follows: AA (34%), AC (57%), and CC (9%) for -607; GG (77%), GC (21%), and CC (2%) for -137 loci. The frequencies of each haplotype were as follows: C-G/C-G haplotype (9%), A-G/C-G haplotype (47%), A-C/C-G haplotype (10%), A-G/A-G haplotype (21%), A-G/A-C haplotype (11%) and A-C/A-C haplotype (2%). No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control group. However, patients with -137CC genotypes showed severe thrombocytopenia at initial diagnosis compared to those with -137GG/GC genotypes (5×109/L vs. 22×109/L, p=0.002). Furthermore, patients with A-C/A-C haplotype showed severe thrombocytopenic state (5×109/L vs. 22×109/L, p=0.002) compared to those without A-C/A-C haplotype. No significant difference of treatment response was observed according to IL-18 polymorphism. Conclusion: No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control. However, -137CC genotypes or AA/CC haplotype was associated with severity of chronic ITP. Our data suggest that the group with low IL-18 inducibility (i.e. -137CC genotype, A-C/A-C haplotype) may have more severe thrombocytopenia. Disclosures: No relevant conflicts of interest to declare.

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The Cytokine Polymorphisms Affect the Severity of Thrombocytopenia at Diagnosis in Chronic Immune Thrombocytopenia.

Blood ◽

10.1182/blood.v120.21.2194.2194 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2194-2194

Author(s):

Takayuki Saitoh ◽

Chiaki Ushie ◽

Atsushi Iwasaki ◽

Norihiko Moriyama ◽

Tomonori Takani ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Platelet Count ◽

Clinical Features ◽

Immune Thrombocytopenia ◽

Steroid Treatment ◽

Severe Thrombocytopenia ◽

Bleeding Tendency ◽

Chain Reaction ◽

Chronic Itp ◽

Polymerase Chain

Abstract Abstract 2194 Introduction: The severity of immune thrombocytopenia (ITP) depends on the degree of the thrombocytopenia and the extent of bleeding. Some investigators have reported the association between the thrombocytopenia and cytokine dysregulation in ITP. We investigated the association between the severity of thrombocytopenia at diagnosis in ITP patients and several cytokine polymorphisms, including IL-10-1082A/G, -819T/C, -592A/C, IL-17F-7488T/C and IL-18-607A/C, −137G/C. Patients and methods: We examined 102 patients (male/female, 24/78; median age, 42) diagnosed with chronic ITP. The definition, response criteria, including complete response (CR)and response (R), loss of CR,and “corticosteroid-dependence” were assessed according to the criteria of the ITP International Working Group. ITP with severe thrombocytopenia (ST group)was defined as thrombocytopenia (platelet count < 10×109/L) at the initial diagnosis of ITP. Genotyping of IL-10 (rs1800870 − 1082 A/G, rs1800871 − 819 T/C, and rs1800872 − 592 A/C) and IL-17F (rs763780, 7488 T/C) polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the genotyping of the IL-18 polymorphism (rs187238 −137G/C and rs1946518−607 A/C) was determined by the allelic specific polymerase chain reaction technique. To confirm the accuracy of the assay, amplification products of several individuals were sequenced using an ABI Prism Genetic Analyzer. Genotype and allele frequencies were compared between the study groups using χ2-test. The characteristics and laboratory features of ITP patients with each polymorphisms were compared using χ2-tests and student t-tests. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated for each study. All patients were provided written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital. Results: Clinical features of chronic ITP: The platelet count ranged from 1×109/L to 98×109/L with a mean of platelet count of 32×109/L at the initial diagnosis. Fifty seven patients (49%) had bleeding tendency. Steroid treatment was given to 68 patients (66.7%) and eradication of Helicobacter pylori (H. pylori) was performed in 32 patients (31.4%), while splenectomy was performed in only 11 patients (10.8%). Clinical features of ST group vs. non-ST group in chronic ITP: Of these 102 patients, 17 (16.7%) had severe thrombocytopenia (platelet count < 10×109/L) (ST group). ST group were significantly older (ST group: median 59 years vs. non-ST group: 41 years, p<0.01) and had more severe bleeding tendency (ST group: 100% vs. non-ST group: 54%, p<0.0001). Steroid treatment was frequently given to ST group than to non-ST group (ST group: 100% vs. non-ST group: 59.5%, p<0.001). Though the response to corticosteroids treatment was not significantly different between ST group and non-ST group (CR rate, ST group: 50% vs. non-ST group: 51.0%, p=0.94), corticosteroid-dependent patients in ST group was significantly higher than in non-ST group (76.9% vs. 25.3%, p<0.005). Polymorphism study of ST group vs. non-ST group in chronic ITP: The frequencies of genotypes of cytokines in patients with chronic ITP according to the definition of criteria of ST were as follows: AA (93.3% vs. 97.1%) and AG (6.7% vs. 2.9%, p=0.48) for IL-10–1082; TT (46.7% vs. 33.3%), TC (33.3% vs.55 %) and CC (20% vs. 11.7%) for IL-10–819; AA (46.7% vs. 33.3%), AC (33.3% vs.55 %) and CC (12.2% vs. 11.5%) for IL-10–592; TT (100% vs. 81%) and TC (0% vs. 19%) for IL-17F; GG (82.4% vs. 74.4%), GC (17.6% vs. 23.2%) and CC (0% vs. 2.4%) for IL-18–137; AA (35.3% vs. 34.1%), AC (58.8% vs. 53.7%) and CC (5.9% vs 12.2%) for IL-18–607 loci (ST group vs. non-ST group, respectively). No significant difference was observed between ST group and non-ST group according to IL-10–1082A/G, −819T/C, −592A/C, and IL-18–607A/C, −137G/C polymorphism. However, the numbers of IL-17F 7488TT genotype (higher function type) in ST group were significantly higher than in non-ST group (ST group: 100% vs. non-ST group: 81% p<0.05). Conclusion: These findings suggest that severe thrombocytopenia at diagnosis have an impact of bleeding tendency and corticosteroid-dependency of chronic ITP. Furthermore, IL-17F polymorphism may affect the severity of thrombocytopenia of chronic ITP. Disclosures: No relevant conflicts of interest to declare.

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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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Maternal and fetal outcomes of primary immune thrombocytopenia during pregnancy: A retrospective study

Obstetric Medicine ◽

10.1177/1753495x17727408 ◽

2017 ◽

Vol 11 (1) ◽

pp. 12-16 ◽

Cited By ~ 4

Author(s):

KS Gilmore ◽

C McLintock

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Post Partum ◽

Bleeding Complications ◽

Platelet Response ◽

Thrombocytopenic Purpura ◽

Primary Immune Thrombocytopenia ◽

Secondary Outcomes ◽

Post Partum Haemorrhage ◽

Auckland Hospital

Objective We reviewed outcomes of 52 pregnancies in 45 women with immune thrombocytopenic purpura who delivered at Auckland Hospital with an antenatal platelet count of <100 × 109/L. Outcome measures Primary outcomes were maternal platelet count at delivery and treatment response. Secondary outcomes included post-partum haemorrhage (PPH). Results Most women had thrombocytopenia at delivery. Treatment with prednisone was given in 14 (27%) pregnancies with responses considered safe for delivery in 11 pregnancies (79%). Women in eight pregnancies also received intravenous immunoglobulin; in five pregnancies (63%) a platelet response acceptable for delivery was achieved. Seventeen pregnancies (33%) were complicated by a PPH ≥500 mL. Ten pregnancies (19%) were complicated by a PPH ≥1000 mL. PPH was reported in all women with a platelet count <50 × 109/L at delivery. Conclusions There were no antenatal bleeding complications but PPH was common among women with platelet counts <50 × 109/L at the time of birth.

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Prognostic evaluation of immune thrombocytopenia outcomes in Egyptian children: a retrospective single-center experience

Pediatric Hematology/Oncology and Immunopathology ◽

10.24287/1726-1708-2021-20-3-26-30 ◽

2021 ◽

Vol 20 (3) ◽

pp. 26-30

Author(s):

Aliaa Mohammed Diab ◽

AlRawhaa Ahmed Abouamer ◽

Ghada Saad Abdel Motaleb ◽

Khaled Abdelaziem Eid ◽

Heba Ismaiel Abdelnaiem

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Laboratory Data ◽

Lactate Dehydrogenase Level ◽

Female Gender ◽

University Hospitals ◽

Female Ratio ◽

Chronic Itp ◽

Egyptian Children ◽

Significant Difference

Immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia in children. This retrospective study was designed to analyze presenting features of ITP cases in Benha, evaluate outcomes in children and determine prognostic factors. This research was accepted by Research Ethics Committee (REC) of Faculty of Medicine, Benha University (chairman: Prof. Nermeen Adly Mahmoud). Ethics comittee refrence number MS 40-3/2019. Records of 308 children with ITP in Benha University Hospitals and Benha Children Hospital haematology clinics between May 2014 and January 2021 were retrospectively analyzed. Socio-demographic, clinical, and laboratory data of the studied children such as age, gender, the type of residence, the date of diagnosis, complaints at presentation, preceding vaccination or infection, the type of bleeding, initial platelet count, LDH (lactate dehydrogenase) level, initial treatment, and outcomes were recorded. A total of 308 children diagnosed with ITP were included, clinical courses were determined as newly diagnosed and chronic in 71.4% and 28.6%, respectively. The median age of patients at diagnosis was 5 ± 3.4 years. The male/female ratio was 1.14. The median age at diagnosis was significantly higher in chronic ITP patients (p < 0.001); patients ≥ 10 years were more likely to develop chronic ITP than younger ones (p = 0.029). Regarding residency, seasonality, type of bleeding and history of preceding infection or vaccination, the difference was not statistically significant. Initial platelet counts > 20 × 109 were significantly more prevalent in chronic ITP (p < 0.001). LDH level at presentation was significantly higher in chronic cases (p = 0.046). Initial lines of treatment were the following: steroids, IVIG, and IVIG with steroids (in 88%, 5.2%, and 2.9% of the cases, respectively). A total of 3.9% of the children did not receive any treatment. There was no significant difference in the outcomes between the initial lines of treatment (p = 0.105). In our study, age > 10 years, female gender, higher platelet count and high LDH level at presentation were found to increase the probability of chronic ITP.

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