Clinical Outcomes in Patients with Immune Thrombocytopenia Treated with All 3 Approved Thrombopoietin Receptor Agonists

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a platelet count < 100 x 109 / L due to accelerated platelet destruction and impaired platelet production (McMillan 1981). At present, there are 3 available thrombopoietin receptor agonists (TPO-RAs) approved for treatment of chronic ITP in adults. All three agents have high response rates, 40-90%, depending on the criteria used to define response (Ghanima et al 2019). Previous studies illustrate efficacy of Romiplostim and Eltrombopag having surprisingly high response rates when switching from one to the other, particularly if there was a response to the first TPO-RA (Gonzalez-Porras et al 2015; Lakhwani et al 2017; Cantoni et al 2018) but no studies have compared all 3 approved TPO-RA. Herein we describe 7 patients with difficult to treat chronic ITP who received all 3 TPO-RA and assess responses of the 7 to each of Eltrombopag, Romiplostim and Avatrombopag. Methods This was a retrospective review of all patients with chronic ITP seen at the Platelet Disorders Program at Weill Cornell Medicine-NY Presbyterian Hospital between July 2019 (following FDA approval of Avatrombopag) and June 2020 who had been treated with Eltrombopag, Romiplostim and Avatrombopag. Seven patients were identified (most had been followed for many years) and information collected on demographics, laboratory results, and clinical data including response and tolerance to ITP treatments, in particular the 3 TPO-RA. Results There were 4 females and 3 males with median age of 64 years (range 33-77). All had primary ITP with median 3 (range 2-13) separate ITP treatments, including investigational therapies, preceding treatment with their first TPO-RA (Table 1). All 7 patients had difficult to treat ITP with episodes of severe thrombocytopenia despite chronic treatments, requiring periodic rescue with IVIg and/or steroids. Three patients received Eltrombopag as their first TPO-RA and 4 patients Romiplostim. All 7 patients received Avatrombopag as their third TPO-RA and all also received other therapies either in conjunction with or in between TPO-RAs (Figure 1). No patient went directly from one TPO-RA to another without intervening treatment. All 7 patients (100%) responded to their first TPO-RA. For the 3 initially on Eltrombopag, duration of treatment ranged from 1 week to 8 years. When these 3 were switched to Romiplostim as a second TPO-RA, they responded with median time on treatment 27 months (range 21-48 months). Reasons prompting the switch from Eltrombopag to Romiplostim included: lost response (1), allergic reaction (1), insurance/financial issues (1). The 4 patients who started with Romiplostim had a median duration on treatment of 18 months (range 4-96 months). Two of these 4 who switched to Eltrombopag as their second TPO-RA responded to Eltrombopag with median time on treatment 5.5 months. Reasons for switching from Romiplostim to Eltrombopag included: unstable platelet response (2), patient preference for an oral agent (2). Prior to taking Avatrombopag, 5 patients returned to a TPO-RA they had previously responded to with 3 requiring higher doses on re-exposure. These patients (4, 6, 7) had switched from that initial agent due to patient preference (1), financial issues (1) and unstable platelet response (1). Five/7 patients (71%) responded to the third TPO-RA, Avatrombopag. Reasons prompting the switch to Avatrombopag from the previous TPO-RA included: patient preference (4), lost response (2), unclear/suboptimal response (1). The 5 responders remain on only Avatrombopag with durations of 3 months to 11 months. Conclusions: All 7 patients responded initially to TPO-RA whereas response rates of around 70% were seen when patients are switched to a second and subsequent third TPO-RA; response was very good to all 3 agents without clear preference of one over the others. Responders to distinct second and third TPO-RAs included patients who switched due to lack of response to a preceding TPO-RA as well as those who switched due to preference (for an oral agent without dietary restrictions) or intolerance/side effects. Loss of response to one TPO-RA should not preclude trying another. Patients may not respond as well on re-exposure to a previously seen TPO-RA; hence, ideally treatment would be maintained if possible with the initial agent. Disclosures Bussel: RallyBio: Consultancy; Momenta: Consultancy; Dova: Consultancy; 3SBios: Consultancy; Regeneron: Consultancy; Principia: Consultancy; Rigel: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Argenx: Consultancy; UCB: Consultancy; CSL Behring: Consultancy; Shionogi: 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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Management of immune thrombocytopenia during COVID-19 pandemic

Hematology and Transfusiology ◽

10.35754/0234-5730-2021-66-1-20-36 ◽

2021 ◽

Vol 66 (1) ◽

pp. 20-36

Author(s):

S. V. Semochkin ◽

T. A. Mitina ◽

T. N. Tolstykh

Keyword(s):

Immune Thrombocytopenia ◽

Remission Rate ◽

Biological Response ◽

Medical Community ◽

Platelet Response ◽

Social Distancing ◽

The Third ◽

Prednisolone Treatment ◽

Thrombopoietin Receptor ◽

Early Transfer

Introduction. The COVID-19 pandemic has challenged health professionals and patients suffering from haematological diseases with embarrassed diagnosis, treatment, surveillance, social distancing and other constraints.Aim — addressing therapy for immune thrombocytopenia (ITP) during the COVID-19 pandemic in the light of own experience, as well as national and international professional medical community guidelines.Main findings. A standard choice in COVID-19-negative ITP patients are conventional, e.g., glucocorticosteroid (GCS) and intravenous immunoglobulin therapies. An early transfer to thrombopoietin receptor agonists (rTPO) appears optimal as reducing the infection risk in GCS withdrawal and significantly improving the stable remission rate without supportive treatment. Combined ITP–COVID-19 patients should consider a prednisolone treatment of 20 mg/day, provided an absent active bleeding. The dose may increase to 1 mg/kg/day in no response after 3–5 days. ITP patients admitted for COVID-19 should start weight‐based LMWH thromboprophylaxis upon attaining a platelet count of ≥ 30 × 109 /L. Chronic ITP patients should carry on usual treatment with standard SARS-CoV-2 preventive and social distancing measures. We exemplify three contrasting clinical cases of COVID-19-comorbid thrombocytopenia and discuss the ITP differential diagnosis and therapy. Two patients received GCSs and rTPO agonists (romiplostim, eltrombopag), while GCSs alone provided for platelet response in the third case. All patients showed a good clinical and biological response. Issues in SARS-CoV-2 vaccination are discussed.

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The Transition from Childhood to Adulthood in Chronic Immune Thrombocytopenia Patients: Clinical Management and the Role of Splenectomy and Thrombopoietin Receptor Agonists in a Single Center Experience

Blood ◽

10.1182/blood-2018-99-114050 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4987-4987

Author(s):

Monica Carpenedo ◽

Marco Spinelli ◽

Sara Pezzatti ◽

Momcilo Jancovic ◽

Rossella Renso ◽

...

Keyword(s):

Chronic Disease ◽

Pharmacological Treatment ◽

Immune Thrombocytopenia ◽

Single Center ◽

Thrombopoietin Receptor Agonists ◽

Chronic Itp ◽

Thrombopoietin Receptor ◽

Limited Compliance ◽

Grade 3

Abstract Introduction. Children diagnosed with Immune thrombocytopenia (ITP) will develop a chronic disease (plt < 100 x 109/L lasting >12 months since the onset) in 20-30% of cases. The transition from ITP started in childhood to adulthood has been scarcely studied and no specific studies have been published Aims.To present the results of a single center retrospective survey on ITP pts diagnosed in childhood who were sent in an adult setting to continue the management Methods. Charts of ITP pts diagnosed in childhood (1-17 yrs) in our Pediatric Dept who developed a chronic disease, need at least one line of therapy and were sent to our adult ITP office from Jan 2013 to Feb 2018, were retrospectively reviewed. Demographic and clinical data were collected and outcome was assessed based on established guidelines Results. Our Pediatric Dept accounts for a mean of 37 newly ITP diagnosis/year in children aged 1-17 yrs, with 32.8% of pts developing a chronic disease. During the selected observation time, 60 pts was expected to become > 18 yrs old with a chronic ITP. Overall 28 pts (14 female) pts were sent to our Adult ITP office at pediatrician's discretion (46.6% of expected). Table 1 summarizes demographic and clinical characteristics of pts. Median age at ITP diagnosis was 9.5 yrs (12 moths to 17 yrs). Median age of pts coming to the adult ITP office was 21 yrs (18 to 37 yrs) and the reason they were sent for was the need to continue a pharmacological treatment in 8 cases (eltrombopag-Elt-), bleeding in 3 cases, pregnancy in 4 cases, plt count < 50 x 109/L in 13 cases. The median n of lines of treatment already received in childhood was 1 (1 to 4). 16 pts have received only steroid since diagnosis (on demand treatment for bleedings), 8 pts were treated with thrombopoietin receptor agonists (TPO-RA) and 1 also with rituximab. One patient, 8 yrs old, was splenectomized because of grade 3 multiple bleedings, with complete response (CR). He was sent to adult ITP office at 37 yrs when ITP relapsed, with grade 3 bleeding. Overall the median follow up from diagnosis, after the transition to adult ITP office is 18 yrs (4-39 yrs), the median n of lines at data cut-off was 2.5 (1-5) and the overall outcome is summarized in Fig 1. 11 patients were treated with TPO-RA (8 pts received Elt since childhood, 2 pts started Elt and 1 Rom in adulthood), ORR was 81.8% (CR=7). Since the transition 4 patients switched the TPO-RA because response to the first TPO-RA was suboptimal or minor side effect (headache) was reported or limited compliance was suspected. Splenectomy was offered to all patients treated with TPO-RA to avoid chronic pharmacological treatment, and to other selected patients with a low plt count and a history of bleeding. 8/11 patients accepted splenectomy. Median time since diagnosis to splenectomy was 8 yrs (1 to 18 yrs) and in all pts a stable CR (plt > 100 x 109/L) was achieved, with a median follow up after surgery of 36.5 months (10-48 months). Surgery was performed also in the previous splenectomized pt (29 yrs later) because an accessory spleen was detected, and a CR was achieved (follow up 40 months). 2 patients stopped TPO-RA on a personal decision, refused splenectomy or other treatments: their plt count is < 30 x 109/L without bleeding. 15 pts were on active follow up without therapy (median plt count 58 x 109/L) and without any bleeding. One patient is waiting for splenectomy, taking prednison. The 4 pregnant patients were treated with steroids and IVIG, had natural labour without adverse events and their babies had a normal plt count. After pregnancy one pt was treated with Elt for 1 year, then she refused treatment and splenectomy. All 4 women returned to a number of plts similar to pre-gestational count. In 1 pt a MYH9 related-disorder was confirm at 21 yrs. Overall a CR was achieved during TPO-RA treatment in 9/11 pts and 9/28 (32%) achieved a stable CR after splenectomy Conclusions. The transition from childhood to adulthood in chronic ITP pts leads clinicians to challenges related to growing age, especially in female pts approaching the fertility and pregnancy specific needs. However only a minority of children with ITP developed a chronic disease which required a prolonged treatment. TPO-RA seems to be effective and well tolerated but chronic administration has limited compliance. Splenectomy, even if performed in adulthood after many yrs since diagnosis, allows to achieve a stable CR sparing young adults from chronic pharmacological treatment. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

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

Blood ◽

10.1182/blood-2011-03-340166 ◽

2011 ◽

Vol 118 (16) ◽

pp. 4338-4345 ◽

Cited By ~ 70

Author(s):

Mehdi Khellaf ◽

Marc Michel ◽

Philippe Quittet ◽

Jean-François Viallard ◽

Magda Alexis ◽

...

Keyword(s):

Platelet Count ◽

Clinical Practice ◽

Immune Thrombocytopenia ◽

Intravenous Immunoglobulins ◽

Interquartile Range ◽

Concomitant Treatment ◽

Platelet Response ◽

Compassionate Use ◽

Chronic Itp ◽

Bleeding Score

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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Antiplatelet Glycoprotein Antibodies Profile in Adult Patients with Primary Immune Thrombocytopenia and the Comparison with Regards to the Treatment Response to Corticosteroids

Blood ◽

10.1182/blood.v126.23.4653.4653 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4653-4653

Author(s):

Tubagus Djumhana Atmakusuma ◽

Lugyanti Sukrisman ◽

Fransiska Hardi

Keyword(s):

Immune Thrombocytopenia ◽

Response Rates ◽

Complete Response ◽

Cross Sectional Study ◽

Adult Patients ◽

Published Data ◽

Newly Diagnosed ◽

Cross Sectional ◽

Chronic Itp ◽

The Mean

Abstract Background: Platelet destruction in immune thrombocytopenia (ITP) is mediated by autoantibodies against platelet antigens. Anti-GPIIb/IIIa and anti-GPIb/IX antibodies are two major antibodies spesific for platelets and megakaryocytes. The diversity of clinical characteristics and therapeutic responses have been thought to be influenced by heterogeneity of spesific glycoprotein complexes. However, there has been no published data regarding either antiplatelet antibodies profile or response rates to corticosteroid, in adult patients with primary ITP. Objectives: To determine antiplatelet glycoprotein antibodies profile in adult patients with primary ITP and to compare the response rate to corticosteroid referring to the profile. Methods: This study is a cross sectional study in adult patients with primary ITP who visited Hematology Clinics in Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia, in a period of March to October 2013. The tests to determine the auto antibodies against the platelet GPIIb/IIIa and GPIb/IX surface antigens were performed by a direct MAIPA technique. Results: A total of 40 patients who were diagnosed as primary ITP have been enrolled into the study. The subjects of the study were divided in two groups, 10 subjects with newly diagnosed ITP, and 30 subjects with persistent or chronic ITP. Most of the subjects were female (82.5 %) with the median age was 24,5 (17-55) years old.. Seventy (??) subjects had ITP Bleeding Score (IBLS) 2.. In a persistent/chronic ITP group (n= 30), the proportion of anti-GPIIb/IIIa was 20 / 30 (66,67 %) with the median optical density (OD) was 0,461 (0,093-2,116) and the proportion of anti-GPIb/IX was 25/30 (83.33%) with the median OD was 0,507 (0,190-1,924). Meanwhile, in a newly diagnosed ITP group (n=10) the proportion of anti-GPIIb/IIIa was 7/10 (70%) with the mean OD was 0,802 ± 0,71 and the proportion of anti-GPIb/IX was 8/10 (80%) with the mean OD 0,82 ± 0,57. The response rates to corticosteroid were as follows: 42.5 % of the subjects achieved complete response, 45 % achieved response, and 12.5 % achieved no response. Comparison between the subjects with and without anti-GPIIb/IIIa and anti-GPIb/IX antibodies showed similarity response rates to prednisone. Conclusion: Sincemost of patients with primary ITP had anti GPIIb/IIIa and anti GPIb/IX antibodies, those antibodies may support a diagnosis of primary ITP. Since no differences in terms of the response rates to corticosteroid between subjects with and without anti-GPIIb/IIIa and anti-GPIb/IX antibodies, those antibodies can not be used as a predictor of the treatment Disclosures Sukrisman: Division of Hematology Medical Oncology: Other: Colleague.

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A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01047-9 ◽

2021 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

Heng Mei ◽

Xiaofan Liu ◽

Yan Li ◽

Hu Zhou ◽

Ying Feng ◽

...

Keyword(s):

Tract Infection ◽

Primary Endpoint ◽

Receptor Agonist ◽

Immune Thrombocytopenia ◽

Phase Iii ◽

Upper Respiratory Tract ◽

Platelet Response ◽

Double Blind ◽

Thrombopoietin Receptor ◽

Thrombopoietin Receptor Agonist

Abstract Background Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. Methods Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 109/L) after 8 weeks of treatment. Results The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83–68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39–86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment. Conclusions In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843, registered July 19, 2017, retrospectively registered.

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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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Effects Of Thrombopoietin Receptor Agonists On APRIL Plasma Levels In Patients With Immune Thrombocytopenia

Blood ◽

10.1182/blood.v122.21.1083.1083 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1083-1083

Author(s):

Nora V. Butta ◽

Mayte Álvarez Román ◽

Ihosvany Fernández Bello ◽

Elena G. Arias Salgado ◽

Isabel Rivas Pollmar ◽

...

Keyword(s):

Platelet Count ◽

T Cell ◽

Regulatory T Cell ◽

Plasma Levels ◽

Immune Thrombocytopenia ◽

Cell Activity ◽

Healthy Controls ◽

Platelet Counts ◽

Chronic Itp ◽

Thrombopoietin Receptor

Abstract Introduction Immune thrombocytopenia (ITP) is an example of an autoimmune disease in which B-lymphocytes produce autoantibodies against platelets. Antibody-mediated platelet destruction and suboptimal platelet production leads to a decrease in platelet count. ITP patients with thrombocytopaenia have increased plasma levels of a proliferation-inducing ligand (APRIL), a factor that can promote B-cell maturation and survival. Two new compounds that bind to the thrombopoietin receptor (TPO-R) and activate the megakaryopoiesis have been recently approved for the treatment of chronic ITP as second-line treatment. Objective It has been recently reported an improved regulatory T-cell activity in patients with chronic ITP treated with TPO-R agonists (TPO-RA) (Bao et al, 2010). So we aimed to evaluate the effect of TPO-RA treatment on APRIL plasma levels in ITP patients before (ITP-1) and after responding (ITP-2) to the treatment. Methods This was an observational and prospective study. Thirteen patients with chronic ITP in whom treatment with a TPO-RA was indicated, and thirty-three healthy controls were included. ITP patients were studied at two times: at inclusion (ITP-1), when platelet count was less than 30x109/L for patients without concomitant medication or less than 65x109/L for patients receiving corticosteroids or intravenous immunoglobulin; and after a response to TPO-RA therapy was elicited (ITP-2). The response to TPO-RA was defined as a platelet count >30x109/L in patients without additional treatment or >65x109/L for those with concomitant treatments. EDTA-anticoagulated whole blood was centrifuged at 1,500 g for 15 min at 23°C to obtain platelet poor plasma which was then centrifuged at 10,000 g for 15 min at room temperature. Supernatant plasma was stored at –70°C until analysis. Plasma TPO and APRIL concentrations were determined using a commercially available enzyme-linked immunosorbent assay (ELISA, Duoset-R&D, Minneapolis, Mn, USA). Platelet counts were determined with a Coulter Ac. T Diff cell counter (Beckman Coulter, Madrid, Spain). Comparisons of quantitative variables were made with ANOVA and Dunn test. Results were expressed as mean±SD. Correlations were calculated with Spearman test. Values of p≤0.05 were considered statistically significant. Results Platelet count in the ITP-1 group ((23±17)x109/L) increased after responding to TPO-RA to values similar to controls (controls: (233±77)x109/L and ITP-2: (140±36)x109/L). TPO plasma level was higher in ITP-1 patients (30.05±26.81 pg/ml, p<0.005) than in healthy controls (7.36±11.74 pg/ml) but not significantly different when compared with the values of the ITP-2 group (26.81±17.62 pg/ml). ITP-1 patients showed significantly higher APRIL plasma levels (37.60+28.73 ng/ml, p<0.0001) than controls (2.20±3.11 ng/ml) and ITP-2 patients (4.92+4.68 ng/ml), indicating that TPO-RA treatment caused a diminution in APRIL plasma levels. When looking into the relationship between APRIL plasma levels and platelet count, a significant correlation was only found in the ITP-1 group (r=-0.5919, p<0.05). This supports the potential role of APRIL in the reduction of platelet counts in ITP patients. Conclusion ITP patients with thrombocytopaenia that responded to TPO-RA treatment increased their platelet count reducing plasma APRIL levels and without changing the moderately high levels of plasma TPO. Reductions in APRIL levels caused by TPO-RA treatment could be an additional mechanism that contributes to an increased platelet count in ITP patients treated with these agents. Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010 Nov 25;116(22):4639-4645 Disclosures: No relevant conflicts of interest to declare.

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Eltrombopag Effectiveness and Tolerability in Chronic Immune Thrombocytopenia: A Meta-Analysis

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/10760296211005555 ◽

2021 ◽

Vol 27 ◽

pp. 107602962110055

Author(s):

Hafiz Abdul Waqas Ahmed ◽

Ahmed Taher Masoud ◽

Jia Han ◽

Ahmed Adel Sofy ◽

Ahmed Saeed Ahmed ◽

...

Keyword(s):

Placebo Group ◽

Relative Risk ◽

Immune Thrombocytopenia ◽

Meta Analysis ◽

Published Data ◽

Platelet Response ◽

Randomized Controlled ◽

Immune Mediated ◽

Thrombopoietin Receptor ◽

Thrombopoietin Receptor Agonist

Eltrombopag is an orally administered, non-peptide, thrombopoietin receptor agonist which initiates thrombopoietin signaling and stimulates the production of normally functioning platelet. We aimed to do a systematic review and meta-analysis of currently available published data to verify whether eltrombopag treatment in patients with chronic immune-mediated thrombocytopenia can prolong survival. We searched for published, randomized, controlled trials in PubMed, Cochrane and Scopus databases using the following search strategy (“Eltrombopag” OR “Benzoates” OR “Hydrazines”) AND (“Idiopathic Thrombocytopenic Purpura” OR “immune thrombocytopenia” OR “Idiopathic Thrombocytopenic Purpuras” OR “Immune Thrombocytopenia” OR “Autoimmune Thrombocytopenia” OR “Werlhof”). The pooled relative risk (RR) showed that eltrombopag group has significantly higher overall platelet response than placebo group (MD = 3.42, 95% CI [2.51, 4.65], P > .0001); pooled results were homogenous ( P = .27, I2 = 22%). The pooled relative risk showed that eltrombopag group has lower incidence of any bleeding than placebo group (MD = 0.65, 95% CI [0.48, 0.87], P = .003); pooled results were heterogenous ( P = .001, I2 = 75%) and the detected heterogeneity was best resolved after excluding Bussel et al ( P = .10). Homogeneous results were still favored eltrombopag group (MD = 0.75, 95% CI [0.60, 0.93], P = .008).

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