The Burden of Disease and IMPACT of Immune Thrombocytopenia (ITP) on Patients: Results from an ITP Survey

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder causing reduced platelet counts <100,000/µL, with potential bleeding consequences and reduced quality of life. Treatment is generally reserved for adults with platelet counts <30,000/µL. Methods: ITP patients from the Platelet Disorder Support Association were recruited to complete a one-time cross-sectional survey online. Eligible adults from the United States self-reported that they had been diagnosed with ITP and received at least 1 treatment. Patients completed a 30-45-minute online survey about demographics, diagnosis experience, symptoms, disease management and treatment. Results: Seventy-six patients completed the survey. Two-thirds had been diagnosed at least 10 years previously. Events leading to diagnosis were petechiae (21%), general check-up (19%), bleeding events (18%), and bruising (16%). Patients with ITP felt well informed about ITP (87.5% reported a score ≥5 on a 7-point Likert scale with 7 being highly knowledgeable) and 97% knew their current platelet count. At the time of diagnosis, platelet counts were < 10 x 109/L in 47% and 10 - 30 x 109/L in 27%. At the time of survey response, platelet count was < 30 x 109/L in 4.62% of participants; 47.69% of respondents had platelet counts > 100 x 109/L. Using a Likert scale (7 = very strongly agree, 1 = very strongly disagree), 58% of patients reported a score ≥5 that ITP-related fatigue interfered with their work, family, or social life. Prior to being treated, 35% reported fatigue daily and 13% reported it twice a week. Despite treatment, a similar proportion reported fatigue daily (39%) or twice a week (16%). Overall, the results of the survey did not suggest that bleeding was a concern for most patients: 59% reported a score ≤3 suggesting that bleeding does not interfere with their work, family or social life. Additionally, only 3% of patients reported that they experienced bleeding related to their ITP daily or twice weekly prior to treatment. However, fear of bleeding interfered with work, family or social life in 47% of patients with score ≥5 ; in contrast an equal number, 47%, reported a score ≤3. 45% of respondents underwent splenectomy without clinical improvement; an additional 31% were offered but declined surgery. Almost 90% of patients had prior treatment with steroids: 72% prednisone first and 15% dexamethasone first. Most had received rituximab (72%) and eltrombopag (55%); 40% received romiplostim. Additional information regarding aspects related to treatment will be presented, including sequencing and preferences associated with different therapies. Conclusions: This survey demonstrates some of the effects of fatigue, bleeding, and treatment on the lives of patients with ITP. On the one hand, almost half the patients had failed splenectomy, although currently very few patients undergo this procedure. Thus those taking the survey were not "random" ITP patients but may likely represent an atypical group that is refractory to treatment or dissatisfied with the course of their ITP despite half the patients having normal platelet counts at the time of the survey. In the course of their ITP, patients received a variety of treatments beyond steroids and results for side effects experienced and satisfaction with treatment will be analyzed and presented. The most surprising finding was that, even in those in whom treatment raised the platelet count, fatigue was not always alleviated. These issues and others remain to be clarified as we further unravel the complexity of ITP. Disclosures Bussel: Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 3S Bio: Speakers Bureau. Kruse:Novartis: Consultancy; UCB: Honoraria; Amgen: Research Funding; Argenx: Research Funding; Dova: Research Funding; Novartis: Research Funding; Momenta: Research Funding; Principia: Research Funding; Octapharma: Research Funding; CSL Behring: Research Funding; UCB: Research Funding. Aggarwal:Dova Pharmaceuticals: Employment. Vredenburg:Dova Pharmaceuticals: Employment, Other: Shareholder. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Effects of Anti-Glycoprotein Antibodies on Response of Immune Thrombocytopenia Patients to Thrombopoietin Receptor Agonists and on Megakaryocytes Viability

Blood ◽

10.1182/blood.v126.23.1048.1048 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1048-1048

Author(s):

Marina Izak Karaev ◽

Alexandra Kruse ◽

Margaret Morrisey ◽

Heyu Ni ◽

Zhu Guangheng ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Treatment Option ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Advisory Committees ◽

Thrombopoietin Receptor Agonists ◽

Platelet Counts ◽

Thrombopoietin Receptor ◽

Equity Ownership

Abstract Background Immune Thrombocytopenia (ITP) is a bleeding disorder due to a combination of increased platelet destruction and reduced production, often secondary to anti-platelet/megakaryocyte antibodies. The presence of antibodies to glycoproteins (GP) IIb/IIIa (integrin αIIbβ3) and GPIb/IX, detected in majority of ITP patients, may correspond to different responses to treatment, i.e., anti-GPIb is associated with more severe disease, and less responsive to intravenous immunoglobulins and steroids. Thrombopoietin Receptor Agonists (TPO-RA) increase platelet production by stimulation of megakaryopoesis. Predictors of response to TPO-RA and influence of antibody profile on response are currently unknown. In our previous study we investigated Absolute Immature Platelet Fraction (A-IPF) prior to TPO-RA treatment and did not find a correlation between A-IPF, anti-GP antibodies, and platelet counts. The aims of this study were to further investigate: 1. The role of anti-GP antibodies in response to TPO-RA; 2. Effect of patients' antibodies on megakaryocyte (MK) viability, maturation, apoptosis and formation of proplatelets (in vitro); 3. The influence of patients' clinical characteristics on response to TPO-RA. Materials and Methods 91 patients with persistent or chronic ITP, were treated at Weill Medical College of Cornell University until January 2015 with TPO-RAs: 52 patients received eltrombopag, 22 romiplostim and 17 avatrombopag. Serum samples of 84 patients were analyzed for the presence of anti-GP by MAIPA assay as previously described. Patients with baseline platelet counts less than <30x109/L were defined as responders to TPO-RA if the average of their six median monthly platelet counts was ≥50x109/L and doubled from average baseline counts (prior to TPO-RA). Patients with baseline platelet counts 30-50x109/L were responders if the average platelet count was ≥75x109/L. MKs were derived from human umbilical cord blood stem cells as previously described. Cells were grown using SFEM medium, adding on day 0 of culture 50 ng/ml recombinant TPO and aliquots of serum of ITP patients or healthy controls. The percentages of immature (CD41+/CD42-), mature (CD41+/CD42+), viable and apoptotic MKs were analyzed by flow cytometry on day 12. Apoptosis was analyzed by measuring Mitochondrial Outer Membane Potential (MOMP) and Phosphatidyl Serine (PS) externalization. MKs were considered apoptotic if they had positive staining for PS externalization, viable if positive for MOMP, and dead if positive for 7-Aminoactinomycin D (7AAD). Proplatelet formation by MKs was analyzed by microscopy. Statistical analysis using unpaired T-test and Pearson correlation test were performed. Results Ninety-one patients were included, 40 male (44%) and 51 female (56%), with a median age of 37.4 years (range 2-87). Median duration of ITP before TPO-RA treatment was 8 years (range 0.3-45). The 18/91 (19.8%) non-responders to TPO-RA were not different from the 73/91 responders in age, gender, number of prior treatments, duration of ITP, and past splenectomy. The presence of either or both anti-GP antibodies was correlated with average lower platelet counts on TPO-RA: 82.3 x109/L versus 123x109/L in patients without detected antibodies ("neither") (p=0.003). However, the response to TPO-RA was not influenced by the type of antibody: in patients with anti-GPIb the average platelet count was 76.1x109/L, and with anti-GPIIb/IIIa 80.7x109/L (Figure 1). In culture, excess dead MKs were found in anti-GPIb group and antiGPIb&antiGPIIb/IIIa group compared to "neither" group (p=0.0013 and p=0.027 respectively) and comparing antiGPIb&antiGPIIb/IIIa to control (p=0.0025). We did not observe changes in the degree of MK apoptisis or in MK maturation in the presence of serum antibodies. In cultures treated with serum of patients having anti-GPIb, less proplatelets were detected comparing to control (p=0.044) or to "neither" (p=0.0039). We conclude that patients with anti-GP antibodies respond less to TPO-RA, however there is no difference in response to TPO-RA between patients having anti-GPIb and anti-GPIIb/IIIa, unlike responses to other treatment modalities (e.g., steroids or immunoglobulins). TPO-RA could be a preferable treatment option in ITP patients having anti-GPIb. Figure 1. Average 6-months platelet counts of TPO-RA-treated ITP patients divided into groups by presence of antibody/ies. Figure 1. Average 6-months platelet counts of TPO-RA-treated ITP patients divided into groups by presence of antibody/ies. Disclosures Off Label Use: Eltrombopag, romiplostim and avatrombopag are a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. In some preliminary studies these medicines found as safe and effective treatment option in children and adolescents. Bussel:amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Novartis: Consultancy, Research Funding; Genzyme: Consultancy; BiologicTx: Research Funding; Ligand: Consultancy, Research Funding; Eisai: Consultancy, Research Funding; Shionogi: Consultancy, Research Funding; momenta: Consultancy; Protalex: Consultancy; Symphogen: Consultancy.

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

Blood ◽

10.1182/blood.v118.21.4667.4667 ◽

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.

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Use of Intravenous Immune Globulin in Patients with Immune Thrombocytopenia Before and After Romiplostim: Real-World Experience

Blood ◽

10.1182/blood.v120.21.4641.4641 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4641-4641

Author(s):

Korinne Hamilton ◽

Lisa J. Toltl ◽

Grace Wang ◽

Naushin S Sholapur ◽

Julie Carruthers ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Immune Globulin ◽

Real World ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Intravenous Immune Globulin ◽

Advisory Committees ◽

Platelet Counts ◽

Before And After

Abstract Abstract 4641 Background: Thrombopoietin receptor agonists such as romiplostim have been shown to increase platelet counts in patients with immune thrombocytopenia (ITP) and reduce the need for concomitant therapies. However, their effect on the utilization of intravenous immune globulin (IVIG) has not been examined in the post-marketing or ‘real world’ setting. The objective of this before-after study was to determine the effect of romiplostim on the utilization of IVIG outside of clinical trials. We determined the completeness of our dataset in this multi-center retrospective study. Methods: The charts of patients with ITP from 4 sites in Canada who had received romiplostim were reviewed until January 31, 2012. Patients were 18 years or older, had ITP according to ASH criteria and had at least 1 full year of data available prior to the first dose of romiplostim. A web-based electronic data capture system was used to collect platelet counts, IVIG use, bleeding as assessed by site and severity using an ITP-specific bleeding assessment tool, treatments and hospitalizations before and after the start of romiplostim treatment. IVIG use was compared after normalizing for the duration of time in observation. A pilot exercise was performed to optimize the quality of data extraction from charts. Results: Twenty-nine patients with ITP were included (15 females; median age 54 years, interquartile range [IQR] 45 – 63). Median platelet counts increased from 28 x109/L (IQR, 12 – 58) before romiplostim to 124 x109/L (IQR, 79 – 182) after romiplostim. The proportion of patients requiring other ITP treatments decreased from 25/29 (86%) to 17/29 (59%); the proportion of patients with any bleeding decreased from 24/29 (83%) to 11/29 (38%); and the proportion of patients with grade 2 or higher bleeding decreased from 13/29 (45%) to 6/29 (21%) after romiplostim. Of 29 patients, 16 (55%) had received IVIG before receiving romiplostim. IVIG use over time decreased in 14 of 16 (88%) patients, including 4 (25%) who did not require any IVIG after romiplostim administration. Two splenectomized patients with refractory ITP had received more IVIG in the period after romiplostim was initiated: One patient had discontinued romiplostim because of no platelet count response and subsequently developed intra-cerebral hemorrhage requiring multiple IVIG treatments; the other patient developed cyclical thrombocytopenia. Three additional patients received 1–3 infusions of IVIG only during the period after romiplostim. Of 128 IVIG infusion episodes, 106 were considered to have sufficient documentation since the dose, date of administration and preceding platelet count (within 1 week) were recorded in the chart. Conclusion: In this real-world cohort of patients with ITP, the proportion of patients who required IVIG decreased after starting romiplostim. A few refractory patients required more IVIG in the period after romiplostim. Retrospective data collection of treatment start and end dates and bleeding severity was limited. Disclosures: Arnold: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman-LaRoche: Research Funding.

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Plerixafor (Mozobil ®)Plus G-CSF Is Effective in Mobilizing Hematopoietic Stem Cells in Patients with Concurrent Thrombocytopenia Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.3229.3229 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3229-3229 ◽

Cited By ~ 1

Author(s):

Ivana N Micallef ◽

Eric Jacobsen ◽

Paul Shaughnessy ◽

Sachin Marulkar ◽

Purvi Mody ◽

...

Keyword(s):

Stem Cell ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Platelet Counts ◽

Cd34 Cells ◽

Low Platelet Count ◽

Equity Ownership

Abstract Abstract 3229 Poster Board III-166 Introduction Low platelet count prior to mobilization is a significant predictive factor for mobilization failure in patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) undergoing autologous hematopoietic stem cell (HSC) transplantation (auto-HSCT; Hosing C, et al, Am J Hematol. 2009). The purpose of this study is to assess the efficacy of HSC mobilization with plerixafor plus G-CSF in patients with concomitant thrombocytopenia undergoing auto-HSCT. Methods Patients who had failed successful HSC collection with any mobilization regimen were remobilized with plerixafor plus G-CSF as part of a compassionate use program (CUP). Mobilization failure was defined as the inability to collect 2 ×106 CD34+ cells/kg or inability to achieve a peripheral blood count of ≥10 CD34+ cells/μl without having undergone apheresis. As part of the CUP, G-CSF (10μg/kg) was administered subcutaneously (SC) every morning for 4 days. Plerixafor (0.24 mg/kg SC) was administered in the evening on Day 4, approximately 11 hours prior to the initiation of apheresis the following day. On Day 5, G-CSF was administered and apheresis was initiated. Plerixafor, G-CSF and apheresis were repeated daily until patients collected the minimum of 2 × 106 CD34+ cells/kg for auto-HSCT. Patients in the CUP with available data on pre-mobilization platelet counts were included in this analysis. While patients with a platelet count <85 × 109/L were excluded from the CUP, some patients received waivers and were included in this analysis. Efficacy of remobilization with plerixafor + G-CSF was evaluated in patients with platelet counts ≤ 100 × 109/L or ≤ 150 × 109/L. Results Of the 833 patients in the plerixafor CUP database, pre-mobilization platelet counts were available for 219 patients (NHL=115, MM=66, HD=20 and other=18.). Of these, 92 patients (NHL=49, MM=25, HD=8 and other=10) had pre-mobilization platelet counts ≤ 150 × 109/L; the median platelet count was 115 × 109/L (range, 50-150). The median age was 60 years (range 20-76) and 60.4% of the patients were male. Fifty-nine patients (64.1%) collected ≥2 × 109 CD34+ cells/kg and 13 patients (14.1%) achieved ≥5 × 106 CD34+ cells/kg. The median CD34+ cell yield was 2.56 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 68.5%. The median time to neutrophil and platelet engraftment was 12 days and 22 days, respectively. Similar results were obtained when efficacy of plerixafor + G-CSF was evaluated in 29 patients with platelet counts ≤ 100 × 109/L (NHL=12, MM=10, HD=3 and other=4). The median platelet count in these patients was 83 × 109/L (range, 50-100). The median age was 59 years (range 23-73) and 60.4% of the patients were male. The minimal and optimal cell dose was achieved in 19(65.5%) and 3(10.3%) patients, respectively. The median CD34+ cell yield was 2.92 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 62.1%. The median time to neutrophil and platelet engraftment was 12 days and 23 days, respectively. Conclusions For patients mobilized with G-CSF alone or chemotherapy ±G-CSF, a low platelet count prior to mobilization is a significant predictor of mobilization failure. These data demonstrate that in patients with thrombocytopenia who have failed prior mobilization attempts, remobilization with plerixafor plus G-CSF allows ∼65% of the patients to collect the minimal cell dose to proceed to transplantation. Thus, in patients predicted or proven to be poor mobilizers, addition of plerixafor may increase stem cell yields. Future studies should investigate the efficacy of plerixafor + G-CSF in front line mobilization in patients with low platelet counts prior to mobilization. Disclosures Micallef: Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacobsen:Genzyme Corporation: Research Funding. Shaughnessy:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Mody:Genzyme Corporation: Employment, Equity Ownership. van Rhee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Evaluation of Bleeding-Related Episodes in Patients with Chronic Immune Thrombocytopenia (ITP) Treated with Romiplostim in Two Phase 3 Placebo-Controlled Clinical Trials.

Blood ◽

10.1182/blood.v114.22.891.891 ◽

2009 ◽

Vol 114 (22) ◽

pp. 891-891 ◽

Cited By ~ 1

Author(s):

Ilene Ceil Weitz ◽

Miguel A Sanz ◽

David H. Henry ◽

Martin Schipperus ◽

Bertrand Godeau ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Rescue Medication ◽

Bleeding Event ◽

Bleeding Events ◽

Phase 3 ◽

Advisory Committees ◽

Platelet Counts ◽

Chronic Itp

Abstract Abstract 891 Background: Chronic Immune thrombocytopenia (ITP) is characterized by low platelet counts and increased risk of bleeding. Rescue medications used to treat or prevent bleeding produce transient increases in platelet counts but may be associated with additional toxicities and costs. Romiplostim, approved for the treatment of adult chronic ITP, is a TPO mimetic peptibody protein that increases platelet production. Previously published data from phase 3 romiplostim trials showed that despite the increased use of rescue medication in the placebo arm, patient (pt) incidence of bleeding was reduced in the romiplostim arm vs placebo arm: 15% vs 34% (p = 0.02) for bleeding of grade ≥2 severity and 7% vs 12% (p=0.36) for grade ≥3 severity. Objective: To evaluate the effects of romiplostim treatment on bleeding outcomes in the phase 3 placebo controlled studies in chronic ITP pts with and without previous splenectomy. Bleeding events were captured as adverse events making it difficult to identify a single event reported multiple times versus persistent or recurrent bleeding. Further, we have developed a composite endpoint, termed bleeding-related episodes (BREs), which combines bleeding events and rescue medication administration to account for use of rescue medications to prevent bleeding. Methods: Adults with chronic ITP and a mean baseline platelet count <30 × 109/L were eligible. The previously published studies were conducted separately in splenectomized and nonsplenectomized populations. Pts were randomized (2:1) to receive romiplostim or placebo by subcutaneous injection once weekly for 24 weeks, with dose adjustments to maintain platelet counts between 50-200 × 109/L. Rescue medications were permitted to treat or prevent bleeding and included immunoglobulins, platelet transfusions, corticosteroids, or an increase in dose or frequency of a concurrent ITP medication. A BRE was defined as an actual bleeding event and/or the use of rescue medication. To collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single BRE. Bleeding events beginning 7 or more days after the start of the initial bleeding event were considered a new BRE. To account for differences in time spent on-study, rates of BRE per 100 pt-weeks were calculated. Results: A total of 125 pts (41 placebo, 84 romiplostim) were enrolled in the two studies. Baseline characteristics were well-balanced between the placebo and romiplostim-treated groups. During the treatment period, the rate of BREs was lower in the romiplostim group than in the placebo group, and results were consistent between splenectomized and nonsplenectomized pts (Table). Across both studies, the rate of BREs was reduced by 55% in pts receiving romiplostim compared to those receiving placebo (95% CI, 41% to 65%). BREs were more frequent at platelet counts <50 × 109/L (Table). BREs associated with hospitalizations were less common among romiplostim- than placebo-treated pts, and occurred at platelet counts <50 × 109/L in 10 of 11 cases. Corticosteroids (58 romiplostim, 38 placebo) and immunoglobulins (30 romiplostim, 73 placebo), were the most commonly used rescue medications and the rate of BREs including immunoglobulins was reduced by 88% in pts receiving romiplostim compared to placebo. Conclusions: In adults with chronic ITP, romiplostim was associated with a significant reduction in BREs compared to placebo. There was a marked reduction in BREs requiring immunoglobulins in the romiplostim arm compared to the placebo arm. Results were comparable in splenectomized and nonsplenectomized populations. The platelet count for a BRE starting ≥1 day after a platelet count measurement was calculated from the 2 proximal weekly measurements. Disclosures: Weitz: Amgen Inc.: Speakers Bureau. Sanz:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Henry:Amgen Inc.: Research Funding, Speakers Bureau; Orthobiotech: Research Funding, Speakers Bureau; Watson Pharma: Research Funding, Speakers Bureau. Schipperus:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Godeau:Amgen Inc.: Consultancy, Research Funding; Laboratoire Français de Fractionnement et de Biotechnologies (LFB): Consultancy; Roche: Research Funding. Gleeson:Amgen Inc.: Consultancy, Research Funding. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

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Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽

10.1182/blood.v118.21.3279.3279 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3279-3279 ◽

Cited By ~ 6

Author(s):

Ann Janssens ◽

Michael D. Tarantino ◽

Robert Bird ◽

Maria Gabriella Mazzucconi ◽

Ralph Vincent V. Boccia ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Platelet Response ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Production ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

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Sports Participation in Children with ITP: A Case for Liberalization?

Blood ◽

10.1182/blood.v120.21.3339.3339 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3339-3339 ◽

Cited By ~ 1

Author(s):

Sophie Brigstocke ◽

Catherine E. McGuinn ◽

James B Bussel

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Sports Participation ◽

Contact Sport ◽

Advisory Committees ◽

Contact Sports ◽

Platelet Counts ◽

Risk Of Injury ◽

Frequency Of Sports Participation

Abstract Abstract 3339 Background: Children with ITP are at risk for bleeding. ITP is one of many conditions for which the American Academy of Pediatrics advises a pre-sports participation evaluation to assess the risk of injury (Rice 2008). However, restrictions in sports participation might deny the many evidence-based benefits of such physical activity usually accessible for US school-aged youth, thereby presenting significant health and quality of life issues. Aims: To better assess the frequency of sports participation and sports-related injury outcomes relative to contact level by gathering data via questionnaire from a convenience sample of children with persistent and chronic ITP. Methods: Fourteen different types of sports activities were included in this IRB-approved questionnaire and were classified as contact, limited contact, or non-contact as determined by the American Academy of Pediatrics Council on Sports Medicine and Fitness (Rice 2008). Questions were aimed at the frequency of sports participation, types of sports played, sports-related injuries (including bleeding), medical care required for injuries, and comfort regarding continued participation in a sport after sustaining an injury. For each sport not played, questions assessed reasons for the subject's decision to refrain from participation. Patients were categorized according to their platelet levels: counts ≤ 50, 50–150, >150; counts ≤ or >50; counts ≤ or >30 (×109/L). Proportions of data involving 2 groups were compared in a contingency table using Fisher's exact test with trends ≤ 0.01 and significance ≤ 0.025. Results: Twelve subjects (19%) did not participate in any sports. Thirty-six (56%), including patients across all platelet counts, participated in at least one contact sport. There was no statistically significant association (p > 0.1) between the subject's platelet count and the contact level of sport chosen to play. However, a significant association was found between higher frequency of sports participation and higher platelet count (analyzed by groups ≤ or >50 and counts ≤ or >30 (×109/L)) when the highest frequency of participation in any sport (regardless of contact level) was assessed (p < 0.025). When only the sport with the highest contact rating was considered, patients with higher counts played their highest contact sport more frequently than did those patients with lower counts. In particular, subjects with counts ≤ 30 ×109/L played their highest contact sport less frequently, eg more commonly < 1x/month, compared to subjects with platelet counts > 30 ×109/L who played more commonly > 1x/month (p=0.025) [figure]. Twenty injuries were recorded across 10 different sports and 17 patients, but no serious bleeding injuries were reported. There was a statistically significant association (p = 0.002) between higher contact levels and greater incidence of injury. However, there was no statistically significant association (p > 0.1) between estimated platelet count at time of injury and the contact level of sport. As recorded by the patients and/or the patients' parents, 26% of general concerns came from physicians, 53% from parents and 21% from patients themselves. Data collected on the participants' personal concerns showed that higher platelet counts were associated with fewer personal concerns being expressed (p < 0.025). However, when each personal concern was analyzed there were no statistically significant trends or associations (p > 0.1) found between any specific concern and platelet count. Across all contact and limited-contact sports, the most frequently expressed concern was that the sport was too dangerous. The most frequently expressed concern for non-contact sports was that the patient was too tired to play. Conclusions: There was a significant association between higher frequency of sports participation, but not higher contact level, with higher platelet counts. Higher incidences of injury were associated with higher contact levels, but not with lower platelet counts, suggesting that children with ITP can participate in non-contact sports and many contact and limited-contact sports with low risk of injury. Therefore, we believe that sports participation for children with ITP is generally too restricted and greater encouragement for children to be athletic in the sport of their choice is warranted. Disclosures: Bussel: Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

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

Blood ◽

10.1182/blood-2021-151435 ◽

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 <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 <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.

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Hepatobiliary and Thromboembolic Events during Long-Term E.X.T.E.N.Ded Treatment with Eltrombopag in Adult Patients with Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v128.22.1368.1368 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1368-1368

Author(s):

Mansoor N. Saleh ◽

James B Bussel ◽

Raymond SM Wong ◽

Balkis Meddeb ◽

Abdulgabar Salama ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Adult Patients ◽

Phase Iii ◽

First Year ◽

Thromboembolic Events ◽

Advisory Committees ◽

Platelet Counts

Abstract Introduction: ITP, characterized by a reduction in platelets leading to thrombocytopenia, which persists for >12 months is considered chronic (cITP). Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of patients with cITP aged ≥1 year refractory to other treatments (eg corticosteroids, immunoglobulins). The recently completed Phase III EXTEND (Eltrombopag eXTENded Dosing) study was a global, open-label, extension study of patients with cITP, who received eltrombopag or placebo in prior eltrombopag clinical studies. The primary objective of EXTEND was to describe the long-term safety and tolerability of eltrombopag treatment in these patients. Here, we examine the occurrence of hepatobiliary and thromboembolic events (TEEs) as adverse events (AEs) of special interest in this study. Methods :Adult patients (≥18 years old) diagnosed with cITP according to ASH/BCSH guidelines were enrolled and received eltrombopag starting at 50 mg/day. Dose was titrated to 25-75 mg per day or less often as required, based on individual platelet count responses (targeted range ≥50-200x109/L). Patients who received 2 years of treatment and transitioned off eltrombopag due to commercial availability of eltrombopag were considered to have completed the study, whether or not they continued treatment with eltrombopag. The primary endpoint included detection and documentation of investigator-reported AEs, which included hepatobiliary AEs and TEEs. Analyses were conducted using the safety population, defined as all subjects who entered the study and had taken at least one dose of the study medication. Results:302 patients were enrolled and received at least one dose of eltrombopag: 67% were female; 38% splenectomized; 49% aged 18-49 years. Median duration of exposure was 2.4 years (range, 2 days to 8.8 years) and mean average daily dose was 50.2 (range, 1-75) mg/day. Overall, 259/302 (86%) achieved platelet counts of ≥50×109/L at least once during the study and 126/248 (51%) patients maintained continuous platelet counts ≥50×109/L for at least 31 weeks. Incidence of bleeding symptoms (WHO grades 1-4) generally decreased over time in patients with available data, from 57% (n=171/302) at baseline to 16% at 1 year (n=13/80), and 21% (12/58) at 2 years. 45 (15%) patients experienced at least one hepatobiliary AE, with the highest incidence within the first year of treatment (Figure A). AEs of increased ALT or AST led to the discontinuation of five and three patients, respectively and four patients discontinued due to an AE of increased blood bilirubin. Nine patients experienced ALT and/or AST >3 x upper limit of normal (ULN) and total bilirubin >1.5xULN. 19 (6.3%) patients experienced a total of 23 TEEs. Most events occurred in the first year (Figure B), and none after year 4. TEEs included deep vein thrombosis (n=6), cerebral infarction (stroke) [n=3], myocardial infarction (n=4), transient ischemic attack (n=2), others (n=8, 1 occurrence of each). A clear association with elevated platelet counts was not observed. Platelets >200x109/L at the time of the TEE were recorded in 8/19 patients; 6/19 experienced the TEE at or shortly after achieving their maximum platelet count. In total, 10 patients discontinued because of TEEs. Conclusions: Long-term treatment with eltrombopag in patients with cITP led to sustained platelet increases and reduced bleeding symptoms. The highest incidences of hepatobiliary AEs and TEEs occurred during the first year of treatment, though several events were recorded after 3 years of therapy. Long-term eltrombopag therapy was well-tolerated with a positive benefit-risk relationship in adults with cITP, with decreasing events after the first year of treatment. Disclosures Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. Bussel:Amgen, Novartis & GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingleheim, Prophylix Pharma, Protalex, Rigel Pharmaceuticals: Research Funding; Momenta Pharmaceuticals, Novartis, Prophylix Pharma, Protalex, Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; UptoDate: Patents & Royalties; Physicians Education Resource: Speakers Bureau. Wong:Bayer, Biogen-Idec and Novartis: Consultancy; Bayer, Biogen-Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and Roche: Research Funding; Biogen-Idec and Novartis: Membership on an entity's Board of Directors or advisory committees. El-Ali:Novartis: Employment. Quebe-Fehling:Novartis: Employment.

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Safety and Efficacy of Romiplostim in over 200 Children with Immune Thrombocytopenia (ITP): Results of an Integrated Database of 5 Clinical Trials

Blood ◽

10.1182/blood-2018-99-109763 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2428-2428 ◽

Cited By ~ 1

Author(s):

Michael D. Tarantino ◽

Jenny M. Despotovic ◽

John Roy ◽

John Grainger ◽

Nichola Cooper ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Platelet Response ◽

Open Label ◽

Advisory Committees ◽

Baseline Platelet Count ◽

Platelet Counts

Abstract Background: Romiplostim is approved globally for use in adults with ITP and in the EU for children with ITP. More comprehensive data are needed on the use of romiplostim in children with ITP. Objective: To examine the safety and efficacy of romiplostim in trials in children with ITP. Methods: Data were combined from 5 romiplostim trials in children with ITP, both placebo-controlled (a phase 1/2 and a phase 3 trial) and open-label (a 3-year trial and 2 extension trials); trial data have been reported previously (Bussel Blood 2011, Bussel PBC 2014, Tarantino Lancet 2016, Tarantino ASH 2017, Grainger ASH 2017). Platelet counts in the 4 weeks after use of rescue medication were excluded from analyses. Descriptive statistics were used. Number (n), mean, standard deviation (SD), median, quartile range (Q1, Q3), minimum (min), and maximum (max) for continuous variables, and number and percentage for categorical variables were provided. Results: Patients (N=286, 24 initially placebo and 262 initially romiplostim) had median (Q1, Q3) age of 10 (6, 13) years, ITP duration of 1.9 (1, 4) years, and baseline platelet count of 14 (8, 23)×109/L. Previously, 88% had received corticosteroids, 87% IVIg, and 21% rituximab; 23% had received >3 prior treatments and 7% had prior splenectomy. Of the 282 patients exposed to romiplostim (20 initially received placebo), the median (min, max) duration of treatment was 65 (8, 471) weeks, with a median (min, max) average weekly dose of 6.6 (0.1, 9.7) μg/kg; total exposure was 468 patient-years. The most common reasons for discontinuing the parent study for romiplostim-treated patients were per protocol (19%; eg, sponsor decision, death, lost to follow-up), consent withdrawn (3%), noncompliance (1%), and administrative decision (1%). Of romiplostim-treated patients, 24% had serious adverse events (SAEs), most commonly epistaxis, low platelet counts, and headache (Table). There were 7 cases of postbaseline neutralizing antibody against romiplostim: 2 transient and 5 persistent. There were no neutralizing antibodies against endogenous TPO. For patients undergoing bone marrow biopsies in the 3-year open-label trial, there were no findings of collagen or bone marrow abnormalities (Year 1 n=27, Year 2 n=5, vs. baseline) (Grainger et al, ASH 2017). One patient had an increase in modified Bauermeister bone marrow grade from 0 to 2 (fine reticulin fiber network) with no associated AEs (the only AEs were a cold and injection site pain); per protocol, there was no follow-up biopsy. Once at a steady dose of 10 μg/kg, most (11/16) of this patient's platelet counts were ≥30×109/L. Investigators reported thrombocytosis AEs; 1 patient had a platelet count of 1462×109/L at Week 14 for 1 week and another had elevated platelet counts 10 times between Weeks 20-172 (max of 872×109/L); there were no associated thrombotic events. Median platelet counts rose quickly and were over 50×109/L from Week 12 on (Figure). Platelet response rates also rose quickly. Overall, 89% of romiplostim-treated patients (vs 8% of placebo) had a platelet response (platelet counts ≥50×109/L; Figure). For romiplostim-treated patients, the first platelet responses occurred after a median of 6 weeks. The median % (Q1, Q3) of months responding was 76% (25%, 93%) and # of months responding was 11 (3, 20); from time of first monthly response, the median (Q1, Q3) % of months responding was 92% (75%, 100%) and # of months responding was 14 (7, 23). Nineteen romiplostim-treated patients discontinued all ITP therapies including romiplostim for ≥6 months while maintaining platelet counts ≥50×109/L (here defined as remission). These treatment-free periods lasted a median (Q1, Q3) of 12 (8, 14) months; no placebo patients remained free of treatment. There were no clear differences between those who did and did not enter remission (ie, age, sex, race, past treatment, ITP duration, baseline platelet count). Bleeding was reported for most (68%) patients: mostly grade 1/2, with 10% having grade 3 bleeding (most commonly epistaxis in 13 patients) and 2 patients having grade 4 bleeding (both reported as "ITP"). Conclusions: In this comprehensive database of romiplostim ITP trials in 286 children with 468 patient-years of romiplostim exposure, romiplostim was well tolerated. With romiplostim, the vast majority (89%) of patients had a platelet response, with some children able to discontinue all ITP treatments for ≥6 months. Disclosures Tarantino: Health Resources and Services Administration: Research Funding; Centers for Disease Control and Prevention: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Other: Reviews grants; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Research Funding, Speakers Bureau. Despotovic:AmGen: Research Funding; Sanofi: Consultancy; Novartis: Research Funding. Grainger:Biotest: Consultancy; Ono Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria, Other: Educational grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooper:Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

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