Assessment of Safety and Efficacy of a New Intravenous Immunoglobulin (IGIV3I 10% Grifols) In Subjects with Chronic Immune Thrombocytopenia

Abstract Abstract 4669 Two similarly designed prospective, uncontrolled, open-label clinical trials were planned to assess the safety and efficacy of a new intravenous immunoglobulin (IVIG), IGIV3I 10% Grifols, in subjects with chronic immune thrombocytopenia (ITP) in the USA, Canada and Europe (Spain, Russia and the United Kingdom). Subjects were candidates to be enrolled if they had a diagnosis of chronic ITP and a baseline platelet count ≤ 20 × 109/l. Eligible subjects received treatment with IGIV3I 10% Grifols 1g/kg for 2 consecutive days or 0.4 g/kg for 5 consecutive days. The primary efficacy endpoint was the response rate, defined as the proportion of subjects reaching or exceeding the threshold value of 50 × 109/l on or before day 8 (American study) or on day 30 (European study) where day 1 is the day of the first infusion. Secondary efficacy endpoints were the time to response, defined as the number of days elapsed from day 1 to achievement of the threshold value; duration of response, defined as the number of consecutive days with a platelet count known to be ≥50 × 109/l; the maximum (peak) platelet count and regression of haemorrhagic diathesis for those subjects presenting with bleeding signs at baseline. Safety endpoints included adverse events (AEs), physical examinations, vital signs and clinical laboratory parameters monitoring. A total of 27 subjects (18 adults and 9 pediatrics) have been enrolled, i.e. administered with at least one infusion of the product at any dose, in the study. Twenty-four (24) subjects (89%) were considered responders. This proportion was higher in pediatric subjects (9/9, 100%) than in adult subjects (15/18, 83%). The mean time to response was 1.6 days (Standard Deviation (SD) 0.9); the mean duration of response was 14.0 days (SD 12.1) and the mean maximum platelet count was 263 × 109/l (SD 195.6). Twenty-three (23) subjects (all the pediatric subjects 9/9 and 14/18 adults) presented with some sign of bleeding at baseline. All subjects (23/23, 100%) experienced an improvement in the haemorrhagic diathesis, regardless of some of them being considered non-responders according to the platelet count criterion. A total of 92 AEs potentially related to study drug were reported. The most common of these were headache (25 events), nausea (8 events), pyrexia (7 events) and chills (6 events). Only 1 AE was reported as definitely related to study drug, an event of palmar erythema. Two serious AEs (SAE) potentially related to the study drug were reported in 2 subjects. One of them was an unexpected laboratory alteration which consisted in leukopenia and decreased hemoglobin and advised to maintain the subject hospitalized for further observation during the weekend. The reaction was transient, without complications or other clinical symptoms and total recovery of the normal laboratory values. The second SAE was an event of thrombosis in the right humeral vein, in a patient with a number of predisposing medical conditions. At the time of discharge the patient's overall condition was satisfactory. Analysis of AEs, clinical laboratory values, physical assessments and vital signs did not indicate any safety concerns for subjects receiving the study drug and are in line with those expected for the ITP population treated with IVIG. Both primary and secondary efficacy endpoints show a good response to the product in terms of rapid elevation of platelet counts to an hemostatic level in line with what is expected for an IVIG product. Moreover, the improvement of the baseline bleeding diathesis even in patients considered as non-responders according to the platelet count criterion is highly suggestive of the clinical efficacy of the product. Overall, these results indicate that treatment with the new IGIV3I 10% Grifols is safe and efficacious for rapidly increasing platelet counts in chronic ITP subjects and improving their bleeding diathesis. Disclosures: Khojasteh: Grifols S.A.: Research Funding. Kato:Grifols S.A.: Research Funding. Parikh:Grifols S.A.: Research Funding. Singleton:Grifols S.A.: Research Funding. Tebbi:Grifols S.A.: Research Funding. Cromwell:Grifols S.A.: Research Funding. Fu:Grifols S.A.: Research Funding. Kessler:Grifols S.A.: Research Funding. Letzer:Grifols S.A.: Research Funding. Ritchie:Grifols S.A.: Research Funding. Sexauer:Grifols S.A.: Research Funding. Saxena:Grifols S.A.: Research Funding. Sirpal:Grifols S.A.: Research Funding. Torres:Grifols S.A.: Research Funding. Loriya:Grifols S.A.: Research Funding. Kovaleva:Grifols S.A.: Research Funding. Sandoval:Grifols S.A.: Research Funding. Sanz:Grifols S.A.: Research Funding. Julià:Grifols S.A.: Research Funding. Montañés:Grifols S.A.: Employment. Navarro:Grifols S.A.: Employment.

Download Full-text

Impact of Non-Alcoholic Fatty Liver Disease (NAFLD) on Platelet Count

Blood ◽

10.1182/blood-2021-145143 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2077-2077

Author(s):

Sarah Tomassetti ◽

David Yashar ◽

Katie LaBarbera

Keyword(s):

Insulin Resistance ◽

Platelet Count ◽

Liver Disease ◽

Fatty Liver Disease ◽

Research Funding ◽

Chronic Viral Hepatitis ◽

Alcoholic Fatty Liver ◽

Platelet Production ◽

The Mean ◽

Alcoholic Fatty Liver Disease

Abstract BACKGROUND: It is well established that alcohol use and chronic viral hepatitis negatively affect the peripheral platelet count. However, less is known about the effects of non-alcoholic fatty liver disease (NAFLD) on the peripheral platelet count. Platelets are anucleate cells made in the bone marrow that are responsible for the initiation of the hemostatic system and ultimately the repair of damaged endothelium. Platelet production is stimulated by thrombopoietin (TPO), a glycoprotein made by the liver that regulates platelet production. Binding of TPO to its receptor, c-MPL, on platelets and megakaryocytes prevents apoptosis of megakaryocytes and increases their number, size, and ploidy. In the setting of liver disease, such as NAFLD, TPO production may be reduced, which could result in lower peripheral platelet counts. NAFLD is a growing concern in the United States where the prevalence of NAFLD is estimated to be 25% and is expected to continue to rise over the next 10-15 years. NAFLD comprises a wide spectrum of disorders from simple steatosis to steatohepatitis. It is caused by excessive fat accumulation in the liver due to a dysregulation of fat synthesis and utilization resulting in oxidative stress. NAFLD is closely tied to insulin resistance. A subset of those with NAFLD develop progressive liver disease characterized by hepatocyte injury, inflammation, and ultimately cirrhosis. Hispanics have the highest prevalence and often have components of metabolic syndrome including obesity, systemic hypertension, dyslipidemia, and insulin resistance or diabetes. Studies show conflicting results as to the association of NAFLD and thrombocytopenia. Thus, the effect of NAFLD on the peripheral platelet count warrants further investigation. METHODS: We performed a retrospective chart review of all patients aged greater than 18 years who presented to Harbor-UCLA Medical Center between October 1, 2015 and March 1, 2021 with the diagnosis of NAFLD based on imaging. Diagnosis was established based on radiologic evidence of NAFLD on abdominal ultrasound or computed tomography scan. Patients were excluded if they had cirrhosis, chronic viral hepatitis, splenomegaly, excessive alcohol consumption (≥ 30 g/day in men or ≥ 20 g/day in women), malignancy, consumption of drugs commonly associated with thrombocytopenia, or known immune thrombocytopenia. Platelet count, body mass index (BMI), bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, protein, cholesterol, triglycerides, prothrombin time (PT), partial thromboplastin time (PTT), and HbA1c were measured. Comorbid conditions including hypertension, obstructive sleep apnea (OSA), cardiovascular disease (CVD), and chronic kidney disease (CKD), were recorded. RESULTS: There were a total of 587 patients with the diagnosis of NAFLD who met the inclusion criteria. 41.7% were female and 58.3% were male. Of these, 51.4% were Hispanic, 8.9% were White (European), 7.0% were African American, 2.7% were Asian, and 2.7% were Southeast Asian, and 27.3% were unknown. The average age was 49 years. The mean platelet count was 249.5 K/cumm. The mean BMI was 33.4. The mean AST was 60.23 (normal 15-41 U/L) and ALT was 20.23 U/L (normal 7-35 U/L). The mean bilirubin, albumin, protein, PT, and PTT were all within normal limits. The mean HbA1c was 6.89%. The mean total cholesterol was 178.81 mg/dL (normal 125-199mg/dL), HDL 44.07 mg/dL (normal >40mg/dL), and LDL 101.65 mg/dL (normal <99 mg/dL). Coexisting hypertension, CKD, CVD, and OSA occurred in 39.2%, 11.1%, 7.8%, and 4.4% respectively. CONCLUSIONS: In this study, we found that NAFLD was not associated with thrombocytopenia. Further studies may be done to elucidate the impact of NAFLD on TPO levels and resulting peripheral platelet levels. Disclosures Tomassetti: Parexel: Research Funding; Novartis: Research Funding; Natera: Research Funding; Beigene: Research Funding; Rigel: Research Funding; Seagene: Research Funding.

Download Full-text

Further Characterization of Thromboembolic Events and Association with Platelet Count Occurring during the Avatrombopag Immune Thrombocytopenia (ITP) Clinical Development Program

Blood ◽

10.1182/blood-2021-150897 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2086-2086

Author(s):

Caroline I. Piatek ◽

Brian Jamieson ◽

Scott Kolodny

Keyword(s):

Platelet Count ◽

Research Funding ◽

Development Program ◽

Mean Value ◽

Clinical Development ◽

Thromboembolic Events ◽

Two Phase ◽

Clinical Development Program ◽

The Mean

Abstract Background: ITP management often requires subsequent therapy beyond current first line treatments (corticosteroids or intravenous immunoglobulin). The use of thrombopoietin receptor agonists (TPO-RAs) as second-line treatment, in lieu of splenectomy or rituximab, has become more common and is supported by recent American Society of Hematology (ASH) guidelines (Neunert, 2019). The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been utilized in patients with ITP for over a decade, whereas avatrombopag (AVA) was more recently approved in June 2019. Thromboembolic events (TEEs) are not uncommon in ITP, with studies showing that up to 8% of patients experience an arterial or venous event (Sarpatwari, 2010; Vianelli, 2013). As agents that potentiate endogenous platelet production, TPO-RAs as a class may increase the risk of thromboembolism, with such events occurring in a variety of TPO-RA ITP studies. However, it is not well-understood what increased risk, over and above the inherent risk associated with ITP, TPO-RAs pose in regard to thromboembolic events (Catala-Lopez, 2015). We previously reported on the general characterization of thromboembolic events occurring during the avatrombopag ITP clinical development program (ASH 2020). Currently, we evaluate platelet counts both prior to and following the specific TEE event and report on any dosage change of avatrombopag in proximity to the TEE event. Aims: To further characterize TEEs occurring across the AVA ITP clinical development program and expand the understanding of any possible role of change in platelet count (PC) as a predictor of TEEs with AVA. Methods: 4 studies were conducted evaluating AVA in patients with ITP (two Phase 2 and two Phase 3 trials). In total, 128 patients received AVA treatment, with an average duration of exposure of ≥180 days. Occurrence of TEEs was an adverse event of special interest that was monitored closely in these studies. At the time of each TEE, the following information was collected: platelet count, AVA dose, study day of event and other medical history and lifestyle factors potentially increasing the risk for thromboembolism. PCs were also collected at each study visit as well as unplanned visits per protocol. Patients with history of arterial or venous thrombosis and more than 2 significant risk factors were excluded from the Phase 3 studies. Results: As previously reported, a total of 11 TEEs occurred in 9/128 (7%) of AVA treated patients, with one patient experiencing 3 events. No clustering of events was noted, with cerebrovascular accident being the only specific event occurring in more than one patient (occurring in 2/11 patients). In the current analysis, variability was observed in the platelet count at the time of TEE, ranging from 19,000 - 571,000/µL. Two patients experienced events at a platelet count >400,000/µL, whereas five events occurred at a PC <50,000/µL. The mean value of three PCs prior to the event in each individual patient were low (PC<130,00/µL) in 7/11 (64%), normal (PC between 130,000/µL-450,000/µL) in 4/11 (36%), and high (PC>450,000/ µL ) in 0/11 (0%) of patients. The mean value of three PCs following the event in each individual patient were low in 6/11 (55%), normal in 4/11 (36%), and high in 1/11 (9%) of patients. The change in mean PC status from prior to the event to following the event was no change in 7/11 (64%), low to normal in 2/11 (18%), low to high in 0/11 (0%), normal to low in 1/11 (9%), and normal to high in 1/11 (9%) of patients. There were no changes in AVA dose within three weeks of any TEE event. The onset of thromboembolic events ranged from study day 8 to 335, with no clear pattern materializing regarding duration of drug exposure and the onset of the TEE. Thromboembolic events were noted at daily doses of AVA ranging from 10 - 40 mg. No deaths were noted in the ITP development program. Conclusions: The TEEs noted with AVA treatment typically occurred at PCs below the upper bound of normal (450,000/µL), without relationship to drug dose and at varying number of days on study drug. No clear patterns regarding the occurrence of thromboembolic events with AVA treatment or platelet count could be determined. Clinicians should carefully monitor PC and assess the risk for thromboembolism in each individual patient treated with a TPO-RA. Figure 1 Figure 1. Disclosures Piatek: Dova: Consultancy, Speakers Bureau; Apellis: Research Funding; Alexion: Consultancy, Research Funding; Rigel: Consultancy, Research Funding. Jamieson: Sobi, Inc.: Current Employment. Kolodny: Sobi, Inc.: Current Employment.

Download Full-text

Bleeding Manifestations and Management of Children with Persistent and Chronic Immune Thrombocytopenia (ITP): Data From the Intercontinental Cooperative ITP Study Group.

Blood ◽

10.1182/blood.v114.22.1315.1315 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1315-1315 ◽

Cited By ~ 2

Author(s):

Cindy Neunert ◽

George R. Buchanan ◽

Paul A. Imbach ◽

Paula HB Bolton-Maggs ◽

Carolyn M. Bennett ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Threshold Value ◽

Acute Onset ◽

Additional Patient ◽

Severe Bleeding ◽

Study Group ◽

Advisory Committees ◽

Fatal Hemorrhage

Abstract Abstract 1315 Poster Board I-339 ITP during childhood is generally characterized by acute onset of thrombocytopenia and bleeding in an otherwise well child. While the platelet count has traditionally been viewed as a marker of disease severity, additional patient characteristics such as bleeding severity have not been well defined. The Intercontinental Cooperative ITP Study Group (ICIS) Registry II was designed to characterize the location, frequency, timing, and severity of bleeding in children with ITP (Blood, 2008;112: 4003-8). We report here data from Registry II with a focus on bleeding symptoms reported at 6 and 12 months. Patients enrolled on Registry II had research visits at diagnosis, and 28 days, 6 months, 12 months, and 24 months following diagnosis. Bleeding manifestations were retrospectively recorded at 6 and 12 months capturing all sites of bleeding (e.g skin, epistaxis, and gastrointestinal) since the last research visit. Of the 1318 children enrolled at diagnosis, 891 were evaluated at 6 months and 718 at 12 months. Mean platelet counts were 198 × 109/l (s.d. 130) and 195 × 109/l (s.d.122) at 6 and 12 months respectively. At 6 months 29% (261/891) of patients still had a platelet count <100 × 109/l; of these 45% (118/261) were <30 × 109/l. At 12 months these values were 28% (203/718) and 40% (82/203) respectively. Number of bleeding sites reported since the last research visit at 6 months and 12 months are outlined in Table 1. There were no reports of intracranial hemorrhage (ICH) or fatal hemorrhage. The most common bleeding site reported at both 6 and 12 months was skin, followed by epistaxis. 4 children with a platelet count <30 × 109/l at both 6 and 12 months were reported as having undergone splenectomy. Red cell transfusions were infrequent (3 reported) and administered only in children with bleeding from ≥ 3 sites. The percentage of patients with a platelet count <30 × 109/l who received platelet count enhancing therapy (including platelet transfusions) is outlined in Table 2. Table 1 Number of bleeding sites reported since last research visit at 6 and 12 months 6 month visit 12 month visit Number of sites Platelet count <100 × 109/l (n= 261) Platelet count <30 × 109/l (n= 118) Platelet count <100 × 109/l (n= 203) Platelet count <30 × 109/l (n= 82) None 60 (23%) 10 (9%) 74 (36%) 16 (19%) 1 110 (42%) 44 (37%) 82 (40%) 33 (40%) 2 61 (23%) 39 (33%) 32 (16%) 21 (26%) 33 30 (12%) 25 (21%) 15 (7%) 12 (15%) Table 2 Patients with platelet count <30 × 109/l reported as having received platelet count enhancing therapy Number of bleeding sites reported between research visits Treatment reported between 28 days and 6 months (n = 118) Treatment reported between 6 and 12 months (n = 82) None 1/10 (10%) 4/16 (8%) 1 29/44 (66%) 19/33 (58%) 32 58/64 (91%) 26/33 (78%) In summary, approximately 30% of children with ITP enrolled on ICIS Registry II remain thrombocytopenic 6 and 12 months later, many still having a platelet count <30 × 109/l, a threshold value sometimes used to determine drug treatment and enrollment in prospective intervention studies. This cut-off may be appropriate since bleeding was more common when the platelet count was <30 × 109/l. However, even below this threshold life-threatening hemorrhage was uncommon, few patients required packed red blood cell transfusions, and approximately half the patients reported no more than one site of bleeding. Treatment was infrequently used in patients in this group if they had no bleeding, and platelet enhancing therapy was often employed if more bleeding sites were involved. These data suggest a trend towards reserving treatment for patients with more severe bleeding manifestations rather than because of a specific platelet count. Disclosures Buchanan: AMG 531: Research Funding. Bolton-Maggs:Baxter: Travel support to meetings; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; United Kingdom Immune Thrombocytopenic Pupura Support Association: Research Funding; Glaxo Smith Kline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blanchette:AMG 531: Membership on an entity's Board of Directors or advisory committees. Kuehne:F. Hoffman-La Roche Ltd: Research Funding; Amgen: Research Funding.

Download Full-text

Laboratory HIT Testing in Critically Ill Patients

Blood ◽

10.1182/blood.v118.21.198.198 ◽

2011 ◽

Vol 118 (21) ◽

pp. 198-198

Author(s):

Mark A. Crowther ◽

Stephan Langevin ◽

Jamie L Cooper ◽

Peter Dodek ◽

John Muscedere ◽

...

Keyword(s):

Platelet Count ◽

Venous Thrombosis ◽

Critically Ill ◽

Risk Score ◽

Critically Ill Patients ◽

Research Funding ◽

Study Drug ◽

Clinical Suspicion ◽

Low Risk ◽

Icu Patients

Abstract Abstract 198FN2 Introduction: Many critically ill patients are frequently suspected of having HIT because heparin exposure is nearly universal and up to 45% of medical-surgical ICU patients have a platelet count of less than 150 × 109. Methods: Our objectives were: (1) To estimate the incidence of suspected and objectively confirmed HIT; and (2) To evaluate whether a published clinical prediction rule (the 4T's score) reliably rules out HIT in ‘low risk' ICU patients. PROTECT was a multinational, concealed, stratified, randomized blinded trial enrolling medical-surgical critically ill patients to evaluate thromboprophylaxis with the low molecular weight heparin (LMWH) dalteparin 5,000U daily vs unfractionated heparin (UFH) 5,000 twice daily on the primary outcome of proximal leg deep vein thrombosis (DVT). Patients were evaluated for HIT and included in this HITEC Substudy if 1) their platelet count decreased to less than 50 × 109/L, 2) if there was an otherwise unexplained platelet count decrease to less than 50% of the patient's baseline (defined as the value found on the first platelet count after ICU admission as long as the count is >100 × 109/L), or 3) if venous thrombosis occurred, and 4) if HIT was otherwise suspected. There were 2 laboratory components to HIT testing (local and central). For local real-time clinical care, HIT was evaluated and treated as per local practice. Centrally, blood samples were analyzed at the laboratory of Dr Ted Warkentin at McMaster University. The 4Ts Score was completed by Research Coordinators (RCs) and by central adjudication. We defined HIT as a clinical suspicion of HIT and a positive serotonin release assay (SRA). Results: The PROTECT trial enrolled 3746 patients of whom 763 patients (397 allocated to UFH and 366 to LMWH) met HITEC enrollment criteria; 151 because of an absolute platelet count of less than 50×109, 253 because of a fall in their platelet count of greater than 50% from the time of ICU admission and 534 because venous thrombosis developed and 128 because of a clinical suspicion of HIT (categories are not mutually exclusive). Of these 763 patients, 475 had a central or local laboratory HIT test performed and were adjudicated. HIT was present in 15/3746 patients enrolled in the PROTECT study (0.4%, 95% CI 0.2% to 0.7%), and 15/475 (3.2%) with local or central testing, while 432 patients with RC 4Ts scores were matched to an adjudicated outcome. Using the 4Ts score, RCs and central adjudication classified patients as low risk (4Ts score of 3 or less) in 71.1% and 86.3% of cases, respectively, moderate risk (score or 4 or 5) in 25.7% and 12.0% of cases, and high risk (score of 6 or more) in 3.2% and 1.7% of cases. There was a good correlation between a low pretest probability according to the RCs' scores and the absence HIT (prevalence of adjudication confirmed HIT 1.6% (95% CI 0.5 to 3.7%).There was a moderate correlation between a low pretest probability according to central adjudication and the absence HIT (prevalence of adjudication confirmed HIT 2.6% (1.3 to 4.7%). Discussion: HIT occured in less than 1% of medical-surgical critically ill patients, and in 3% of patients who had at least one criterion to suspect HIT. We failed to confirm our pre-specified criteria for successful implementation of the 4T's score (that the upper boundary the 95% confidence interval about the proportion of patients with confirmed HIT and a low 4Ts score was less than 3%) and thus we conclude that use of the 4Ts score does not rule out the presence of platelet-activating antibodies in medical surgical critically ill patients with clinically suspected HIT; SRA testing is recommended. Funding: Canadian Institutes for Health Research and Heart and Stroke Foundation of Canada Disclosures: Crowther: CSL Behring: Consultancy; Leo Pharma: Consultancy, Research Funding; BI: Research Funding; Bayer: Research Funding; Pfizer: Consultancy, Research Funding; Octapharm: Consultancy; Artisan: Consultancy. Off Label Use: Dalteparin is not indicated for prolonged DVT prophylaxis in medical intensive care unit patients. Zytaruk:Pfizer: donated study drug dalteparin for PROTECT. Cook:Pfizer: donated study drug dalteparin for PROTECT. Warkentin:GTI Diagnostics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Pfizer Canada: Speakers Bureau; Sanofi-Aventis: Speakers Bureau; Informa: Patents & Royalties; Canyon Pharma: Consultancy, Speakers Bureau.

Download Full-text

Rituximab (Ritux) Maintenance Infusions in Immune Thrombocytopenia (ITP) to Prolong Remission Following Relapse after Initial Ritux Induction but Responded to a Second Course

Blood ◽

10.1182/blood-2018-99-114242 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3753-3753 ◽

Cited By ~ 1

Author(s):

Manoj P Rai ◽

Eun-Ju Lee ◽

James B. Bussel

Keyword(s):

Research Funding ◽

Jc Virus ◽

Standard Dose ◽

Controlled Trial ◽

Maintenance Phase ◽

Fisher Exact Test ◽

Evans Syndrome ◽

Exact Test ◽

Duration Of Response ◽

The Mean

Abstract Introduction: ITP is an autoimmune disease characterized by low platelet counts and variable bleeding. Ritux treatment of ITP patients (pts) receiving 375 mg/m2 once a week for 4 weeks results in 50-60% achieving complete responses (CR). However, most pts will relapse, usually around 1 year from initial treatment. In a previous study, 20 pts were retreated with a second round of 4 infusions of ritux and 16 (80%) had essentially the same response to retreatment with ritux with the second set of 4 infusions (Hasan A, AmJHem, 2009). Maintenance ritux infusions in Non-Hodgkin Lymphoma are now well-demonstrated to increase cure despite variable infusion schedules. This retrospective study explores ritux maintenance in pts with ITP or / and other autoimmune cytopenias who responded to but relapsed after a first induction with Ritux and who then received a 2nd to 4th induction with ritux. Methods: We enrolled 17 pts with ITP, Autoimmune hemolytic anemia (AIHA), Autoimmune Neutropenia (AIN) and/or Evans syndrome, who previously responded to but then relapsed following induction with 4 ritux infusions. Ritux was administered to relapsed pts at standard dose during weeks 1, 2, 3, and 4 of induction. During the maintenance phase, single infusions of ritux were given at 1 dose of 375 mg/m2 every 4 months for a total of 2 years or until relapse or development of unacceptable adverse effects or infections or withdrawal from the study (to become pregnant); 3 pts with shorter remission times following previous ritux were treated at 3 month intervals. 5 pts received 40mg/day of dexamethasone (Dex) with the ritux maintenance infusions: 3 4-day cycles of Dex at 2 weekly intervals (Chapin, AJH, 2016) with induction and single dose dex with each maintenance infusion. The primary endpoint was the duration of response. Secondary endpoints included safety. Statistical analysis was largely descriptive. Comparisons of first and second ritux treatments (without and with maintenance) were made using the Fisher Exact test. Results: Of the 17 pts who received ritux maintenance, 11 had ITP, 2 AIHA, and 4 had Evans syndrome. Three pts had AIN as part of their Evans syndrome. 7 had received more than 1 ritux induction (2-4) in the past. At initiation of maintenance, there were 10 males and 7 females and 13 adults and 4 children. Three had undergone splenectomy prior to starting ritux. The mean duration of response following the first cycle of 4 ritux standard infusions was 19 months, while the mean duration of response with maintenance schedule was 48 months. Fifteen of 17 patients achieved CR with ritux re-induction; of these 7 relapsed. 2 patients achieved PR, 1 relapsed. The mean duration of response with ritux maintenance was 36.8 months in adults and 63.8 months in children; it was 48 months each in males and females; it was 49 months in the 3 patients who had undergone splenectomy and also in those who had not undergone splenectomy. Fisher exact test did not show any statistical difference in clinical parameters including the type of autoimmune cytopenia. Pts with more previous ritux inductions did worse than those receiving their 2nd reinduction. Three patients developed hypogammaglobulinemia and needed IVIG prophylaxis against infections; one patient had bacteremia. One patient developed sepsis secondary to hypogammaglobulinemia requiring ICU admission. JC virus cultures were negative in all tested pts. No pts developed transaminitis or signs of renal failure. Discussion: The expectation for these 17 very difficult to treat pts was that they would have all relapsed in 1 year or less following a "routine" ritux re-induction based on past data and clinical experience. The number of pts reported who achieved lasting remission following a second or third course of ritux is very small. Dex was added to reinduction in 5 of these multiply-induced pts, but curative effects occur only in female pts treated within 1 year of diagnosis, and these were pts with years of disease so this would not explain the results. Being able to achieve lasting remission over many years in half this group appears to be a significant improvement on their expected outcomes. Hypogammaglobulinemia became clinically significant in 1 pt who stopped coming for checkups; it has been reported primarily with the combination of dex-ritux but even then in only 10% of patients. A randomized controlled trial is needed to test these exciting findings. Figure. Figure. Disclosures Bussel: Prophylix: Consultancy, Research Funding; Momenta: Consultancy; Rigel: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Uptodate: Honoraria; Amgen Inc.: Consultancy, Research Funding; Protalex: Consultancy.

Download Full-text

Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood.v130.suppl_1.lba-1.lba-1 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. LBA-1-LBA-1 ◽

Cited By ~ 1

Author(s):

Marie Scully ◽

Spero R Cataland ◽

Flora Peyvandi ◽

Paul Coppo ◽

Paul Knöbl ◽

...

Keyword(s):

Platelet Count ◽

Drug Treatment ◽

Board Of Directors ◽

Treatment Period ◽

Research Funding ◽

Thromboembolic Event ◽

Study Drug ◽

Adamts13 Activity ◽

Advisory Committees

Abstract Introduction: Acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) is a life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. Inhibitory autoantibodies cause a severe deficiency of the von Willebrand factor (vWF) cleaving enzyme ADAMTS13, leading to intravascular vWF-platelet aggregation and microvascular thrombosis. The mainstays of treatment are plasma exchange (PE) and immunosuppression. Caplacizumab, a bivalent Nanobody, targets the A1 domain of vWF, inhibiting the interaction between ultra-large vWF and platelets. Methods: Patients with an acute episode of aTTP who had received one PE treatment were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and a SC dose was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug (Figure 1). Primary endpoint was time to platelet count response, defined as platelet count ≥ 150×109/L with stop of daily PE within 5 days. There were 4 key secondary endpoints, hierarchically ranked. The 1st was a composite of aTTP-related death, aTTP recurrence, or major thromboembolic event during the study drug treatment period. A blinded, independent committee adjudicated aTTP-related deaths and major thromboembolic events. The 2nd looked at recurrences during the entire study period, including the follow up period. The 3d evaluated refractoriness to therapy, defined as absence of platelet count doubling after 4 days of treatment and LDH still above normal. The 4th was the time to normalization of 3 organ damage markers: LDH, cardiac troponin I and serum creatinine. Results: 145 patients were randomized, 73 to placebo and 72 to caplacizumab. Demographics and baseline disease characteristics were balanced between groups, except for a higher proportion of initial episodes in the caplacizumab arm. Compared to patients treated with placebo, those on caplacizumab were >50% more likely to achieve a platelet response at any given time point (platelet count normalization rate 1.55, 95% CI 1.10 - 2.20, p <0.01). During the study drug treatment period, treatment with caplacizumab resulted in a 74% reduction in TTP-related death, recurrence of TTP, or a major thromboembolic event (p <0.0001, Table 1). During the overall study period, 28 patients in the placebo group experienced a recurrence versus 9 patients in the caplacizumab group, a 67% reduction (p <0.001, Table 2). In all 6 caplacizumab-treated patients with a relapse during the follow up period, ADAMTS13 activity was still <10% at stop of study drug, reflecting ongoing disease. No caplacizumab-treated patients were refractory to therapy, while 3 patients on placebo were (p =0.057). Treatment with caplacizumab was associated with a trend toward faster normalization of the 3 organ damage markers. Safety is summarized in Table 3. In the caplacizumab group, the most common study drug-related TEAEs were epistaxis, gingival bleeding, and bruising. During the study drug treatment period, 3 patients on placebo died. One death occurred during the follow up period in a caplacizumab-treated patient and was assessed by the investigator as not related to study drug. Conclusions: Results of the Phase 3 HERCULES study confirm that treatment with caplacizumab reduces the time to platelet count response, resulting in faster resolution of aTTP. Treatment with caplacizumab also resulted in a highly clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment. The relapses after stop of study drug in patients with ADAMTS13 activity <10% suggest that treatment should be continued until complete resolution of the underlying disease. Caplacizumab has a favorable safety profile, with mucocutaneous bleeding the most frequently reported AE. Caplacizumab, through rapid blocking of vWF-mediated platelet aggregation, represents a novel treatment option for patients with aTTP. (clinicaltrials.gov: NCT02553317) Disclosures Scully: Ablynx: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Novartis: Honoraria; Alexion: Honoraria. Cataland:Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Peyvandi:Ablynx, Roche: Membership on an entity's Board of Directors or advisory committees; Ablynx, Bayer, Grifols, Novo Nordisk, Sobi: Speakers Bureau;Freeline, Kedrion, LFB, Octapharma: Consultancy. Coppo:Ablynx: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Knöbl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Kremer Hovinga:Baxalta/Shire: Other: unrestricted grant hereditary TTP registry; Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Metjian:Ablynx NV, Shire, Omeros: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Other: Honoraria; Celgene: Other: Honoraria; Janssen: Other: Honoraria. Pavenski:Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Ablynx: Other: participation in industry sponsored RCT; CSL Behring: Research Funding. Callewaert:Ablynx NV: Employment. Biswas:Ablynx NV: Employment. De Winter:Ablynx NV: Employment. Zeldin:Ablynx NV: Employment.

Download Full-text

Rituximab Yielded a Significantly Longer Response Compared to Placebo in Steroid Free Population - a Post Hoc Analysis of the Ritp Study

Blood ◽

10.1182/blood-2019-126975 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2358-2358

Author(s):

Waleed Ghanima ◽

Marc Michel ◽

Abderrahim Khelif ◽

Bernadette Darne ◽

Pal André Holme

Keyword(s):

Platelet Count ◽

Treatment Failure ◽

Research Funding ◽

Post Hoc Analysis ◽

Risk Of Bleeding ◽

Adequate Response ◽

Duration Of Response ◽

Bleeding Episodes ◽

Time To Relapse ◽

Post Hoc

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by immune mediated platelet destruction causing thrombocytopenia and increase risk of bleeding. Treatment is indicated in patients who present with bleeding or are at risk of bleeding. Corticosteroids (CS) are the main first-line treatment in adult patients, but since not all patients achieve adequate response to CS, most patients require a second line therapy. Rituximab is one of the most widely used second line therapies; its advantages include the ability to induce relatively long lasting remissions after 2-4 infusions and its favorable safety profile. The RITP study was a randomized placebo-controlled trial in which ITP patients who failed to achieve adequate response to CS were randomized to receive rituximab or placebo. The study outcomes were treatment failure (splenectomy or meeting criteria for splenectomy), response rates and duration of response during an 18-month follow-up period. Apart from a longer duration of response in the rituximab arm, the study showed no significant differences in the other outcomes (Ghanima et al. Lancet 2015; 385: 1653-61). The use of stable dose of CS was allowed during the study. This report represents a post-hoc analysis of the RITP trail, restricting the population to those who did not receive any CS during the study, until relapse or treatment failure in the two arms. By this we aimed to eliminate the possible interference resulting from concomitant use of CS on the effect and safety of rituximab and placebo. For effect, we estimated the duration of response, splenectomy rates, platelet counts, and time to bleeding and for safety we estimated time to infection episodes in both arms. We included patients who did not receive CS before treatment failure or relapse or until the end the of the study, if none of the endpoints was achieved. The duration of response was estimated from time of achieving response to relapse (platelet count <30x109/L). Kaplan Meier plots were constructed to depict time to relapse, bleeding and infections using log-rank test to determine statistical significance between the two study groups. Of the 109 included patients, 45 (41%) patients did not receive CS in the two arms. Of these 45 patients, 27 achieved a response during the study; 14 in the rituximab arm and 13 in the placebo arm. Median duration of response was significantly longer in the rituximab arm (median 308 days; IQR: 168- not reached) vs placebo (41 days; IQR: 36-42) arm (p=0.0019), figure 1. Splenectomy rates did not differ between the two arms; 4 in the rituximab arm vs 3 in the placebo. A trend towards lower bleeding episodes was observed in the rituximab arm (p=0.12), figure 2. Mean platelet count was higher during the study in the rituximab arm compared to placebo as shown in figure 3. There was no difference in time to infection in both arms. One of the limitations of the RITP study was that CSs (prednisolone) were allowed in an unstandardized fashion. Thus, use of corticosteroids could have reduced the difference in effect between the two treatment arms masking some of the benefit of rituximab. Interestingly, no difference was found in the rate of response in the 2 arms; however, almost all those who were classified as responders in the placebo arm, relapsed within the first few weeks, whereas a much longer time to relapse was observed after rituximab. The unexpectedly high response rates in the placebo arm may be explained by the use of pre-medications, with CS received prior to infusion. Although the duration of response was also significantly longer in the original study, a greater difference was observed when restricting the population to those who did not use CS. Nevertheless, splenectomy rates were similar. In conclusion, rituximab yielded significantly longer duration of response and although response to rituximab was transient, half of the patients, displayed a treatment free response of more than 10 months, as well as it resulted in higher platelet count and less bleeding episodes without causing more infections. Disclosures Ghanima: Amgen: Consultancy, Honoraria; Pfizer/BMS: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Michel:Novartis: Consultancy; Amgen: Consultancy; Rigel: Consultancy. OffLabel Disclosure: Rituximab for ITP

Download Full-text

Tinzaparin Versus Dalteparin for Peri-Procedure Thromboembolic Prophylaxis in Patients with Dialysis Dependent Renal Disease.

Blood ◽

10.1182/blood.v114.22.3136.3136 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3136-3136

Author(s):

Marc Rodger ◽

Tim Ramsay ◽

Martin Mackinnon ◽

Margit Westphal ◽

Melissa Spero ◽

...

Keyword(s):

Research Funding ◽

Primary Outcome ◽

Study Drug ◽

Dalteparin Sodium ◽

Invasive Procedures ◽

Bridging Therapy ◽

Prophylactic Dose ◽

Significant Difference ◽

The Mean ◽

Therapeutic Doses

Abstract Abstract 3136 Poster Board III-73 Background Low-molecular-weight heparins (LMWHs) can be administered in fixed subcutaneous doses permitting predictable parenteral anticoagulation in an out-of-hospital setting. The renal clearance of LMWHs leads to uncertainty about the safety of use of LMWHs in patients on hemodialysis given the potential for bioaccumulation of anticoagulant effect which may lead to bleeding. Methods We conducted a randomized open label trial to investigate the feasibility and safety of a perioperative anticoagulation protocol in hemodialysis patients comparing two LMWHs preparations as outpatient bridging therapy when warfarin is interrupted for invasive procedures. The primary objective of the study was to compare if tinzaparin and dalteparin differentially bioaccumulate in hemodialysis (HD) patients after three therapeutic doses. Warfarin therapy was discontinued in these patients 5 to 6 days prior to surgery. Patients were randomized to either 3 doses of tinzaparin (175 IU/kg/day) or dalteparin (200 IU/kg/day) with two dialyses in the interval between the first dose of study drug and inavsive procedure. Primary outcome was pre-dialysis anti-Xa levels 20-24hrs post third therapeutic LMWH dose to determine if these LMWHs accumulated in HD patients, and if they differentially accumulated. After procedure, patients received a daily prophylactic dose of tinzaparin (4500 IU) and dalteparin (5000 IU) for 3 to 4 days along with dialysis. Post- procedure pre- and post- dialysis anti-Xa levels were also monitored. Results Of 29 eligible and consenting patients, 17 patients (58.6%) received tinzaparin sodium and 12 patients (41.4%) received dalteparin sodium. Two patients were withdrawn prior to invasive procedure and the invasive procedures were canceled (1 for important bio-accumulation in the dalteparin arm; 1 for major bleed in the tinzaparin arm). Primary outcome anti-Xa samples were not analyzable in 2 patients (1 contaminated with heparin; 1 drawn too early). There was important and significant bioaccumulation in both study drug arms. The mean primary outcome pre-dialysis anti-Xa level 20-24hrs post third tinzaparin dose was 0.40 IU/ml (SD= 0.21). The mean primary outcome pre-dialysis anti-Xa level 20-24hrs post third dalteparin dose was 0.57 IU/ml (SD= 0.43). There was no statistically significant difference between the two study drug groups (student's t-test (p value = 0.33). Postoperatively 16/21 (76%) of patients tested had undetectable pre-dialysis anti-Xa levels 20-24hrs post prophylactic dose, with the remaining 5 patients having a mean anti-Xa level of 0.23 IU/ml (SD = 0.25). During subsequent follow-up, 2 patients experienced serious adverse events (one non-STEMI in patient who died of sepsis (tinzaparin group) and one upper extremity DVT (dalteparin group)). Conclusions Tinzaparin and Dalteparin significantly accumulate at therapeutic doses in HD patients with no statistically significant difference detected in accumulation between the drugs. Neither drug importantly accumulates at prophylactic doses in HD patients. “Bridging therapy” with LMWHs at therapeutic doses in patients on hemodialysis who require temporary interruption of warfarin for invasive procedures is risky and of uncertain risk benefit. Disclosures Rodger: Bayer: Research Funding; Leo Pharma: Research Funding; Pfizer: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Biomerieux: Research Funding; GTC Therapeutics: Research Funding.

Download Full-text

Thrombopoietic Agents in the Treatment of Childhood Immune Thrombocytopenia (ITP): Clinical Treatment At 2 Centers

Blood ◽

10.1182/blood.v118.21.2230.2230 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2230-2230

Author(s):

Kavitha Ramaswamy ◽

Loan Hsieh ◽

Hatice Melda Ürekli ◽

Diane J. Nugent ◽

James B Bussel

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Rescue Therapy ◽

Bone Marrow Fibrosis ◽

Advisory Committees ◽

Equity Ownership ◽

The Mean ◽

Marrow Fibrosis

Abstract Abstract 2230 Introduction: Thrombopoietic agents (TPO-A) are widely used in adults for difficult ITP. However only 1 study has been published describing the use of a TPO mimetic (Nplate) in 22 children with ITP. This study is a post hoc analysis of 32 children (<21yr) who received clinical treatment (off study) with either Nplate or Promacta. Methods: All children described are from 2 centers:,Weill Cornell in New York (n=22, 9 on Nplate, 13 on Promacta) and Childrens Hospital Orange County (10, all on Nplate). All patients in this abstract were treated off study although some had previously participated in the AMGEN195 (Pediatric) followed by AMGEN 213 (long term maintenance) studies. Responses (taken from the published study) were defined as platelet count (plt ct) > 50k on 2 consecutive weeks, plt increase ≥ 20k on 2 consecutive weeks, and the percent of weeks at ≤ 50k independent of rescue therapy. Rescue therapy e.g. IVIG, steroids, plt transfusion, resulted in counts being considered “non-responder” for 2 full weeks after initiation of treatment. Bone marrows were evaluated for reticulin fibrosis (RF) using consensus grades 0–3. Several patients had more than one marrow during treatment; in these cases, the most recent on-therapy marrow was used. Results: The median age of patients on Nplate was 10 years of age (2–19) while for those on Promacta it was 16 years (5–19). Of the 32 patients treated with TPO-A, 24 responded with a plt ct ≥ 50k twice; 19/32 received Nplate and 15/19 responded; 13/32 received Promacta and 9/13 responded. Plt increases ≥ 20k were seen in 23 of 32 patients. The number of patients whose platelet count was ≥ 50k for at least 50 percent of visits was 20/32. The mean number of previous treatments for responders to Nplate was 3.2 while for Nplate non-responders it was 2.25. For Promacta, the mean for responders was 2.9 treatments and for non-responders 3 treatments. Younger patients did not seem to respond as well to treatment with either TPO-A (see table). Nplate patients received treatment for a mean of 19.2 weeks; for patients treated with Promacta it was 13.7 weeks. Baseline bone marrows were available in 17 patients of whom 6 had grade 1 reticulin fibrosis (RF). There were 10 children with marrows performed after the start of TPO-A: 2 with RF score=0, 7 with score=1+, and 1 with score=2+ Adverse events (AEs) other than bone marrow fibrosis and bleeding (lack of efficacy) were all 1–2+ and not related to TPO-A. In particular, no thrombosis or development of malignancy was seen. In conclusion, TPO-A were an effective treatment of chronic ITP in the 32 consecutive children retrospectively analyzed here from 2 centers. Younger children in this study seemed not to respond as well as older children, in contrast to small numbers of young children in published data who responded very well. No major changes were seen in the bone marrows but a formal baseline and on therapy study in children is needed to assess this issue. AEs were infrequent and tolerable. Additional studies with both Nplate and Promacta, either planned or in progress, are needed to clarify the response rates, AEs eg bone marrow fibrosis, and effects in subgroups of children. Disclosures: Bussel: Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding.

Download Full-text

Evaluation of Primary Screening Test for Platelet Homeostasis in Patients with Chronic Kidney Disease

Bangladesh Journal of Medicine ◽

10.3329/bjmed.v21i2.13610 ◽

2013 ◽

Vol 21 (2) ◽

pp. 55-57

Author(s):

Md Nazrul Islam ◽

Shah Md Sarwer Jahan ◽

Shah Md Badrudduza ◽

Md Zakir Hossain

Keyword(s):

Chronic Kidney Disease ◽

Platelet Count ◽

Kidney Disease ◽

Screening Test ◽

Bleeding Time ◽

Bleeding Diathesis ◽

Platelet Function Test ◽

Function Test ◽

The Mean

This observational study was done on 50 cases of predialytic chronic kidney disease (CKD) patients. The aim of the study was to determination of total platelet count and bleeding time, comparison of the platelet count and bleeding time with the severity of chronic kidney disease. The mean age of the patients was 41.22±2.0 years, mean haemoglobin 4.96 ±0.32gm/dl, serum creatinine430.74± 11.92 ?mol/L, platelet count 246.50 ± 13.63x109/L and bleeding time were 4.13± 0.28 min respectively. Thrombocytopenia (<150x109/L) were found in 19(38%) cases. Bleeding time was prolonged (>9min) 6(12%) cases , among them only 4(8% ) cases were thrombocytopenic. There was no significant relationship between platelet count and serum creatinine. No correlation was found between platelet count and bleeding time. No significant correlation was also found in Bleeding time and creatinine. Therefore, it can be concluded that platelet count is highly variable in chronic kidney disease and it is not a reliable screening test for bleeding diathesis in chronic kidney disease patients. Bleeding time is the best platelet function test that correlates clinical bleeding.DOI: http://dx.doi.org/10.3329/bjmed.v21i2.13610 Bangladesh J Medicine 2010; 21: 55-57

Download Full-text