Tag: Immune Thrombocytopenic Purpura

SUMMARY: Immune Thrombocytopenic Purpura (ITP), also referred to as Idiopathic Thrombocytopenic Purpura, is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. The diagnosis of ITP is established based on a platelet count of less than 100×10⁹/L and exclusion of other causes of thrombocytopenia. Infection with the Hepatitis C Virus should be considered in all patients with acute ITP. The autoantibodies identified in patients with ITP are often directed against platelet glycoprotein IIb/IIIa, although antibodies directed against glycoprotein Ib/IX have also been detected. The glycoprotein complex IIb/IIIa plays an important role in platelet adhesion by binding fibrinogen, fibronectin, vitronectin, and von Willebrand factor. Glycoprotein Ib/IX is the main receptor for von Willebrand factor. Platelet autoantibodies destroy platelets resulting in persistent thrombocytopenia. Platelet autoantibodies have also been implicated in impaired platelet production by megakaryocytes.

There are presently no reliable diagnostic tests or standard biomarkers to diagnose ITP. A response to immunosuppressive therapy remains the most useful diagnostic and therapeutic strategy in patients suspected with ITP. The utility of platelet autoantibody tests in ITP remains unclear, as the sensitivity and specificity of these tests is variable.

This study was conducted to understand the role of platelet autoantibody testing in patients with suspected ITP. Investigators extracted data from three online databases, Ovid Medline, PubMed, and Web of Science and conducted a systematic review and meta-analysis of 18 studies that included a total of 1170 patients with ITP and 225 controls without ITP. The analysis included studies that tested at least 20 or more ITP patients, for autoantibodies against the major platelet antigens GPIIb/IIIa or GPIb/IX, either directly on the platelet surface or indirectly in serum or plasma.

Pooled estimates for sensitivity and specificity were calculated and it was noted that the sensitivity and specificity of direct antiplatelet autoantibody testing for either antiglycoprotein IIb/IIIa or antiglycoprotein Ib/IX were 53% and 93%, respectively. For indirect testing, the pooled estimates for the sensitivity and specificity were 18% and 96%, respectively.

It was concluded from this study that platelet autoantibody testing in ITP patients has a high specificity but low sensitivity. A positive autoantibody test can help confirm a diagnosis of ITP, but a negative test does not rule out ITP. The sensitivity and specificity of platelet autoantibody testing in immune thrombocytopenia: a systematic review and meta-analysis of a diagnostic test. Vrbensky JR, Moore JE, Arnold DM, et al. J Thromb Haemost. 2019;17:787-794

SUMMARY: The FDA on May 21, 2018, approved DOPTELET® (Avatrombopag) for thrombocytopenia in adults with Chronic Liver Disease (CLD) scheduled to undergo a procedure. Thrombocytopenia is the most common hematological abnormality encountered in patients with Chronic Liver Disease (CLD), occurring in 65-85% of patients. Thrombocytopenia is an indicator of advanced disease and is associated with a poorer prognosis, and can impact routine care of patients with CLD, interfering with diagnostic and therapeutic interventions. Therefore treatment options that can safely and effectively raise platelet levels could have a significant impact on care of these patients.

The cause of thrombocytopenia in CLD is multifactorial and can be due to decreased production, splenic sequestration, and increased destruction. Thrombopoietin (TPO) regulates platelet production and maturation, and CLD is associated with depressed Thrombopoietin levels . Bone marrow suppression can be also be caused by alcohol, viruses, medications and iron overload. Hypersplenism causes splenic platelet sequestration. Increased platelet destruction in cirrhosis can be due to increased shear stress, increased fibrinolysis, increased platelet aggregation related to infections, or immune mediated platelet destruction secondary to antiplatelet antibodies.

DOPTELET® (Avatrombopag), a second generation orally administered Thrombopoietin Receptor Agonist (TPO-RA), designed to mimic the effects of TPO, the primary regulator of normal platelet production. DOPTELET® stimulates the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells and results in increased production of platelets.

The approval of DOPTELET® by the FDA was based on two identically designed, international, randomized, double-blind, placebo-controlled phase III trials, ADAPT-1 (N=231) and ADAPT-2 (N=204). In these two studies totaling 430 patients with Chronic Liver Disease and thrombocytopenia (N=430), patients were randomized 2:1 to DOPTELET® (N=274) or placebo (N=156) daily for 5 days prior to a scheduled procedure, and had at least 1 post-dose safety assessment. Patients randomized to DOPTELET® received differential dosing based on mean platelet count at entry. Patients with a baseline platelet count less than 40,000/uL (low baseline platelet cohort) received DOPTELET® 60 mg orally once daily for 5 consecutive days. Those with a baseline platelet count of 40,000 to less than 50,000/uL (high baseline platelet cohort) received DOPTELET® 40 mg orally once daily for 5 consecutive days. Eligible patients were scheduled to undergo their procedure 5 to 8 days after the last dose of study drug. Patients were stratified according to HepatoCellular Cancer status and bleeding risk associated with the elective procedure (low, moderate, or high). The Primary efficacy endpoint was the proportion of patients, or responders, who did not require a platelet transfusion or any rescue procedure for bleeding after randomization, and for up to 7 days following an elective procedure.

In both trials, DOPTELET® exhibited superiority compared to placebo, in increasing the proportion of patients not requiring platelet transfusions or rescue procedures for bleeding up to 7 days, following a scheduled procedure. In the low baseline platelet cohort, 66% and 69% of patients treated with DOPTELET® responded in the ADAPT-1 and ADAPT-2 trials, respectively. For those receiving placebo, 23% (treatment difference 43%, P<0.0001) and 35% (treatment difference 34%, P=0.0006) responded in the ADAPT-1 and ADAPT-2 trials, respectively. In the high baseline platelet cohort, 88% of DOPTELET®-treated patients in both trials responded compared to 38% and 33% of placebo-treated patients. Treatment difference was 50% (P<0.0001) in the ADAPT-1 trial and 55% (P<0.0001) in the ADAPT-2 trial. Additionally, DOPTELET® was statistically superior to placebo at the two Secondary efficacy endpoints in each trial which included proportion of patients with platelet count of 50,000/uL or more by procedure day, and mean change in the platelet count from baseline to procedure day. The most common adverse reactions reported in at least 3% of patients were pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema.

It was concluded that DOPTELET® is the first orally administered treatment option approved by the FDA for patients with Chronic Liver Disease who routinely undergo multiple, invasive procedures. The availability of this new oral agent can lead to a measured increase in platelets and minimize the risk of bleeding and need for platelet transfusions. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm608323.htm

SUMMARY: The FDA on April 17, 2018, approved TAVALISSE® (Fostamatinib tablets) for the treatment of thrombocytopenia in adult patients with chronic Immune Thrombocytopenic Purpura (ITP), who have had an insufficient response to a previous treatment. ITP can manifest as an acute self limited disease often seen in children (Acute ITP) or in a chronic form (Chronic ITP) seen in adults with the thrombocytopenia lasting for 6 months or longer.

TAVALISSE is an oral Tyrosine Kinase Inhibitor that targets SYK kinase (Spleen Tyrosine Kinase). SYK associates with Fcγ receptors (FcγR) on the cell surface of various inflammatory cells, including macrophages, which are in turn responsible for platelet clearance in ITP. Inhibition of SYK by the active metabolite of TAVALISSE® reduces the destruction of platelets by macrophages, that are activated in the immune system. TAVALISSE® is the first and only SYK inhibitor indicated for adults with Chronic ITP and the present study validated the therapeutic effect of SYK inhibition in an autoimmune disease.

The approval of TAVALISSE® was supported by data from two randomized placebo-controlled phase III trials and an open label extension study, as well as an initial proof-of-concept study. FIT-1 and FIT-2 are two identical, multicenter, randomized, double-blind, placebo-controlled, phase III trials that included 150 patients with persistent or Chronic ITP, who had an insufficient response to previous treatment, which included Corticosteroids, Immunoglobulins, Splenectomy, and/or a Thrombopoietin Receptor Agonist (TPO-RA). Patients were randomized 2:1 to receive either TAVALISSE® 100 mg orally twice daily or placebo for 24 weeks. Dose could be escalated to 150 mg orally twice daily after one month. The median age was 54 years and enrolled patients had three documented platelet counts of 30,000/µL or less. Patients had ITP for a median of 8.5 years prior to enrollment and the median baseline platelet count was 16,000/μL. The most common prior treatments for ITP were Steroids (94%), TPO-RAs (47%), Splenectomy (35%), and Rituximab (32%). The Primary endpoint was Stable platelet response of 50,000/ µL or more on at least 4 of the 6 biweekly visits between Weeks 14 and 24 of the study, without rescue treatment.

The Overall Response Rate with TAVALISSE® in the two trials, FIT-1 and FIT-2 was 29% versus 2% in the placebo group (P<0.001). Among the responders on TAVALISSE®, Stable Response (Primary end point) was noted in 18% versus 1% in the placebo group (P=0.007) and Intermediate Response (defined as at least 2 consecutive biweekly platelet counts of 50,000/μL or more, without rescue treatment) was noted in 11% versus 0% in the placebo group (P<0.001).

Among patients treated with TAVALISSE®, the median platelet counts at 24 weeks of follow up was 95,000/μL for those who had a Stable Response, 49,000/μL for those who had Intermediate Response, and 20,500/μL in non-responders. For those in the placebo group, however, median platelet counts only reached 17,500/μL. More than half of patients treated with TAVALISSE® (54%) had increment in platelet count (20,000/μL or more), compared with 29% of patients receiving placebo (P=0.005). The median time to response (platelet count of 50,000/μL or more) in those treated with TAVALISSE®, was two weeks. Rescue medications (including Platelet transfusions and intravenous Immunoglobulin) were required in 26% of responding patients in the TAVALISSE® group and for 45% of patients in the placebo group. Response rates were not influenced by Age, Sex, baseline platelet count, Splenectomy or prior treatment with a TPO-RA. Among patients who had received and later failed to respond to a TPO-RA before enrollment, 17% had a Stable Response to TAVALISSE®. Serious bleeding was not noted in the 29% of patients who achieved a response, whereas it occurred in 5.6% of non-responders and 10.2% of those receiving placebo.

Patients from FIT-1 and FIT-2 trials were also included in an open label expansion cohort (FIT-3). In this study, 23% of those who received placebo in FIT-1 or FIT-2 had a Stable platelet response to TAVALISSE®. The most common toxicities were rash, fatigue, nausea, diarrhea, abdominal pain, hypertension, liver function abnormalities and neutropenia.

It was concluded that TAVALISSE® is the first and only Spleen Tyrosine Kinase (SYK) inhibitor, and by its unique mechanism of action, is an important alternative for patients with difficult to treat chronic ITP. Bussel J, Mayer J, Cervinek L, et al. Treatment of primary adult chronic immune thrombocytopenia (CITP) with fostamatinib, an oral SYK inhibitor: results of two randomized, placebo-controlled phase 3 studies. Abstract #S435. Presented at the 22nd Congress of the European Hematology Association, June 24, 2017; Madrid, Spain.

In the November 11, 2010 issue of the NEJM, David Kuter and colleagues reported the results of an open label randomized trial comparing 52 weeks of Romiplostim (Nplate) to “standard of care” in patients with ITP ( Immune Thrombocytopenic Purpura). In this study, Romiplostim was associated with superior platelet response rates, lower rates of treatment failure, improved quality of life and even more importantly, no significantly increased adverse events compared to the standard of care.

In the “Research Regimens”  section at www.oncoprescribe.com, we have a detailed write up on a previous study on Romoplostim by the same author published in Lancet 2008. The Oncoprescribe Blog also has a brief write up on the REMS program.

Romiplostim was approved by the FDA on August 22, 2008 for the treatment of thrombocytopenia in patients with chronic Immune  Thrombocytopenic Purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Armed with the recently published data, it is likely that Romiplostim for ITP could be taking the front row seat.

The approval of Romiplostim (Nplate®), as well as Eltrombopag (PROMACTA®) included a mandatory Risk Evaluation and Mitigation Strategy (REMS) for the following reasons. There has been some concern raised with regards to long term risks associated with TPO receptor agonists, in particular bone marrow reticulin formation and risk for bone marrow fibrosis. These adverse events however were not noted in the phase III clinical trials. The Risk Evaluation and Mitigation Strategy is intended to ensure that the product is safely used with proper informed consent. It is therefore mandatory that all parties including the prescribers, patients, as well as institutions and pharmacies that wish to provide these drugs, register through the Nplate NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) program for Romiplostim (Nplate®) and  through PROMACTA® CARES for Eltrombopag (PROMACTA®) respectively. These patient registries are meant to monitor long term safety of these agents. REMS will soon be be mandated for ESA’s as well.

The long-term safety and efficacy of (PROMACTA® (Eltrombopag) was evaluated in an open label phase III extension study (EXTEND STUDY) and this study demonstrated that Eltrombopag (PROMACTA®) given for up to two years appears to have consistent benefit in raising the platelet counts without any significant adverse events. A new paradigm has emerged with the availability of a new class of agents such as PROMACTA®, targeting platelet production. Additional trials are underway evaluating the role of this agent in chemotherapy induced thrombocytopenia as well as Myelodysplastic Syndromes and the results are eagerly awaited with renewed interest.