Treatment of Refractory Idiopathic Thrombocytopenia Purpura

Treatment of Refractory Idiopathic Thrombocytopenia Purpura Richard Walgren 19 yo female with persistent ITP • July of 2004 presented with vaginal bleeding, found to have “severe thrombocytopenia”. She was treated with steroids, anti-Rh, and IVIG and initially had a good response. • 8/9/04 admitted to OSH for vaginal bleeding, platelet count = 1000. – Non-compliant with PO steroids? – Restarted on prednisone 60 mg QD. • 10/6/04 lap splenectomy – 2 days later plt = 85K and prednisone was tapered over 1 month to 20 mg QOD. • 11/3/04 plt again < 10K with bleeding – Failed to improve with anti-Rh or steroids. – Ptn was started on rituximab and in one week plt = 366K. • 1/2/05 ptn adm to OSH for vaginal bleeding and petechial rash, plt = 4 K. – Ptn was then started on decadron 40 mg QD with normalization of plt. ITP • Immune or Idiopathic Thrombocytopenic purpura • Autoimmune disorder characterized by autoantibody-induced platelet destruction. • Acute form: – lasts  6 months, – often post-viral, – generally observed in pediatric population • Adult or Chronic form ITP Chronic ITP • • • • Estimated to affect 1 in 10,000 in the general population. ~ 30,000 new case each year in USA and Europe. Accounts for ~ 0.2% of admissions. Presentation is variable – Asymptomatic mild thrombocytopenia – Development of petechiae, purpura, or ecchymoses over several days. – Rarely can present with acute severe thrombocytopenia with GI or CNS bleeding. – Patients appear to otherwise be in good health. • Frequency of death in ptn with plt < 30,000 is 1.6 -3.9% per patient year. Treatment of ITP • Initial therapy – prednisone 1-2 mg/kg/day for 4-6 weeks then taper. – 0.25 to 0.5 mg/kg/day may be as effective. – Response rate is 60 to 90% with ~ 50% demonstrating normalization of counts – Majority will see a decline in plt counts on weaning. Treatment of ITP • Splenectomy is standard therapy after steroid failure. – 2/3 of ptn will obtain a durable, complete remission. – Relapse rate is ~15% – The rate a relapse may be balanced by the rate of late remissions. – Younger age appears to be a predictor of response. Persistent ITP – There is no consensus on appropriate management for persistent thrombocytopenia after splenectomy. – In the absence of bleeding, its not clear if any treatment should be used rather than observation alone. – For this patient population there are no randomized, controlled trials comparing one treatment with another or with observation alone. Persistent ITP • Vesely et al reviewed 90 articles with 22 treatments aimed at this population. Three treatments were identified as promising: azathioprine, cyclophosphamide, and rituximab. – Complete response rates ranged from 17 to 27% – However, 36 to 42% had no response to these 3 treatments Recent Approaches to Therapy • Majority of therapy targets reduction of autoimmune response to decrease platelet clearance. • Differences in the rate of platelet production have been observed in ITP suggesting a role for platelet supportive therapy. Tpo and Tpo-R Chromosome Length Mass Variants Tpo 3q26 6 exons 332 aa 38 kDa predicted 18-85 kDa observed 71kDa Tpo Tpo-2 (4aa deletion, inactive) Mpl-I Mpl-II Mpl-S Tpo-R c-Mpl 1p34 12 exons 635 aa Tpo and Tpo-R • Tpo-R is structurally similar to the Epo receptor. Ligand binding → homodimerization → JAK-STAT and Ras • Receptor localized to pluripotent hematopoietic stem cells (CD34+/CD38-) • Tpo produced in liver, proximal tubule epithelial cells, bone marrow, hippocampus, and amygdala. • Cleared via receptor mediated endocytosis (platelets) • Plasma plt count and Tpo levels are inversely associated – But not in ITP Tpo-R Agonists • rTpo – stimulated platelet production - stimulated anti-Tpo antibody production • AMG 531 • SB-497115-GR AMG 531 AMG-531 Phase I Study B Wang, J Nichols, J Sullivan. Clin Pharmacol Ther 2004; 76:628-38. • Dose finding study. • Single center, single dose, randomized, double-blind, placebocontrolled study with health subjects. • 48 Patients were followed for 42 days. • Doses: – IV 0.3, 1, 10 µg/kg - SC 0.1, 0.3, 1, 2 µg/kg • Only male patients enrolled. AMG-531 B Wang, J Nichols, J Sullivan. Clin Pharmacol Ther 2004; 76:628-38. • Increase similar after IV or SQ inj of the same dose. •Plt counts approached baseline by 28 days postinjection. •No serious ADE. •Most frequently reported events were mild to moderate headache and sore throat. AMG 531 Phase II D Kuter et al Blood 2004, 104; 11: Abstract 511 • Multicenter, randomized, double blind, placebo controlled study of weekly dosing in ptns with ITP. • Eligibility: – Plt < 30,000 or < 50,000 on steroids for at least 3 months – Must have had 1 previous treatment – 18  age  65 • Pts received up to 6 weeks of treatment with placebo, 1, or 3 µg/kg. • Dose was held if plts > 500,000 AMG 531 Phase II D Kuter et al Blood 2004, 104; 11: Abstract 511 • 21 ptns enrolled – 71% female, median age 49, 71% post-splenectomy, 33% on steroids – Median baseline plts = 16,000 • • • • 3 ptns (drug) stopped early by protocol for high platelets 1 ptn (placebo) discontinued after intracranial hemorrhage. 7/8 (88%) on 1 µg/kg reached target of  50,000 plts, 3/8(38%) on 3 µg/kg reached target and 2 additional exceeded 450,000. AMG 531 Phase II D Kuter et al Blood 2004, 104; 11: Abstract 511 • Median time to response was 8 days. • Most frequent adverse events were: – Contusion (53 vs 50% A:P) – Epistaxis (41 vs 50%) – Headache (29 vs 0%) • No anti-AMG531 or anti-TPO antibodies were detected. SB-497115-GR • hydrazino-naphthalenesulfonic acid derivative identified as a Tpo-R agonist in a high-throughput reporter gene assay based on the activation of STAT transcription factors. • Lead optimization lead to a biphenyl carboxylate with oral bioavailability. • Phase I data: with PO dosing for 10 days, subjects receiving ≥ 20 mg / day demonstrated at least a 1.3-fold increase in plt and the response was dose dependent. Summary • For patients with ITP prednisone is the standard initial therapy. 60-90% of patients will have some improvement but most will see a decline on withdrawal from steroids. • Splenectomy is the standard second-line therapy. 2/3 will have a durable remission. • For persistent ITP there is no consensus on management, but promising therapies are in development.