the role of thrombopoietin in immune thrombocytopenia：在免疫性血小板减少性紫癜血小板生成素的作用课件

Benign Hematology Update: ASH, ISTH, and the Literature 2013,Craig M Kessler, MD, MACP Professor of Medicine and Pathology Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC,Disclosures,Research- Amgen, Baxter, Bayer, Biogen, Esai, Grifols, NovoNordisk, Octapharma Advisory Boards-Amgen, Baxter, Bayer, Biogen, Esai, Grifols, NovoNordisk, Octapharma Stock- Not applicable Employment Not applicable Speakers Bureau Not applicable,Topics,Autoimmune thrombocytopenia Target specific oral anticoagulation New antiplatelet agents New developments in von Willebrand disease Advances in the treatment of sickle cell anemia Miscellaneous,Pathophysiology of Immune Thrombocytopenic Purpura,Phagocyte-mediated accelerated clearance of antiplatelet AB coated platelets in the RES Dysregulated T-cell function Direct cytotoxicity against megakaryocytes and platelets T-helper cell support for biosynthesis of Abs by B-cells Abnormal number and function of T-regs Suboptimal platelet production,What is the best approach to corticosteroids for de novo ITP?,Abs 325: A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment of Nave Patients With Idiopathic Thrombocytopenic Purpura Matsche J et al,Week 1: All pts received prednisone (1 mg/kg/d) followed by a 1:1 randomization between daily prednisone and pulsed dexamethasone Prednisone given at 1 mg/kg/d; after remission dose tapered 19 weeks to maintenance dose 25 mg/d at wk 13 and 7.5 mg/d at wk 19 If no remission at 2 wks, prednisone increased to 2 mg/kg/d for another 2 weeks. If remission, tapered as above ( 50K platelets) Dexamethasone given q 3 wks for 6 courses (0.6 mg/kg day 1 to 4) Failure to achieve a remission: pts crossed over to the alternative treatment Prednisone: no remission after 4 wks at 1-2 mg/kg/d Dexamethasone: no remission after two cycles,Abs 325: A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment of Nave Patients With Idiopathic Thrombocytopenic Purpura Matsche J et al,Remission duration (platelets 50x109/l) in ITP pts receiving daily prednisone versus pulsed dexamethasone,No statistically significant difference in time to remission (p=0.55) Remission duration significantly longer with dex vs prednisone (p=0.0139) Median tx duration = 85 d (range: 28 153) for pred; Median tx cycles 5 (range: 3 7) for dex Median cumulative cortisol equivalent dose = 15.780 mg for pred; and 34.560 mg for dex No difference in Grade 3 or 4 bleeding events No difference in Grade 3 or 4 adverse events: 1 pt on pred (hypertension) and 2 pts on dex (hyperglycemia, hypokalemia).,% Control Megakaryocytes,Suppression of Megakaryocyte Maturation and Platelet Production by ITP Plasma,100,75,50,25,0,ITP-1,ITP-2,ITP-3,ITP-4,ITP-5,ITP-6,ITP-7,ITP-8,ITP-9,ITP-10,ITP-11,ITP-12,McMillan R, et al. Blood. 2004;103:1364-1369.,Heterogeneous responses in vitro: Anti-platelet ABs affect megakaryocytes and circulating platelets,How Does Rituximab Affect ITP Outcome?,Abs 449: Rituximab As Second Line Treatment For Adult Immune Thrombocytopenia (ITP): A Multicentre, Randomized, Double Blind, Placebo-Controlled Study The Ritp Study Ghanima W et al,First randomized placebo-controlled, double blind study to assess both short and long-term efficacy and safety of RTX in steroid-unresponsive ITP Pts randomized to 4 weekly infusions of 375mg/m2 RTX or placebo Steroids allowed throughout the study Main inclusion criteria: 1- unsplenectomized with primary ITP; platelets 2 wks or relapse during steroid-tapering/discontinuation,Abs 449: Rituximab As Second Line TreatmentFor Adult Immune Thrombocytopenia (ITP): A Multicentre, Randomized, Double Blind, Placebo-Controlled Study The Ritp Study Ghanima W et al,Abs 449: Rituximab As Second Line TreatmentFor Adult Immune Thrombocytopenia (ITP): A Multicentre, Randomized, Double Blind, Placebo-Controlled Study The Ritp Study Ghanima W et al,Time to Complete Response (days) Placebo Rituximab,Per Cent of Patients NOT Achieving Complete Response,RTX did not reduce the rate of overall treatment failure Lower rate of splenectomy in the RTX-arm RTX induced significantly higher rate of CR at 24 wks,Do TPO-RAs Enhance Rituximab Effectiveness?,Abs 329: Recombinant Human TPO and Rituximab vs Rituximab Monotherapy in Corticosteroid-Resistant Primary ITP: a Multicenter Randomized Controlled Study Xiu M et al,Characteristics and result of RTX group and rhTPO plus RTX,Kaplan-Meier plot of time to relapse in patients achieving response or complete response,RTX + rhTPO yields shorter time to response vs RTX only Combination extended time to relapse,1. Harker LA. Br J Haematol. 1970;19:95-104. 2. Branehg I, et al. Br J Haematol. 1974;27:127-143. 3. Stoll D, et al. Blood. 1985;65:584-588. 4. Ballem PJ, et al. J Clin Invest. 1987;80:33-40.,Platelet Production in ITP: Decreased Turnover Equates to Impaired Thrombopoiesis,Thrombopoietin (TPO): Properties and Pertinent Facts,TPO = c-mpl ligand; c-mpl = TPO receptor c-mpl is the murine retroviral oncogene causing a “myeloproliferative leukemia (mpl)” in mice c-mpl found in platelets and megakaryocytes TPO gene on human chromosome 3 TPO is synthesized predominantly by hepatocytes TPO mRNA also found in kidney, marrow, and brain-? Hematopoietic importance,Platelet Production May Not Be Maximal in ITP Patients,Autologous 111In-labeled platelet studies show platelet production reduced or normal in 2/3 of ITP patients Autoantibodies bind megakaryocytes Inhibit Mk growth in vitro and promote apoptosis TPO levels normal in 75% of ITP patients Prior studies with PEG-rHuMGDF in ITP 6/6 HIV ITP patients respond1 One patient treated for almost 6 years with complete response2 3 of 4 Japanese patients had good responses3,1. Harker LA et al. Blood. 1998;92:707a. 2. Rice L et al. Am J Hematol. 2001;68:210. 3. Nomura S et al. Blood. 2002;100:728.,HIV, human immunodeficiency virus; PEG-rHUMGDF, pegylated recombinant human megakaryocyte growth and development factor; TPO, thrombopoietin,The Oncologist January 1, 2009 vol. 14 no. 1 12-21,TPO affects viability of early progenitors of all lineages but affects the late maturation only of megas: TPO only stimulates production of platelets but not RBCs or WBCs,Increasing ploidy,Kuter DJ. The Oncologist 1996, 1:98-106.,The Physiological regulation of TPO levels,Normal Levels,Increased Levels,Endogenous TPO Concentrations Are Minimally Elevated in ITP Patients,Nichol J. In: Kuter DJ et al, eds. Thrombopoiesis and Thrombopoietins: Molecular, Cellular,AA, aplastic anemia,Makar, R. S., et al. Am. J. Hematol doi: 10.1002/ajh.23562,Can Serum TPO Levels Predict Response to TPO mimetics?,(ELISA, R&D Systems, Minn, MN).,21 patients with ITP,Serum TPO levels 95 pg/mL predicts for reduced and less durable responses to TPO receptor agonists in ITP patients = inadequate megakaryopoiesis as basic pathology,AMG 531: Characteristics,Unique platform “peptibody” Made in E. coli MW=60,000 D 4 Mpl binding sites,No sequence homology with TPO Cleared endothelial FcRn Recycled Cleared RES Binds to same site on TPO receptor as does eTPO,Molineux G, Newland ABrit J Haematol. 2010;150(1):9-20,AMG 531: Mechanism of Action,Thrombopoietin Receptor,Inactive Receptor,Active Receptor,Cell Membrane,Cytoplasm,Signal Transduction,Increased Platelet Production,RAS/RAF,MAPK,p42/44,JAK,STAT,SHC GRB2,SOS,P,P,P,P,AMG 531,Kuter DJ. Int J Hematol (2013) 98:1023,Promotion of cell growth,Potentiate maturation,Anti-apoptosis,Practical Considerations for Romiplostim,T1/2 = 120 140 hours whether IV or SQ Not formulated for IV use T1/2 not affected by renal or hepatic function Not recommended during pregnancy since can cross placental barrier via FcRn receptor Pregnancy registry- ? Safety with breastfeeding Start at 1 g/Kg/wk; titrate up to 10 g/Kg/wk Effective mean dose in most studies = 4-5 g/Kg Do not withhold dose precipitous nadirs Dose reduce 25-50% for 400K platelets,Eltrombopag (SB497115): Thrombopoietin Receptor Agonist,Small molecule (MW=546) Hydrazinonapthalene derivative Orally bioavailable Once-daily dosing Stimulates megakaryocyte proliferation and differentiation Increases platelet counts Not immunogenic Does not activate platelets Binds to transmembrane portion of TPO receptor,Eltrombopag (SB497115): Mechanism of Action,Thrombopoietin Receptor,Eltrombopag,Inactive Receptor,Active Receptor,Cell Membrane,Cytoplasm,Signal Transduction,Increased Platelet Production,RAS/RAF,MAPK,p42/44,JAK,STAT,SHC GRB2,SOS,P,P,P,P,Kuter DJ. Int J Hematol (2013) 98:1023,Promotion of cell growth,Potentiate maturation,Anti-apoptosis,Pharmacologic Considerations for Eltrombopag,Activates signal transduction pathways differently than TPO or romiplostim Weaker stimulator of JAK and STAT phosphorylation Does not activate AKT pathway at all, unlike TPO or romiplostim Eltrombopag effect is additive to TPO in vitro. ? In vivo significance,Growth of TPO-dependent cell line,Kuter DJ. Internat J Hematology. 2013;98(1):10-23,Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial: No significant difference in romiplostim dose between splenectomized vs non-splenectomized,htKuter DJ et al. Lancet. 371;9610;2008:395-403 tp://10.1016/S0140-6736(08)60203-2,Mean dose of romiplostim or placebo per week at every study visit for splenectomized (A) and non-splenectomised (B) ITP patients,Long-term safety and tolerability of romiplostim in ITP: Pooled analysis of 13 clinical trials (653 patients),HM = Hematologic malignancies,(Baseline cytogenetics consistent with MDS),All received 26 wks tx; all 8- 18 g/kg/wk; 5/13 10g/kg/wk,HM=hematological malignancies: Rom-CLL, AML, lymphoma (2), MPN SOC/placebo: lymphoma, MDS,(PMF),Rodeghiero F et al. Eur J Haematol 2013;91(5) doi:10.1111/ejh.12181,Long-term safety and tolerability of romiplostim in ITP: Pooled analysis of 13 clinical trials (653 patients), grade 3 bleeding: requiring PRBCs,”Serious” bleeds,Rodeghiero F et al. Eur J Haematol 2013;91(5) doi:10.1111/ejh.12181,ROM: 7.5% (11.2 events/100 pt yrs) Placebo/SOC: 8.7% (17.3 events/100 pt-yrs),1 fatal bleed in ROM cohort: ICH on d4 post discontinuation of ROM and addition of ASA to treat thrombosis,Can Patients Eventually Discontinue TPO Agnonists?,Abs 327: Prolonged Remission After TPO-Receptor Agonist Discontinuation In Adults With Chronic ITP. Results Of a French Observational Study Mahvas M et al.,Romiplostim PR (29.6%) In 20 out of 28 pts achieving a CR, TPO-RA was discontinued after median 10 mos (1-70) Among the 14 evaluable pts: 6 (30%) relapsed within 10 d, requiring rescue therapy 8 pts (70%) with CR over median follow-up of 13.5 mos (range: 5-27) No predictors of sustained response (age, gender, duration of ITP, previous types/number of therapies before TPO-RA) Summary: 15 % pts treated with TPO-RA achieve a durable response after treatment discontinuation. A prospective trial is needed,Longterm safety and tolerability of romiplostim in patients with ITP: a pooled analysis of 13 clinical trials,European Journal of Haematology Volume 91, Issue 5, pages 423-436, 17 SEP 2013 DOI: 10.1111/ejh.12181,KaplanMeier plot comparing venous/arterial thromboembolic events in patients receiving romiplostim vs. placebo/standard of care (cumulative hazard rate),No difference in overall cumulative risk between the two treatment groups over time ROM: 5.9% (7.5 events/100 pt yrs) SOC/Placebo: 3.6% (5.5 events/100 pt yrs),Thrombotic Events in Adult ITP: Metaanalysis,Estimated frequency of thromboembolism: 3.1% (95% CI, 1.8-4.4%) for TPOr agonists 1.7% (95% CI, 0.3-3.1%) for controls TPOr agonists show a numerically but non-statistically significant trend to increase the occurrence of thromboembolic events Underpowered Use of IVIg, ASA, splenectomy not accounted for,Catala-Lopez F et al. Med Clin (Barc). 2012 Oct 20;139(10):421-9. doi: 10.1016/j.medcli.2011.11.023. Epub 2012 Jan 23,Thrombotic Events in Adult ITP,D-dimer not predictive of VTE occurrence in ITP1 Aledort LM: 5% thromboses in ITP; 50% splenectomized; 30% 65 yrs; 28% of thromboses are arterial2 Enger C: 0.8% VTE; 4.7% arterial events (57% of all thromboses are arterial); RR=1.703,1.Ghanima W:British Journal of Haematology. 2012;158(6):811814, 2. Am. J. Hematol. 76:205213, 2004; 3. Enger C. Int J Hematol (2010) 92:289295,Median Platelet Counts on Eltrombopag: Open-label EXTEND study,Saleh MN. Blood. 2013;121(3):537-545,Median platelets50K by week 2 No new or increased ITP treatments: 80% splenectomized and 88% for nonsplenectomized Prolonged response (platelets 50 000/L sustained for12 weeks after the last dose of eltrombopag without rescue treatment) in 4%,Safety Issues with Eltrombopag: Open-label EXTEND study,Bleeding-At baseline 56% vs 11% at 156 wks 16% with Grades 2-4 at baseline vs 0 at 156 wks Concurrent meds: 49% permanently discontinued all baseline ITP medications in the absence of any rescue medications. Thrombosis: 3% had prior hx TEE; 5% (16/299) developed new TEE; 9 DVTs; 4 CVAs; 4 Mis; 3 PEs; 3.17 TEE/100 pt yrs; no relation to platelet counts; all pts had 1 risk factor for TEE,Saleh MN. Blood. 2013;121(3):537-545,Safety Issues with Eltrombopag: Open-label EXTEND study,LFT elevation-10% (29/299) had 1 abn LFT; 6/29 left study; 19/29 abn LFTs resolved Cataracts: 1%; BM Fibrosis: 8% had Grade 2 at baseline (none higher); 11 repeat BMs at 2 yrs, no grade 3; 2 decr grade; 1 incr from grade 0 to 1; 8 no change Deaths: total of 5 deaths-none drug related: 3 in non-responders (10/210 pts non-responders) (GI bleed, ICH with 10K platelets); 1 multiorgan failure and sepsis in post splenectomized pt; 1 MVA HM: 1 DLBCL post 64 days tx,Saleh MN. Blood. 2013;121(3):537-545,Novel Approaches to the Treatment of ITP,Oral Syk inhibitor R788 Syk is downstream signal transduction regulator of monocyte and macrophage phagocytosis Blockage of Syk pathway hypothetically should inhibit platelet destruction Pilot study (N=16), 50% ITP pats demonstrated sustained platelet counts 50K 1 Anti-CD40 ligand CD40L is critical for T-cell-dependent B-cell expansion; autoreactive CD4+ T-cells increased in ITP IDEC-131 and hu5c8 (anti-CE40L monoclonal AB) had overall response rate of 13-16% 2 1. Podolanczuk A et al. Blood.2009;113:3154; 2. Patel VL et al. Br J Haematol.2008;141:545,In clinical development: Betrixaban (not FDA approved),Clinical Comparisons of the Novel Oral Anti-Xa Anticoagulants,Edoxaban,Oral direct factor Xa inhibitor with a rapid onset of action and half-life of 1014 hours 60 mg once daily dose was selected based on phase II data Dose of 30 mg in case of moderate renal impairment (CrCl 30 - 50mL/min) low body weight, i.e., 60 Kg concomitant use of P-gp inhibitors,R,edoxaban,warfarin,3 M,6 M,12 M,initial (LMW)Heparin placebo warfarin placebo edoxaban,Day 6- 12,Sham INR,INR,Day 1- 5,Symptomatic confirmed VTE event,Aim: To evaluate whether initial (LMW)heparin followed by edoxaban only is non-inferior to initial (LMW)heparin overlapping with warfarin, followed by warfarin only in the treatment of subjects with acute symptomatic venous thromboembolism for the prevention of symptomatic recurrent venous thromboembolism during a 12-month study period,Efficacy outcomes,* Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin group respectively * Denominator is number of patients with index PE : 1650 and 1669 in edoxaban and warfarin group respectively,42,Primary Efficacy Outcome,1.00,0,0.70,1.13,0.89,Hazard Ratio,Edoxaban superior,Edoxaban non-inferior,1.50,Overall,On-Rx,TTR : 63.5%,Safety outcomes, some patients have more than 1 bleeding,Principal Safety Outcome,Number of patients at risk,Baseline characteristics,Efficacy,Safety,Abs 211: Edoxaban For Long-Term Treatment Of Venous Thromboembolism In Cancer Patients,771 CA pts enrolled (208 with active cancer/563 with CA history) Median duration of tx for edox = 267 d vs 266 d for warf (180 to 360 d in both groups) Recurrent VTE in active CA pts: 3.7% in edox; 7.1% in warf (HR 0.55) Clinically relevant bleeding in 18.3% on edox (major= 4.6%) vs 25.3% on warf (major = 3.0%) (HR = for clinically relevant bleeding 0.72) For non-CA pts: recurrent VTE = 2.8% for edox; 2.7% for warf (HR = 1.03) For non-CA pts: relevant bleeding = 7.7% on edox; (1% major); 9.1% on warf (1.3% major) (HR = 0.83) Edoxaban is as effective, and possibly more effective, than warfarin in CA pts with VTE Bleeding is appreciable during anticoagulant therapy, but may be less with edox than warf in CA pts Need additional studies of edox for longer duration and vs LMWH alone rather than warf,Venous Thromboembolism Prevention in High Risk Cancer Outpatients,% VTE in the anticoagulant & placebo arms of SAVE-ONCO and PROTECHT: Full population versus high-risk subgroups (risk score 3),J Natl Compr Canc Network. 2013;11:1435,Predictive Scoring Identifies High Risk CA Patients Who May Benefit from VTE Prophylaxis,Abs 580: Randomized Controlled Trial Of Dalteparin For Primary Thromboprophylaxis For Venous Thromboembolism (VTE) In Patients With Advanced Pancreatic Cancer (APC): Risk Factors Predictive Of VTE Vadhan-Raj S et al,Table:,Predictors of VTE (multivariate logistic regression),OR = 1.40, for every 500 unit increase from baseline D-dimer level,85 ambulatory pts with locally advanced or metastatic CA and active chemotx N=38 (dalteparin 5000 U sq/d for 16 wks during chemotx) N=37 (placebo) VTE: 22% placebo vs 5% dalteparin p=0.02 (75% reduction in VTE) No major bleeds w/dalteparin D-dimer 5000 ng/ml predicts baseline incidental VTE,Does Renal Function Affect the Safety of Dabigatran vs Warfarin for Treatment of Acute VTE?,Abs 212: Influence Of Renal Function On The Efficacy and Safety Of Da