Clinical decision making in ITP: When to treat and how to treat

Transcription

1 Clinical decision making in ITP: When to treat and how to treat Beng Hock Chong MBBS,PhD,FRACP, FRCPA,FRCP Professor of Medicine, University of New South Wales, Sydney and Director of Hematology, St George and Sutherland Hospitals, Sydney, Australia.

2 Outline of Talk o When to treat : factors influencing clinical decision making. o How to treat first, second and post- first and second line therapies o New developments in ITP pathogenesis and treatment o New treatments: TPO receptor agonists, efficacy, toxicity and when to use them o ITP treatment: my perspective. o ITP Case discussion

3 Management of ITP: When to treat Factors that influence treatment: Age: children ( acute ) vs adults (chronic) Advance age Fatal hemorrhage: age-dependent <40 yr: cases per patient-year, > 60yr: 0.13 cases per patient-year, Presence of bleeding Platelet count YC Cohen et al Arch Intern Med 2000; 160: Risk factors for bleeding Side effects of treatment Life style, patient s preference

4 Platelet count & risk of bleeding Platelet count Bleeding, any count Treatment Yes < 10 x 10 9 /L Yes x 10 9 /L Usually Yes After evaluation of other risk factors x 10 9 /L Usually NO > 50 x 10 9 /L NO

5 5 Platelet count & Safety for Surgery Platelet count Procedure >10 x 10 9 /L dentistry > 30 x 10 9 /L Extraction, dental block > 50 x 10 9 /L Minor surgery, vaginal delivery > 80 x 10 9 /L Major surgery, Cesarean section Spinal or epidural anesthesia From the British Committee for Standards in Hameatology, General Haematology Task Force

6 Risk Factors for Bleeding Chronic liver disease Uremia Peptic ulcer Uncontrolled hypertension Alcoholism Platelet function defects Aneurysm

7 Quality of Life in Adult Patients with Chronic Adult ITP ITP N=73 Mean age= 45.1 yrs; F:56 /M:17 Duration of ITP: >10yrs: 26, 5-10yrs: 15; 1-5yrs: 19 ; <1yr: 13 Post-splenectomy: 42(58%); 38 (52%) on 1 or more meds. McMillan R, Bussel JB, George JN, Deepa L, Nichol JL. Am J Hematol. 83: , 2008

8 Summary: Key points Bleeding risks, Age Life style, person preference No or mild bleeding: Platelets <30 x 10 9 /L Significant Bleeding, platelets >30 x 10 9 /L No or mild bleeding: platelets >30 x 10 9 /L Treat Treat Don t Treat Final judgments: based on individual circumstances

9 Management: watch-and-wait Is it safe to watch and wait? Yes Mortality rate <1% No indications for Rx if: No symptoms or signs Platelets > 30 x 10 9 /L (Grade C) YC Cohen et al Arch Intern Med 2000; 160: JE Portielje et al. Blood 2001; 97(9):

10 10 When NOT to treat? No or mild bleeding: o When platelet counts persistently >30 x 10 9 /L, o ITP is refractory to treatment, and treatment cause unacceptable adverse effects.

11 First Line Steroids IVIg Anti-D International Consensus ITP Treatments Second Line Splenectomy Prednisone Danazol Rituximab Azathioprine Cyclophosphamide Cyclosporin A Dapsone Mycophenolate mofetil Vinca alkaloids TPO receptor agonists If fail 1 st and 2 nd Line Rx options with sufficient data TPO receptor agonists Rx options with minimal data and potential for considerable toxicity Campath-1H Combination of 1st and 2 nd line Rxs Combination chemotherapy Hemopoietic stem cell BMT

12 First-line treatment: Corticosteroids Dexamethasone 40mg/d x 4d every 2-4 wks up to 3 6 cycles Methyl-prednisolone up to 30mg/kg/d x7d 95% 90% initially Prednisone 0.5-2mg/kg/d 70-80% initially for 2-4wks Response rates Provan D et al. International consensus report on the investigation and management of ITP. Blood. 115(2): , 2010.

13 Treatment IV anti-d First-line treatment Response rate up to 50-75ug/kg 80% Time to response 2 4 days Duration of response 3-4 weeks IVIg 0.4g/kg/d x 5 d up to 1g/kg/d 1-2 days 80% 4-5 days 2-4 weeks Provan D et al. Blood. 115(2): , 2010.

14 Chong BH, Ho SJ. Autoimmune thrombocytopenia (State of Art Paper). J Thromb Haemostat. 3: , Emergency Treatment: IVIG Prednisone, dexamethasone or IV Methylprednisolone + Platelet transfusion + Supportive measures: Fibrinolysis inhibitors Direct pressure on bleeding sites Blood transfusion- keep Hb >10G/L + Factor VIIa + Emergency splenectomy Chong BH, Ho SJ. Autoimmune thrombocytopenia (State of Art Paper). J Thromb Haemostat. 3: , 2005.

15 Second line therapies Azathioprine Cyclophosphamide Cyclosporin A Danazol Dapsone Mycophenolate mofetil Rituximab Splenectomy Vinca alkaloids TPO receptor agonists Grade B Grade A

16 Treatments after failing 1 st and 2 nd line therapies Treatment Response rate Eltrombopag ~80% Romiplostim Time to response Category A: treatment with sufficient data 2 weeks Duration of response Sustained if drug continues Category B: treatment with minimal data and potential considerable toxicity Campath -1 H Combination chemotherapy Haematopoietic stem cell tansplantation

17 16 Therapies whose use is not justified Ineffective or too toxic Colchicine Interferon-a Protein A immunoadsorption columns Plasmapheresis Vitamin C rviia

18 New understanding of Mechanisms of Thrombocytopenia in ITP Increased platelet destruction Decreased platelet production

19 Specificity of Anti-platelet Antibodies in ITP Anti-GP IIb/IIIa only 19/40 (48%) Anti-GP Ib-IX only 5/40 (12%) Both 16/40 (40%) 88% 52% Brighton T, Evans S, Castaldi PA, Chesterman CH, Chong BH. Blood 88: , 1996.

20 Thrombopoietin Levels in ITP Platelet Count (x 10 9 /L) Healthy Donors ITP Amegakaryocytic thrombocytopenia 5 0 Serum TPO (fmoles/ml) Mukai HY, et al. Thromb Haemost. 1996;76:

21 25 Thrombopoietin: Mechanism of Action TPO Thrombopoietin Receptor Inactive Receptor Cell Membrane Cytoplasm Signal Transduction STAT Transcription factors: GATA-1, Fli-1, NF-E2 Nucleus GATA-1 P P P JAK SHC GRB2 P p42/44 Active Receptor SOS MAPKK RAS/RAF Increased Platelet Production

22 Revolade(Eltrombopag): Mechanism of Action Eltrombopag Thrombopoietin Receptor Inactive Receptor Cell Membrane Cytoplasm Signal Transduction STAT Transcription factors: GATA-1, Fli-1, NF-E2 Nucleus GATA-1 P P P JAK SHC GRB2 P p42/44 Active Receptor SOS MAPKK RAS/RAF Increased Platelet Production

23 Romiplostim: Mechanism of Action Romiplostim TPO-R Binding peptide Fc Thrombopoietin Receptor Romiplostim Inactive Receptor Cell Membrane Cytoplasm Signal Transduction STAT Transcription factors: GATA-1, Fli-1, NF-E2 Nucleus GATA-1 P P P JAK SHC GRB2 P p42/44 Active Receptor SOS MAPKK RAS/RAF Increased Platelet Production

24 Studies with Romiplostim in ITP Phase I: Open label study of 24 subjects treated in groups of 4 at six dose levels: 0.2, 0.5, 1.0, 3.0, 6.0, 10.0 µg/kg SQ Phase II: Double-blind, placebo-controlled trial of 1 or 3 µg/kg romiplostim (16 subjects) vs placebo (4 subjects) Phase II: Double-blind, placebo-controlled trial in 22 children on romiplostim and 5 placebo divided by age Phase III: Double-blind, placebo-controlled trial of romiplostim vs placebo in patients with or without splenectomy Phase III: Romiplostim vs standard of care in ITP with or without splenectomy Extension Study (213): Open label safety and efficacy study of long-term weekly treatment of subjects from Phase 1-3 Bussel JB, et al. N Engl J Med. 2006;355: Newland A, et al. Br J Haematol. 2006;135: Kuter DJ, et al. Lancet. 2008; 371: Bussel JB, et al. Blood. 2009;114: Abstract 681. Kuter DJ, et al. Blood. 2009:114: Abstract 679. Buchanan GR, et al. Blood. 2009;114: Abstract 680.

25 Studies with Eltrombopag in ITP Phase II/III: Double-blind, placebo-controlled trials 773A: placebo or 30, 50, 75 mg daily for 6 weeks 773B: placebo or 50 mg daily for 6 weeks Phase II: REPEAT three cycles of 6 weeks each of active, ope n-label treatment Phase III: RAISE double-blind, placebo-controlled trial for 6 months of variable doses of eltrombopag vs placebo in patie nts with or without splenectomy Extension Study: EXTEND Open label safety and efficacy stud y of long-term weekly treatment of subjects from Phase II-III Phase II: (Ongoing): PETIT Study of eltrombopag in children w ith persistent and chronic ITP in 3 age cohorts Bussel JB, et al. N Engl J Med. 2007;357: Bussel JB, et al. Blood. 2009;112: Saleh et al. Blood. 2009;114: Abstract 682. Stasi R, et al. Haematologica. 2009;94(Suppl 2):231.

26 Median Platelet Count (x 10 9 /L) 30 Eltrombopag: Phase III RAISE Study Platelet Response Odds of response 8 times higher in ELTROMBOPAG subjects (OR (99% CI) = 8.2 (3.59,18.73) p< ) 150 Placebo Eltrombopag During treatment Follow-up period BL Day 8 Day 15 Day 22 Day 29 Day 36 Day 43 Wk 10 Wk 14 Wk 18 Wk 22 Wk 26 Wk 1 Wk 2 Wk 4 Cheng G, et al. Blood. 2008;112: Abstract 400.

27 Platelet Count (x 10 9 /L) EXTEND: Durable Platelet Count Elevation 79% of patients achieved a platelet count of > 50 x 10 9 /L at least once and 78% of these patients maintained platelets > 50 x 10 9 /L for over 50% of their time in the study BL Week Bussel JB, et al. Blood. 2008;112: Abstract % of subjects had a response for 10 weeks

28 Responders, % Overall Platelet Response* Placebo Eltrombopag P< P< P=n/e n = 39 n = 95 n = 12 n = 37 n = 27 n= 58 All Patients Splenectomy No splenectomy Stasi R, et al. Haematologica. 2009;94(suppl 2): Abstract 231.

29 Percentage of Subjects EXTEND: Durable Bleeding Reduction Week Patients, n Grade 1-4 Bleeding Grade 2-4 Bleeding BL Bussel JB, et al. Blood. 2008;112: Abstract 3432.

30 Overall Efficacy Conclusions Clinical benefit demonstrated in 5 studies Durable increase of platelet counts Reduced bleeding Reduced concurrent ITP medication Patients overcame haemostatic challenges Eltrombopag improves HRQoL, Effective regardless of stratification criteria Splenectomy status Baseline platelet count

31 35 Long TermAdverse Effects (EXTEND) Hepatotoxicity Bone marrow reticulin formation Thromboembolic events Cataract Malignancy 36 /302 (12%) 8 stop treatment 2 had grade 2 increase In reticulin 3 stop treatment 19 patients (6%) 2.7 /100 patient-years 25/299 patients (8%) 2 patients had lymphoma in 266 patient-years

32 Splenectomy vs TPO mimetics Splenectomy 60-70% log term remission Small risk of peri-op complications Immunosuppression- Risk of infection with capsulated orgisms Increase thrombotic risk Overwhelming infectionsmortality: 0.73 per 1000 pt-yr Expensive? TPO mimetics: Sustained response if drug continues?7 Sustained remission Long-term side-effects uncertain?increase thrombotic risk Expensive

33 ITP therapy: Two approaches Continued chronic administration Steroids Immunosuppressives TPO-R agonists: + splenectomy 2 broad approaches Given once (or 1 course) to induce long remission: Rituximab + dexamethasone Splenectomy Provan D et al. Blood, 115: (2010)

34 2nd approach to treatment: Aim for a cure/long remission

35 % Cell Proliferation 40 Defective Suppressive Effect of CD4+CD25+ Cells on Autologous CD4+CD25- in Chronic ITP Patients: Reversal After Rituximab Pre 3 mos (R) 3 mos (NR) Controls Stasi R, et al. Blood. 2008;112(4):

36 Oligoclonal T Cells Shift to Polyclonal After Successful Rituximab Treatment Stasi R, et al. Blood. 2007;110(8):

37 Pathophysiology of ITP: Progressive evolution to more resistant cells with time and treatment Normal: Polyclonal phenotype ITP: oligo-clonal phenotype T-cell APC B-cell B-cell B-cell B-cell Respond to treatment Treatment refractory Time

38 Selected 1st and 2 nd line monotherapies Treatment Dexamethasone 40mg/d x 4d every 2-4 wks, 3 6 cycles Rituximab 375mg/m 2 x4 Response rate up to 90% initially 57% remission Time response Several days- weeks 1-8wks Duration of response 50%-80%, 3-6 cycles 2-5 yr Followup 1 yr: 40% 5yr: 21%

39 55 Treatment Zaja et al (2008 & 2009) Response rate at: 6 months 20 months A. Dexamethasone 40mg/d x 4d 37% 25% B. Dexamethasone 40mg/d x 4d plus Rituximab 375mg/m 2 x4 77% 55% o Whole group - Splenectomy rate: 5% n=63 per protocol n=53 at 20mths Zaja F et al. Blood (suppl). 112: abstr 1, 2008 Zaja F et al. Blood (suppl). 114: abstr 2415, 2009

40 My perspective of ITP Treatment: How I treat ITP?

41 Diagnosis of ITP Emergency Treatment: Serious bleeding or Emergency surgery needed, Platelet count < 10x10 9 /L Treatment: Platelet count < 30x10 9 /L, particularly < 20x10 9 /L No treatment: Risk factors for bleeding Platelet count >30x10 9 /L, No bleeding Peptic ulcer Trauma/ surgical wounds Platelet function defects Bleeding, treat. Also look for a medical or surgical cause of bleeding e.g. anti-platelet therapy Chronic liver disease Uremia Chong BH, Ho SJ. Autoimmune thrombocytopenia (State of Art Paper). J Thromb Haemostat. 3: , 2005.

42 45 Chong BH, Ho SJJ Thromb Haemostat. 3: , 2005.

43 Initial Treatment (1 st Line) Prednisone (1mg/kg/d) for 2-4 weeks, then taper or high dose dexamethasone (40mg/d x 4d/month) + IVIG Subsequent Treatment (2 nd line) if platelet count persistently <30x10 9 /L for 6-12 mths, Splenectomy, fail or refused splenectomy Low dose prednisone or high dose dexamethasone + rituximab ( if available) + elthrombopag or romiplostim( if available) + danazol, cyclosporin + azathioprine, cyclophosphamide or vincristine Bleeding/ platelet Benefits counts Drug toxicity/ splenectomy Risk complications

44 Splenectomy Treatment of refractory ITP or Post 1 st and 2 nd Line treatments Chong BH, Ho SJJ Thromb Haemostat. 3: , 2005.

45 50 Sudden drop in platelets S.S. 40 yr female Enrolled in elthormbopag in April, 2007 Responded well with platelet counts x10 9 /L. In August 2010, platelets suddenly dropped to 29x10 9 /L URTI

46 Platelets Serial Platelet Counts of Ms S.S. Take home message: A sudden drop in platelet count may be due to concommitant infection? URTI

47 Wild swings in platelet counts Mrs CL N. 38 yr female with chronic ITP Enrolled in romplostim trial in August 2007 Good response till August Platelets <30x109/L, Treated with high prednisone, and later rituximab which caused side-effects. She had and failed splenectomy. Retreated with romiplostim. Swing platelet counts

48 Platelets 53 Serial Platelet Counts Take home message: Wild swing in platelet counts may occur with romiplostim. Minimize dose changes.

49 Mrs R.D. 56 year old female She had ITP since 1972 (> 30 years) Splenectomy in She had become refractory to almost all available drugs for ITP treatment. Platelet counts persistently low : average 3x10 9 /L Continuously tired with bruising, intermittent epistaxis and haematuria, and occasional GIT bleed. Started on Elthrombopag in Oct 08, platelet rose to 12-15x10 9 /L, very occassonally 30 x10 9 /L. Marked symptomatic improvement Take home message: A small platelet response, not reaching 30 x10 9 /L, can make a dramatic and significant impact clinically

50 55 62 yr female Patient O. C. Refractory after 2 year treatment Enrolled in elthrombopag trial Repeat in April Responded well. Enrolled in romiplostim trial, Repeat in August Good response with platelet counts rose from 17/L to x10 9, for Some periods x10 9. After 2 years, platelet dropped to < 20x x10 9, needing small doses of prednisone to keep platelets >30x x10 9 Take home message: A response to one TPOR mimetic does not ensure prolonged response to another. Combination therapy can still work.

51 Summary New advances in pathogenesis have led to new ITP treatments including TPO receptor agonists. These drugs have ~80% response rate even in patients who are refractory to multiple drugs. Their short-term toxicity is acceptable but the long term toxicity is still uncertain. They decrease bleeding, increase quality of life, allow toxic ITP drugs to be withdrawn and clinically needed surgery to be performed. Management of a small % of patients can be challenging but clinicians need to gain more experience.

52 Aknowledgements Current Research : Team : Collaborators F. Yan XM Jaing J Perdomo S Liang Z. Ahmedi Jaa Yin New Sheng-yi Liu Philip Choi M.C. Berndt Jing-fei Dong J.Lopez (Monash Uni,Aust.) (Uni Washington, Seattle, USA) Past Students & Post-Doc A. Philips S Ramacnathan E. L Fock W Hu Lacey Johnson S. Pan J. Burgess S. Tait P. Asvadi H. Tao M Holmes R. Sungaran M.Eisbacher Clinical trail unit & Center of Thromobisis and Bleeding disorders R Ristuccia S Davidson E Simon M Louzou Karina Liu Lorraine King All ITP investigators / GSK co-sponsor

53 Thank you for your attention