Evolution of clinical guidelines for ITP: Role of Romiplostim

Transcription

1 Slovenian Haematological Society 16 April 2010, Podčetrtek Evolution of clinical guidelines for ITP: Role of Romiplostim Dr. Roberto Stasi Department of Haematology St George's Hospital London

2 Is there a need for new guidelines for ITP? Existing guidelines outdated (ASH, 1996; BCSH 2003) Little evidence based on randomized trials and many recommendations based on expert opinion UK and US practice varies New drugs available Countries with limited resources (alternative approaches)

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4 Assessment of evidence Computer-assisted search of the literature Papers were graded using a specific scoring system Randomized controlled trials (RCTs) were graded as providing the highest level of evidence Case studies and expert opinion the lowest. Grades of recommendation were based on the supporting evidence levels

5 ITP: Definition Isolated thrombocytopenia (Plts <100 x 10 9 /l) with otherwise normal CBC and peripheral smear Previous criteria: Plts <150 x 10 9 /l No other conditions or factors that can cause (or be associated with) thrombocytopenia Previous criteria: same Rodeghiero et al. Blood 2009;113:

6 Isolated thrombocytopenia: initial assessment Full clinical history Determine type of bleeding and family history Examine patient Assess type and severity of bleeding Other presenting features Exclude other conditions that might cause Laboratory investigations Determine the risk: treatment is indicated? Previous guidelines: same

7 Laboratory investigations Basic (mandatory/highly recommended) Tests of potential utility Tests of unproven benefit

8 Basic evaluation Tests of potential utility Patient/family history Glycoprotein-specific antibody TPO Physical examination Complete blood count and reticulocyte count Peripheral blood film Quantitative immunoglobulin level measurement* Bone marrow examination (in selected patients) Blood group (Rh) Direct antiglobulin test H. Pylori** HIV** HCV** Antiphospholipid antibodies (including anticardiolipin and lupus anticoagulant) Anti-thyroid antibodies and thyroid function Pregnancy test in women of childbearing potential Antinuclear antibodies Viral PCR for parvovirus and CMV Tests of unproven benefit Reticulated platelets PalgG Bleeding time Platelet survival study Serum complement *Quantitative immunoglobulin level measurement should be considered in children with ITP and is recommended in those children with persistent of chronic ITP as part of reassessment evaluation **Recommended by the majority of the panel for adult patients regardless of geographic locale Rh, rhesus; H. pylori, Helicobacter pylori; HIV, human immunodeficiency virus; HCV, hepatitis C virus; PCR, polymerase chain reaction; CMV, cytomegalovirus; TPO, thrombopoietin; PaIgG, platelet associated immunoglobulin G

9 Changes from previous guidelines Bone marrow examination is appropriate in patients >60 years old and in patients not responding to first-line therapy options HIV and HCV and H. pylori should be routinely tested in adult patients Quantitative Ig level testing is indicated to exclude an immune deficiency syndrome or when treatment with intravenous immunoglobulin is considered

10 Assessing the need for treatment Complex analysis Involves Actual bleeding Patient s age (risk of bleeding) Patient s lifestyle (quality of life) Need for safe counts during surgery

11 Management of ITP: Watch and wait Mortality rate <<1% No indication for therapy if: no symptoms or signs are present platelets > 30 x 10 9 /l (Grade C)

12 Initial treatment for newly-diagnosed ITP Corticosteroids is the standard first-line treatment for adults with ITP who need treatment and do not have a relative contraindication to its use (e.g. diabetes, psychiatric disorders). IVIg or IV anti-d may be appropriate in patients with bleeding, at high risk of bleeding, and those who are unresponsive or have contraindications to steroids (e.g. insulin-dependent diabetes). Previous guidelines: same

13 Emergency treatment (on-demand treatment) High-dose IV corticosteroids IVIg Platelet transfusions Previous guidelines: same

14 Second-line therapy Medical TPO-receptor agonists - NEW Mycophenolate Rituximab Other Immunosuppressive agents Danazol Dapsone Surgical Splenectomy

15 Second-line therapy in adults medical TPO-receptor agonists Grade A recommendation, Evidence level Ib Response 80-85%. Cessation of treatment will lead to return of thrombocytopenia in most cases.

16 Second-line therapy in adults medical Rituximab Grade B recommendation, Evidence level IIa Initial response ~50%. Long-term durable responses in 15 20% Hepatitis B status needs to be determined prior to treatment (Grade C recommendation, Evidence level IV).

17 Second-line therapy in adults medical Immunosuppressive agents Include cyclosporin A, mycophenolate mofetil, cyclophosphamide and azathioprine. Variable responses Danazol and dapsone useful in elderly patients and in those in whom splenectomy is contraindicated (Grade B recommendation, Evidence level IIa/IIb).

18 Second-line therapy in adults Splenectomy Historically, the treatment with the highest likelihood of producing cure Wait at least 6 months from diagnosis (chance of spontaneous remission) Indium-labeled autologous platelet scanning may be useful prior to splenectomy to confirm that the spleen is the main site of platelet sequestration (Grade B recommendation, Evidence level III).

19 Splenectomy in ITP Indicated in case of: 1 Severe thrombocytopenia (Plt <10-20 x 10 9 /L) High risk of bleeding for Plt counts <30 x 10 9 /L Requirement of continuous glucocorticoid therapy to maintain safe platelet counts CR rate of 66%; OR 88% 2 Mortality rate with laparoscopic splenectomy 0.2% 2 Potential lifelong infection risk 1. Stasi et al. Thromb Haemost 2008;99: Kojouri et al. Blood 2004;104:

20 Adults failing first- and second-line therapies TPO-receptor agonists (romiplostim and eltrombopag - NEW Grade A recommendation, Evidence level Ib Miscellaneous (combination chemotherapy, campath-1h and HSCT) The side effects of these treatment options may be severe and the data supporting their use are limited Grade B recommendation; Evidence level IIb

21 ITP during pregnancy 1 line: oral corticosteroids or IVIg Grade C recommendation IV anti-d in Rh(D)-positive nonsplenectomized women appears to be well tolerated and effective based on results from a pilot study Grade B recommendation, Evidence Level IIb Previous guidelines: same

22 Management of delivery and newborn infants The mode of delivery must be determined by obstetric indications Grade B recommendation Cordocentesis and fetal scalp blood sampling should be avoided in the management of ITP in pregnancy Grade C recommendation Previous guidelines: same

23 Childhood ITP Clinical classification should be used to define disease severity - NEW Evidence level IIb, Grade B recommendation Treatment should be considered based on a combination of clinical symptoms, the circulating platelet count and impact of ITP on the patient s quality of life Evidence level IIb, Grade B recommendation

24 Grade of severity and management of children with ITP Bleeding/quality of life Grade 1. Minor bleeding, few petechiae ( 100 total) and/or 5 small bruises ( 3 cm diameter); no mucosal bleeding Grade 2. Mild bleeding, many petechiae (>100 total) and/or >5 large bruises (>3 cm diameter); no mucosal bleeding Grade 3. Moderate bleeding, overt mucosal bleeding, troublesome lifestyle Management approach Consent for observation Consent for observation or for treatment in selected children Intervention to reach Grade 1/2 in selected children Grade 4. Mucosal bleeding or suspected internal hemorrhage Intervention Modified from Buchanan & Adix; Bolton-Maggs & Moon; Imbach et al

25 First-line treatments in childhood ITP IVIg and anti-d can raise the platelet count rapidly. Grade A recommendation, Evidence level Ib Anti-D 75 μg/kg has similar efficacy to IVIg and is rarely associated with severe hemolysis Grade A recommendation, Level Ib evidence PDN 1 2 mg/kg/day of prednisone may be given, with treatment titrated against the platelet count Grade A recommendation, Evidence level Ib Alternatively, a higher dose of corticosteroids 4 mg/kg/day for 4 days may be used Grade B recommendation, Evidence level III

26 Treatment options in children with persistent or chronic ITP Pulsed high-dose steroids or regular IVIg/anti-D may control bleeding while awaiting spontaneous remission or while considering disease-altering treatment. Rituximab Grade B recommendation, Evidence level IIa and IIb TPO-receptor agonists Grade C recommendation, Evidence Level IV Combination therapies (see adult section) Grade C recommendation, Evidence Level IIb, III

27 Splenectomy in children with chronic ITP Rarely indicated in childhood ITP Grade C recommendation It may be justified for children with chronic unremitting and severe ITP with bleeding symptoms, whose disease has been present for more than months resulting in impairment of their quality of life Grade B recommendation, Evidence level IIb Previous guidelines: same

28 New Guidelines: Conclusions (1) Few substantial changes Diagnosis: still of exclusion; more emphasis on screening for infections Adults: 1st line therapy: no change (CS, IVIG, Anti-D) 2nd line therapy: TPO-R agonists if contraindications to splenectomy 3rd line therapy: TPO-R agonists

29 New Guidelines: Conclusions (2) Childhood ITP: Clinical classification to define disease severity 1st and 2nd line therapy: no change 3rd line therapy: Rituximab 4th line therapy: TPO-R agonists; splenectomy usually not considered Pregnancy: No change Target platelet count for surgery: No change

30 TPO peptide mimetics: Romiplostim (nplate ) No sequence similarity to natural TPO Therefore, does not elicit anti-tpo antibodies

31 Romiplostim: Mechanism of Action romiplostim thrombopoietin receptor inactive receptor active receptor Cell membrane P SHC GRB2 P SOS RAS/RAF Cytoplasm STAT P P JAK MAPKK p42/44 Signal Transduction Increased platelet production

32 Romiplostim (AMG 531) in healthy volunteers Phase I study Wang et al. Clin Pharmacol Ther 2004;76:628-38

33 Comparison of platelet responses in subjects receiving single IV or SC administration Wang et al. Clin Pharmacol Ther 2004;76:628-38

34 Romiplostim (AMG 531) in chronic ITP Phase I-II studies Bussel et al. New Engl J Med 2006;371:

35 Peak Individual Platelet Counts in Phase I The shaded area shows the targeted platelet range Bussel et al. New Engl J Med 2006;371:

36 Peak Individual Platelet Counts in Phase II The shaded area shows the targeted platelet range Bussel et al. New Engl J Med 2006;371:

37 Romiplostim in Chronic ITP Phase III study Weekly, s.c. romiplostim in slowly escalating doses (1 µg/kg up to 15 µg/kg) for 24 weeks Dose adjusted to achieve a platelet count of 50, ,000 Inclusion criteria: Age 18; ITP with platelet count <30,000 Other treatments were discontinued at least 4 weeks before entry Randomized, double-blind, Phase 3 trial (n = 125) Splenectomy (n = 63) Non-splenectomized (n = 62) Placebo (n = 21) Romiplostim 1 mcg/kg SQ q wk, target Plt x10 9 /L (n = 42) Placebo (n = 21) Romiplostim 1 mcg/kg SQ q wk, target Plt x109/L (n = 41) Kuter DJ et al. Lancet 2008;371:

38 Platelet Counts Splenectomised Range = middle 2 quartiles Non-splenectomised Kuter et al. Lancet. 2008;371:

39 Dose Adjustments Target platelet count 50, ,000 Splenectomised ±SEM Non-splenectomised Kuter et al. Lancet. 2008;371:

40 Definition of platelet response Durable Platelets 50,000/µL for at least 6 of the last 8 weeks of treatment Transient Four or more weekly platelet responses (Plt 50,000/µL) at any time during the study Kuter et al. Lancet. 2008;371:

41 Phase III: Overall Platelet Response Overall Platelet Response, % 100 Placebo Romiplostim (P<.0001) (P<.0001) (P<.0001) Splenectomized Nonsplenectomized Total Kuter DJ, et al. Lancet.2008;371(9610):

42 Patients receiving rescue therapies Kuter et al. Lancet. 2008;371:

43 Adverse Events Placebo Romiplostim Severe or lifethreatening bleeding 5/41 (12%) 6/84 (7%) Thrombosis 1 1 popliteal art. thrombosis 1 CVA Death 1 ICH 1 PE 1 ICH after starting aspirin to treat thrombosis Increased bone marrow reticulin 1 (reversible) Kuter et al. Lancet. 2008;371:

44 Romiplostim Long-term Treatment S C R E E N I N G Treatment Period Romiplostim starting dose: 1 µg/kg or last dose on prior study Individual dose adjustment based on platelet count Target platelet count: x10 9 /L Maximum dose 10 µg/kg* Reductions in concurrent ITP therapies allowed when platelet counts > 50 x 10 9 /L Rescue medications allowed * A small number of patients are on doses up to 17 µg/kg. Initial maximal dose 30 µg/kg, later reduced to 15 µg/kg, and then 10 µg/kg. I N T E R I M A N AL Y S I S Day - 8 Day 1 Study drug administered SC weekly End of Study Longest continuously reported active treatment study with a TPO mimetic Bussel JB, Kuter DJ et al. Blood 2007;110: abstract 568

45 Bussel et al. Blood. 2009;113: Long term treatment

46 Potential Adverse Consequence of Thrombopoietic Growth Factors Thrombocytosis Thrombosis Stimulation of tumor growth Stimulation of leukemia cell growth Interactions with other cytokines Autoantibody formation Stem cell depletion Reduction in threshold for platelet activation Rebound worsening of thrombocytopenia Increased bone marrow reticulin

47 Increased Bone Marrow Reticulin 11 of 210 patients in romiplostim studies showed increased reticulin No chromosome abnormalities Many at high doses (>10 µg/kg) Many with minimal response to drug Decreased in two who had subsequent bone marrow

48 Conclusions Romiplostim has no sequence homology to endogenous TPO Romiplostim has the same mechanism of action of TPO Romiplostim given once a week subcutaneously for 24 weeks produces a durable platelet response in ~40% of splenectomized and ~60% of non-splenectomized patients with ITP and allows discontinuation of other medications in many patients The drug is well tolerated Long-term treatment appears feasible