Corso Nazionale di Aggiornamento in Ematologia Clinica Bolzano giugno 2009

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1 Corso Nazionale di Aggiornamento in Ematologia Clinica Bolzano giugno 2009 Nuove prospettive terapeutiche nelle piastrinopenie autoimmuni Marco Ruggeri UO Ematologia, Ospedale San Bortolo, Vicenza

2 Primary Immune ThrombocytoPenia (no longer Idiopathic Thrombocytopenic Purpura) Primary = absence of any initiating/underlying disease (opposed to Idiopathic) Immune = immune-mediated pathogenesis Avoid Purpura: a minority of patients present bleeding at the onset of the disease ThrombocytoPenia: to save acronym ITP (utility in electronic database search)

3 Mechanisms of thrombocytopenia: great heterogeneity! Autoimmune mechanisms Antiplatelet antibodies secretion by autoreactive B lymphocytes (> 80% initial response rate to IVIg and splenectomy) Dysfunctional cellular immunity (autoreactive T cells) T cell- mediated cytotoxicity Natural killer activation Impaired thrombopoiesis Autoantibody suppression of megakaryopoiesis and thrombopoiesis Thrombopoietin dysregulation

4 Treatment options Mechanism Interfere with clearance of antibodycoated platelets Clear antibody from circulation Treatment options Splenectomy Corticosteroids Ig Plasmapeheresis T cell immunosuppression Interfere with B or T Cell participation in antibody synthesis Increase platelet supply Corticosteroids Azathioprine; Cyclophosphamide Cyclosporine Ig Ab anti CD 20 Platelet transfusion Increase platelet production TPO-receptor agonists Gernsheimer T, The Oncologist, 2009

5 Heterogeneity of Primary ITP Increase identification of inciting events and immune defects!

6 Central tolerance defect: More cell types involved; less responsive to therapy Peripheral tolerance defect: More platelet-specific; more responsive to therapy

7 Epidemiology of Primary ITP Crude incidence: 3.9 per person-years (95% CI: ) Overall average incidence rate: F: 4.4 per person-years; 95% CI: ) M:3.4 per person-years; 95% CI: )

8 Epidemiology of Primary ITP

9 ITP: phases of the disease (Rodeghiero and IWG members, Blood 2009) OLD TERMINOLOGY T 0 6 months D I A G N O S I S T 0 «Acute» ITP Chronic ITP 3 months Newly-diagnosed ITP NEW TERMINOLOGY Persistent ITP 12 months Chronic ITP Refractory ITP: Need of treatment after splenectomy Severe ITP: Presence or high risk of bleeding demanding treatment, regardless of the phase of the disease or of platelet count

10 No treatment Natural history with the traditional approach PRIMARY ITP (plt < 100X10 9 /L) Incidence: /10 5 /yr -- Prevalence: / Cured or responsive Cured or responsive Cured or responsive NEWLY DIAGNOSED ITP Corticosteroids, IVIg, anti-d PERSISTENT ITP Corticosteroids, IVIg, anti-d CHRONIC or REFRACT. ITP (25%) Splenectomy Cured or responsive Months from dx 3 12 Immuno suppr. 2-3% of initially treated cohort not responding to any treatment

11 The Vicenza adult ITP cohort ( ) Traditional approach 244 ITP pts (plt count < 100x10 9 /L) 152 (62%) treated 92 (38%) never treated 6 yrs median follow up: (66%) CR + R (32 after splenectomy) - 40 (26%) NR (12 after splenectomy) - 11 (8%) deaths, 1 due to hemorrhage n. 44 (29%) 26% of initial cohort requires continuous treatment

12 Why do we need to change the traditional approach? Toxicity of corticosteroid and immunosuppressant therapy Limitations and risks of splenectomy (effective in 70%): 30% not responding Response unpredictable Thrombosis Infection Death (< 0.5 1%) Late complications: overwhelming sepsis (< 1/500) Some patients not eligible for splenectomy (age, comorbidities, refusal) Cost of IVIg ( 3024 / 1g/kg / 60kg) or anti-d (plus toxicity) Risk-benefit ratio often unfavorable, low cure rate, apart from splenectomy

13 Answers from the novelties of the last years? Splenectomy-sparing strategy High dose steroids Anti D Ig Ab anti CD 20 TPO agonists New drugs for chronic refractory ITP Helicobacter pylori eradication Ab anti CD 20 TPO agonists

14 ITP and Helicobacter pylori (H.P.) Literature revision: 16 studies, published from 1998 to 2003 (Veneri et al, Haematologica, 2003) 365 ITP patients Prevalence of ITP H.P. +: 61% (Italy and Japan) Eradication successful: 88% Platelet response (complete + partial): 55%

15 ITP and Helicobacter pylori (H.P.) Prospective clinical trial (Michel et al, Blood 2004) 74 consecutive patients, female 67%, median age 41 y., 90% chronic ITP (28% splenectomized) Prevalence of H.P.+ : 16/74 (21.6%) vs 32.5% general population USA (p= 0.04) Eradication successful : 14/15 (93%) Response : 1/14 (7%) Response after eradication therapy in 9 ITP (HP-): 0/9

16 ITP and Helicobacter pylori a systematic review of the literature 25 studies identified, including patients; 696 were evaluable for H.P. eradication effect on platelet count CR (plt > 100 x 10 9 /L) : 42.7% (CI 31.8%-53.9%) R (plt > 30 x 10 9 /L): 50.3% (CI 41.6%-59%) If basal platelet count < /L: CR (plt > 100 x 10 9 /L) : 20.1% (CI 13.5%-26.7%) R (plt > 30 x 10 9 /L): 35.2% (CI 28.%-42.4%) Stasi R et al, Blood 2009

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19 Rituximab as first-line therapy Zaja F et al (GIMEMA study), communication at ASH patients randomized to Rituximab (1 dose weekly for 4 wks) +DEXA (40 mg/day for 4 days) vs DEXA Response criteria: PLT > 50 x 10 9 /L after 6 months, without any other treatment

20 DEXAMETHASONE PLUS RITUXIMAB VS DEXAMETHASONE IN PREVIOUSLY UNTREATED ADULT PATIENTS WITH ITP D D D D ARM A: Dexamethasone days ARM B: Dexamethasone + Rituximab D D D D RTX RTX RTX RTX days D: Dexamethasone 40 mg po, on days 1, 2, 3, 4 RTX: Rituximab 375 mg/m 2 IV, on days 7, 14, 21, 28 ML18542 study Clinica Ematologica-Udine

21 EFFICACY: SUSTAINED RESPONSE Sustained response, (month PLT 50 x 10 9 /L (Sustained Response) PLT 100 x 10 9 /L PLT 150 x 10 9 /L +6) Dexa Dexa + RTX P Dexa Dexa + RTX P Dexa Dexa + RTX P Intention 36% 63% % 53% % 43% to treat Per 39% 85% < % 77% < % 65% protocol ML18542 study Clinica Ematologica-Udine

22 Rituximab as an alternative to splenectomy in adults with chronic ITP : Results of multicentric prospective phase II study Godeau B et al. Blood 2008 N = 60 patients (not splenectomized) plt ct <30K 1 yr N = 24 responses* (40%) 2 partial responses N = 34 (60%) non responders 2 yrs Lasting response in 20 patients (33%) Relapse in 4 patients N = 25 splenectomies * Plt 50 x 10 9 /L at least twice the pre treatment count

23 Anti CD 20 (Rituximab) in ITP (375 mg/m 2 per week i.v. for 4 consecutive weeks) Systematic review (Arnold D et al, Ann Intern Med 2007) 19 reports on efficacy (313 pts); 29 on safety (306 pts); 54% had undergone splenectomy All case series were collected retrospectively Overall response (Plt > 50 x 10 9 /L): 62.5%; response lasted from 2 to 48 months 66/306 (21.6%) mild or moderate side-effects 10/306 (3.7%) severe or life-threatening events 9/306 (2.9%) died

24 Rituximab in ITP: data from the literature* First author Design Number of patients (number of splenectomized patients) Overall immediate response Overall sustained response Follow-up with sustained response Braendstrup retrospective 35 (16) 44% not done 47 weeks Cooper and Stasi retrospective 57 (31) 54% 30% 72 weeks Penalver retrospective 89 (47) 55% 35% 36 weeks Zaja retrospective 16 (2) 50% 31% 28 weeks Shanafelt * retrospective 12 (10) 42%* 25% 36 weeks Giagounidis pilot study 12 (11) 59% 33% 229 weeks Saleh ** pilot study 12 (7) 25% 25% 12 to 24 weeks Narat retrospective 6 (3) 83% 50% 46 weeks * in the retrospective study of Shanafelt et al, 3 responders were simultaneously receiving other drugs for ITP during rituximab therapy. * Studies published after Arnold s review ** in the pilot study of Saleh et al only 7 patients received rituximab at a dosage of 375 mg/m2 x 4

25 Rituximab in ITP: PROS Efficacy rate ~ 40% at 1 year One shot therapy Can induce a long-lasting response (+ 3 years) Can be effective pre or post-splenectomy Good short term safety profile May reverse the auto-immune process ( curative ) 90% of the responders respond within 8-10 weeks after the 1st infusion

26 PML: rare demyelinating disease of CNS from reactivation of latent JC polyoma virus (92% adult population is JCV-positive) PML occurs in patients with suppressed cellular immunity Risk of PML in hematologic malignancies is 0.07%

27 57 cases of PML after rituximab (median age 61 y) 52 with B-cell lymphoproliferative diseases 2 with SLE 1 with rheumatoid arthritis 1 with autoimmune cytopenia 1 with ITP (steroids; danazol, IVIg, azathioprine, rtpo agonist) 90% case-fatality rate

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29 Rituximab in ITP: CONS Major concerns on long-term safety Reports on progressive multifocal leukoencephalopathy) due to reactivated JC virus Need to associate additional therapies (steroids and/or Ig) in cases with slow response No controlled or randomized clinical trials (apart from Zaja) No clinical or biological markers to identify responders High cost, need of admission, no EMEA/FDA registration

30 Thrombopoietin (TPO) involved at all stages Stimulates platelet production by promoting: Proliferation Survival Differentiation of megakaryocyte precursors into mature megakaryocytes Platelet release

31 TPO: mechanism of action TPO TPO receptor Inactive receptor Active receptor Cell membrane P SHC GRB2 P SOS RAS/RAF Cytoplasm STAT P P JAK MAPKK Signal Transduction and Activation of Transcription p42/44 Increased platelet production Kuter DJ. Blood, 2007

32 TPO levels are inversely proportional to the platelet count normal platelet count thrombocytopenia plasma TPO platelet [TPO] total [TPO] free normal normal normal increased

33 TPO levels are inversely proportional to the platelet count (not in ITP!) Mukai HY et al; Thromb Haemostas, 1996

34 Proposed feedback mechanism: TPO levels are inversely related to the combined platelet and megakaryocyte mass, because these cells bind and degrade TPO In steady state conditions, plasma concentrations of plateletbound TPO and free TPO are fixed When platelet and megakaryocyte mass decrease, free TPO increases In ITP there is usually increased megakaryocyte mass and accelerated removal of TPO by the increased platelet turnover Free TPO is not sufficiently increased to compensate for thrombocytopenia

35 Thrombopoietic growth factors 1994: -purification and cloning human TPO -rhtpo and PEG-rhMGDF studied in several thrombocytopenic disorders FIRST GENERATION Recombinant human thrombopoietins rhtpo PEG-rHuMGDF Recombinant TPO fusion proteins Promegapoietin (TPO/IL3 fusion protein) 1998: clinical trials stopped for auto Ab against PEGrhMGDF and endogenous TPO in some patients no development of rhtpo

36 Thrombopoietic Growth Factors Second generation: same effects on rtpo, without antigenicity property (no homology sequence with TPO) TPO peptide mimetics Fab 59 AMG 531 (s.c. administration) Peg TPOmp TPO non-peptide mimetics Eltrombopag (orally available) AKR-501 (orally available) TPO agonist antibodies Minibodies (VB22B sc(fv)2) MA01G4G344 Kuter DJ, Blood 2007

37 TPO-r agonists Structure Romiplostim: Nplate Dipeptide linked to the Fc fragment of IgG ( half-life). Structurally unrelated to TPO Eltrombopag: Revolade / Promacta Small molecule TPO-R agonist (mw=442). Structurally unrelated to TPO Target Targets TPO-R Interacts with transmembrane segment of TPO-R Dosage and bioavailability 1-10 µg/kg (average: 2-3 µg/kg) Subcutaneous (weekly) Tablets of mg (average: 50 mg/day) Orally (daily) Interacts with food plt production YES, peak after ~15 days YES, peak after ~15 days Immunogenecity NO or little NO Availability (June 2009) US FDA approval (22/08/2008) EMEA approval US FDA approval (20/11/2008) EMEA: under evaluation Compassionate use

38 Patients admitted to phase II, III and extension clinical studies, double blind, placebo-controlled, for romiplostim or eltrombopag Adults ITP lasting more than 6 months Platelet count < /µL at enrollment and after failing at least one line of therapy (20-30% requiring ongoing treatment to sustain platelet count) Splenectomized or not Extension studies: participants to previous studies, either placebo or active arm (blinded), if plt < 30 x 10 9 /L after wash out

39 Efficacy data for romiplostim Type of study N. treate d pts/pl acebo Intervention Resp. N. (%) Romipl ostim Plac ebo Criteria for response Plt x 10 9 /L 1 Open-label µg day 1 & 15 9 (60) - Any > 50 < 450 Phase 1-2 during observ. period 2 Open-label dose escalation µg/kg/b.w. day 1 & µg/kg/b.w. day 1 & 15 1 (8) 7 (58) - Any > 50 < 450 during observ. period Double-blind vs placebo 17/4 1-6 µg/kg/b.w. once a week for 6 wks 10 (59) 1 (25) Any > 50 < 450 during observ. period 3 Doubleblind vs placebo Splen. Not splen 42/21 41/21 1 µg/kg/b.w. weekly as starting dose (to 10 µg/kg/ b.w.) for 24 wks 16 (38) 25 (56) 0 (0) 1 (2) > 50 during 6 or more of the last 8 wks of treatment 4 Open-label Single arm long term Extension for 106 pts up tp 24 wks µg/kg/b.w. weekly as starting dose (to 10 µg/kg/ b.w.) 124 (87) for 67% of time in study 1: Newland et al, Br J Hematol : Bussel et al, NEJM 2006; 3: Kuter et al, Lancet : Bussel et al, Blood > 50 x 109/L and double baseline. F/U: 69 wks (mean)

40 Platelet count by study week median and 25 and 75 percentile Extension study, Bussel et al, Blood 2009

41 Efficacy data for eltrombopag Type of study N. of treated pts/placeb o Intervention Resp. N. (%) Eltrom bopag Place bo Criteria for response Plt x 10 9 /L 1 Double-blind vs placebo 29 / / 26 / 30 mg/day for 42 days 50 mg/day for 42 days 75 mg/day for 42 days 8 (28) 19 (70) 21 (81) 3 (11) > 50 x 10 9 /L at day 43 2 Double-blind vs placebo 76 / mg/day for 42 days 43 (59) 6 (16) > 50 x 10 9 /L at day 43 3 RAISE Double-blind vs placebo 135 / mg/day for 6 months 8 times more likely to respond median plt vs < 30 > 50 x 10 9 /L during 6 months 4 EXTEND Open-label ongoing extens mg/day (for days) 159 (79) - > 50 x 10 9 /L during observ. period + additional criteria 5 REPEAT Open-label Ph II 65 (cycle 1) 52 (cycle 2-3) cycle: 50 mg/day for 6 wks followed by 4 wks wash out 52 (80) 45 (87) - - > 50 x 10 9 /L at day 43 of each cycle 1: Bussel et al NEJM 2007; 2: Bussel et al, Lancet 2009; 3: RAISE (abstr. ASH 2008) 4: EXTEND (abstr. ASH 2008) 5: REPEAT (abstr. ASH 2008)

42 Platelet count by study week median and 25 and 75 percentile EXTEND study, Bussel et al, abstract ASH 2008

43 Male, 58 years-old 1986: ITP; PDN : PDN, IVIg, Aza, CSP 2008: DEXA hd; Rituximab; splenectomy 2009: PDN; IVIg; CSP; DEXA hd; Rituximab

44 : muco-cutaneous bleeding; PLT 10 x 10 9 /L Therapy: PDN+CSP+Danazol PLT count x 10 9 /L Time (weeks) rtpo-agonist

45 TPO-r agonists in ITP PROS Predictable of plt count and bleeding even in refractory patients Efficacy over prolonged time Available orally or sc Good safety profile Controlled studies Approved in USA and (Romiplostim)in Europe

46 Severe adverse effects for romiplostim Study N. of treated pts/plac ebo Romiplostim N. of severe adverse effects Placebo Newland et al Br J Hematol / 0 1 worsening of thrombocytopenia; 1 headache - Bussel et al Dose escalation 12 / 0 12 / 0 1 vertigo; 1 worsening of thrombocyt.; 1 life-threat. subdural hemorrh. - NEJM 2006 Double blind vs placebo 17 / 4 1 worsening of thrombocytopenia 1 asthma; 1 DVT after splenectomy + intracranial hemorrhage Kuter et al Lancet 2008 Splen. Not splen. 42 / / 21 2 thrombosis; 1 increase bone marrow reticulin; 6 severe bleeding (1 fatal); 1 fatal pulmonary embolism; 1 death (atypical pneumonia) + 5 severe bleeding (1 fatal); Bussel et al (extension) Blood / 0 7 thrombosis; 8 bone marrow reticulin increase; 12 bleeding -

47 Severe adverse effects for eltrombopag Study N. of treated pts/placebo Eltrombopag N. of severe adverse effects Placebo Bussel et al 29 / 27 1 legs pain; 1 pneumonia 1 salmonella infect. 1 toxic hepatitis; 1 convulsion; 1 varicise vein rupture NEJM pneumonia (fatal); 1 herpes zoster; 1 thrombocytopenia; 1 rectal hemorrh trigger finger; 1 rash; 1 menorrhagia - Bussel et al In press (p.c.) 76 / 38 6 transaminase elevation; 1 abnormal hepatic function; 3 cataracts; 2 hemorrhages 1 transaminase elevation; 1 trauma; 1 cataract; 5 plt ct worsening; 1 hemorrhage RAISE abstr. ASH / 62 Not reported Not reported EXTEND abstr. ASH thromboembolic events + 39 events in 17 pts (8%) not specified: e.g. reticulin increase? - REPEAT (abstr. ASH 2008) 65 1 pneumonia -

48 TPO-r agonists in ITP CONS - Plt fluctuations on stable dose - Close monitoring required - Not curative - Response after days - Long-term safety? - Reticulin increase ( 5%) - Increased risk of thrombosis(?) - Worsening of thrombocytopenia - Cost?

49 Thromboembolic events among adult ITP: data from UK GPR Database 840 adult ITP matched with 3360 non-itp patients Thromboembolic events during the study periods: 47/840 (6.7%) in ITP patients vs 172/3360 (5.7%) non-itp patients OR 1.09 ( ); p=0.57 Sarpatwari A et al, ASH meeting 2008

50 Thromboembolic events among adult ITP: data from UK GPR Database: 840 adult ITP matched with 3360 non-itp patients Outcome Incidence rate/ pt-y HR p ITP NO ITP Venous TE ns ( ) ( ) ( ) Arterial TE ns ( ) ( ) ( ) Combined ns ( ) ( ) ( ) Sarpatwari A et al, ASH meeting 2008

51 Thrombosis in ITP Assuming an incidence of 3% pt-year in ITP+TPO patients 630 ITP+TPO patients should be followed for 1 year to demonstrate that the upper 95% CI is below 5% (β: 0.80) Both retrospective or prospective design possible

52 How to integrate new agents into traditional approach (I) Newly diagnosed patients: traditional approach (corticosteroids, IVIg, anti-d); consider H.P. eradication Treatment with curative potential should be offered in persistent or chronic ITP Splenectomy 1 st choice Patients waiting for curative approach: TPO-r agonists appear a reasonable choice In preparation for a scheduled surgery or invasive procedure TPO-r agonists vs IVIg

53 How to integrate new agents into traditional approach (II) TPO-r agonists preferred choice in patients refractory to curative approach and demanding treatment for the low plt count (usually < x 10 9 /L) and bleeding manifestations Target: restore plt count in the range x 10 9 /L Consider also QoL Immunosuppressive treatment or chemotherapy last choice

54 No treatment Cured or responsive Cured or responsive Cured or responsive Natural history of ITP for the future? PRIMARY ITP NEWLY DIAGNOSED ITP Corticosteroids, hd Dexa, IVIg, anti D Ig PERSISTENT ITP TPO-r agonist; Ritux CHRONIC or REFR. ITP Ritux. TPO-r agonist immuno suppr. Splenectomy Cured or responsive < 2-3 % of initial treated cohort not responding to any treatment? Months from dx