Il Rituximab nella ITP

Transcription

1 Il Rituximab nella ITP Monica Carpenedo U.O.C Ematologia e TMO, Ospedale San Gerardo, Monza

2 Burning questions about Rituximab and ITP What is the mechanism of action? What is long term effect of treatment? What is the most appropriate regimen? Is the treatmente really safe? Can this treatment be administered before splenectomy? Has the TPO mimetic availability changed the role of rituximab?

3 Burning questions about Rituximab and ITP What is the mechanism of action? What is long term effect of treatment? What is the most appropriate regimen? Is the treatmente really safe? Can this treatment be administered before splenectomy? Has the TPO mimetic availability changed the role of rituximab?

4 Tregs prevent autoimmune disease by maintaining self-tolerance (interaction between Tregs, Th cells, and antigen-presenting cells). Tregs suppress B cells The use of rituximab in ITP is associated with a sustained B-cell depletion and a decrease or disappearance of antiplatelet antibodies Chong BH, Blood 2010

5 Rituximab, B cells and T cells The pre-treatment T-cell abnormalities elevated Th1/Th2 (and Tc1/Tc2) cytokine ratios (increase IL 1 and IFN-γ) Elevated CD4 T-cell associated Bcl-2/ BaxmRNAlevels, oligoclonal T-cell expansion, Augmented release of TGF- β 1 were completely reversed by 3 months after treatment with rituximab (observed only in those patients who responded to rituximab therapy) [ Stasi R, Blood. 2007;110: ] In patients with ITP, response to B-cell depletion induced by rituximab is associated with significant changes of the T-cell compartment: B-cell depletion induced by rituximab can revert the abnormalities of the T-cell compartment in patients with ITP who respond to treatment. [ Stasi R, Blood. 2007;110: ]

6 Burning questions about Rituximab and ITP What is the mechanism of action? What is long term effect of treatment? What is the most appropriate regimen? Is the treatmente really safe? Can this treatment be administered before splenectomy? Has the TPO mimetic availability changed the role of rituximab?

7 First reports of Rituximab and ITP Zaja ITP mg/m2 x 4 2CR 4+ Zaja F et al. Hematologica 2002

8 Sistematic review: efficacy and safety of Rituximab in ITP 19 eligible reports on efficacy (313 patients) 29 eligible reports on safety (306 patients) Platelet count response, x 10 9 /L % (95% CI) Contributing reports (pts n) Overall (>50) 62.5 ( ) 19 (313) Complete (>150) 46.3 ( ) 13 (191) Partial (50-150) 24.0 ( ) 16 (284) Arnold DM et al, Ann Intern Med. 2007;146:25-33.

9 Relationship between sample size and overall response (>50 x 10 9 ) small studies tended to report greater response rates than larger studies Arnold DM et al, Ann Intern Med. 2007;146:25-33.

10 Duration of response Variable Median Range Contributing reports (pts n) Time to response, wk (123) Response duration, mo (252 Follow up, mo (187) Lack of controlled trials Extreme heterogeneity (duration of ITP, splenectomy status, previous treatment) Poor methodological quality of observational studies Arnold DM et al, Ann Intern Med. 2007;146:25-33.

11 Long term follow-up results 25 patients ITP relapsed or refractory Prognostic factors of response: -Younger age -Lower interval from diagnosis and RTX Median time of observation 56.5 months (39-77m) CR 14/26 (54%) PR 4/26 (15%) 11/26 (42%) no more therapy 9/26 (35%) maintened response (57 m) 9/18 relapsed, median 21 m (8-66 m) 5 years Relapse Free Survival: 61% 5 years Therapy Free survival: 72% Medeot M et al, Eur J Haem 2008

12 Long term follow up results : other experience Long term follow up on 138 pts (72 adults) with response to rituximab ongoing after one year after treatment (plt > 50 x 10 9 /L) without additional treatment. 24% of enrolled patients previously splenectomized Of responders at 1 year: CR (Plt >150 x 10 9 /L) : 69% PR (Plt x 10 9 /L): 31% Patel V et al, ASH 2010

13 5 years follow up Response rate % adult children # * * * # * previous published data achieved in this study Patel V et al, ASH 2010

14 B cell repopolation after rituximab infusion in patients with initial response responders > 2.5 ys relapsers CD19 + B cell count (x 10 9 /L) p< Days post first rituximab infusion Patel V et al, ASH 2010

15 Burning questions about Rituximab and ITP What is the mechanism of action? What is long term effect of treatment? What is the most appropriate regimen? Is the treatmente really safe? Can this treatment be administered before splenectomy? Has the TPO mimetic availability changed the role of rituximab?

16 Low dose rituximab and ITP Rationale: The B-cell total mass in ITP is much less than in patients with lymphoma, so a reduced dosage of Rituximab might still be sufficient in ITP First experience (28 pts) with 100 mg Rituximab i.v weekly, for 4 weeks: OR 75%, CR 43%, PR 32%. TFS 78% at 11 months And with more data... N patients 48 OR 29 (60.5%) CR (plt > 100 x 10 9 /L) 19 (39.5%) PR (plt > 50 x 10 9 /L) 10 (21%) NR 19 (39.5 %) Relapse rate 16/29 (55%) Zaja F et al, Haematologica 2008; 93:930 Relapse free survival (12 m) Relapse free survival (24 m) 61% 45% Median time of observation 18 m (3-49 m) Zaja F et al, Eur J Haemat 2010

17 Efficacy an safety ol low dose rituximab CR rate was in inverse relation with weight and age Relapse probability increases as weight and time from diagnosis increase. Low dose rituximab is active but has moderate long term effect Zaja F et al, Eur J Haemat 2010

18 Standard vs low dose rituximab Standard dose Low dose OR 73% 60% CR 54% 39.5% Median time response 7 days 35 days Sustained response 18/37 (49%) 13/48 (27%) With obvious limit of indirect comparison between different studies

19 Burning questions about Rituximab and ITP What is the mechanism of action? What is long term effect of treatment? What is the most appropriate regimen? Is the treatmente really safe? Can this treatment be administered before splenectomy? Has the TPO mimetic availability changed the role of rituximab?

20 Safety of Rituximab Arnold DM: 306 pts 21.6% mild or moderate AE (grade 1-2) ; 3.7% severe or life-threatening events (grade 3-4) 9 patients died (2.9%) Arnold DM et al, Ann Intern Med. 2007;146: Carson K: 57 confirmed cases of drugassociated PML (mortality rate 89%) [52 lynphoproliferative diseases 2 SLE, 1 AR, 1 ITP ] in HIV neg Carson K. Blood 2009 Cohen SB (311 pts with RA) 5.2% infections in RTX treated patients vs 3.7 % in control patients Cohen SB et al. Arthritis Rheum, 2006

21 Burning questions about Rituximab and ITP What is the mechanism of action? What is long term effect of treatment? What is the most appropriate regimen? Is the treatmente really safe? Can this treatment be administered before splenectomy? Has the TPO mimetic availability changed the role of rituximab?

22 Rituximab in splenectomy candidates Multicenter prospective, open label study to assess RTX safety and efficacy in adult splenectomy candidates with chronic ITP GR: > 50 x 10 9 /L IR: x 10 9 /L NR: < /L Godeau B et al, Blood 2008

23 Dexamethasone plus Rituximab vs Dexamethasone First randomized clinical trial to evaluate the efficacy of rituximab in previously untreated 103 pts with ITP Primary objective: Sustained Response (SR)= Plt> 50 x 10 9 /L at month 6 after treatment initiation Secondary objective: SR 100 and SR 150; adverse events, early response (<28 days), efficacy of salvage therapy DXM 40 mg, 4 days R Rescue treatment allowed < d 28 (IVIg, steroid) Salvage therapy if plt < 20x 10 9 DXM 40 mg, 4 days + Rituximab 375 mg/m 2 (7,14,21,28) Day 28 Month 6 Study interrupt: 81% vs 29%, Δ 52%, P.001, 98.3% CI, Zaja F et al, Blood 2010; 115

24 Dexamethasone plus Rituximab vs Dexamethasone Primary objective: to compare the rates of Sustained Response (SR) defined as Plt> 50 x 10 9 /L at 6 months Responders (%) DXM DXM + Rit p 19(36) 31(63).004 SR In previously monotherapy DXM non responders: 15/27 (56%) DXM DXM + Rit p DXM DXM + Rit p Responders (%) 17(33) 26(53).019 Responders (%) 13(25) 21(43).029 SR 100 SR 150 Zaja F et al, Blood 2010; 115

25 Dexamethasone plus Rituximab vs Dexamethasone The addition of rituximab to a single course of dexamethasone therapy improves outcomes in treatment-naive patients with ITP The dexamethasone-rituximab regimen was effective as salvage therapy (SR 56%) in the subgroup of patients who were refractory to dexamethasone monotherapy Patients in the experimental arm exhibited a greater incidence of grade 3 to 4 adverse event, not significant (6% vs 2%, P.284, 95% CI, to 0.119) Zaja F et al, Blood 2010; 115

26 Burning questions about Rituximab and ITP What is the mechanism of action? What is long term effect of treatment? What is the most appropriate regimen? Is the treatmente really safe? Can this treatment be administered before splenectomy? Has the TPO mimetic availability changed the role of rituximab?

27 Current/future therapeutic strategy for adult ITP management Oral PRDN DXM HD-MP IVIg Platelet < 30 x 10 9 /L and bleeding Splenectomy Rituximab Immunosoppression Diagnosis 6 months to 1 yr

28 Current/future therapeutic strategy for adult ITP management Oral PRDN DXM HD-MP IVIg Platelet < 30 x 10 9 /L and bleeding Splenectomy Rituximab Immunosoppression Rituximab Diagnosis 6 months to 1 yr TPO mimetics

29 ITP: a long way has been run until now... Harrington WJ et al. J Lab Clin Med 1951 Zucker-Franklin & Karpatkin S, N Engl J Med 1977

30 ..and now... ITP: new questions after recent answers?

31

32 Splenectomy: before of after rituximab Against splenectomy: Spontaneous remission can occur Unpredictable results Irreversible procedure Morbidity (surgery complication, thrombosis, infections) Role of new treatment Pros early splenectomy A century of history and experience Durable long term responses for most patients (63% overall response rate) Prediction of response (Ilabelled plt scan) Safety profile of procedure accettable Limited long term efficacy of rituximab Stasi R et al, Ann Hematol 2010

33 25 patients with chronic refractory ITP Treated if plt < 20 x 10 9 /L regardless of symptoms 2-5 prior treatment (8 had failed splenectomy) After 4 courses of Rituximab (375 mg/mq weekly) 5 CR (Plt > 100 x 10 9 /L) 5 PR (Plt x 10 9 /L) 3 minor response (Plt < 50 x 10 9 /L) Peak response up to 4 weeks of treatment 28% had responses lastings more than 6 months

34 Low dose rituximab and ITP Rationale: The B-cell total mass in ITP is much less than in patients with lymphoma, so a reduced dosage of Rituximab might still be sufficient in ITP 28 adult patients with ITP that had relapsed or were refractory at least to a full course of steroid therapy Treatment: fixed dose of 100 mg Rituximab i.v weekly, for 4 weeks Zaja F et al, Haematologica 2008; 93:930

35 Low dose rituximab and ITP Overall response 21/28 (75%) Complete Response 12/28 (43%) [plt>100 x 10 9 and discontinuation of steroid] Partial Response 9/28 (32%) [plt x 10 9 and discontinuation of steroid] [78% at 11 months] [64% at 11 months] TFS: treatment free survival RFS: relapse free survival Zaja F et al, Haematologica 2008; 93:930

36 ...and with more data... N patients 48 OR 29 (60.5%) CR 19 (39.5%) PR 10 (21%) NR 19 (39.5 %) Relapse rate 16/29 (55%) Relapse free survival (12 m) Relapse free survival (24 m) 61% 45% Median time of observation 18 m (3-49 m) Zaja F et al, Eur J Haemat 2010

37 Start point The monoclonal anti-cd20antibody is an efficacious therapy in patients with non- Hodgkin lymphoma. In idiopathic thrombocytopenic purpura (ITP) B cells produce auto-antibodies against platelet antigens (GPIIb/IIIa and /or GPIb-IX)

38 Repeated courses of rituximab: 3 different regimens 20 patients relapsed after standard dose RTX repeat standard dose 17 patients relapsed after standard dose RTX randomized to R+CVP or double dose RTX (DDR) 75% of previous treated showed similar response Neither R-CVP nor DDR induced responses in any patient who had previously failed to respond to rituximab, No substantially longer-lasting responses among previous responders Hasan A et al; Am J Hematol 2009