Second line therapy for ITP should be TPO agonists. Nichola Cooper Imperial Health Care NHS Trust

Transcription

1 Second line therapy for ITP should be TPO agonists Nichola Cooper Imperial Health Care NHS Trust COHEM 2012

2 Antiplatelet antibodies Platelet count after infusion with patient plasma Hours Days T cells expand in response to own platelets CD4 IL-2 IFN-γ IL-15 Active Disease (Th1) Cytotoxic T cells against platelets IL-4 IL-10 TGF-β Remission (Th2/3)

3 Steroids: infections, diabetes, HT, osteoporosis, psychosis B cell depletion: 50% RR, infections PML (?), hypogamma (?) Splenectomy; Sepsis, pulmonary hypertension Immunoglobulins (IVIG and Anti-D): short term, expensive? IVH Megakaryocyte stimulation:??? Immunosuppression: low response rates, infections

4 Majority of patients treated with rituximab will relapse Duration of response to rituximab in 20 splenectomized and 24 nonsplenectomized patients with chronic ITP with response > 1 year 9 Percentage ofpatients responding to rituximab over 1 year (platelet counts > 30 x 10 /l) Nonsplenectomized 66.6% Splenectomized 60.0% Year 3 Year Weeks from initial rituximab infusion

5 Immunoglobulins fall after repeated rituximab in some patients with ITP Rituximab IVIG replacement therapy Immunoglobullins following B cell depletion for ITP IgA g/l, IgM g/l, IgG g/dl IgG IgA IgM monthly intervals January 02 January 03 January 04 January 05 January 06 January 07 January 08

6 Abnormal T cells in patients who don t respond to rituximab Number of abnormal CDR3 size patterns and response to rituximab Number of abnromal CDR3 size patterns Pre-treatment Post treatment Increased numbers of abnormal CDR3 patterns in those with longer duration of ITP Stasi Blood 2007

7 Morbidity/mortality ITP Majority of patients are asymptomatic despite low platelet counts Increased mortality only in patients with persistently low platelet counts Morbidity and mortality as much from complications of immunosuppressive treatment as from bleeding 1 Portejle et al 2000, 2 Cohen et al 2002

8 Platelet kinetics before and after prednisone treatment or splenectomy: decreased platelet turnover in ITP Platelet count (/L) Recovery (%) Survival (days) Production (platelets/l/d) Normal 256 x 10 9 ± 44 x ± ± x 10 9 ± 5 x 10 9 Prednisone Baseline 36 x 10 9 ± 12 x ± ± x l0 9 ± 17 x l0 9 Posttreatment 111 x 10 9 ± 42 x ± ± x 10 9 ± 19 x 10 9 Splenectomy (successful) Baseline 123 x 10 9 ± 61 x ± ± x 10 9 ± 36 x 10 9 Posttreatment 458 x 10 9 ± 186 x ± ± x 10 9 ± 19x 10 9 Data are means ± SD. 8 Adapted from Gernsheimer et al. N Eng J Med 1989;320:

9 Suppression of megakaryocyte production by ITP plasma Reproduced from McMillan. Blood 2004;103: , with permission from Springer

10 Inadequate platelet production in ITP Spleen, B and T-cells involved in the destruction of platelets

11 Stimulation with TPO TPO agonist Spleen, B and T-cells still involved in the destruction of platelets, TPO agonists over-produce platelets and overwhelm the destruction

12 Eltrombopag: RCT platelet responses Median platelet count Eltrombopag Placebo % patients responding to treatment Median platelet count Cheng Lancet 2010

13 Overall platelet response romiplostin Kuter Lancet 08

14 Patients receiving rescue medication: romiplostin Kuter Lancet 08

15 Mean platelet count: romiplostin Kuter Lancet 08

16 Eltrombopag reduced the incidence and severity of bleeding (RAISE) 76% reduction in the odds of any bleeding (P <0.001) 65% reduction in the odds of clinically significant bleeding (P<0.001) Cheng Lancet 2010

17 Quality of life changes with Eltrombopag Cheng Lancet 2010

18 Long term remissions after cessation of TPO agonists Eltrombopag 14 or 299 patients (5%) prolonged remissions off treatment 5 post splenectomy 9 to 128 months of ITP Median treatment with eltrombopag 160 days Romiplostim 4 patients off treatment remission 6 to 49 years of ITP

19 Immune induction by increasing the platelet count? Bao et al Blood 2010

20 Side effects Increased reticulin: 8 of 142 from romiplostin open-label (mean 69 weeks) - reversible Thrombosis: (occurred in treatment and placebo arms) Cataracts in animal studies: eltrombopag Increased LFTs: eltrombopag reversible Rebound thrombocytopenia (both) on stopping Stem cell proliferation: no evidence TPO receptors on other cells: no evidence

21 Who should we be treating? Morbidity and mortality as much from infections (complications of treatment) as from bleeding 1 Morbidity increases with persistently low platelet counts 2 Who gets an intracranial haemorrhage? Mucosal bleeding: mouth, nose, haematuria (?) 1 Portejle et al 2000, 2 Cohen et al 2002

22 Use of TPO agents Limitations: Cost (NICE decision awaited) May depend on the length of time required for agent. As most patients are asymptomatic despite thrombocytopenia, only a minority of patients will require therapy Will there be any long term toxicity with continuous bone marrow stimulation? (no evidence so far)

23 Risk analysis in treating ITP! Low platelet count: Intracranial haemorrhage? Infections? Fatigue? Poor wound healing Treatment: Infections PML Osteoporosis Diabetes Blood born infections Thrombosis?? Stem cell effects?