Management of itp

recent advances in management of ITP

1. ADVANCES IN MANAGEMENT OF ITP Dr. M SAITEJ REDDY GANDHI MEDICAL COLLEGE SECUNDERABAD

2. ITP – AT A GLANCE Primary immune thrombocytopenia (ITP, also called idiopathic thrombocytopenic purpura , immune thrombocytopenic purpura ) is an acquired thrombocytopenia caused by autoantibodies against platelet antigens.

3. TERMINOLOGY International working group on ITP published in 2009 Primary ITP   –is acquired ITP due to autoimmune mechanisms leading to platelet destruction and platelet underproduction that is not triggered by an associated condition. Secondary ITP   –is ITP associated with another condition ( eg , HIV, HCV, SLE, chronic lymphocytic leukemia [CLL]). Drug-induced immune thrombocytopenia  – Drug-induced immune thrombocytopenia (DITP) is thrombocytopenia due to drug-dependent platelet antibodies that cause platelet destruction.

4. Newly diagnosed  – Up to 3 months since diagnosis Persistent  – 3 to 12 months since diagnosis Chronic  –>12 months since diagnosis Severe ITP  – Severe ITP refers to ITP with bleeding symptoms sufficient to require treatment, this typically occurs when platelet counts are below 20,000/ microL . Refractory ITP  – Refractory ITP refers to ITP that has failed to respond to (or relapsed after) splenectomy and is severe ( ie , associated with bleeding or bleeding risk that requires therapy).

5. PATHOGENESIS   The pathogenesis of ITP is incompletely understood. Reduced platelet lifespan due to antibody-mediated destruction is the predominant hypothesis Other mechanisms are likely important, including autoreactive cytotoxic T cells, as well as humoral and cellular autoimmunity directed at megakaryocytes, causing impaired platelet production. The principal mechanism is thought to involve specific immunoglobulin G (IgG) autoantibodies produced by the patient's B cells, most often directed against platelet membrane glycoproteins such as  GPIIb / IIIa .

6. Clearance of Antibody-Coated Platelets by Phagocyte Fcγ Receptors

7. Initial Diagnostic Evaluation of ITP in Adults . Basic Initial Evaluation  Patient history  Blood group (Rh)  Family history  Direct antiglobulin test  Physical examination  Helicobacter pylori  Complete blood count  HIV  Reticulocyte count  HCV  Peripheral blood film  Bone marrow (in select patients) Assays of Potential Value Platelet glycoprotein-specific antibodies Antiphospholipid antibodies (including anticardiolipin and lupus anticoagulant) Antithyroid antibodies and thyroid function Pregnancy test in women of childbearing potential Antinuclear antibodies Viral PCR for parvovirus and CMV Assays of Unproven Benefit Thrombopoietin Reticulated platelets Platelet-associated immunoglobulins Platelet survival studies Bleeding time Serum complement

8. Clinical Situation Therapy Options First line (initial treatment for newly diagnosed ITP) Corticosteroids: dexamethasone , methylprednisolone , prednis ( ol )one Anti D IVIg Azathioprine Cyclosporin A Cyclophosphamide Danazol Second line Dapsone My cophenolate mofetil Rituximab Splenectomy TPO receptor agonists (romiplostim and eltrombopag) Vinca alkaloids Treatment for patients failing first- and second-line therapies Category A*: TPO receptor agonists Category B † : campath-1 H, combination of first- and second- line therapies, combination chemotherapy, HSCT * Category A: treatment options with sufficient data Category B: treatment options with minimal data and considered to have potential for considerable toxicity

9.   1A, 1B, 1C, 2A, 2B, 2C Number: strength of recommendation   1-we recommend..  2- we suggest.. Alphabetical: quality of evidence  A- RCTs or exceptionally strong observation studies  B- RCTs with limitation or strong observation studies  C-RCTs with serious flaws , weaker observations or indirect evidence Blood. 2011;117(16):4190-4207

10.  S u gg e s t  Treat newly diagnosed patients with platelet count < 30 ,000/cu.mm (2C )  Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment (2B)  IVIG combined with steroid if more rapid increase in platelet count desired(2B)  IVI g or anti-D as first line if steroid contraindicated(2C)  IVI g dose : 1g/Kg as one-time dose, repeated higher doses if necessary ( 2B )

11.  Recommend   TPO agonists for risk of bleeding who relapse after splenectomy or who have contraindication to splenectomy or failing at least one other therapy (1B) Suggest  TPO for risk of bleeding who failed one line of therapy ( steroid or IVIG ) and had no splenectomy (2C)  Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy) (2C)

12. Dexamethasone is a corticosteroid that has an anti-inflammatory effect that is >6 times more potent than prednisone with a longer halflife (36–72 h compared with 12–36 h). We aimed to evaluate the long-term efficacy and safety of high-dose corticosteroids as an initial treatment for adults or children

13. Methods We searched MEDLINE, Embase , Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Library Database for papers published from 1970 to July 2016 , and abstracts from American Society of Hematology annual meetings published from 2004 to 2015 for randomised trials comparing different corticosteroid regimens for patients with previously untreated immune thrombocytopenia who achieved a platelet count response. The primary endpoint was overall (platelets >30 × 10⁹/L) and complete (platelets >100 × 10⁹/L) platelet count response at 6 months with high-dose dexamethasone compared with standard-dose prednisone.

14. Results 9RCTs(n=1138) were included. Of those, 5 (n=533) compared one to three cycles of dexamethasone (40 mg per day for 4 days) with prednisone (1 mg per kg) for 14–28 days followed by dose tapering in adults. We found no difference in overall platelet count response at 6 months (pooled proportions 54% vs 43%, relative risk [RR] 1.16, 95% CI 0.79–1.71; p=0.44). At 14 days , overall platelet count response was higher with dexamethasone (79% vs 59%, RR 1.22, 95% CI 1.00–1.49; p=0.048). The dexamethasone group had fewer reported toxicities. Long-term response rates were similar when the data were analysed by cumulative corticosteroid dose over the course of treatment.

15. In summary, we found that durable platelet count responses were not different with high-dose dexamethasone or standard-dose prednisone in adults with previously untreated immune thrombocytopenia. High-dose dexamethasone was associated with improved platelet count responses by 14 days in adults, fewer bleeding events, and less toxicity than prednisone over the course of treatment. Another advantage is that the regimen is short , lasting only 4 days, as opposed to prednisone, which is often continued as a protracted course of therapy resulting in high corticosteroid exposures.

16. High-dose dexamethasone might be preferred over prednisone for patients with severe immune thrombocytopenia who require a rapid rise in platelet count ( eg , for severe bleeding) in conjunction with other treatments that work even faster such as intravenous immunoglobulin.

17. Intravenous Anti-Rh(D)  Creates RBC hemolysis and Fcγ receptor blockade Initial dose: 50 µg/kg IV over 2- 5 minutes    – Reduce if Hgb < 10 g/dL > 70% responders; duration > 21 days in 50% All patients drop Hgb (0.8 g/dL) Recommended only for Rh- positive pts with no history of splenectomy      Patients should be closely monitored in a health care setting for at least 8 hrs after administration Dipstick urinalysis should be performed at baseline, 2 hrs, 4 hrs post administration and prior to end of monitoring period Rare but severe AE: intravascular hemolysis and disseminated intravascular coagulation Severe DIC in 1 in 20,232 infusions FDA Black Box Warning

18. Corticosteroids are the mainstay of therapy and though 60–70 % of patients show an initial response to corticosteroids, majority of responders relapse leading to a sustained response in only 15– 40 %. Thus needs second line drugs Eltrombopag is a small-molecule, oral, nonpeptide , thrombopoietinreceptor -agonist (TPO-RA) widely approved for treatment of patients with chronic ITP who are older than 1 year. Eltrombopag increases platelet production by binding to the transmembrane domain of the TPO-R and activating proliferation of megakaryocytes from bone marrow progenitors.

19. AIM: to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period.

20. Study done between Nov 2006 and July 2007, from 75 sites in 23 countries. double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months’ duration who had baseline platelet counts lower than 30 000 per μL . Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months.

21. Patients were assessed for response to treatment (defined as a platelet count of 50 000–400 000 per μL ) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo .

22. Interpretation On the basis of these findings, eltrombopag seems to be beneficial for patients who have refractory immune thrombocytopenia, who have not responded to splenectomy , or who have had temporary or negligible responses to treatments such as corticosteroids, immunoglobulins , or rituximab and continue to have bleeding symptoms. Less effective in splenectomised patients than in non-splenectomised patients

23. EXTEND ( Eltrombopag EXTENded Dosing) was a phase 3, openlabel , long-term extension study of the safety, tolerability, and efficacy of eltrombopag in patients with ITP of at least 6 to 12months’ duration who had completed a previous eltrombopag study.

24. EXTEND: STUDY DESIGN 1. Eltrombopag initiated at 50 mg OD adjusted to keep plt. ≥ 50,000/µL Reduce concomitant ITP medications, keep plt. ≥ 50,000/µL Identify the minimal dose to maintain plt. ≥ 50,000/µL (25-75 mg OD or less frequently) ± minimal concomitant medication Evaluate safety and efficacy of long-term dosing ± minimal concomitant medication

25. For the 302 patients enrolled, median duration of eltrombopag treatment was 2.37 years (2 days-8.76 years). Median platelet counts increased to 50,000 or more by week 2 and were sustained throughout the treatment period. Overall, 259 patients (85.8%) achieved a response (platelet count ‡50,000L at least once), and 133 (52%) of 257 patients achieved a continuous response of 25 weeks or longer. Responses in patients with platelet counts lower than 15,000, more previous therapies, splenectomy were somewhat lower.

26. Thirty-four (34%) of 101 patients receiving concomitant ITP medication discontinued 1 or more medication. In patients with assessments, bleeding symptoms decreased from 57% at baseline to 16% at 1 year.

27. Forty-one patients (14%) withdrew because of adverse events. Hepatobiliary adverse events (n 57), cataracts (n 54), deep vein thrombosis (n 53), cerebral infarction (n 52), headache (n 5 2), and myelofibrosis (n 5 2) occurred in more than 1 patient; the remaining adverse events occurred only once. Rates of thromboembolic events (6%) and hepatobiliary adverse events (15%) did not increase with treatment duration past 1 year.

28. Median platelets during EXTEND Efficacy end points n = 299 Platelet count ≥ 50,000/µL at least once Splenectomized Nonsplenectomized Baseline plt. < 30,000/µL 85% 80% 88% 80% Median no. of cumulative wk with plt. ≥ 50,000/µL 44

29. CONCLUSION Eltrombopag increased platelet counts in most patients with ITP in a consistent fashion to adequate levels, was well-tolerated, and appeared safe, with a low frequency of Severe adverse effects and BM fibrosis. It was effective in essentially all patient subgroups, although less effective in splenectomized and heavily pretreated patients and in those with very low baseline platelet counts.

30. AIM To assess the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP.

31. Methods In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with platelet counts <30,000 were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks . The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count ≥50×10⁹/L during 6 or more of the last 8 weeks of treatment) and treatment safety .

32. The starting dose of study drug ( romiplostim or placebo) was 1 μg /kg. To achieve the target platelet count of 50,000 to 2 lakhs , doses could be increased according to the following algorithm: 2 μg /kg every week if the count was 10,000 or less and 2 μg /kg every 2 weeks if 11,000 to 50,000. Once platelets reached more than 50×10⁹/L, the maintenance algorithm was used: dose was increased by 1 μg /kg every week if 10×10⁹/L or less; increased by 1 μg /kg after 2 weeks if 11×10⁹/L to 50×10⁹/L; reduced by 1 μg /kg after 2 consecutive weeks at 201×10⁹/L to 400×10⁹/L; withheld if more than 400×10⁹/L and subsequent doses reduced by 1 μg /kg and given after count was less than 200×10⁹/L. The maximum allowed dose was 15 μg /kg.

33. Findings A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4–52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo ( 56% [38.7–73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001).

34. Interpretation Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

35. lancet

36. Background Despite the absence of supporting evidence, rituximab is frequently used off -label in patients with immune thrombocytopenia. We aimed to assess the efficacy of rituximab as compared with placebo as a splenectomy -sparing treatment in patients who were previously treated with corticosteroids.

37. Multicenter, randomized, double-blinded, placebo-controlled trial Inclusion criteria: corticosteroid unresponsive primary ITP pts with plt < 30,000/µL Primary outcome: rate of treatment failure within 78 weeks Splenectomy or meeting criteria for splenectomy after week 12 Secondary outcome: response rate, relapse rate and duration of response study period - Aug 2006 and June 30 2011

38. STUDY DESIGN 1:1 randomization to receive rituximab or placebo in a double-blinded fashion Treatment: 4 weekly infusion of rituximab 375 mg/m 2 or placebo Corticosteroid use with dose tapering to keep plt count >20,000/µL was allowed Follow up visit q 6 wks during the study for 78 wks or for 12 wks after splenectomy Lancet 2015;385:1653-1661

39. Rituximab Placebo p value (n=55) (n=54) Treatment failure 32 (58%) 37 (68%) 0.65 Splenectomy 8 (15%) 14 (26%) 0.12 Overall response 40 (73%) 36 (67%) 0.15 Loss of overall response 27 (68%) 28 (78%) 0.01 Median duration of OR, wk 36 (13-not reached) 7 (5-69) 0.01 Complete response 28 (51%) 21 (39%) 0.12 Loss of complete response 14 (50%) 13 (62%) 0.19 Median duration of CR,wk 76 (32-not reached) 49 (20-95) 0.19 Bleeding 21 (38%) 27 (50%) 0.08 Infection 22 (40%) 13 (24%) 0.09 RESULTS Lancet 2015;385:1653-1661

40. RITP STUDY: SUMMARY First double-blinded, placebo-controlled study to assess the long-term efficacy (78 weeks) of rituximab as second-line treatment in ITP Rituximab does not significantly reduce the rate of long-term treatment failure compare with placebo A small benefit of rituximab cannot be ruled out  A longer duration of response and higher response rate was observed in the rituximab group

41. Patients and methods This was a retrospective analysis of all patients with ITP with platelet counts <50,000, treated at our center with dapsone between June 1996 and July 2002.

42. Dapsone was used at a dose of 1–2 mg/kg/d for at least 3 months. Response to treatment with dapsone was classified as partial response (PR) if the increase in the platelet count was between 50,000 to 1lakh and complete response (CR) if the increase in the platelet count was >1 lakh No response (NR) was defined as a platelet count remaining below 50,000 Continuous CR (CCR) was defined as CR maintained for >6 months with or without dapsone therapy.

43. The only factor, which had an influence on the response rate, was the platelet count prior to therapy, which was higher in the CR group when compared with the group with no response. The duration of symptoms prior to therapy did not affect the response.

44. Summary Present data show that dapsone provides an inexpensive and well tolerated therapy for chronic ITP that is effective in both children and adults, who have had an inadequate response to steroids or other immunosuppressive therapy. The high response rates with low adverse effects raises the possibility of its use as second-line therapy in patients who are steroid-refractory or -dependent. Further studies are needed to determine the optimal duration of treatment as also a randomized comparison with other drugs that are used in the treatment of ITP.

45. Results 106 ( 79% ) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 ( 28% ) patients in the placebo group. 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0.016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0.001).

46. Hematological journal 2013

47. The treatment of choice in steroid-resistant immune thrombocytopenia is still controversial due to the recent advent of new drugs (anti-CD20 antibodies and thrombopoietin mimetics ) that have encouraged a generalized tendency to delay splenectomy . Consequently, it is extremely importance to define the efficacy and safety of splenectomy in the long term.

48. Study design This was a retrospective, multicenter study that analyzed the outcome of 233 consecutive ITP patients who underwent open splenectomy between 1959 and 2001 in six European Hematology Centers and who were observed for a minimum of ten years.

49. Resuts Of the 233 patients, 180 (77%) achieved a complete response and 26 (11%) a response. Sixty-eight of 206 (33%) responsive patients relapsed, mostly (75%) within four years from first response. In 92 patients (39.5%), further treatment was required after splenectomy that was effective in 76 cases (83%). In 138 patients (59%), response was maintained free of any treatment at last contact. No significant association between baseline characteristics and likelihood of stable response was found.

50. A stable response to splenectomy was associated with a lower rate of infections ( P=0.004) and hemorrhages (P<0.0001). Splenectomy achieved a long-term stable response in approximately 60% of cases.

51. Although studies comparing splenectomy and medical treatments second-line are lacking, our retrospective data indicate that splenectomy should be still considered the therapeutic treatment of choice with the higher curative potential in eligible patients with chronic disease.

52. The purpose of this research is to study the outcomes of splenectomy for chronic and persistent immune thrombocytopenia (ITP). This study is a retrospective analysis of 254 patients with chronic or persistent ITP who underwent splenectomy at CMC, Vellore, India between 1995 and 2009.

53. 167adults and 87 children with a median age of 29 years (range 2–64) with persistent (n = 103) or chronic ITP (n = 151) was studied. Response was seen in 229 (90.2 %) including CR in 74.4 % at a median time of 1 day (range 1– 54). Infections following splenectomy were reported in 16 %. Deaths related to post splenectomy sepsis occurred in 1.57 % and major bleeding in 0.78 %.

54. Splenectomy is an effective treatment modality for patients with chronic ITP, who have failed to achieve durable remissions with steroid therapy or who are steroid dependent. Female sex, steroid sensitivity and higher platelet count at splenectomy are factors that predict response to splenectomy . Splenectomy is associated with low morbidity and mortality, and a significant proportion of patients undergoing splenectomy for chronic and persistent ITP achieve long-term control of their disease

55. SECOND-LINE TREATMENT OF ADULT ITP Treatment Dose Time to initial response Time to peak response Rituximab 375 mg/m 2 /dose iv (4 weekly dose) 7-56 d 14-180 d Splenectomy 1-56 d 7-56 d Vincristine Up to 2 mg/dose iv (4-6 weekly doses) 7-14 d 7-42 d Vinblastine 0.1 mg/kg/dose iv (6 weekly doses) 7-14 d 7-42 d Danazol 400-800 mg po OD 14-90 d 28-180 d Azathioprine 2 mg/kg po OD 30-90 d 30-180 d Romiplostim 3-10 µg/kg weekly SC 5-14 d 14-60 d Eltrombopag 25-75 mg po OD 7-28 d 14-90 d

56. Splenectomy Rituximab TPO-RA Efficacy High cure rate, Long- Initial response Maintenance treatment term response 60%- 70% at 5-10 y 50%-60%, sustained response 20% at 3-5 y response rate 60%-80% Safety Surgery related morbidty, infection Infusion-related side effects, neutropenia, viral reactivation, serum sickness BM reticulin fibrosis, thrombosis, rebound thrombocytopenia Contraindication Unfit for surgery, Immun o d e fici e nc y , Active hepatitis B, allergy e.g. Serum sickness Pregnancy, lactation secondary ITP ASH 2011 recommendation 1B after failure of S teroids Recommended for adults who have failed corticosteroid therapy, with similar efficacy with open or laparoscopic procedures. 2C after failure of steroids May be considered for adults at risk of bleeding who have failed one line of therapy such as corticosteroids, IVIg , or splenectomy . 1B after failure of S teroids Recommended for adults at risk of bleeding who relapse after splenectomy or who have a contraindication to splenectomy and who have failed at least one other therapy.

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