Expert Review: Updates in Immune Thrombocytopenia Reference Slides
Immune Thrombocytopenia (ITP): Overview ITP causality 1,2 Suboptimal platelet production Dysregulated adaptive immune system Increased clearance of platelets ITP defined 3 Primary: Undiscovered cause of thrombocytopenia, autoimmune destruction of platelets Secondary: Presence of an underlying disorder leading to the thrombocytopenia, frequently resolves with treatment of primary disorder/disease Refractory: Patients who have failed or relapsed after splenectomy as well as have severe ITP or risk of bleeding that requires therapy 1. Ballem PJ, et al. J Clin Invest. 1987;80(1):33-40. 2. McMillan R, et al. Blood. 2004;103(4):1364-1369. 3. Rodeghiero F, et al. Blood. 2009;113(11):2386-2393.
Chronic ITP (citp) 1-2 Diagnosis 3 month 12 month Newly diagnosed Persistent Chronic Spontaneous remission relatively common in children, lower rates in adults Risk of bleeding increases with age Increased risk of infection ITP patients in general higher Immunosuppressive agents Thrombopoietin receptor agonists 1. Rodeghiero F, et al. Blood. 2009;113(11):2386-2393. 2. Neunert C, et al. Blood. 2011;117(16):4190-4207.
Treatment Options for Adult ITP
Treatment Options for Frontline ITP in Adults Corticosteroids Intravenous immunoglobulin (IVIg) Anti-D (if Rh-positive)
Treatment Options for Unresponsive or Relapsed ITP in Adults Splenectomy Rituximab Other immunosuppressive drug regimens Thrombopoietin receptor agonists (TPO RAs) Eltrombopag Romiplostim
Treatment Options of Pediatric ITP
Treatment Options for Pediatric Frontline Symptomatic citp Corticosteroids Intravenous immunoglobulin (IVIg) Anti-D (if Rh-positive)
Treatment Options for Unresponsive or Relapsed ITP in Pediatrics Splenectomy Rituximab Other immunosuppressive drug regimens Thrombopoietin receptor agonists Eltrombopag Romiplostim
Thrombopoietin Receptor Agonists
Mechanism of Action Thrombopoietin affects viability of early progenitors of all lineages but affects the late maturation only of megakaryocytes. Thrombopoietin only stimulates production of platelets but not RBCs or WBCs Thrombopoietin receptor Inactive Active Eltrombopag Romiplostim Cell membrane Cytoplasm STAT Promotion of cell growth Signal transduction P P P JAK SHC P p42 or p44 GRB2 SOS MAPK RAS/RAF Potentiate maturation Antiapoptosis pathways Increased platelet production 1. Kuter DJ. Blood. 2007;109(11):4607-4616. 2. Imbach P, et al. N Engl J Med. 2011;365(8):734-741. 3. Kuter DJ. Int J Hematol. 2013;98(1):10-23.
TPO-RAs Clinical Trials in Adults With citp
TPO-RAs Clinical Trials in Adults With citp Eltrombopag 1,2 Romiplostim 3,4 277 patients ITP for >6 months Platelet count <30,000 Inadequate response or intolerant to at least one prior therapy Randomized to oral qd eltrombopag vs placebo ~40% had a splenectomy 54%-70% of patients had plt count >50,000 at any time during the treatment period Response similar among patients who had or had not received a splenectomy 317 patients ITP for 2 years Platelet count <30,000 Inadequate response or intolerant to at least one prior therapy Randomized to SQ weekly romiplostim vs placebo ~50% had a splenectomy 50%-70% of patients had plt count >50,000 at any time during the treatment period Response similar among patients who had or had not received a splenectomy Plt, platelet; qd, every day; SQ, subcutaneous 1. Eltrombopag. European Medical Association Website. www.ema.europa.eu/ema. Accessed December 2, 2015. 2. Promacta (eltrombopag) [package insert]. Research Triange Park, NC: GlaxoSmithKline; 2015. 3. Romiplostim. European Medical Association Website. www.ema.europa.eu/ema. Accessed December 2, 2015. 4. Nplate (romiplostim) [package insert]. Thousand Oaks, CA: Amgen Inc; 2014.
TPO-RAs Clinical Trials in Adults With citp Eltrombopag 1,2 Romiplostim 3,4 Most important serious adverse reactions are hepatotoxicity and thrombotic/thromboembolic events 1 Adverse events experienced by at least 5% more patients with citp on drug vs placebo include vomiting and nausea 2 Most important serious adverse reactions include thrombotic/ thromboembolic complications and progression of existing MDS to AML 3 Adverse events experienced by at least 5% more patients with citp on drug vs placebo include arthralgia, dizziness, insomnia, myalgia, pain, dyspepsia, and paresthesia 4 AML, acute myeloid leukemia; MDS, myelodysplastic syndrome 1. Eltrombopag. European Medical Association Website. www.ema.europa.eu/ema. Accessed December 2, 2015. 2. Promacta (eltrombopag) [package insert]. Research Triange Park, NC: GlaxoSmithKline; 2015. 3. Romiplostim. European Medical Association Website. www.ema.europa.eu/ema. Accessed December 2, 2015. 4. Nplate (romiplostim) [package insert]. Thousand Oaks, CA: Amgen Inc; 2014.
Reticulin Fibrosis in citp After TPO-RA Therapy Bone marrow fibrosis has been reported for both eltrombopag and romiplostim 1-6 Increase in reticulin in the bone marrow of some patients 1-8 Regression may occur with discontinuation 1,2,4 Bone marrow hypercellularity 7 1. Brynes R, et al. Am J Hematol. 2015;90(7):598-601. 2. Bussel JB, et al. Blood. 2009;113(10):2161-2171. 3. Ghanima W, et al. Haematologica. 2014;99(5):937-944. 4. Kuter DJ, et al. Blood. 2009;114(18):3748-3756. 5. Eltrombopag. European Medical Association Website. www.ema.europa.eu/ema. Accessed December 2, 2015. 6. Nplate (romiplostim) [package insert]. Thousand Oaks, CA: Amgen Inc; 2014. 7. Boiocchi L, et al. Mod Pathol. 2012;25(1):65-74. 8. Romiplostim. European Medical Association Website. www.ema.europa.eu/ema. Accessed December 2, 2015.
Switching Between TPO-RAs Multiple reasons why may be considered, including resistance, platelet fluctuations, treatment adverse event profile, patient preference TPO-RAs are not cross-resistant 1 Patients with ITP and inadequate responses to one TPO-RA 1-5 50%-80% of patients effectively impacted platelet count and resolved adverse events of first agent 2 1. D Arena G, et al. Blood. 2013;121(7):1240-1242. 2. Khellaf M, et al. Haematologica. 2013;98(6):881-887. 3. Tsukamoto S, et al. Br J Haematol. 2013;163(2):286-289. 4. Kuter DJ, et al. Int J Hematol. 2015;101(3):255-263. 5. González-Porras JR, et al. Br J Haematol. 2015;169:111-116. 6. Cantoni S, et al. Blood. 2015;126: Abstract 3462.
Thrombopoietin Receptor Agonist Clinical Trials in Pediatrics With citp
Clinical Trial of Eltrombopag in Pediatrics Key Eligibility Criteria Age 1 year to 17 years with a diagnosis of primary ITP (per IWG guidelines 1 ) for >12 months Relapsed or refractory disease after at least one therapy or ineligible for other ITP therapies Platelet counts 30 x 10 9 /L R (2:1) N = 92 Eltrombopag* (n = 63) Placebo (n = 29) Open-label Eltrombopag (n = 87) Stratification at randomization: Age group (1-5, 6-11, and 12-17 years) Study endpoints Primary: proportion of patients with platelet count of 50 x 10 9 /L in the absence of rescue medications for 6 weeks from weeks 5-12 of the double-blind period Secondary: maximum period of continuous platelet counts of 50 x 10 9 /L; use of rescue medications; bleeding; safety IWG, International Working Group *Patients in the cohorts of age 6-11 or 12-17 years of at least 27 kg started at 50 mg/day (25 mg/day for east Asian patients). Those weighing less than 27 kg started at 37.5 mg/day (25 mg/day for east Asian patients). Patients in the cohort of age 1-5 years started at 1.2 mg/kg/day (0.8 mg/kg/day for east Asian patients). Dose was adjusted to a maximum of 75 mg/day on basis of individual platelet counts. 1. Rodeghiero F, et al. Blood. 2009;113(11):2386-2393. Grainger JD, et al. Lancet. 2015;386(10004):1649-1658.
Clinical Trial of Eltrombopag in Pediatrics Double-blind period Open-label period Grainger JD, et al. Lancet. 2015;386(10004):1649-1658.
Clinical Trial of Romiplostim in Pediatrics Key Eligibility Criteria Age 1 year to <18 years with a diagnosis of primary ITP (per 1996 ASH guidelines 1 ) for 6 months Persistent disease after at least one therapy or ineligible for other ITP therapies Mean platelet counts 30 x 10 9 /L (mean of two measurements during screening) with no count >35 x 10 9 /L R (2:1) N = 62 Romiplostim* (n = 42) Placebo (n = 20) Stratification at randomization: Age group Study endpoints Primary: Proportion of patients with 6 weekly platelet count of 50 x 10 9 /L (excluding 4 weeks after rescue medication) during the final 8 weeks Secondary: Proportion of patients with 4 weekly platelet count of 50 x 10 9 /L (excluding 4 weeks after rescue medication) during weeks 2 to 25; use of rescue medications; bleeding; safety ASH, American Society of Hematology. *Dose adjusted weekly from 1-10 µg/kg to target platelet counts of 50-200 x 10 9 /L 1. George JN, et al. Blood. 1996;88(1):3-40. Tarantino MD, et al. Blood. 2015;126: Abstract 7.
Platelet Response Rates Over Time Patients With a Response, % 100 80 60 40 20 Romiplostim (n = 42) Placebo (n = 20) 0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Weeks Romiplostim 42 33 32 34 34 33 33 Placebo 20 14 11 13 12 13 12 Tarantino MD, et al. Blood. 2015;126: Abstract 7.
% TPO-RA Adverse Events Eltrombopag 1 n = 63 Placebo 1 n = 29 *One patient randomized to placebo withdrew consent before receiving investigational product, hence n =19 (not 20) 20% in romiplostim group or 6% in eltrombopag group. Romiplostim 2 n = 42 Placebo 2 n = 19* Most common Headache 10 10 43 58 non-bleeding Upper respiratory tract 11 3 38 26 infection Cough 11 0 Oropharyngeal pain 26 5 Nasopharyngitis 17 7 Rhinitis 16 7 Vomiting 3 10 26 21 Diarrhea 24 16 Nausea 21 37 Abdominal pain 10 0 Pyrexia 6 3 21 11 All bleeding 71 69 83 74 Epistaxis 13 21 48 53 Serious AEs 8 14 24 5 1. Grainger JD, et al. Lancet. 2015;386(10004):1649-1658. 2. Tarantino MD, et al. Blood. 2015;126: Abstract 7.
Serious Adverse Events With Eltrombopag % Grainger JD, et al. Lancet. 2015;386(10004):1649-1658. Eltrombopag n = 63 Placebo n = 29 Any serious adverse event 8 14 Gingivitis 2 0 Influenza 2 0 Aseptic meningitis 2 0 Pneumonia 2 0 Fungal pneumonia 2 0 Abnormal ALT* 2 0 Abnormal AST* 2 0 Epistaxis 0 3 Petechia 0 3 Hemorrhage 0 3 Hypertensive crisis 0 3 *Deemed treatment related ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Serious Adverse Events With Romiplostim Patient Serious adverse event Background 1 2 Epistaxis Nephrotic syndrome Confusion Headache Nausea Vomiting *Deemed treatment related One placebo-treated patient reported SAEs of animal bite and hematuria Tarantino MD, et al. Blood. 2015;126: Abstract 7. Patient discovered to have MYH9-related disease, so ineligible for study Deemed likely secondary to IVIg, resolved the next day without treatment 3 Bronchitis Resolved with steroid, salbutamol, and amoxicillin 4 Fever History of fever, not taking antibiotics for asplenia, resolved with ceftriaxone 5 Urinary tract infection Resolved with ceftriaxone 6 Headache* Thrombocytosis* Headache resolved with aspirin, no SAEs after rechallenge with romiplostim 7 Epistaxis Resolved with IVIg 8 Confusion After trauma 9 Petit mal epilepsy History of seizures, receiving clobazam 10 Petechiae Resolved with IVIg
Conclusions
Unmet Needs in citp Treatment Optimal management of platelet fluctuations during treatment Risk and minimization of risk for thrombotic events
Conclusions Initial therapy for pediatric and adult patients is the same, corticosteroids ± IVIg, possibly with anti-d in Rh+ patients Indicators for initial treatment Pediatrics only with symptomatic mucosal bleeding Adults patient-specific, the decision involves age, bleeding risk, and comorbidities Second-line therapy for relapsed citp includes splenectomy, rituximab, TPO-receptor agonists, along with other options Physicians need to be aware of the approved indications for the TPO-receptor agonists, differences in clinical trials, and treatment strategies for pediatric and adult populations
Immune thrombocytopenia (ITP) is a diagnosis of exclusion, if isolated (ie, no underlying disease is able to be identified), defined as primary ITP Primary ITP is defined as chronic when present for more than 12 months Treatment decision for asymptomatic adults is made at platelet levels between 20,000-30,000 in order to decrease the risk of bleeding, while in children, treatment is only given to patients with active mucosal bleeding Patients with ITP have an elevation of thrombotic events, unclear is the role, if any, of thrombopoietin receptor agonists Dosing of thrombopoietin receptor agonists is higher per body weight in children (versus adults)