Primary immune thrombocytopenia (ITP) is an acquired immune-mediated disorder characterized by isolated thrombocytopenia, defined as a peripheral blood platelet count less than 100 x 109/L in the absence of other underlying causes2. The incidence ranges from 1-5 per 100,000 adults, but prevalence is higher due to the chronic nature of the disorder3,4. International consensus classifies ITP by duration into newly diagnosed (<3 months), persistent (3-12 months duration), and chronic (≥ 12 months duration)1 .
ITP can occur in both the pediatric and adult populations. In children, the disease typically acute following a viral illness and is usually self-limited remitting spontaneously within six months with about 15% developing chronic ITP 5. In adults, ITP is extremely heterogeneous, ranging from asymptomatic to severe bleeding. For most adults, the morbidity and mortality related to ITP are low and severe bleeding is rare5. Risk of serious bleeding is increased when platelet counts are less than 30 x 109/L, platelets remain persistently low, increasing age, medical comorbidities, and failure to respond to treatment 5 6,7. In the subset of patients at high risk for life-threatening bleeding, the goal of therapy is the prevention of severe bleeding including potentially life-threatening bleeding such as intracranial hemorrhage, gastrointestinal bleeding, or skin and mucosal hemorrhage. Patients with persistent severe thrombocytopenia that does not respond to therapy within the first two years have considerable morbidity and a 6-fold increase in mortality8.
Various terminologies have been used in the literature on ITP, which has made it more difficult to compare studies as definitions are variable. International consensus defined the following: Severe ITP is defined as the presence of bleeding symptoms or occurrence of new bleeding symptoms requiring additional therapeutic intervention usually with platelet counts < 20 x 109/L1,2. A response is defined as platelet count ≥30 x109/L but ≤100 x 109/L1 and at least doubling of the baseline platelet count and a complete response defined as platelet count >100 x 109/L1. Lack of response is defined as platelet count <30 x109/L or less than 2-fold increase in baseline platelets and loss of response is defined as platelet count <30 x109/L or less than 2-fold increase in baseline platelets following a response 1.
The goal of treatment is to prevent severe bleeding, but the risk of bleeding can be difficult to estimate. Individual considerations, including risk factors and lifestyle, must be considered. Treatment is rarely indicated in patients with platelet counts above 30 x 10/9L and should be based on symptoms and signs rather than arbitrary platelet threshold2,9. The balance between the risk of bleeding and treatment itself must be considered as overall morbidity and mortality may be increased with treatment 8. Treatment is not medically necessary in children with no bleeding or mild bleeding (skin manifestations only such as bruising and petechiae) regardless of platelet count (grade 1B) or adults with platelet count ≥ 30 x109/L in the absence of bleeding (grade 2C)10. Treatment is clearly indicated in the setting of severe ITP (bleeding) and in preparation for procedures or surgery with risk of bleeding and may also be indicated in an adult with platelets count ≤30 x109/L (grade 2C) especially if risk factors for bleeding are present. Predisposing comorbidities such as uncontrolled hypertension, active peptic ulcer disease, anticoagulation, recent surgery or head trauma or lifestyle risk factors may increase the risk of bleeding10,11.
Corticosteroids are the standard first-line treatment when treatment is required and consistent with society guidelines (grade 1B)2,10. They are inexpensive, easy to administer, and raise platelet counts within 2-5 days in approximately 75% of patients. Effectiveness has been demonstrated in multiple randomized control trails indicating approximately two-thirds of adults with newly diagnosed ITP maintain a response at six months, but relapse occurs in 60-70% beyond 1-2 years 9,12. Long term used is limited by corticosteroid side effects13.
Intravenous immune globulin (IVIg) has been demonstrated to be effective in controlled trails with an initial response in 24-48 hours and duration of 2-6 weeks14. Side effects are typically mild, but rare adverse reactions can occur. A meta-analysis comparing treatment with corticosteroids and IVIg with the primary outcome of platelet count >20 x 10/9L at 48 hours in children showed that 26% fewer children achieved this outcome who received steroids as compared to IVIg without significant differences in clinical outcomes15. IVIg may be used as first-line therapy when corticosteroids are contraindicated or not tolerated (Grade 2C) or in combination with corticosteroids when a more rapid increase in platelets is required (Grade 2B) such as serious bleeding 10.
Intravenous anti-D is an alternative to conventional IVIg suitable for those who are Rh(D) positive and have not undergone splenectomy and is approximately 80% effective5. Anti-D has been shown to induce a longer response time than IVIg and may also reduce the need for splenectomy5,16. Risks include hemolysis (15%) and is contraindicated in those with a history of autoimmune hemolytic anemia. There is an FDA black box warning against the use of in children due to the risk of severe hemolysis.
Second line therapies are indicated in chronic and severe ITP when a patient fails to respond to first-line therapy. 2011 International Consensus Report ranked existing second-line therapies in alphabetical order due to insufficient date to rank in order of efficiacy5,13. There are no randomized controlled comparative studies or systematic review of the available data, and a lack of sufficiently large numbers to make definitive recommendations5,17,18. Another challenge in the literature is the primary endpoint studies is usually platelet response, but how that translates into clinical outcomes is unclear. According to a 2019 International Consensus Report no study has addressed the correct sequence of subsequent therapies; and panel recommendations are consensus-based.19The American Hematology Association (AHA) 2019 Guidelines for ITP recommends “In adults with ITP lasting 3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests either splenectomy or a TPO-RA (conditional recommendation based on very low certainty in the evidence of effects)”20. Additionally, the AHA guidelines recommends rituximab over splenectomy, and TPO-RA over rituximab both conditional recommendations based on very low certainly evidence20. NEJM review paper summarizes “there were weak recommendations for the use of rituximab and thrombopoietin-receptor agonists before splenectomy”21. AHA encourages patient education and shared decision-making. The 2019 guidelines state “If possible, splenectomy should be delayed for at least 1 year after diagnosis because of the potential for spontaneous remission in the first year. Patients who value avoidance of long-term medication may prefer splenectomy or rituximab. Patients who wish to avoid surgery may prefer a TPO-RA or rituximab. Patients who place a high value on achieving a durable response may prefer splenectomy or TPO-RAs.”20
Splenectomy has a long history in the treatment of chronic ITP, rates of splenectomy have declined as alternative second-line treatments have emerged with fewer than 25% of chronic patients undergoing splenectomy as second-line treatment22. Splenectomy for patients who have failed corticosteroids therapy is supported by the medical literature (Grade 1B) for patients who are acceptable surgical candidates and offers the potential for a sustained response without the need for maintenance therapies10,14. A systematic review reported a complete response in two-thirds, a response in an additional 22% with an overall response in 88% at one-year post splenectomy23. Splenectomy has the advantage of offering the potential of long term complete and sustained response without the need for maintenance therapy23,24. There is not a reliable test to predict response, and 14% do not respond to splenectomy with 10% to 20% of splenectomy responders eventually relapse25. Risk of splenectomy includes operative risk, thrombosis, and life-time increased risk of infections. Complications have been reported to be higher with open as compared to laparoscopic surgical technique and in elderly patients (>65 years old) 23,26. . Pre-operative vaccinations for elective splenectomy should be given per CDC guidelines27.The potential benefit of splenectomy must be balanced against the risk23 Consensus guidance recommends delaying splenectomy for 12-24 months after diagnosis as some patients have a spontaneous remission during this time if the patient is medically stable to delay the procedure (Grade C recommendation)19,20. The likelihood of a response may be reduced in older patients 28.. Several cohort studies reported patients who maintain a post-splenectomy platelet count of >30 x 10/9L experienced no mortality from bleeding which supports recommendation against further treatment in asymptomatic patients after splenectomy who have platelet counts >30 x 10/9L 10. The 2019 International Consensus Report supports laparoscopic approach for splenectomy (Grade B recommendation)19.
Thrombopoietin agonist (TPO-RA) are small molecule peptides and non-peptide agents, romiplostim, eltrombopag and avatrombopag have been FDA-approved, for treatment for chronic ITP. TPO-RA’s have been studied in prospective randomized control trials with a response in splenectomized and non-splenectomized patients with chronic ITP with efficacy reported at approximately 80% (Grade 1B)10,29-31. In most cases, the response is not sustained; therefore, it is considered a maintenance medication with durable response rate about 45%14. Cohort studies have reported sustained response in up to 30% of patients, but the full impact of TPO-RAs on remission is yet to be fully understood and, therefore, considered for maintenance32,33. A Cochrane review reiterated the increased platelet but also reported that there was no evidence to support that treatment with TPO-RA’s improved incidence of significant bleeding events34. Since the literature on TPO-PA does not address the impact on significant bleeding events, further information is needed to understand their impact on overall survivial34.
The studies do provide data on drug safety for up to 5 years with some additional data extending to 10 years. A long term, single arm , open-label study with primary outcome of long term safety of romiplostim reported 5 years of data from 200 patients demonstrating infrequent treatment-related serious adverse events, no new adverse events or tachyphylaxis emerging35 A similar designed open-labeled study followed 300 patients on eltrombopag for median duration of 2.37 years (maximum 8.76 years) reported hepatobiliary adverse events in 15% unrelated to duration on the drug and, therefore it is recommended to monitor liver function on this formula. In this study, the question of bone marrow fibrosis was addressed with bone marrow biopsy analysis that did not demonstrate a significant impact on bone marrow reticulum36. Both studies report a rate of thrombosis of 6-6.5%, and mostly affected patients had underlying risk factors35,36. An integrated analysis of long term safety with the use of romiplostim including data from 14 trials and pooling data from placebo and treatment arms report that the rate of thrombosis was comparable among the groups, but the number who received placebo were low and additional research to fully understand this effect is lacking37. An advantage of this class is that it avoids immunosuppression and disadvantages include the need for long term maintenance and side effects.
Rituximab is a chimeric monoclonal antibody directed against the B cell surface protein CD20 and has been used off-label for the treatment of ITP. The initial response to Rituximab is approximately 60%, and a long term remission is reported in 15-30% of patients in prospective and retrospective cohort studies, systematic reviews and meta-analysis in both splenectomized and non-splenectomized patients (Grade 2C)10,38-40. There are multiple systematic reviews and meta-analysis in the literature; however, most studies were not randomized control trails and did not offer a control arm limiting the data sets. A systematic review of patients who failed first-line therapies (19 studies, 313 adult patients half who had splenectomy) reported a complete response in 44% and a response in 63% with a median duration of 11 months29. A meta-analysis of non-splenectomized patients (5 RT/463 patients) reported a complete response in 47% and response in 58%, which was comparable to a prior meta-analysis that also included observational studies38,39. A multi-centered, randomized, double-blinded, placebo controlled trial with the longest duration comparing rituximab or placebo after initial corticosteroids demonstrated only a modest response at 1.5 years41, however also reported a small benefit with rituximab could not be ruled out based on longer duration of response, numerically higher responses, and late reponders29. Factors predictive of a response have not been clearly established, but older age and longer disease duration (>10 years) seem to reduced response42,43. There is a lack of long term safety data with reports of rare risk of progressive multifocal leucoencephalopathy and hypogammaglobulinaemia 32,38. There is an FDA black box warning for the potential to cause reactivation of hepatitis B necessitating testing for hepatitis B before use. Rituximab is included as second-line therapy in the 2018 ASH guidelines as it offers the potential for a treatment-free remission without surgical intervention14.
Azathioprine, cyclosporine, cyclophosphamide, danazol, dapsone, mycophenolate mofetil, vinblastine, and vincristine have been used off-label as second-line therapies with limited published reports of any kind13,29,32. Fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, has been FDA-approved for the treatment of chronic ITP in adults. A Phase 3 placebo-controlled RCTs in patients with chronic ITP, a median of 3 prior ITP treatments and baseline platelet count <20x109/L demonstrated response in 43% at 12 weeks and 18% at 24 weeks32. ASH practice guidelines for ITP state that research on these therapies is inadequate to allow evidence-based recommendations at this time10. 2018 ASH guideline update does not include any of these agents as options for second-line therapy10.
