Summary Of Evidence

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 disorder^3,4. 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/L^1,2. 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 threshold^2,9. 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 bleeding^10,11.

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 splenectomy^5,16. 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 efficiacy^5,13. There are no randomized controlled comparative studies or systematic review of the available data, and a lack of sufficiently large numbers to make definitive recommendations^5,17,18. 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 therapies^10,14. 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 therapy^23,24. 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 maintenance^32,33. 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 factors^35,36. 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 studies^38,39. 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 response^42,43. 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 kind^13,29,32. 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.

Analysis of Evidence

One of the challenges in primary ITP treatment is determining who needs treatment due to the heterogeneous nature of the disease and difficulty in predicting bleeding. Treatment based on a platelet threshold has gradually been replaced by clinical assessment of acute bleeding, the risk for bleeding, and lower platelet thresholds to determine candidates for treatment. The risk of fatal bleeding is lower than previously thought, and the potential morbidity and mortality related to treatment must be balanced with the need for treatment. The emergence of second-line treatment option has overall improved outcomes and mortality in severe cases.

ASH evidence-based practice guidelines and international consensus support the use of first-line treatment with corticosteroids ^10,13,14. IVIg and Anti-D are the appropriate first-line treatment in cases where a rapid rise in platelet count is needed or corticosteroids are contraindicated or not tolerated (grade 2C) ¹⁰. IVIg and anti-D are associated with more side effects, and there is no clear long-term benefit compared to corticosteriods¹⁴. Corticosteroids should be discontinued once a response is achieved. Most patients will respond to first-line therapy, and disease may remit spontaneously in the first 6-12 months.

Patients who develop chronic ITP and who fail to respond to first-line treatment have a poorer prognosis and increase the risk of morbidity and mortality related to ITP. The optimal treatment of this group is controversial. The international consensus guidelines determined they could not rank the second line options based of evidence since the literature was not sufficient to make this determination, but the American Society of Hematology (ASH) does support splenectomy and the use of TPO-RA in a select patient population^10,13,14. Since 2011 additional literature has emerged, but the optimal treatment remains unclear¹⁴.

The decision for splenectomy includes the desirable effect of high remission rate (77%, range 58-91%) balanced against the lifelong risk of infection, thromboembolic events, and surgical complications¹⁴. Splenectomy is still recommended as the standard therapy for patients with chronic ITP given the high probability of durable platelet response²⁹. Splenectomy rates have declined since the emergence of newer medical therapies, especially in patients who are not good surgical candidates such as patients who are elderly and with multiple medical co-morbidities. Splenectomy is the recommended second-line therapy due to the potential for a treatment-free response without the need for maintenance therapy support by (Grade 1B) medical evidence (Grade 1B) ^10,1318.

TPO-RA has been studied in RCT, systematic reviews, and meta-analysis and determined to be effective agents to achieve a response with a durable response rate of 45%. While there are reports of TPO-RA's inducing remission, this is not supported by high-quality evidence and TPO-RA's are considered maintenance medication¹⁴. Romiplostim requires weekly subcutaneous injection and eltrombopag, a daily oral medication, can interfere with liver enzymes, cannot be taken within four hours of polyvalent cations and requires monitoring of liver function which may limit compliance. Avatrombopag is a daily oral medication without dietary restrictions, but has not been as rigorously studied. It has not been determined, the optimal duration of therapy and when a trail off of medication may be indicated. The benefits profile of TPO-RA includes avoiding immunosuppression, and this must be balanced against the need for long term use and very limited long-term (>10 years) safety data¹⁴. ASH guidelines recommend TPO-RA for patients who need second-line treatment who are determined to not be a candidate for splenectomy, at risk for bleeding who relapse after splenectomy and have failed at least one other therapy (grade 1B)^10,14.

Rituximab has been studied in multiple trails with conflicting results but overall favorable with durable response rate similar to TPO-RA of approximately 40% (Grade 2C). The potential advantage of Rituximab is the possibility for durable remission³². Rituximab is administered intravenously weekly for four consecutive weeks, and if there is a response, it may reduce the need for chronic maintenance therapy³². The use of Rituximab is off-label, and high-quality evidence is lacking. It is included in the ASH Guidelines as it offers the potential for treatment-free remission. The guidelines include a trial of rituximab may be desirable before splenectomy as it has the potential to be splenectomy sparing. If there is the rationale for the decision not to perform splenectomy the literature and guidelines support Rituximab as a second-line option and evidence-based reviews (other than the ASH Guidelines) rank the quality of evidence as Grade 2B^14,32.

There is a paucity of data or low-quality data surrounding the other alternative second-line therapies, and they are not included in the 2018 ASH Guidelines¹⁴. These options are considered investigational and not covered.

Treatment of Primary Immune Thrombocytopenia (ITP)

Treatment

Treatment is not medically necessary in the following scenarios:

1. Children with no bleeding or mild bleeding (skin manifestations only such as bruising and petechiae) regardless of platelet count
2. Adults with platelet count ≥ 30 x10⁹/L in the absence of bleeding

Treatment may be indicated with documentation of at least one of the following conditions:

1. Severe ITP (bleeding)
2. Adult with platelets count ≤30 x10⁹/L especially if risk factors for bleeding are present
3. In preparation for procedures or surgery with risk of bleeding
4. Professional or lifestyle risk factors for trauma

Risk factors for bleeding include predisposing comorbidities that increase the risk of bleeding such as uncontrolled hypertension, active peptic ulcer disease, anticoagulation, recent surgery, or head trauma.

First-Line Therapy

First-line pharmacologic treatment in children and adults is corticosteroids in dosing regimens standard to ITP treatment.

Intravenous Immune globulin (IVIg) may be used first-line with documentation of at least one of the following conditions:

1. Documented need for rapid response (<48 hours)
2. Documented contraindication or inability to tolerate corticosteroids
3. Lack of response to corticosteroids

Lack of response is defined as platelet count <30 x10⁹/L or less than 2-fold increase in baseline platelets¹.

Intravenous anti-D may be used first-line in adults with documentation of at least one of the following conditions in patients who are Rh positive and nonsplenectomized:

1. Documented need for rapid response (<48 hours)
2. Documented contraindication or inability to tolerate corticosteroids
3. Lack of response to corticosteroids

Second-Line Treatment

Coverage of second-line treatment requires a documented lack of response to at least one first-line therapy. Shared decision making to consider the risk and benefit of the various second-line options should be documented in the medical record. This should include a discussion of surgical and non-surgical options.

Splenectomy will be covered when all of the following criteria are met:

1. Documented lack of response of at least one first-line therapy
2. Documented risk for bleeding (at least one of the following)
   1. Severe ITP (bleeding symptoms)
   2. Adult with platelets count ≤30 x10⁹/L especially if risk factors for bleeding are present
   3. In preparation for procedures or surgery with risk of bleeding
   4. Professional or lifestyle risk for trauma
3. Persistent or chronic disease (>6 months) OR documented indication for more immediate surgical intervention (<6months) such as serious bleeding
4. Pre-operative vaccinations per CDC guidelines
5. Patient desires treatment-free remission and willing to accept the risk associated with splenectomy (surgical, infection and thrombosis)

Thrombopoietin receptor agonist (TPO-RA) will be covered when all of the following criteria are met:

1. Documented lack of response of at least one first-line therapy
2. Documented risk for bleeding (at least one of the following)
   1. Severe ITP (bleeding symptoms)
   2. Risk factors for bleeding are present
   3. In preparation for procedures or surgery with risk of bleeding
   4. Professional or lifestyle risk factors for trauma
3. Persistent or chronic disease (>6 months)

Rituximab will be covered when all of the following criteria are met:

1. Documented lack of response of at least one first line therapy
2. Documented risk for bleeding (at least one of the following)
   1. Severe ITP (bleeding symptoms)
   2. Risk factors for bleeding are present
   3. In preparation for procedures or surgery with risk of bleeding
   4. Professional or lifestyle risk for trauma
3. Persistent or chronic disease (>6 months)