Management of adult immune thrombocytopenia: Recommendations by an expert Saudi panel

Hazzaa Al-Zahrani; Aamer Aleem; Fahad Al Mohareb; Said Yousuf Ahmed; Ahmed M Al-Suliman; Hussain H Al Saeed; Mubarak S Al-Ghamdi; Hani Al-Hashmi

doi:10.4103/joah.joah_51_19

REVIEW ARTICLE

Year : 2019 | Volume : 10 | Issue : 3 | Page : 77-83

Management of adult immune thrombocytopenia: Recommendations by an expert Saudi panel

Hazzaa Al-Zahrani¹, Aamer Aleem², Fahad Al Mohareb¹, Said Yousuf Ahmed³, Ahmed M Al-Suliman⁴, Hussain H Al Saeed⁵, Mubarak S Al-Ghamdi⁶, Hani Al-Hashmi⁷
¹ Section of Adult Hematology and Hematopoietic Stem Cell Transplantation, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
² Hematology/Oncology Division, Department of Medicine, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
³ Department of Hematology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
⁴ Blood Disorders Center, King Fahad Hospital, Hofuf, Saudi Arabia
⁵ Qatif Central Hospital, Qatif, Saudi Arabia
⁶ Department of Internal Medicine, Hematology, and Stem Cell Transplantation, King Fahad Medical City, Riyadh, Saudi Arabia
⁷ Oncology Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia

Date of Web Publication

14-Nov-2019

Correspondence Address:
Prof. Aamer Aleem
Department of Medicine (38), P.O. Box 7805, King Khalid University Hospital, King Saud University, Riyadh 11472
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/joah.joah_51_19

Abstract

Immune thrombocytopenia (ITP) is a disorder characterized by an isolated thrombocytopenia in the absence of an identifiable cause. Management of ITP patients varies according to the clinical presentation, physicians' experience, availability of resources, and patient preferences. Currently, multiple therapeutic options are available for the management of chronic ITP and include splenectomy, rituximab, thrombopoietin-receptor agonists, and immunosuppressant agents. To develop a common approach on the management of adult ITP patients, a meeting of a panel of hematologists experienced in the management of ITP was convened. This review focuses on the expert opinion based on local experience in the field, in light of relevant literature and guidelines, and provides expert recommendations for the diagnosis and management of adult patients with ITP in Saudi Arabia.

Keywords: Immune thrombocytopenia, management, Saudi Arabia

How to cite this article:
Al-Zahrani H, Aleem A, Mohareb FA, Ahmed SY, Al-Suliman AM, Al Saeed HH, Al-Ghamdi MS, Al-Hashmi H. Management of adult immune thrombocytopenia: Recommendations by an expert Saudi panel. J Appl Hematol 2019;10:77-83

How to cite this URL:
Al-Zahrani H, Aleem A, Mohareb FA, Ahmed SY, Al-Suliman AM, Al Saeed HH, Al-Ghamdi MS, Al-Hashmi H. Management of adult immune thrombocytopenia: Recommendations by an expert Saudi panel. J Appl Hematol [serial online] 2019 [cited 2023 Mar 24];10:77-83. Available from: https://www.jahjournal.org/text.asp?2019/10/3/77/271028

Introduction

Immune thrombocytopenia (ITP) is an immune-mediated condition characterized by isolated thrombocytopenia (platelet count <100 × 10⁹/L) in the absence of a clinically apparent associated condition or other causes of thrombocytopenia.^[1] Traditionally, ITP has been thought to be caused by autoantibody-mediated platelet destruction. However, recent evidence suggests the involvement of more complex mechanisms including impaired platelet production and T-cell mediated effects.^{[2],[3],[4],[5],[6]}

ITP is classified by disease duration into newly diagnosed (<3 months), persistent (3–12 months), and chronic (>12 months).^[1] Symptoms and signs of this disease vary widely, and range from being asymptomatic or evident with minimal bruising to severe life-threatening gastrointestinal and intracranial hemorrhage. However, adult ITP is expected to follow an insidious, chronic course.^[7] Patients with ITP have a bleeding risk that correlates with the platelet count, but this may not always be the case.^[8],[9] The presence of comorbidities and other contributing factors affect the risk and severity of bleeding in patients with ITP.

The management of ITP patients varies according to clinical presentation, physicians' experience, availability of resources, and patient preferences. For this reason, international guidelines cannot be readily adopted without adjusting for local factors. Furthermore, as guidelines usually lag behind the clinical practice, a review and update of current therapeutic options are beneficial in ITP management.^[10] Unfortunately, Saudi epidemiologic and outcome data about ITP are scarce, and therefore, guidelines based on local evidence cannot be developed at present. To develop a common strategy on the management of adult ITP patients, a meeting of a panel of hematologists experienced in the management of ITP was convened. After a thorough discussion and review of the relevant literature, recommendations were developed and presented here. The paper was written by a professional writer and supported by Novartis Oncology, Saudi Arabia. Final draft of the paper was reviewed and edited by all the authors. The sponsor had no role in the opinion presented in this paper.

This review provides expert opinion for the diagnosis and management of adult patients with ITP in Saudi Arabia, based on wide local experience in the field, in light of relevant literature and guidelines. Final judgment regarding the care of an individual patient, however, lies with the treating physician and should be based on careful attention to the personal circumstances.

Diagnosis of Immune Thrombocytopenia

ITP is an isolated thrombocytopenic disorder without an associated illness, but this condition may arise secondary to various conditions including lymphoproliferative or autoimmune disorders, and infectious diseases.^[11] Therefore, clinicians must be vigilant in attempting to identify potentially treatable causes. It is recommended that the following steps be followed for diagnosing ITP:

History: Bleeding consistent with thrombocytopenia, usually mucocutaneous bleeding, and in the absence of constitutional symptoms such as weight loss, bone pain, and night sweats. Recent history of a febrile or viral illness. A thorough history of drugs taken currently or in the recent past and a history of chronic disorders like systemic lupus erythematosus and infections like hepatitis-C virus or human immunodeficiency virus (HIV)
Family history of inherited thrombocytopenias
Physical examination: Absence of hepatosplenomegaly, lymphadenopathy, or signs of congenital disorders (e.g., café-au-lait spots, polydactyly, nail dystrophy, etc).
Complete blood count: Isolated thrombocytopenia (platelet count <100 × 10⁹/L). Evidence of anemia only if secondary to significant blood loss. Otherwise, normal red cell indices, normal white cell count, and normal differential white blood cell count without additional abnormalities
Peripheral blood smear: Absence of platelet clumps, normal to large platelets, normal red cell and white cell morphology, absence of abnormal cells (e.g., blast cells, schistocytes, smudge cells, May–Hegglin anomaly), and manual platelet count to rule out pseudothrombocytopenia.

Bone marrow evaluation

Bone marrow examination may not be necessary for patients with typical features of ITP outlined above and no other abnormal findings on a carefully examined peripheral blood smear. However, bone marrow evaluation is recommended in patients older than 60 years to look specifically for myelodysplastic syndrome-related changes, in those with bleeding that is out of proportion to the severity of thrombocytopenia, refractory disease to initial therapy, or when abnormal cells/features on peripheral blood smear are observed.

Additional diagnostic workup

In patients with suspected ITP, it is recommended that screening for hepatitis B virus (HBV) and hepatitis C virus as well as HIV be undertaken owing to the relatively high prevalence of hepatitis B and C in Saudi Arabia. Some patients may have occult HBV infection with surface antigen negative but HBV-DNA positive, with or without hepatitis B core antibody (anti-HBc). Anti-HBc is the most sensitive marker of previous HBV and should be part of screening.

In addition, antinuclear antibody, lupus anticoagulant, and antiphospholipid antibody testing should be performed to rule out other autoimmune causes of thrombocytopenia. Finally, screening for Helicobacterpylori is recommended in patients with refractory ITP, and those who present with the gastrointestinal symptoms. An association between H. pylori infection and ITP has been suggested, and several studies found that the platelet count increased after H. pylori eradication.^[12] However, as the prevalence of H. pylori is relatively high in Saudi Arabia, screening should be considered as a routine. Patients should be informed that eradication of H. pylori, if found, does not guarantee a cure from ITP.^{[13],[14],[15],[16]} Other tests may need to be ordered based on the clinical picture and may include thyroid function and antithyroid antibody tests.

Antiplatelet antibody tests may be relevant in an occasional individual patient but there is insufficient evidence supporting their routine use.^[1]

Management of Immune Thrombocytopenia

The goal of all ITP treatment strategies is to achieve a safe platelet count to ensure adequate hemostasis rather than a normal platelet count. The choice of treatment should be individualized, involving a discussion with the patient, consideration of the severity of the bleeding episodes, comorbidities, the toxicity profile of each therapy option, drug availability, anticipated surgical procedures, the cost of therapy, and patient age, lifestyle, and quality of life.^[17],[18]

Assessment of disease status

What type of bleeding is the patient experiencing?
Determine the timing, location, and severity of bleeding symptoms
Does the patient have any additional risk factors for bleeding such as the use of antiplatelet or antithrombotic agents or high-risk occupation?
Is a surgical procedure anticipated?
Is this patient likely to comply with recommended treatment(s)?
Is the bleeding experienced by the patient interfering with his or her daily activities and lifestyle or causing significant anxiety?

First-line management

All patients should be counseled regarding lifestyle changes and medications to avoid, including aspirin and other nonsteroidal anti-infiammatory drugs
Most patients with no or minimal bleeding (limited to skin manifestations only) may be observed, provided that their platelet count continues to be >20–30 × 10⁹/L
First-line medications include corticosteroids, intravenous immunoglobulin (IvIg), or anti-D immunoglobulin (anti-D)

Corticosteroids:

Standardfirst-line therapy and expected to induce a clinically meaningful response in 3–5 days but may take longer.
Caution is required while using steroids for the following patient populations

Patients with type 2 diabetes
Those with uncontrolled hypertension
Pregnant women
Elderly individuals
Those with an active viral illness.

Corticosteroids may be used in the following manner:

Dexamethasone 40 mg/day for 4 days (can be repeated monthly up to four cycles).
Prednisolone 0.5–2 mg/kg/day for 2–4 weeks, and taper once response is observed
Pulse methylprednisolone.

IvIg:

Can induce a rapid response within 1–2 days and is therefore useful in the emergency settings (ongoing bleeding, surgery)
IvIg is expensive and is not without side effects which include anaphylaxis, renal failure, and thrombosis
IvIg can be dosed in the following manner:

1 g/kg/day for 1–2 days.

Anti-D:

Not commonly used; should be used with caution given some recent reports of severe and fatal hemolysis
Not advised in patients with active bleeding causing a decline in hemoglobin or those with evidence of autoimmune hemolysis
Use of Anti-D is limited to Rh +ve patients who have an acceptable hemoglobin level and a functional spleen.

Second-line management

Patients, who fail to exhibit significant response withfirst-line therapy or relapse after the initial response, require second-line therapy. About 20% of patients failfirst-line therapy including splenectomy, and an estimated 10%–20% experience eventual relapse after splenectomy. Due to improved awareness on therapeutic options for ITP, many patients are hesitant to undergo splenectomy and prefer to try other medical therapiesfirst.

Patients with a high bleeding risk or significantly disrupted quality of life require second-line therapy. However, not all second-line options are similar. Therefore, factors including comorbidities, age, and patient preference play a major role in the choice of therapy. The role of several agents has been studied in the literature, including thrombopoietin-receptor agonists (TPO-RAs), which are expected to be increasingly used with wider availability and patient preference over other therapeutic modalities like splenectomy. In the next section, we briefiy discuss different second-line therapeutic modalities for ITP. Therapeutic options, for patients who fail to respond to thefirst-line therapy or relapse after the initial response, are given in [Table 1].

Table 1: Therapeutic agents and their doses for immune thrombocytopenia patients who fail to respond to first.line therapy or relapse after the initial response

Click here to view

Rituximab

Use of rituximab for chronic ITP remains widely practiced even though this indication is off-label, as it has not received the US Food and Drug Administration (FDA) approval for use in ITP. Overall response rates of approximately 40%–60% are achieved, with a median time to response of 6 weeks, and complete response in up to 40% of patients, with a median duration of response of 11 weeks.^{[19],[20],[21],[22],[23],[24]} About 20%–40% of patients will have a long-term response, but the response may be delayed for 2–3 months. However, responses to rituximab are unlikely to be sustained long-term. One study from Saudi Arabia showed that long-term responses to rituximab after 1 year were low, in the range of 20%.^[23]

Infusion reactions with rituximab are fairly common and should be monitored. Concerns including long-term suppression of B-cell function (up to 1 year), reactivation of viral infections, delayed neutropenia, and reports suggesting cases of progressive multifocal leukoencephalopathy as a side effect of rituximab, should not be overlooked.^{[19],[20],[21],[22],[23],[24]} ITP patients, who harbor HBV infection and require rituximab treatment, should be started on antiviral agents like entecavir before starting rituximab.

Treatment with the combination of rituximab and dexamethasone resulted in higher response rates, longer time to relapse, and rescue treatment in a study of adult patients with newly diagnosed ITP, but the incidence of Grade 3–4 adverse events was higher in the rituximab plus dexamethasone group.^[25] Rituximab is not recommended for thefirst-line therapy of ITP; however, its use may be justified in a resistant case where thefirst-line therapies have failed, and patient remains at risk of bleeding due to low platelet count.

Thrombopoietin-receptor agonists

Eltrombopag and romiplostim have been extensively studied and are the only second-line medications that have been approved for ITP by the US FDA. Multiple clinical trials have demonstrated that both drugs are effective in increasing the platelet count in both healthy volunteers and ITP patients.^{[24],[25],[26],[27],[28],[29]}

Eltrombopag has also been approved for children with cITP who are aged 1 year or older.^[30] A recent study found that 80% of patients who were switched from romiplostim to eltrombopag for reasons including lack of efficacy, platelet count fiuctuations, and side effects, exhibited a response and two-thirds had a complete response.^[31] In addition, a study on patients who had complete remission of ITP with eltrombopag found that half of the patients had a sustained response after discontinuation, for a median of 9 months of follow-up.^[32] The long-term, open-label EXTEND study found that bleeding symptoms dropped from 56% at baseline to 11% at 3 years. Splenectomized and nonsplenectomized patients maintained target platelet response for a median of 70% and 95% of cumulative study weeks, respectively.^[33] A long-term study of romiplostim showed that responses were sustained for up to 4 years on continuous therapy, with most patients able to decrease or discontinue concurrent corticosteroid therapy.^[34]

Neither drug is widely available currently, but there is a trend for increasing use as it matches many of the unmet needs of ITP patients. Unlike romiplostim, which is administered once weekly subcutaneously, eltrombopag is oral with once-daily dosing. TPO-RAs are safe and effective in diabetic, hypertensive, elderly and immunocompromised patients, and they are an attractive option as a second-line treatment for ITP patients. Physicians need to bear in mind that the ultimate goal is not to normalize the platelet count, but to reach a safe level that prevents life-threatening bleeding; the dose can, therefore, be adjusted once a satisfactory platelet count has been achieved. The main limitation of TPO-RA is the need for continuous treatment (and associated cost), although some patients may be able to stop treatment and maintain the response.

Hepatic enzyme elevations of about 10% of patients have been reported in clinical trials of eltrombopag in patients with ITP. Due to these reports, there is a boxed warning about hepatotoxicity and the possibility of hepatic decompensation when treating patients with chronic hepatitis C, and in these patients, close monitoring of liver function is recommended. However, there have been no published reports of clinically significant liver injury attributable to eltrombopag therapy.^{[26],[27],[28],[29],[30],[31],[32],[33],[34],[35]}

Splenectomy

Sustained responses are obtained in 60%–80% of ITP patients undergoing splenectomy.^{[35],[36],[37],[38]} It is widely available and cheaper as compared to the newer, more expensive therapies for ITP. However, because of the surgical nature of the treatment, many patients are reluctant to undergo this procedure before trying medical therapies. Although a safe procedure, many physicians are also hesitant to refer patients because of the potential risk of surgical and other complications, such as increased risk of infection and thrombosis and possible requirement for additional intervention(s).^[37] Overall, splenectomy provides an effective treatment option for ITP, but the risk of complications related to the procedure versus the benefit of an increased platelet count should be considered. In patients who fail second-line therapies such as rituximab and TPO-RA, splenectomy will continue to be an important option.^{[36],[37],[38],[39],[40],[41],[42]}

ITP patients should receive appropriate postoperative thromboprophylaxis as well as prophylactic polyvalent pneumococcal, meningococcal C conjugate, and Haemophilus infiuenza B vaccines at least 4 weeks before (preferably) or 2 weeks after splenectomy. In addition, patients should be revaccinated every 5 years after splenectomy and receive antibiotic (penicillin) prophylaxis.^{[39],[40],[41],[42]}

Danazol

Danazol can be used alone or in combination with other agents to augment its response. Responses are seen in up to two-thirds of patients. Older age, female gender, and splenectomy are associated with higher response rate. However, it should be used with caution in patients with preexisting liver disease, and female patients should be warned about the virilizing side effects of this drug. It is better suited for older patients with ITP. Physicians prescribing this agent should be aware that its effect may be delayed for up to 6 months.^[43],[44]

Dapsone

Dapsone may be considered in patients who are refractory to or dependent on corticosteroids before opting for more expensive and more toxic second-line therapies. Dapsone can be used in combination with other drugs, especially corticosteroids. Dapsone is expected to exhibit a response within 1–3 months of starting therapy in those who respond but may take up to 6 months. Splenectomized patients exhibited a poor response. Dapsone is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and given the relatively high prevalence of G6PD deficiency in Saudi Arabia, we recommend that all male candidates for dapsone therapy should be screened for it before initiating therapy.^{[43],[45],[46],[47],[48]}

Sustained responses for up to almost 3 years have been achieved with dapsone in those who did not respond to corticosteroids. Splenectomized patients exhibited a poor response.^{[43],[45],[46],[47],[48]}

Immunosuppressive agents

These include azathioprine, cyclosporine A, mycophenolate mofetil, cyclophosphamide, and vinca alkaloids. Most of the studies of these agents in ITP are old with very few studies conducted in recent times.^{[43],[49],[50],[51],[52],[53],[54],[55],[56],[57]} Our experience shows that patients are usually hesitant to accept therapy with any of these agents and these agents are only occasionally used currently. In addition, the risk-benefit profile of immunosuppressive agents is less acceptable in the presence of other safer and more effective therapeutic options, and they are usually reserved as the third-line option after failure of second-line therapies.

Nevertheless, they may be the only treatment available in some peripheral centers and in patients refractory to other therapies and should, therefore, be kept as an option when other alternatives have been exhausted or not available. Time to response, response rates, and selected toxicities of the immunosuppressive agents used in ITP are given in [Table 2].

Table 2: Time to response, response rates, and side effects of immunosuppressive agents used in immune thrombocytopenia patients

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New agents

Two new drugs were recently approved for ITP by the US FDA and many other agents are on the horizon.

Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor that is orally bioavailable. It was approved for the treatment of chronic ITP in adults in 2018.^[58],[59] Fostamatinib blocks phagocytosis of Fc receptor–bound, antibody-coated platelets, and its approval was based on favorable results in 2 phase III clinical trials in adults with persistent or chronic ITP after failure of other therapies including rituximab, TPO-RA, and/or splenectomy. Median time to response was 15 days. Most common adverse effects include gastrointestinal toxicity and hypertension.^[58]

Avatrombopag is another TPO-RA and was approved in May 2019 for the treatment of adult patients with chronic ITP who have had an insufficient response to a previous treatment.

Rozanolixizumab is an antineonatal Fc receptor (FcRn) inhibitor that decreases circulating pathologic IgG by blocking FcRn. Studies in murine autoimmune disease demonstrated favorable results, so the effect of this agent was evaluated in ITP and other autoimmune diseases. The interim analysis of an ongoing phase II multiple-dose study of rozanolixizumab in adult ITP showed encouraging results with 30 percent of treated patients achieving an improvement in the platelet count.^[60]

Monoclonal antibodies and other thrombopoietin agonists with the potential to enhance platelet production are in various stages of development and hold promise for the future.

Conclusions

Many patients require second-line therapy for ITP. Classical options with varying efficacy and safety include splenectomy, rituximab, danazol, dapsone, and immunosuppressive agents. TPO-RAs are a relatively recent class of drugs, for which multiple randomized clinical trials have confirmed their safety and efficacy in patients with ITP. TPO-RAs are likely to become the preferred second-line option, once they are widely available because of the efficacy and favorable safety profile. In the meantime, we recommend that patients who require second-line therapy, be counseled for all available options and the pros and cons of each therapy, before starting the treatment.

Financial support and sponsorship

Nil.

Confiicts of interest

There are no confiicts of interest.

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