Abstract

This article summarizes our approach to the management of children and adults with primary immune thrombocytopenia (ITP) who do not respond to, cannot tolerate, or are unwilling to undergo splenectomy. We begin with a critical reassessment of the diagnosis and a deliberate attempt to exclude nonautoimmune causes of thrombocytopenia and secondary ITP. For patients in whom the diagnosis is affirmed, we consider observation without treatment. Observation is appropriate for most asymptomatic patients with a platelet count of 20 to 30 × 109/L or higher. We use a tiered approach to treat patients who require therapy to increase the platelet count. Tier 1 options (rituximab, thrombopoietin receptor agonists, low-dose corticosteroids) have a relatively favorable therapeutic index. We exhaust all Tier 1 options before proceeding to Tier 2, which comprises a host of immunosuppressive agents with relatively lower response rates and/or greater toxicity. We often prescribe Tier 2 drugs not alone but in combination with a Tier 1 or a second Tier 2 drug with a different mechanism of action. We reserve Tier 3 strategies, which are of uncertain benefit and/or high toxicity with little supporting evidence, for the rare patient with serious bleeding who does not respond to Tier 1 and Tier 2 therapies.

Case 1

A 10-year-old male was diagnosed with primary immune thrombocytopenia (ITP) 5 months ago when he presented with epistaxis, petechiae, bruising, and a platelet count of 5 × 109/L. He responded transiently to intravenous immunoglobulin G (IgG), but epistaxis recurred 2 weeks later. He subsequently received a short course of oral corticosteroids to which he had a temporary response in platelet count and cessation of epistaxis. Since discontinuing corticosteroids, he has had only occasional bruising and petechiae. His platelet count is currently 13 × 109/L. He states that ITP is not interfering with activities.

Introduction

ITP treatment may be conceptually divided into rescue therapy and maintenance therapy. The objective of rescue therapy is a swift rise in platelet count in a patient with active hemorrhage, a high risk for bleeding, or need for a critical procedure. In selecting rescue therapy, a premium is placed on rapidity of response with relatively less regard for durability of response, patient convenience, or safety and tolerability with long-term use. Maintenance therapy, in contrast, is given with the goal of achieving a sustained platelet response while minimizing short- and long-term treatment-related toxicity. Goals and standard treatment options for rescue and maintenance therapy are summarized in Table 1.

Table 1

Goals and standard treatment options for rescue and maintenance therapy

 Rescue therapy Maintenance therapy 
Goals of treatment Rapid platelet response Durable platelet response 
 Short-term safety Long-term safety and tolerability 
  Patient convenience 
Desired time to response Hours to days Days to weeks 
Standard treatment options Corticosteroids Splenectomy 
 IVIG  
 Anti-D*  
 Rescue therapy Maintenance therapy 
Goals of treatment Rapid platelet response Durable platelet response 
 Short-term safety Long-term safety and tolerability 
  Patient convenience 
Desired time to response Hours to days Days to weeks 
Standard treatment options Corticosteroids Splenectomy 
 IVIG  
 Anti-D*  

IVIG, intravenous immunoglobulin G.

*

Indicated only in Rh(D)-positive, nonsplenectomized patients.

Management of the patient with ITP whose platelet count does not respond to standard therapy (Table 1) can be frustrating and terrifying for clinicians and patients, particularly if there is active bleeding or severe thrombocytopenia. The purpose of this article is to summarize our approach to the management of children and adults with primary ITP who do not respond to or cannot tolerate standard maintenance therapy (ie, splenectomy). Much of the evidence in this area is limited to case reports and uncontrolled series.1  There are few direct comparisons of different treatment strategies. Where evidence is available, it is cited. Suggestions are otherwise based on our experience and opinions.

What is refractory ITP?

An International Working Group (IWG) defined refractory ITP as disease that does not respond to or relapses after splenectomy and that requires treatment to reduce the risk of clinically significant bleeding.2  The American Society of Hematology ITP Guidelines endorsed this definition as a means of identifying the most severely affected patients.3  Given that splenectomy remains the surest means of “curing” ITP with long-term complete platelet response rates of 60% to 70%,4,5  this characterization remains pertinent.

Nevertheless, several limitations of the IWG definition2  must be acknowledged. First, it may not be applicable to certain patient populations such as children, those with significant comorbidities, and those unwilling to undergo splenectomy. In these patients, avoidance of splenectomy may be desirable or even necessary. Indeed, the IWG acknowledged that it was unable to achieve consensus on the definition of refractory disease in children.2  Second, the IWG definition stipulates that treatment be deemed necessary for bleeding symptoms or presumed high risk of bleeding. It is conceivable that, for some patients, the indication for treatment after splenectomy failure might relate to something other than bleeding symptoms such as improvement in health-related quality of life (HRQoL).6,7  HRQoL is a multidimensional construct that focuses on the impact of health on physical, mental, social, and emotional functioning.8  Third, the IWG classification does not include refractoriness to rescue therapy.

Herein, we use a broader definition of refractoriness than the IWG does. Regarding patients refractory to maintenance therapy, we include not only patients who require treatment to mitigate bleeding risk after splenectomy but also patients who are unable or disinclined to undergo splenectomy and patients in whom the primary objective of treatment is improvement in HRQoL.

ITP refractory to maintenance therapy

Figure 1 illustrates our approach to the patient who is refractory to or ineligible for splenectomy. Key features include reassessment of the diagnosis, consideration of observation without treatment, a 3-tiered approach to treatment, and the use of combination therapy.

Figure 1

Approach to the patient with refractory ITP. We begin by reassessing the diagnosis of ITP and excluding nonautoimmune causes of thrombocytopenia and secondary ITP. After ITP has been affirmed, we consider whether treatment is indicated. Observation alone is appropriate for most adults with a platelet count >20 to 30 × 109/L and no bleeding or impaired HRQoL and for most children without bleeding or impaired HRQoL. For patients who require treatment, we treat with a Tier 1 agent (Table 2). We select an agent based on age, comorbidities, drug availability, cost, and patient preference. In patients who do not respond to or cannot tolerate a Tier 1 agent, we move on to another Tier 1 agent. In patients who have exhausted all options in Tier 1, we consider enrollment in a clinical trial. If a suitable trial is not available, we initiate a Tier 2 agent (Table 3). We often use Tier 2 agents in combination with Tier 1 or other Tier 2 agents with different mechanisms of action. For the rare patient with serious bleeding who does not achieve an acceptable response with Tier 2 agents, we again consider enrollment in a clinical trial or initiation of a Tier 3 treatment (Table 4).

Figure 1

Approach to the patient with refractory ITP. We begin by reassessing the diagnosis of ITP and excluding nonautoimmune causes of thrombocytopenia and secondary ITP. After ITP has been affirmed, we consider whether treatment is indicated. Observation alone is appropriate for most adults with a platelet count >20 to 30 × 109/L and no bleeding or impaired HRQoL and for most children without bleeding or impaired HRQoL. For patients who require treatment, we treat with a Tier 1 agent (Table 2). We select an agent based on age, comorbidities, drug availability, cost, and patient preference. In patients who do not respond to or cannot tolerate a Tier 1 agent, we move on to another Tier 1 agent. In patients who have exhausted all options in Tier 1, we consider enrollment in a clinical trial. If a suitable trial is not available, we initiate a Tier 2 agent (Table 3). We often use Tier 2 agents in combination with Tier 1 or other Tier 2 agents with different mechanisms of action. For the rare patient with serious bleeding who does not achieve an acceptable response with Tier 2 agents, we again consider enrollment in a clinical trial or initiation of a Tier 3 treatment (Table 4).

Reassessment of the diagnosis

There is no gold standard diagnostic test for ITP. The most compelling evidence for the presence of ITP is a platelet response to standard therapy (Table 1). Nonresponsiveness to treatment should therefore prompt reassessment of the diagnosis and a concerted effort to exclude nonautoimmune causes of thrombocytopenia and secondary ITP. The reader is referred elsewhere for a discussion of diagnostic evaluation.3,9,10  It is likewise imperative that a manual platelet count be performed because automated cell counters may misclassify large or agglutinated platelets, leading to an underestimation of the platelet count and potentially inappropriate treatment decisions.

Observation

In accordance with American Society of Hematology guidelines,3  we recommend observation without treatment in most asymptomatic adults after splenectomy with a platelet count of 20 to 30 × 109/L or greater. In a prospective cohort study, patients who maintained a platelet count above this threshold after splenectomy had no bleeding-related deaths. In contrast, patients with a platelet count below 30 × 109/L had a bleeding-related mortality of 36.7%.11  In a separate study of 47 patients who were unable to maintain a platelet count of 100 × 109/L after splenectomy, there were 3 deaths over a median follow-up of 7.5 years. All 3 had a baseline platelet count below 20 × 109/L.12  A platelet count threshold above 30 × 109/L may be preferred in some patients because of their occupation, participation in sports, need for antithrombotic therapy, or control of other symptoms that track with platelet count (eg, fatigue, HRQoL). Conversely, some patients have little or no bleeding at platelet counts well below 30 × 109/L and are more concerned about adverse effects of treatment than bleeding. These individuals may elect to defer therapy at lower platelet counts. This is particularly relevant to children, who have low bleeding risk even in the setting of severe persistent or chronic thrombocytopenia.13  Observation may be appropriate in asymptomatic or minimally symptomatic children, as in Case 1 above, irrespective of the platelet count. We prioritize bleeding symptoms and HRQoL over platelet count in decision-making in this population (Figure 1).

Tiered approach to treatment

For patients with refractory ITP who require therapy to maintain a hemostatic platelet count, numerous treatments are available. We divide these options into 3 tiers based on efficacy, safety, and quality of evidence.14  Treatment options in Tier 1 have a relatively favorable therapeutic index and are supported by reasonably good evidence. Options in Tier 3, in contrast, have a less auspicious efficacy/safety profile and/or a weak evidentiary basis.

There are no direct comparisons of treatment options within a given tier. We therefore individualize choice of treatment on the basis of age, comorbidities, drug availability, cost, and patient preference. We exhaust options in each tier before proceeding to the subsequent tier. When a durable platelet response cannot be attained with monotherapy, we consider combining agents with different mechanisms of action.

Case 1 continued

The child has been managed with observation for the past 3 months and is now 8 months from his diagnosis. He continues to have no bleeding symptoms apart from bruising and petechiae. His platelet count has varied between 10 and 30 × 109/L. Football season will begin shortly and he desires to have a platelet count that is safe for participation.

Tier 1

Low-dose corticosteroids.

Rarely, patients who are highly responsive to corticosteroids at standard rescue therapy doses (eg, prednisone 1 mg/kg/d, dexamethasone 40 mg/d × 4) may be able to sustain hemostatic platelet counts at very low maintenance doses of prednisone (≤5 mg/d).15  Long-term treatment at such doses is generally well tolerated but is not devoid of risk for cumulative toxicities, including weight gain, diabetes mellitus, hypertension, decreased bone mineral density, and cataract formation (Table 2).16  Monitoring for toxicities, including periodic bone density assessment, is indicated. Calcium and vitamin D supplementation and regular weight-bearing exercise are recommended to reduce the risk of osteoporosis.

Table 2

Tier 1 treatment options

Drug Dose Response rate* Time to response (wk) Selected toxicities 
Low-dose prednisone ≤5 mg orally once per day <10% N/A† Weight gain, hyperglycemia, hypertension, osteoporosis, cataracts 
Rituximab 375 mg/m2 IV once per week × 4 (lower doses may be effective) 60% overall, 40% complete, 20%-25% at 5 y 1-8 Infusion reactions, serum sickness, HBV reactivation, PML (rare) 
Romiplostim 1-10 μg/kg SC once per week 80% overall, 40%-50% persistent 1-4 Reticulin fibrosis, rebound thrombocytopenia, thrombosis 
Eltrombopag 25-75 mg orally once per day 80% overall, 40%-50% persistent 1-2 Reticulin fibrosis, rebound thrombocytopenia, thrombosis, hepatotoxicity 
Drug Dose Response rate* Time to response (wk) Selected toxicities 
Low-dose prednisone ≤5 mg orally once per day <10% N/A† Weight gain, hyperglycemia, hypertension, osteoporosis, cataracts 
Rituximab 375 mg/m2 IV once per week × 4 (lower doses may be effective) 60% overall, 40% complete, 20%-25% at 5 y 1-8 Infusion reactions, serum sickness, HBV reactivation, PML (rare) 
Romiplostim 1-10 μg/kg SC once per week 80% overall, 40%-50% persistent 1-4 Reticulin fibrosis, rebound thrombocytopenia, thrombosis 
Eltrombopag 25-75 mg orally once per day 80% overall, 40%-50% persistent 1-2 Reticulin fibrosis, rebound thrombocytopenia, thrombosis, hepatotoxicity 

HBV, hepatitis B virus; IV, intravenous; N/A, not applicable; PML, progressive multifocal leukoencephalopathy; SC, subcutaneous.

*

Studies vary in their definition of response.

In patients who are responding to intermediate or high doses of prednisone, we taper to low-dose prednisone. We do not start low-dose prednisone de novo.

Rituximab.

Rituximab is a chimeric monoclonal anti-CD20 antibody that depletes B lymphocytes. Its efficacy was evaluated in a systematic review and meta-analysis collectively involving 19 studies and 313 patients, approximately half of whom had undergone splenectomy. A response (platelet count >50 × 109/L) was achieved in 63% of patients. Median time to response was 5.5 weeks, and median duration of response was 11 months.17  In a long-term observational study of 72 adults and 66 children, the response rate to rituximab at 5 years was 21% and 26%, respectively.18  Published evidence suggests that the likelihood and duration of platelet response are similar in splenectomized and nonsplenectomized patients.17,19  Complete responders who relapse ≥1 year after treatment are likely to respond to retreatment.

The optimal dose of rituximab for ITP treatment has not been established. We use 375 mg/m2 once per week × 4 weeks, but lower doses may be effective (Table 2).20  Rituximab is generally well tolerated. Toxicities include infusion reactions, serum sickness, and prolonged immune suppression. Patients should be screened for hepatitis B before receiving rituximab because of the risk of viral reactivation. We generally avoid rituximab in patients with hepatitis B, although we consider co-administration of antiviral therapy21  in patients who do not respond to or are ineligible for all other Tier 1 options. One case of progressive multifocal leukoencephalopathy has been reported in a patient with ITP treated with rituximab.22  We provide immunizations before beginning treatment because rituximab attenuates response to vaccines for up to 6 months.23 

Thrombopoietin receptor agonists.

Thrombopoietin receptor agonists (TRAs) bind to the thrombopoietin receptor and stimulate megakaryocyte maturation and platelet production. Two TRAs, romiplostim and eltrombopag, have been approved by the US Food and Drug Administration. We do not have experience with recombinant human thrombopoietin, which is available in jurisdictions outside the United States.

Romiplostim is given as a once-per-week subcutaneous injection. The starting dose is 1 μg/kg. The dose is increased by 1 μg/kg each week (maximum dose 10 μg/kg) until a platelet count of ≥50 × 109/L is achieved (Table 2). In a randomized, placebo-controlled trial of 63 splenectomized adult patients, the rate of overall response (platelet count ≥50 × 109/L at any time during the study) and durable response (platelet count ≥50 × 109/L for at least 6 of the final 8 weeks of the study) was 79% and 38% in the romiplostim group and 0% and 0% in the placebo group, respectively.24  Romiplostim also reduced bleeding and improved HRQoL. An extension study enrolled 95 splenectomized patients. A platelet response (≥50 × 109/L) was achieved in 90% of the patients and persisted for a median 67% of time on study.25  Thirty-nine patients with prior splenectomy were enrolled in a French compassionate use program. Many of them had also received rituximab and other immunosuppressive agents. Despite refractoriness to previous therapies, 45% met the criteria for long-term response at 2 years.26 

Romiplostim is not approved for treatment of children, but preliminary data suggest that it may be effective and safe in this population. In a randomized controlled trial of children (ages 6 months to 17 years), 15 of 17 patients allocated to romiplostim and 0 of 5 assigned to placebo had a platelet response (≥50 × 109/L for 2 consecutive weeks). Of 6 splenectomized children in the romiplostim arm, 4 demonstrated a platelet response. There were no treatment-related serious adverse events.27  In a subsequent open-label extension study, romiplostim maintained platelet responses for more than 4 years without significant toxicity.28  The results of a larger placebo-controlled trial (NCT01444417) that completed enrollment in 2015 have not yet been reported.

Eltrombopag is formulated as a pill to be taken once per day. The starting dose is 50 mg/d (25 mg/d in individuals of East Asian ancestry, those with liver impairment, or those age 1 to 5 years). The dose may be increased to a maximum of 75 mg/d to achieve a platelet count ≥50 × 109/L (Table 2). In a phase III trial, 197 adults were randomly assigned to eltrombopag or placebo for 6 months. Seventy-one of these patients had undergone splenectomy. A durable platelet response (50 to 400 × 109/L for at least 6 of the last 8 weeks on study) was observed in 51% of splenectomized patients assigned to eltrombopag. Eltrombopag was associated with reduced bleeding and concomitant medication usage.29  In a 6-week randomized trial, 114 patients were allocated to eltrombopag or placebo. Among the 45 splenectomized patients in the trial, a platelet response (≥50 × 109/L at 6 weeks) was more common in the eltrombopag arm than in the placebo arm (62.1% vs 15.4%).30  An open-label extension study included 115 splenectomized patients observed for up to 3 years of treatment with eltrombopag. Eighty percent achieved a platelet count ≥50 × 109/L at least once during the study.31  In a real-world retrospective study of 164 Spanish patients taking eltrombopag (104 of whom had undergone splenectomy), 88.5% manifested a response (platelet count ≥30 × 109/L and doubling from baseline).32 

Eltrombopag is approved by the Food and Drug Administration for children age 1 year old or older with chronic ITP who have not achieved an appropriate response by using other medications or with splenectomy. Approval was based on the placebo-controlled PETIT trials, which showed that 36% to 40% of eltrombopag-treated children maintained a platelet count of ≥50 × 109/L for the majority of time on study compared with 0% to 3% who received placebo. In the open-label extension studies that followed the randomized trials, 80% of patients achieved a platelet count ≥50 × 109/L on at least one time point during the study. Less than 10% of patients enrolled in the PETIT trials had been previously splenectomized.33,34 

The TRAs are generally well tolerated. In a pooled analysis of 14 trials of adults with ITP treated with romiplostim, bone marrow reticulin was observed in 17 of 921 patients.35  In the eltrombopag extension study, 2 of 117 bone marrow biopsies showed moderate to marked reticulin fibrosis.36  Systematic investigations of bone marrow fibrosis have not been undertaken in children. TRAs may increase the incidence of thromboembolism in some populations, but a meta-analysis suggested that these agents do not increase thrombosis in patients with ITP compared with placebo.37  When TRAs are discontinued, the platelet count generally returns to and may temporarily fall below baseline (rebound thrombocytopenia). Some patients experience prolonged platelet responses after discontinuation of therapy.38  Hepatotoxicity may occur with eltrombopag, and monitoring of liver function tests is mandatory.

Case 1 continued

Eltrombopag was initiated to achieve a sufficient platelet count for football season. The platelet count remained between 95 and 200 × 109/L for 4 months. After football season, eltrombopag was discontinued, and the patient maintained a platelet count >150 × 109/L without need for further treatment.

Case 2

A 64-year-old man was diagnosed with primary ITP 18 months ago when he presented with epistaxis, petechiae, and a platelet count of 8 × 109/L. He had a robust response to corticosteroids but relapsed when prednisone was tapered. One year ago, he received rituximab 375 mg/m2 once per week × 4 without response. Six months ago, he underwent laparoscopic splenectomy. Although his platelet count rose briefly after surgery, it subsequently fell to 10 × 109/L. Trials of eltrombopag and then romiplostim produced intermittent spikes in the platelet count but did not lead to a sustained response or permit reduction in the dose of prednisone. He remains dependent on prednisone 20 mg daily to maintain a platelet count of 20 to 30 × 109/L. He complains of insomnia, weight gain, and dysphoria on corticosteroids. A bone density scan shows osteopenia.

Tier 2

If a patient is unable to maintain a hemostatic platelet count with single-agent therapy using the options in Tier 1, we encourage participation in a clinical trial. If a suitable clinical trial is not available, we proceed to Tier 2 agents. We frequently prescribe Tier 2 agents not as monotherapy but in combination with a Tier 1 or another Tier 2 drug. Myriad multiagent regimens exist, but few have been formally studied.39-47  We prefer to combine drugs with different mechanisms of action, which allows for potential synergy between agents. For example, we often use a TRA to boost platelet production in combination with a drug that interferes with platelet clearance (eg, low-dose prednisone or danazol) or autoantibody production (eg, azathioprine or mycophenolate mofetil [MMF]). This approach may induce a more rapid increase in the platelet count than monotherapy, given the delayed time to response of many Tier 2 agents (Table 3).

Table 3

Tier 2 treatment options

Drug Dose Response rate (%)* Time to response Selected toxicities 
6-mercaptopurine 50-75 mg/m2 orally once per day 83 Not reported Hepatotoxicity, neutropenia, infection, pancreatitis 
Azathioprine 1-2 mg/kg orally once per day (maximum 150 mg/d) 40-60 3-6 mo Hepatotoxicity, neutropenia, infection, pancreatitis 
Cyclosporin A 5-6 mg/kg/d orally divided into 2 doses per day (titrate to blood levels of 100-200 ng/mL) 30-60 3-4 wk Nephrotoxicity, hypertension, tremor, parathesias, gingival hyperplasia 
Cyclophosphamide 0.3-1.0 g/m2 IV repeated once every 2 to 4 weeks × 1 to 3 doses; 50-200 mg orally once per day; after response has been achieved, dose can be tapered to 50 mg 24-85 1-16 wk Neutropenia, nausea/vomiting, infertility, secondary malignancy 
Danazol 50-800 mg/d orally divided into 2 to 4 doses per day 10-70 3-6 mo Hepatotoxicity, virilization, amenorrhea 
Dapsone 75-100 mg orally once per day 40-75 3 wk Hemolysis (in patients with G6PD deficiency), rash, nausea, methemoglobinuria 
Mycophenolate mofetil 250-1000 mg orally twice per day 11-80 4-6 wk Headache, diarrhea, nausea, anorexia, infection 
Vinca alkaloids Vincristine: 1 to 2 mg IV once per week × 3 weeks
Vinblastine: 10 mg IV once per week × 3 weeks 
10-75 5-7 d Peripheral neuropathy, vesication at infusion site, constipation, fever, neutropenia 
Drug Dose Response rate (%)* Time to response Selected toxicities 
6-mercaptopurine 50-75 mg/m2 orally once per day 83 Not reported Hepatotoxicity, neutropenia, infection, pancreatitis 
Azathioprine 1-2 mg/kg orally once per day (maximum 150 mg/d) 40-60 3-6 mo Hepatotoxicity, neutropenia, infection, pancreatitis 
Cyclosporin A 5-6 mg/kg/d orally divided into 2 doses per day (titrate to blood levels of 100-200 ng/mL) 30-60 3-4 wk Nephrotoxicity, hypertension, tremor, parathesias, gingival hyperplasia 
Cyclophosphamide 0.3-1.0 g/m2 IV repeated once every 2 to 4 weeks × 1 to 3 doses; 50-200 mg orally once per day; after response has been achieved, dose can be tapered to 50 mg 24-85 1-16 wk Neutropenia, nausea/vomiting, infertility, secondary malignancy 
Danazol 50-800 mg/d orally divided into 2 to 4 doses per day 10-70 3-6 mo Hepatotoxicity, virilization, amenorrhea 
Dapsone 75-100 mg orally once per day 40-75 3 wk Hemolysis (in patients with G6PD deficiency), rash, nausea, methemoglobinuria 
Mycophenolate mofetil 250-1000 mg orally twice per day 11-80 4-6 wk Headache, diarrhea, nausea, anorexia, infection 
Vinca alkaloids Vincristine: 1 to 2 mg IV once per week × 3 weeks
Vinblastine: 10 mg IV once per week × 3 weeks 
10-75 5-7 d Peripheral neuropathy, vesication at infusion site, constipation, fever, neutropenia 

G6PD, glucose 6-phosphate dehydrogenase.

*

Studies vary in their definition of response.

Vinca alkaloids.

Evidence for vinca alkaloids (VAs) is drawn mostly from studies conducted in the 1970s and 1980s, with few reports from the modern era.48-57  Published studies vary in which VAs were used (vincristine vs vinblastine), the dose and number of infusions, use of maintenance dosing, and definition of response. Although initial reports were promising, relatively poor durability of response has dampened enthusiasm for VAs. In an early report of 21 patients, two-thirds achieved a platelet count ≥50 × 109/L.55  Several subsequent studies showed similar response rates. However, later studies found that most responses were transient.48-51,53  In a prospective trial, 35% of patients treated with vincristine achieved a platelet count >100 × 109/L, but a 40% decline in the platelet count was observed as soon as 8 weeks after completion of 3 infusions.51  The fleetingness of response to VAs must be balanced against their toxicities, which include vesication, constipation, and peripheral neuropathy (symptoms generally arise after cumulative vincristine doses of 30 to 50 mg).48,49,51-55  Because patients have a relatively short time to response (5 to 7 days), we consider VAs for those who require a rapid rise in platelet count and do not respond to standard rescue therapy (Table 1). VAs are generally not a good option for induction of long-term remission.

Dapsone.

Dapsone was first discovered as a potential agent for ITP in 1988 when it improved the platelet count in a patient with systemic lupus erythematosus.58  There are no randomized clinical trials of dapsone in ITP. Its use is based on prospective and retrospective cohort studies.59-61  In one of the largest series, 66 patients with chronic ITP were treated with oral dapsone at a dose of 75 to 100 mg. A platelet count >50 × 109/L was achieved in 33 patients (50%), 20 of whom continued to respond for a median duration of 12.5 months.59  In a literature review of dapsone, overall response rates ranged from 40% to 75%.62 

Toxicities of dapsone include methemoglobinemia, agranulocytosis, aplastic anemia, hypersensitivity, gastrointestinal complications, and hemolysis in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency.62  We screen males for G6PD deficiency before beginning dapsone.

Danazol.

Danazol is an attenuated androgen. Response rates vary widely—from 10% to 70%—between studies.63-69  One factor that may account for this variation is heterogeneity in dosing, with some studies investigating low-dose danazol (50 mg orally once per day)64,65  compared with conventional dosing (400 to 800 mg divided into 2 to 4 doses per day).63,66,67,69  The effect of danazol appears to be greatest when patients are able to remain on therapy for a prolonged period. In a series of 96 patients, 7 (70%) of the 10 patients in whom danazol therapy was discontinued relapsed within 6 months. Responses were more durable for patients who remained on therapy for at least 1 year.69 

It has been our observation that danazol is more likely to elicit a response in patients who respond well to corticosteroids. Therefore, we use corticosteroid responsiveness as a criterion for selecting danazol. Liver function tests must be monitored regularly. We rarely use danazol in women because of its virilizing effects.

Cyclophosphamide.

Cyclophosphamide may be given intravenously (500 to 1000 mg/m2 once every 3 to 4 weeks × 2 to 3 courses) or orally (1 to 2 mg/kg once per day). Evidence for its use in ITP is limited to 2 early studies, which showed complete or excellent responses in 50% of patients and partial responses in an additional 20% of patients.70,71  Although these response rates compare favorably with other Tier 2 agents, we use cyclophosphamide infrequently because of a paucity of data and the potential for serious long-term sequelae, including malignancy and infertility. Patients receiving cyclophosphamide should drink at least 2 L of fluids per day to prevent hemorrhagic cystitis, and blood counts should be monitored once per week.

Antimetabolites.

The antimetabolites, azathioprine, 6-mercaptopurine, and MMF have been studied in patients with refractory ITP. Azathioprine demonstrated an overall response rate of 64% in a study of 53 adult patients. When the drug was discontinued, 42% remained in remission for a variable follow-up of 7 to 43 months.72  Smaller series also showed favorable results.73,74  One study of 6-mercaptopurine in pediatric autoimmune cytopenias has been published. In that series of 29 patients, there was an 83% response rate, yet only 4 children (2 with ITP) remained in remission without additional immunosuppressive therapy.75  Major toxicities of azathioprine and 6-mercaptopurine include myelosuppression, hepatotoxicity, and pancreatitis.

A greater number of studies have investigated MMF.76-82  We begin MMF at a dose of 500 mg orally twice per day and increase the dose to 1000 to 1500 mg twice per day after 2 weeks. Protocols that use this approach have demonstrated overall response rates of 50% to 60%.76-81  Durability of response after discontinuation of therapy is variable.77,79,82  MMF is generally well tolerated; principal adverse effects include headache and gastrointestinal symptoms.

Cyclosporin A.

Several small studies highlight the effectiveness of cyclosporine A for the management of refractory ITP.83-85  In the largest study of 20 patients, response rates were 50% to 60%. Adverse effects, which include hypertension and nephrotoxicity, led to discontinuation in 6 patients (30%).85  A study of 14 children reported a response rate of ∼30% and 1 life-threatening fungal infection.84  Patients require regular monitoring of blood pressure, renal function, and drug levels.

Case 2 continued

Danazol was initiated at a dose of 200 mg twice per day and increased to 400 mg twice per day while the patient remained on romiplostim 10 μg/kg once per week and prednisone 20 mg once per day. The patient tolerated danazol well without transaminitis or other toxicities. Three months after beginning danazol, his platelet count was 60 × 109/L. Over the ensuing 6 weeks, prednisone was tapered off. The patient remains on danazol and romiplostim with a platelet count of 40 to 50 × 109/L.

Tier 3

In the rare patient with serious bleeding who does not respond to or is ineligible for all Tier 1 and Tier 2 treatment options, including combination therapy, we recommend enrollment in a clinical trial. If a suitable trial is not available, we consider Tier 3 approaches (Figure 1). Tier 3 options are characterized by low response rates and/or high toxicity. Many studies of Tier 3 agents are small and include a mix of patients with newly diagnosed and intractable disease, which clouds the interpretation of response rates in refractory ITP. Because Tier 3 treatment options have a weak evidentiary basis and unfavorable therapeutic index, we reserve them for severely refractory patients with a history of serious or life-threatening bleeding. Table 4 summarizes these approaches, highlighting evidence from studies of 10 or more patients.86-100 

Table 4

Tier 3 treatment options

Treatment Reference Dose Response rate (%) Selected toxicities 
ATRA 86 10 mg orally 3 times per day 29 Retinoic acid syndrome, flu-like symptoms, musculoskeletal pain, nausea/vomiting, peripheral neuropathy 
Autologous HSCT 87 Cyclophosphamide 50 mg/kg IV once per day × 4 days (conditioning) 43 Neutropenic fever, infection 
Colchicine 88 1.2 g orally once per day 21 Agranulocytosis, neuritis, diarrhea, nausea/vomiting 
Interferon α 89-92 Various 0-36 Neutropenia, fever, influenza-like symptoms, hepatotoxicity 
Plasma exchange 93-95 One plasma volume exchange once per day × 1 to 8 days 29-80 Hypocalcemia, anaphylactoid reactions 
Protein A immunoadsorption 96 Average of 6 treatments (0.25 to 2.0 L plasma per treatment) over 2 to 3 weeks 21 Hypersensitivity reactions, pain, nausea/vomiting 
Cardiopulmonary complications 
Vitamin C 97-100 2 g orally once per day 0-82 Dsypepsia, nausea/vomiting 
Treatment Reference Dose Response rate (%) Selected toxicities 
ATRA 86 10 mg orally 3 times per day 29 Retinoic acid syndrome, flu-like symptoms, musculoskeletal pain, nausea/vomiting, peripheral neuropathy 
Autologous HSCT 87 Cyclophosphamide 50 mg/kg IV once per day × 4 days (conditioning) 43 Neutropenic fever, infection 
Colchicine 88 1.2 g orally once per day 21 Agranulocytosis, neuritis, diarrhea, nausea/vomiting 
Interferon α 89-92 Various 0-36 Neutropenia, fever, influenza-like symptoms, hepatotoxicity 
Plasma exchange 93-95 One plasma volume exchange once per day × 1 to 8 days 29-80 Hypocalcemia, anaphylactoid reactions 
Protein A immunoadsorption 96 Average of 6 treatments (0.25 to 2.0 L plasma per treatment) over 2 to 3 weeks 21 Hypersensitivity reactions, pain, nausea/vomiting 
Cardiopulmonary complications 
Vitamin C 97-100 2 g orally once per day 0-82 Dsypepsia, nausea/vomiting 

ATRA, all-trans retinoic acid; HSCT, hematopoietic stem cell transplant

Conclusion

Refractory ITP is challenging to treat and may be associated with poor outcomes.11,12  Our approach to management involves confirmation of the diagnosis, consideration of observation, and a tiered treatment strategy for those who require therapy (Figure 1). With recent advances in treatment, including rituximab and the TRAs, a greater proportion of patients than ever before are able to maintain hemostatic platelet counts with acceptable tolerability and safety. Still, current therapeutic options fail for a subset of highly refractory patients. For these individuals, new treatments are sorely needed. Novel agents, including an anti-CD40 ligand (BMS-986004) and splenic tyrosine kinase inhibitor (fostamatinib) as well as a number of repurposed drugs (eg, decitabine, oseltamivir, sirolimus, and thalidomide), are currently in clinical trials. We encourage patients and physicians to participate in clinical trials to support development of new treatments so that the number of patients with truly intractable disease may continue to decrease.

Authorship

Contribution: A.C. and C.E.N. searched the literature and wrote the manuscript.

Conflict-of-interest disclosure: A.C. has served as a consultant for Amgen, Bracco, CSL Behring, and Genzyme; has received research support from Spark Therapeutics and T2 Biosystems; and has provided expert witness testimony related to immune thrombocytopenia. C.E.N. has served as a consultant for Genzyme.

Correspondence: Adam Cuker, Hospital of the University of Pennsylvania, Penn Blood Disorders Center, Dulles 3, 3400 Spruce St, Philadelphia, PA 19014; e-mail: adam.cuker@uphs.upenn.edu.

References

References
1
Vesely
SK
Perdue
JJ
Rizvi
MA
Terrell
DR
George
JN
Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review.
Ann Intern Med
2004
, vol. 
140
 
2
(pg. 
112
-
120
)
2
Rodeghiero
F
Stasi
R
Gernsheimer
T
, et al. 
Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.
Blood
2009
, vol. 
113
 
11
(pg. 
2386
-
2393
)
3
Neunert
C
Lim
W
Crowther
M
Cohen
A
Solberg
L
Jr
Crowther
MA
American Society of Hematology
The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.
Blood
2011
, vol. 
117
 
16
(pg. 
4190
-
4207
)
4
Kojouri
K
Vesely
SK
Terrell
DR
George
JN
Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications.
Blood
2004
, vol. 
104
 
9
(pg. 
2623
-
2634
)
5
Mikhael
J
Northridge
K
Lindquist
K
Kessler
C
Deuson
R
Danese
M
Short-term and long-term failure of laparoscopic splenectomy in adult immune thrombocytopenic purpura patients: a systematic review.
Am J Hematol
2009
, vol. 
84
 
11
(pg. 
743
-
748
)
6
McMillan
R
Bussel
JB
George
JN
Lalla
D
Nichol
JL
Self-reported health-related quality of life in adults with chronic immune thrombocytopenic purpura.
Am J Hematol
2008
, vol. 
83
 
2
(pg. 
150
-
154
)
7
Snyder
CF
Mathias
SD
Cella
D
Isitt
JJ
Wu
AW
Young
J
Health-related quality of life of immune thrombocytopenic purpura patients: results from a web-based survey.
Curr Med Res Opin
2008
, vol. 
24
 
10
(pg. 
2767
-
2776
)
8
Office of Disease Prevention and Health Promotion. Health-Related Quality of Life and Well-Being. https://www.healthypeople.gov/2020/about/foundation-health-measures/Health-Related-Quality-of-Life-and-Well-Being. Accessed 31 March, 2016
9
Provan
D
Stasi
R
Newland
AC
, et al. 
International consensus report on the investigation and management of primary immune thrombocytopenia.
Blood
2010
, vol. 
115
 
2
(pg. 
168
-
186
)
10
Lakshmanan
S
Cuker
A
Contemporary management of primary immune thrombocytopenia in adults.
J Thromb Haemost
2012
, vol. 
10
 
10
(pg. 
1988
-
1998
)
11
McMillan
R
Durette
C
Long-term outcomes in adults with chronic ITP after splenectomy failure.
Blood
2004
, vol. 
104
 
4
(pg. 
956
-
960
)
12
Bourgeois
E
Caulier
MT
Delarozee
C
Brouillard
M
Bauters
F
Fenaux
P
Long-term follow-up of chronic autoimmune thrombocytopenic purpura refractory to splenectomy: a prospective analysis.
Br J Haematol
2003
, vol. 
120
 
6
(pg. 
1079
-
1088
)
13
Neunert
CE
Buchanan
GR
Imbach
P
, et al. 
Intercontinental Cooperative ITP Study Group Registry II Participants
Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS).
Blood
2013
, vol. 
121
 
22
(pg. 
4457
-
4462
)
14
McMillan
R
Classical management of refractory adult immune (idiopathic) thrombocytopenic purpura.
Blood Rev
2002
, vol. 
16
 
1
(pg. 
51
-
55
)
15
Stasi
R
Stipa
E
Masi
M
, et al. 
Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
Am J Med
1995
, vol. 
98
 
5
(pg. 
436
-
442
)
16
Kavanaugh
A
Wells
AF
Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis.
Rheumatology (Oxford)
2014
, vol. 
53
 
10
(pg. 
1742
-
1751
)
17
Arnold
DM
Dentali
F
Crowther
MA
, et al. 
Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura.
Ann Intern Med
2007
, vol. 
146
 
1
(pg. 
25
-
33
)
18
Patel
VL
Mahévas
M
Lee
SY
, et al. 
Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia.
Blood
2012
, vol. 
119
 
25
(pg. 
5989
-
5995
)
19
Cooper
N
Evangelista
ML
Amadori
S
Stasi
R
Should rituximab be used before or after splenectomy in patients with immune thrombocytopenic purpura?
Curr Opin Hematol
2007
, vol. 
14
 
6
(pg. 
642
-
646
)
20
Zaja
F
Vianelli
N
Volpetti
S
, et al. 
Low-dose rituximab in adult patients with primary immune thrombocytopenia.
Eur J Haematol
2010
, vol. 
85
 
4
(pg. 
329
-
334
)
21
Koutsianas
C
Thomas
K
Vassilopoulos
D
Prevention of HBV reactivation in patients treated with biologic agents [published online ahead of print on 6 February, 2016].
Expert Rev Clin Pharmacol
22
Carson
KR
Evens
AM
Richey
EA
, et al. 
Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.
Blood
2009
, vol. 
113
 
20
(pg. 
4834
-
4840
)
23
Nazi
I
Kelton
JG
Larché
M
, et al. 
The effect of rituximab on vaccine responses in patients with immune thrombocytopenia.
Blood
2013
, vol. 
122
 
11
(pg. 
1946
-
1953
)
24
Kuter
DJ
Bussel
JB
Lyons
RM
, et al. 
Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial.
Lancet
2008
, vol. 
371
 
9610
(pg. 
395
-
403
)
25
Kuter
DJ
Bussel
JB
Newland
A
, et al. 
Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy.
Br J Haematol
2013
, vol. 
161
 
3
(pg. 
411
-
423
)
26
Khellaf
M
Michel
M
Quittet
P
, et al. 
Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program.
Blood
2011
, vol. 
118
 
16
(pg. 
4338
-
4345
)
27
Bussel
JB
Buchanan
GR
Nugent
DJ
, et al. 
A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.
Blood
2011
, vol. 
118
 
1
(pg. 
28
-
36
)
28
Bussel
JB
Hsieh
L
Buchanan
GR
, et al. 
Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP).
Pediatr Blood Cancer
2014
, vol. 
62
 
2
(pg. 
208
-
213
)
29
Cheng
G
Saleh
MN
Marcher
C
, et al. 
Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study.
Lancet
2011
, vol. 
377
 
9763
(pg. 
393
-
402
)
30
Bussel
JB
Provan
D
Shamsi
T
, et al. 
Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial.
Lancet
2009
, vol. 
373
 
9664
(pg. 
641
-
648
)
31
Saleh
MN
Bussel
JB
Cheng
G
, et al. 
EXTEND Study Group
Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study.
Blood
2013
, vol. 
121
 
3
(pg. 
537
-
545
)
32
González-López
TJ
Alvarez-Román
MT
Pascual
C
, et al. 
Eltrombopag safety and efficacy for primary chronic immune thrombocytopenia in clinical practice [published online ahead of print 28 December, 2015].
Eur J Haematol
33
Bussel
JB
de Miguel
PG
Despotovic
JM
, et al. 
Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study.
Lancet Haematol
2015
, vol. 
2
 
8
(pg. 
e315
-
e325
)
34
Grainger
JD
Locatelli
F
Chotsampancharoen
T
, et al. 
Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial.
Lancet
2015
, vol. 
386
 
10004
(pg. 
1649
-
1658
)
35
Cines
DB
Gernsheimer
T
Wasser
J
, et al. 
Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim.
Int J Hematol
2015
, vol. 
102
 
3
(pg. 
259
-
270
)
36
Brynes
RK
Orazi
A
Theodore
D
, et al. 
Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study.
Am J Hematol
2015
, vol. 
90
 
7
(pg. 
598
-
601
)
37
Catalá-López
F
Corrales
I
de la Fuente-Honrubia
C
, et al. 
Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials.
Med Clin (Barc)
2015
, vol. 
145
 
12
(pg. 
511
-
519
)
38
Cuker
A
Prak
ET
Cines
DB
Can immune thrombocytopenia be cured with medical therapy?
Semin Thromb Hemost
2015
, vol. 
41
 
4
(pg. 
395
-
404
)
39
Arnold
DM
Nazi
I
Santos
A
, et al. 
Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura.
Blood
2010
, vol. 
115
 
1
(pg. 
29
-
31
)
40
Choi
PY
Roncolato
F
Badoux
X
Ramanathan
S
Ho
SJ
Chong
BH
A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4).
Blood
2015
, vol. 
126
 
4
(pg. 
500
-
503
)
41
Li
Y
Wang
YY
Fei
HR
Wang
L
Yuan
CL
Efficacy of low-dose rituximab in combination with recombinant human thrombopoietin in treating ITP.
Eur Rev Med Pharmacol Sci
2015
, vol. 
19
 
9
(pg. 
1583
-
1588
)
42
Bussel
JB
Lee
CS
Seery
C
, et al. 
Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration.
Haematologica
2014
, vol. 
99
 
7
(pg. 
1264
-
1271
)
43
Cui
ZG
Liu
XG
Qin
P
, et al. 
Recombinant human thrombopoietin in combination with cyclosporin A as a novel therapy in corticosteroid-resistant primary immune thrombocytopenia.
Chin Med J (Engl)
2013
, vol. 
126
 
21
(pg. 
4145
-
4148
)
44
Gómez-Almaguer
D
Solano-Genesta
M
Tarín-Arzaga
L
, et al. 
Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias.
Blood
2010
, vol. 
116
 
23
(pg. 
4783
-
4785
)
45
Williams
JA
Boxer
LA
Combination therapy for refractory idiopathic thrombocytopenic purpura in adolescents.
J Pediatr Hematol Oncol
2003
, vol. 
25
 
3
(pg. 
232
-
235
)
46
Figueroa
M
Gehlsen
J
Hammond
D
, et al. 
Combination chemotherapy in refractory immune thrombocytopenic purpura.
N Engl J Med
1993
, vol. 
328
 
17
(pg. 
1226
-
1229
)
47
Boruchov
DM
Gururangan
S
Driscoll
MC
Bussel
JB
Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP).
Blood
2007
, vol. 
110
 
10
(pg. 
3526
-
3531
)
48
Manoharan
A
Slow infusion of vincristine in the treatment of idiopathic thrombocytopenic purpura.
Am J Hematol
1986
, vol. 
21
 
2
(pg. 
135
-
138
)
49
Fenaux
P
Quiquandon
I
Caulier
MT
Simon
M
Walter
MP
Bauters
F
Slow infusions of vinblastine in the treatment of adult idiopathic thrombocytopenic purpura: a report on 43 cases.
Blut
1990
, vol. 
60
 
4
(pg. 
238
-
241
)
50
Burton
IE
Roberts
BE
Child
JA
Montgomery
DA
Raper
CG
Responses to cinvristine in refractory idiopathic thrombocytopenic purpura.
BMJ
1976
, vol. 
2
 
6041
pg. 
918
 
51
Sikorska
A
Słomkowski
M
Marlanka
K
Konopka
L
Górski
T
The use of vinca alkaloids in adult patients with refractory chronic idiopathic thrombocytopenia.
Clin Lab Haematol
2004
, vol. 
26
 
6
(pg. 
407
-
411
)
52
Cervantes
F
Montserrat
E
Rozman
C
Diumenjo
C
Feliu
E
Grañena
A
Low-dose vincristine in the treatment of corticosteroid-refractory idiopathic thrombocytopenic purpura (ITP) in non-splenectomized patients.
Postgrad Med J
1980
, vol. 
56
 
660
(pg. 
711
-
714
)
53
Stirnemann
J
Kaddouri
N
Khellaf
M
, et al. 
Vincristine efficacy and safety in treating immune thrombocytopenia: a retrospective study of 35 patients.
Eur J Haematol
2016
, vol. 
96
 
3
(pg. 
269
-
275
)
54
Facon
T
Caulier
MT
Wattel
E
Jouet
JP
Bauters
F
Fenaux
P
A randomized trial comparing vinblastine in slow infusion and by bolus i.v. injection in idiopathic thrombocytopenic purpura: a report on 42 patients.
Br J Haematol
1994
, vol. 
86
 
3
(pg. 
678
-
680
)
55
Ahn
YS
Harrington
WJ
Seelman
RC
Eytel
CS
Vincristine therapy of idiopathic and secondary thrombocytopenias.
N Engl J Med
1974
, vol. 
291
 
8
(pg. 
376
-
380
)
56
Ahn
YS
Harrington
WJ
Mylvaganam
R
Allen
LM
Pall
LM
Slow infusion of vinca alkaloids in the treatment of idiopathic thrombocytopenic purpura.
Ann Intern Med
1984
, vol. 
100
 
2
(pg. 
192
-
196
)
57
Szczepanik
AB
Sikorska
A
Slomkowski
M
Konopka
L
The use of vinca alkaloids in preparation for splenectomy of corticosteroid refractory chronic immune thrombocytopenic purpura patients.
Int J Lab Hematol
2007
, vol. 
29
 
5
(pg. 
347
-
351
)
58
Moss
C
Hamilton
PJ
Thrombocytopenia in systemic lupus erythematosus responsive to dapsone.
BMJ
1988
, vol. 
297
 
6643
pg. 
266
 
59
Godeau
B
Durand
JM
Roudot-Thoraval
F
, et al. 
Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases.
Br J Haematol
1997
, vol. 
97
 
2
(pg. 
336
-
339
)
60
Oo
T
Hill
QA
Disappointing response to dapsone as second line therapy for primary ITP: a case series.
Ann Hematol
2015
, vol. 
94
 
6
(pg. 
1053
-
1054
)
61
Patel
AP
Patil
AS
Dapsone for immune thrombocytopenic purpura in children and adults.
Platelets
2015
, vol. 
26
 
2
(pg. 
164
-
167
)
62
Rodrigo
C
Gooneratne
L
Dapsone for primary immune thrombocytopenia in adults and children: an evidence-based review.
J Thromb Haemost
2013
, vol. 
11
 
11
(pg. 
1946
-
1953
)
63
Ahn
YS
Harrington
WJ
Simon
SR
Mylvaganam
R
Pall
LM
So
AG
Danazol for the treatment of idiopathic thrombocytopenic purpura.
N Engl J Med
1983
, vol. 
308
 
23
(pg. 
1396
-
1399
)
64
Ahn
YS
Mylvaganam
R
Garcia
RO
Kim
CI
Palow
D
Harrington
WJ
Low-dose danazol therapy in idiopathic thrombocytopenic purpura.
Ann Intern Med
1987
, vol. 
107
 
2
(pg. 
177
-
181
)
65
Mylvaganam
R
Ahn
YS
Garcia
RO
Kim
CI
Harrington
WJ
Very low dose danazol in idiopathic thrombocytopenic purpura and its role as an immune modulator.
Am J Med Sci
1989
, vol. 
298
 
4
(pg. 
215
-
220
)
66
Edelmann
DZ
Knobel
B
Virag
I
Meytes
D
Danazol in non-splenectomized patients with refractory idiopathic thrombocytopenic purpura.
Postgrad Med J
1990
, vol. 
66
 
780
(pg. 
827
-
830
)
67
Maloisel
F
Andrès
E
Zimmer
J
, et al. 
Danazol therapy in patients with chronic idiopathic thrombocytopenic purpura: long-term results.
Am J Med
2004
, vol. 
116
 
9
(pg. 
590
-
594
)
68
Andrès
E
Zimmer
J
Noel
E
Kaltenbach
G
Koumarianou
A
Maloisel
F
Idiopathic thrombocytopenic purpura: a retrospective analysis in 139 patients of the influence of age on the response to corticosteroids, splenectomy and danazol.
Drugs Aging
2003
, vol. 
20
 
11
(pg. 
841
-
846
)
69
Ahn
YS
Rocha
R
Mylvaganam
R
Garcia
R
Duncan
R
Harrington
WJ
Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women.
Ann Intern Med
1989
, vol. 
111
 
9
(pg. 
723
-
729
)
70
Reiner
A
Gernsheimer
T
Slichter
SJ
Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura.
Blood
1995
, vol. 
85
 
2
(pg. 
351
-
358
)
71
Verlin
M
Laros
RK
Jr
Penner
JA
Treatment of refractory thrombocytopenic purpura with cyclophosphamine.
Am J Hematol
1976
, vol. 
1
 
1
(pg. 
97
-
104
)
72
Quiquandon
I
Fenaux
P
Caulier
MT
Pagniez
D
Huart
JJ
Bauters
F
Re-evaluation of the role of azathioprine in the treatment of adult chronic idiopathic thrombocytopenic purpura: a report on 53 cases.
Br J Haematol
1990
, vol. 
74
 
2
(pg. 
223
-
228
)
73
Sussman
LN
Azathioprine in refractory idiopathic thrombocytopenic purpura.
JAMA
1967
, vol. 
202
 
4
(pg. 
259
-
263
)
74
Goebel
KM
Gassel
WD
Goebel
FD
Evaluation of azathioprine in autoimmune thrombocytopenia and lupus erythematosus.
Scand J Haematol
1973
, vol. 
10
 
1
(pg. 
28
-
34
)
75
Sobota
A
Neufeld
EJ
Lapsia
S
Bennett
CM
Response to mercaptopurine for refractory autoimmune cytopenias in children.
Pediatr Blood Cancer
2009
, vol. 
52
 
1
(pg. 
80
-
84
)
76
Taylor
A
Neave
L
Solanki
S
, et al. 
Mycophenolate mofetil therapy for severe immune thrombocytopenia.
Br J Haematol
2015
, vol. 
171
 
4
(pg. 
625
-
630
)
77
Colović
M
Suvajdzic
N
Colović
N
Tomin
D
Vidović
A
Palibrk
V
Mycophenolate mophetil therapy for chronic immune thrombocytopenic purpura resistant to steroids, immunosuppressants, and/or splenectomy in adults.
Platelets
2011
, vol. 
22
 
2
(pg. 
153
-
156
)
78
Provan
D
Moss
AJ
Newland
AC
Bussel
JB
Efficacy of mycophenolate mofetil as single-agent therapy for refractory immune thrombocytopenic purpura.
Am J Hematol
2006
, vol. 
81
 
1
(pg. 
19
-
25
)
79
Zhang
WG
Ji
L
Cao
XM
, et al. 
Mycophenolate mofetil as a treatment for refractory idiopathic thrombocytopenic purpura.
Acta Pharmacol Sin
2005
, vol. 
26
 
5
(pg. 
598
-
602
)
80
Kotb
R
Pinganaud
C
Trichet
C
, et al. 
Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias: a single center preliminary study.
Eur J Haematol
2005
, vol. 
75
 
1
(pg. 
60
-
64
)
81
Howard
J
Hoffbrand
AV
Prentice
HG
Mehta
A
Mycophenolate mofetil for the treatment of refractory auto-immune haemolytic anaemia and auto-immune thrombocytopenia purpura.
Br J Haematol
2002
, vol. 
117
 
3
(pg. 
712
-
715
)
82
Hou
M
Peng
J
Shi
Y
, et al. 
Mycophenolate mofetil (MMF) for the treatment of steroid-resistant idiopathic thrombocytopenic purpura.
Eur J Haematol
2003
, vol. 
70
 
6
(pg. 
353
-
357
)
83
Zver
S
Zupan
IP
Cernelc
P
Cyclosporin A as an immunosuppressive treatment modality for patients with refractory autoimmune thrombocytopenic purpura after splenectomy failure.
Int J Hematol
2006
, vol. 
83
 
3
(pg. 
238
-
242
)
84
Perrotta
S
Amendola
G
Locatelli
F
, et al. 
Treatment with short-term, high-dose cyclosporin A in children with refractory chronic idiopathic thrombocytopenic purpura.
Br J Haematol
2003
, vol. 
121
 
1
(pg. 
143
-
147
)
85
Kappers-Klunne
MC
van’t Veer
MB
Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy.
Br J Haematol
2001
, vol. 
114
 
1
(pg. 
121
-
125
)
86
Dai
L
Zhang
R
Wang
Z
, et al. 
Efficacy of immunomodulatory therapy with all-trans retinoid acid in adult patients with chronic immune thrombocytopenia.
Thromb Res
2016
, vol. 
140
 (pg. 
73
-
80
)
87
Huhn
RD
Fogarty
PF
Nakamura
R
, et al. 
High-dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia.
Blood
2003
, vol. 
101
 
1
(pg. 
71
-
77
)
88
Strother
SV
Zuckerman
KS
LoBuglio
AF
Colchicine therapy for refractory idiopathic thrombocytopenic purpura.
Arch Intern Med
1984
, vol. 
144
 
11
(pg. 
2198
-
2200
)
89
Donato
H
Kohan
R
Picón
A
, et al. 
Alpha-interferon therapy induces improvement of platelet counts in children with chronic idiopathic thrombocytopenic purpura.
J Pediatr Hematol Oncol
2001
, vol. 
23
 
9
(pg. 
598
-
603
)
90
Fujimura
K
Takafuta
T
Kuriya
S
, et al. 
Recombinant human interferon alpha-2b (rh IFN alpha-2b) therapy for steroid resistant idiopathic thrombocytopenic purpura (ITP).
Am J Hematol
1996
, vol. 
51
 
1
(pg. 
37
-
44
)
91
Dubbeld
P
Hillen
HF
Schouten
HC
Interferon treatment of refractory idiopathic thrombocytopenic purpura (ITP).
Eur J Haematol
1994
, vol. 
52
 
4
(pg. 
233
-
235
)
92
Proctor
SJ
Jackson
G
Carey
P
, et al. 
Improvement of platelet counts in steroid-unresponsive idiopathic immune thrombocytopenic purpura after short-course therapy with recombinant alpha 2b interferon.
Blood
1989
, vol. 
74
 
6
(pg. 
1894
-
1897
)
93
Buskard
N
Rock
G
Nair
R
Canadian Apheresis Group
The Canadian experience using plasma exchange for immune thrombocytopenic purpura.
Transfus Sci
1998
, vol. 
19
 
3
(pg. 
295
-
300
)
94
Blanchette
VS
Hogan
VA
McCombie
NE
, et al. 
Intensive plasma exchange therapy in ten patients with idiopathic thrombocytopenic purpura.
Transfusion
1984
, vol. 
24
 
5
(pg. 
388
-
394
)
95
Marder
VJ
Nusbacher
J
Anderson
FW
One-year follow-up of plasma exchange therapy in 14 patients with idiopathic thrombocytopenic purpura.
Transfusion
1981
, vol. 
21
 
3
(pg. 
291
-
298
)
96
Snyder
HW
Jr
Cochran
SK
Balint
JP
Jr
, et al. 
Experience with protein A-immunoadsorption in treatment-resistant adult immune thrombocytopenic purpura.
Blood
1992
, vol. 
79
 
9
(pg. 
2237
-
2245
)
97
Jubelirer
SJ
Pilot study of ascorbic acid for the treatment of refractory immune thrombocytopenic purpura.
Am J Hematol
1993
, vol. 
43
 
1
(pg. 
44
-
46
)
98
van der Beek-Boter
JW
van Oers
MH
von dem Borne
AE
Klaassen
RJ
Ascorbate for the treatment of ITP.
Eur J Haematol
1992
, vol. 
48
 
1
(pg. 
61
-
62
)
99
Brox
AG
Howson-Jan
K
Fauser
AA
Treatment of idiopathic thrombocytopenic purpura with ascorbate.
Br J Haematol
1988
, vol. 
70
 
3
(pg. 
341
-
344
)
100
Verhoef
GE
Boonen
S
Boogaerts
MA
Ascorbate for the treatment of refractory idiopathic thrombocytopenic purpura.
Br J Haematol
1990
, vol. 
74
 
2
(pg. 
234
-
235
)