Second-line therapies in immune thrombocytopenia

Transcription

1 WHEN ANTIBODY RESPONSE GOES AWRY Second-line therapies in immune thrombocytopenia Rachael F. Grace 1 and Cindy Neunert 2 1 Pediatric Hematology/Oncology, Dana-Farber/Boston Children s Cancer and Blood Disorder Center, Boston, MA; and 2 Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, NY Immune thrombocytopenia (ITP) is a rare, acquired autoimmune condition characterized by a low platelet count and an increased risk of bleeding. Although many children and adults with ITP will not need therapy beyond historic first-line treatments of observation, steroids, intravenous immunoglobulin (IVIG), and anti-d globulin, others will have an indication for second-line treatment. Selecting a second-line therapy depends on the reason for treatment, which can vary from bleeding to implications for health-related quality of life (HRQoL) to likelihood of remission and patient preference with regard to adverse effects, route of administration, and cost. Published studies of these treatments are limited by lack of comparative trials, in addition to inconsistent outcome measures, definitions, and efficacy endpoints. This article provides an up-to-date comparison of the second-line treatments, highlighting important outcome measures including bleeding, HRQoL, fatigue, and platelet counts, which influence treatment selection in a shared decision-making model. Learning Objectives Describe the outcome measures that can used to assess efficacy of ITP treatments Recognize the limitations and difficulties in comparing outcomes of clinical trials of second-line ITP treatments Develop an approach to a shared decision-making model for selecting a second-line treatment in a patient with ITP Immune thrombocytopenia (ITP), characterized by isolated thrombocytopenia and a risk for hemorrhage, is a heterogeneous disorder with variable clinical symptoms. Bleeding events are unpredictable with currently available laboratory testing. Many patients with ITP, even in the setting of severe thrombocytopenia, do not exhibit significant bleeding. Although bleeding may be the indication for treatment, often hematologists choose to treat patients with pharmacologic therapies for a variety of other reasons, including implications for health-related quality of life (HRQoL), debilitating fatigue, perisurgical planning, or to induce a remission. For this reason, the goal of the therapy or the efficacy measure of a response may differ among patients. Historic first-line therapies for ITP include observation, steroids, intravenous immunoglobulin (IVIG), and anti-d globulin. These common approaches are used up front in newly diagnosed patients. Steroids, IVIG, and anti-d globulin may also be used periodically throughout the disease course in patients managed primarily with observation, during times of breakthrough bleeding, surgeries, or specific activities. Second-line treatments, which, for this manuscript, include therapies beyond observation, steroids, IVIG, and anti-d globulin, can induce a sustained increase in the platelet count with ongoing treatment and/or may alter the disease. Studies comparing treatments in ITP are scarce, and the outcome measures used across studies are inconsistent, despite the establishment of standard guidelines for diagnosis and response criteria. 1,2 Novel types of therapies for ITP continue to expand, and selecting second-line treatments remains a standard, yet challenging, aspect of providing ITP care. Shared decision-making is also critical, given that these agents vary considerably with regard to cost, ease of administration, potential adverse effects, and likelihood of remission, all of which may influence patient preference. By comparing secondline treatments with a focus on important patient-related outcomes (Tables 1 and 2), clinicians and patients can make better-informed decisions based on the indication for treatment. Measures of ITP treatment response Platelet count The platelet count has been the historic surrogate primary outcome of response to ITP treatment, because it is objective and easily compared. If the goal of treatment is to raise the platelet count, the aim is often to obtain a safe platelet count in which active bleeding or risk of serious bleeding is thought to be low. The International Working Group has defined ITP treatment response on the basis of platelet count and recommends that the cumulative time with a sustained response be calculated. 1 Despite these guidelines, historic clinical trials and case series report platelet response using a wide range of criteria; thus, directly comparing the effect of individual treatments by platelet count, the most objective and used response measure, is challenging (Table 1). This inconsistency also highlights the fact that clinicians and investigators have varying ideas of the optimal platelet response to treatment. In clinical practice, for providers and patients, a definition of response may reflect a platelet count that achieves a specific primary Conflict-of-interest disclosures: R.F.G. has received research funding from Agios Pharmaceuticals. C.N. declares no competing financial interests. Off-label drug use: Rituximab for the treatment of ITP, Dapsone for the treatment of ITP, Mycophenolate mofetil for the treatment of ITP, and Romiplostim for treatment of pediatric ITP. 698 American Society of Hematology

2 Table 1. Comparison of reported efficacy of second-line treatments with regard to platelet count, bleeding, HRQoL, and fatigue Platelet count* Bleeding HRQoL Fatigue Splenectomy Early response: 66-92% 28 No studies No improvement in ITP-PAQ 16 No studies Durable response: 60-70% 29 Lower ITP-PAQ scores as compared with those without splenectomy 34 Rituximab Platelet counts /L 6 mo postinfusion: 40-60% 38 No difference (9.2% vs Durable response: 21-26% 5 y after infusion %) compared with non-rituximab treatment or placebo 37 No improvement as measured by change in Possible increase with 22% ITP-PAQ or SF-36 16,39 of patients receiving rituximab reporting fatigue (8% on placebo) 39 Romiplostim Adult trials Platelet count $ /L during $6 of the last 8 wk of treatment: 38% No difference compared romiplostim vs 0% placebo 11 with non-romiplostim Platelet count $ /L: 71-92% romiplostim vs 0-51% placebo or treatment or placebo 11 non-romiplostim treatment 46 Improvement in symptoms, activity, psychological health, and overall HRQoL as measured with the ITP-PAQ and EQ-5D 7 No improvement meeting MID measured by ITP- PAQ 16 Long-term response ($5 y): maintained by all patients for a median of 92% of study visits on stable doses 24 Pediatric trials Platelet count /L for 2 consecutive weeks: 88% romiplostim No difference compared vs 0% placebo 47 with non-romiplostim treatment or placebo 11 Platelet counts /L were maintained for a median of 7 wk vs 0 wk for the placebo 47 Reduced parental burden 17 Platelet count /L for $6 of 8 wk: 52% romiplostim vs 10% placebo 12 Long-term response ($4 y): continued response on a tapering dose of romiplostim 48 Eltrombopag Adult trials Platelet count /L on day 43: 59% eltrombopag vs 16% Decreased bleeding from placebo 18 baseline shown across trials Platelet count /L at least once; 79% eltrombopag vs 28% in adults and children 19,20 Improvement from baseline in physical, emotional, and mental function, as measured by SF-36v2 and FACT-thrombocytopenia 18 Improvement in vitality on SF-36v2 compared with placebo 27 placebo 49 Fatigue was reported as an Long-term response ($3 y): 62% platelet count /L in.50% of study assessments 27 Pediatric trials Platelet count /L: 62-75% eltrombopag vs 21-32% Decreased bleeding from placebo 19,21 baseline shown across trials in adults and children 19,20 adverse effect in 15% of patients in the EXTEND trial 27 No improvement in HRQoL by Kids ITP Tool Improvement in vitality on scores 21 SF-36v2 compared with placebo 27 Fatigue was reported as an adverse effect in 15% of patients in the EXTEND trial 27 Dapsone 40-62% 45 No studies No studies No studies Mycophenolate mofetil 52-69% 41 No studies No studies No studies Sirolimus 25-58% 50,51 No studies No studies No studies *Measure of platelet count response by platelet count is not consistent or comparable among studies. Hematology

3 Table 2. Comparison of second-line treatments with regard to dosing, monitoring, and populations for consideration Dosing/administration In support In opposition Recommended screening and monitoring Populations for consideration Splenectomy Laparoscopic or open total splenectomy Possibility of permanent remission or response that would alleviate the need for pharmacologic treatment Immediate response Risk for perisurgical complications Presplenectomy and Permanent immunocompromise/risk for infection Possible increased risk for thrombosis 40% long-term risk for failure postsplenectomy vaccinations and boosters ( cdc.gov/vaccines/); lifetime fever guidelines and antibiotic prophylaxis Primary ITP Life-threatening bleeding (ie, intracranial hemorrhage) Fully immunized children age.5 y with chronic ITP refractory to medical therapy Fully immunized adults who have failed steroids Rituximab Intravenous infusion in the physician office setting; Optimal dosing regimen in ITP is uncertain, and multiple dosing regimens are reported (eg, 375 mg/m 2 IV weekly for 4 wk) Infusion with a potential platelet effect for a median of 11 mo Possibility of long-term remission in up to 20-25% of patients Long-term immunosuppression even in nonresponders, in whom rescue therapies may further immune suppress Risk for infusion-related adverse effects Risk for infection, including PML Risks for recurrent, repeated courses are unknown Expensive Delayed response (1 wk-3 mo) B/T subsets, immunoglobulin levels, HIV, and hepatitis B/C screening before start; consider vaccinations before treatment; consider immunoglobulin G levels every few months after infusion Primary or secondary ITP, but must be cautious in patients with an immunodeficiency Fully immunized children with chronic ITP Fully immunized adults with ITP who have failed steroids Romiplostim Weekly subcutaneous 1-10 mg/kg injection, mainly only available for injection in physician s office Does not suppress immune system Expensive Monitor weekly complete blood Bridge therapy (eg, before surgery Steady and predictable platelet Weekly injection at a physician s count; consideration of annual or chance of remission) count office bone marrow exams Patients who need to avoid immune Straightforward to wean off Requires regular monitoring suppression (eg, failure of Not curative therapy splenectomy or rituximab) Slightly delayed response (1-4 wk, depending on starting dose and weekly dose increases) Risk for thrombosis and bone marrow reticulin Children or adults who have failed steroids Eltrombopag Oral medication, mg daily, decreased efficacy if taken with food Does not suppress immune system Expensive Monitor monthly complete blood Steady and predictable platelet Requires regular monitoring count Not curative therapy Straightforward to wean off Slightly delayed response (1-4 wk) Risk for thrombosis, bone marrow reticulin, hepatotoxicity, and cataracts count and LFTs; annual ophthalmologic exam; consideration of annual bone marrow exams Bridge therapy (eg, before surgery or chance of remission) Patients who need to avoid immune suppression (eg, failure of splenectomy or rituximab) Children or adults who have failed steroids Mycophenolyate mofetil Oral medication 400 mg/m 2 twice daily, maximum 1 g twice daily Straightforward to wean off Risk for infection Monthly complete blood count/ Inexpensive Requires regular monitoring differential, LFTs, creatinine Delayed response (2 wk-3 mo) Patients with a likelihood of remission Primary or secondary ITP Patients who fail other agents LFTs, liver function tests. 700 American Society of Hematology

4 Table 2. (continued) Recommended screening and monitoring Populations for consideration Dosing/administration In support In opposition Patients who fail other agents Baseline glucose-6-phosphate dehydrogenase screen; monthly complete blood count; monitor methemoglobin levels Dapsone 1-2 mg/kg by mouth daily Straightforward to wean off Risk for hemolysis and Inexpensive methemoglobinuria Requires regular monitoring Delayed response (2 wk-3 mo) Regular trough levels; Immune cytopenias associated with immunodeficiency, particularly ALPs Straightforward to wean off Risk for infection, Inexpensive hypertriglyceridemia, hyperlipidemia, mucositis Sirolimus Loading dose 3 mg/m 2, then 1-2 mg daily maintenance, adjust to target trough levels (5-15 ng/ml) Patients with primary ITP who fail other agents Monthly complete blood count, LFTs, cholesterol, triglycerides, creatinine, urinary protein; Requires regular laboratory monitoring Monitor blood pressure Delayed response (2 wk-3 mo) LFTs, liver function tests. goal, such as fewer bleeding symptoms or activity restrictions, even if this is below the response threshold set by the International Working Group. Furthermore, the goal of complete response may come with more adverse effects, when a lower platelet count response would have similarly met the aim of the treatment. Although consistent platelet criteria are needed in clinical trials to allow for comparisons among treatments, in clinical practice, the success of a treatment by platelet count needs to be considered alongside HRQoL, adverse effects, and bleeding response. HRQoL Because the overall effect of ITP and its treatments are not adequately measured by the platelet count, HRQoL measures can be used to account for additional variables that affect daily well-being. The pediatric ITP instrument, the Kids ITP Tool, a 26-item questionnaire with a child, proxy, and parent version, was the first ITP-specific HRQoL tool to be developed, validated, and incorporated into clinical trials. 3 General HRQoL measures, such as the SF-36 and EQ-5D, were initially used in clinical trials for adults with ITP. In 2007, a 50-item ITP-Patient Assessment Questionnaire (ITP-PAQ) was developed and validated in adults. 4 The ITP-PAQ captures domains of physical health (ITP-related symptoms, fatigue/sleep, bother-physical health, and activity), mental health (psychological distress and fear), work, social activity, reproductive health, and overall quality of life. HRQoL questionnaires, such as the ITP-PAQ, can be used to describe changes over time in a treatment group, but must be interpreted after derivation and in relationship to the smallest difference a patient would identify as important, or the minimal important difference (MID). Overall, the effect of medications on HRQoL is understudied, and greater emphasis should be given to HRQoL in interventional trials and prospective natural history cohorts. Fatigue Fatigue is an important domain of HRQoL, although ITP-associated fatigue is not well understood. 5 Hypothetical causes of fatigue include the effect of activity restrictions, immune activation and pro-inflammatory state, toxicity of medical therapy, and existing comorbidities. Although fatigue symptoms appear to correlate with severity of thrombocytopenia, the effect of pharmacologic treatments in raising the platelet count, and thereby decreasing ITP-related fatigue, has not been well established. 6 The Fatigue Impact Scale assesses the effect of fatigue on psychosocial, cognitive, and physical function, and approximately 22% to 39% of surveyed patients with ITP report significant fatigue (Fatigue Impact Scale $40). Additional validated measures for ITP-associated fatigue include the physical health domain in the ITP-PAQ and the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. When measures of fatigue have been integrated as a secondary outcome measure in clinical trials, the baseline assessment of fatigue in ITP is worse than in the general US population and, in some studies, is the most severely affected of all the HRQoL domains. 7,8 Given its prevalence in ITP, changes in fatigue must be considered in addition to other HRQoL measures in clinical trials of ITP treatments. Bleeding Because the platelet count is a poor correlate for bleeding, bleeding scales have been developed to quantitate bleeding symptoms and provide an objective outcome. 9 One of the first ITP-specific tools, developed by Bolton-Maggs and Moon, uses an ordered categorical scale and measures interference of symptoms with daily living. The Buchanan and Adix scale, with an overall bleeding score of 0 to 5, measured during the last 24 hours, is easy to apply in pediatric Hematology

5 clinical practice. The Page scale is more complex, addressing bleeding at 9 anatomical sites during the prior week, both by history and exam. A more detailed and extensive bleeding assessment tool has been proposed for clinical trials; however, the complex nature of this measure, with 11 site-specific assessments across 1 to 3 bleeding grades, is more onerous, and improved precision with the use of this tool has not been demonstrated. Despite the existence of ITP-specific bleeding tools, the World Health Organization bleeding scale, a 5-point scale, has most commonly been used in clinical trials. Although capturing and reporting bleeding events is a highly relevant outcome, it is unlikely that bleeding will ever be the primary outcome for clinical trials. Because of the rarity of severe bleeding events, an unreasonably large number of patients would be required to adequately power a trial aimed at demonstrating a reduction of severe bleeding events. ITP treatments and response as measured by platelet count, HRQoL, fatigue, and bleeding Thrombopoietin receptor agonists The thrombopoietin receptor agonists (TPO-RAs) bind to and stimulate the TPO receptor and increase platelet production. Two recombinant TPO-RAs, eltrombopag and romiplostim, are approved by the US Food and Drug Administration for adults with chronic ITP. Eltrombopag is also approved for children older than 1 year who have chronic ITP. These agents are not considered curative based on their mechanism of action. The literature supports that there is no cross-resistance between the 2 agents, and therefore, if 1 agent is not effective, trialing the other agent may be beneficial. 10 Among the second-line treatments, the most robust data exist for these agents with regard to their effect on platelet count, bleeding, fatigue, and HRQoL. Romiplostim Platelet response Randomized trials in children and adults have demonstrated an acute platelet response with romiplostim of approximately 79% to 88%, and a durable response with ongoing treatment of 38% to 52% (Table 1). 11,12 Reports of adult and pediatric real-world use are similar to reported clinical trial results, although response patterns are more variable. 13 A case series demonstrated remission after treatment; however, larger studies are needed to confirm whether the incidence of remission is greater than the expected spontaneous remission rate. 14 Bleeding response Using a composite outcome for bleeding, including actual bleeding events or use of rescue medication to prevent bleeding, the effect of a treatment on actual bleeding is less clear. Romiplostim has been shown to reduce composite bleeding episodes; however, this effect is not seen if actual bleeding events alone are examined (3.7 vs 5.6 per 100 patient-weeks; P 5.66). 15 Furthermore, bleeding events may not be an independent outcome, as no effect on bleeding is seen in overall romiplostim cohorts, but all bleeding events occur at a platelet count lower than /L. HRQoL and fatigue response Improvement of HRQoL while receiving romiplostim has been reported in several adult and pediatric studies. The ITP-PAQ was administered to adults randomly assigned to receive romiplostim vs nonromiplostim medical therapy over the course of 52 weeks. 16 Romiplostim significantly improved report of symptoms, activity, psychological health, and overall HRQoL compared with baseline. 7 These improvements exceeded the MID estimates, indicating a clinically significant improvement. However, when compared with baseline, the nonromiplostim group also had significant improvements in HRQoL, and the difference between romiplostim and nonromiplostim medical therapy did not exceed the MID value. In children, only parental burden is significantly reduced when receiving romiplostim in comparison with placebo. 17 Adults with a platelet count response to romiplostim had a significant improvement in fatigue, as measured by the IT-PAQ, but not above the MID estimate. 16 This finding has been consistent across studies in which treatment has not led to a consistent or clinically significant improvement in fatigue. If fatigue in ITP is related to immune dysregulation or activation, one would not expect the TPO-RAs to improve fatigue, even in those with a platelet response. 5 Eltrombopag Platelet response Randomized trials in children and adults have demonstrated an initial platelet response with eltrombopag of 59% to 75%, and a durable response with continued treatment of 62% (Table 1). 18,19 Similar to romiplostim, eltrombopag is not thought to induce remission of ITP, but several case series report patients with remission after eltrombopag. Bleeding response In the RAISE trial, the odds of clinically significant bleeding measured by the World Health Organization scale were 65% lower among treated patients compared with those in the placebo group. An analysis of 5 eltrombopag trials reported a decrease in bleeding from 50% to 73% at baseline to 26% to 39% at week 2 in treated patients, which was maintained throughout the study period. 20 The PETIT 1/2 pediatric trials have similarly shown that eltrombopag reduces bleeding compared with placebo. 21 HRQoL and fatigue response Although early trials did not show a change of SF-36-measured HRQoL in adults treated with eltrombopag compared with those receiving placebo, in the RAISE trial, significantly greater improvements from baseline in the SF-36v2 (physical, emotional, and mental function) and Functional Assessment in Cancer (FACT)- thrombocytopenia scale were seen in eltrombopag-treated patients. 18 Patients receiving eltrombopag also demonstrate an improvement in vitality, a marker of fatigue on the SF-36v2, compared with those receiving placebo. Of note, however, fatigue has also been reported as an adverse event in eltrombopag trials. In PETIT1, children receiving eltrombopag had a small improvement in the Kids ITP Tool score, but did not meet criteria for a MID. 21 Thus, the effect of eltrombopag on HRQoL in children with ITP is not clear. Safety and tolerability of TPO-RAs Long-term follow-up data are available for both agents (romiplostim,.5 years; eltrombopag, ~3 years). Both are generally welltolerated (Table 2). However, in the United States, romiplostim is a weekly subcutaneous injection requiring weekly visits to the physician s office. This adds to missed school or work and decreased flexibility with travel, and is a difficult mode of delivery for some patients. Eltrombopag absorption is affected by food and dairy, which makes administration more difficult for some patients, in that it must be taken 1 hour before or 2 hours after a meal and at least 2 hours before dairy. Major adverse effect concerns include bone marrow reticulin formation (approximately 2%) and thrombotic events (approximately 4%) Data suggest bone marrow reticulin may be reversible with discontinuation of the drug; however, only a small number of patients with reticulin have been evaluated off-therapy. 22, American Society of Hematology

6 Neutralizing antibodies have been reported with loss of treatment response to romiplostim, and eltrombopag can be associated with hepatotoxicity 2% (~10% rate of transaminitis) and cataract formation (approximately 5%), which occurred almost exclusively in patients with prior chronic corticosteroid use. 19,26,27 Splenectomy Splenectomy is the most predictable method for achieving a durable remission. The spleen is the major site of platelet destruction in most patients and is an important organ for B-cell development and diversification of the T-cell repertoire. Consideration of splenectomy is given most strongly to those with life-threatening bleeding (ie, intracranial hemorrhage), adults who fail corticosteroids, and patients with chronic primary ITP. Platelet response According to a systematic review of 2623 splenectomized adults, a 66% complete response was seen after a median length of follow-up of 29 months. 28 In a second review of 1223 patients with laparoscopic splenectomies for ITP, 92% had an early platelet count response rate with a 72% response rate at 5 years. 29 Indium-labeled autologous platelet scanning has been proposed to predict the likelihood of response to splenectomy, in that those with splenic clearance are theoretically more likely to respond to splenectomy than those with hepatic or mixed patterns. A pooled analysis found that this technique predicts response to splenectomy with an odds ratio of 15.4 (CI, ) in those with a platelet sequestration pattern. 30 Since that time, several additional analyses have shown similar findings, whereas others demonstrate poor predictability Importantly, in all studies, many patients with hepatic clearance or mixed patterns have a complete response to splenectomy. Furthermore, clearance patterns may change after splenectomy, which could explain why the platelet response can wane over time. Availability and expertise of the indium scan is currently limited. Bleeding response Systematic studies of bleeding response to splenectomy have not been performed. HRQoL and fatigue response HRQoL was studied using ITP-PAQ scores in 1 small subanalysis of adults with ITP pre- and postsplenectomy (n 5 13), and no change was found. 16 A Web-based support group survey found that patients with splenectomy had lower ITP-PAQ scores for the domains of work, bother, psychological, fear, and social activity compared with nonsplenectomized individuals; however, the overall response to splenectomy was not reported, and the cohort may have been biased by being derived from a support network. 34 No studies report the effect of splenectomy on fatigue. Safety and tolerability The reported mortality rate for splenectomy for ITP is less than 1%, mainly as a result of perisurgical bleeding. 28 Short-term complications of splenectomy include bleeding, local infection, and thrombosis. Splenectomy is associated with a lifelong risk for life-threatening infection, historically at a rate of 0.73 per 1000 patient-years. The current risk is likely lower, given modern-day immunizations and sepsis precautions. However, evaluation for underlying immunologic disorders, such as autoimmune lymphoproliferative disorder, and secondary ITP is critical before splenectomy as a result of the increased risk of overwhelming sepsis and death in these patients. 35 Splenectomy may also cause an increased risk for thrombosis, including vascular concerns for cardiovascular disease and pulmonary hypertension. 36 However, this is less well studied in ITP than in conditions associated with hemolysis. Splenectomy is also irreversible, and often treating physicians and/or patients do not wish to trade the risk of bleeding resulting from a low platelet count for the risk for infection. Rituximab Rituximab is an anti-cd-20 monoclonal antibody, used in a wide variety of autoimmune conditions including ITP, and causes a rapid depletion of CD-20-positive B cells responsible for antibody production, a decrease in serum immunoglobulin levels, and an increased number of T-regulatory cells. Dosing was first established in oncology trials, and therefore ideal dosing for autoimmune conditions such as ITP remains unclear. Platelet response A meta-analysis of 5 randomized trials (467 nonsplenectomized adults) of rituximab vs corticosteroids, IVIG, and/or anti-d globulin demonstrated a platelet count of /L or higher at 6 months in 46.8% of those treated with rituximab vs 32.5% in the other medical therapy group (P 5.002). 37 For some patients, the chance of a durable remission is the reason for selecting rituximab; however, response wanes over time with durable remission rates of 21% to 26% at 5 years. 38 This calls into question whether rituximab is truly a curative therapy. Bleeding response Studies comparing bleeding symptoms between rituximab vs corticosteroids, IVIG, and/or anti-d globulin or placebo found no significant difference (9.2% vs 5.2%; P 5.44). 37 HRQoL and fatigue A substudy of 16 adults with chronic ITP treated with rituximab found no change in the HRQoL, using ITP-PAQ scale scores, before and after treatment. 16 A randomized trial found no effect of rituximab on physical or mental quality of life compared with placebo, using the SF In addition, 22% of patients who received rituximab reported fatigue compared with 8% of patients who received placebo. Safety and tolerability For many patients, such as those in whom adherence is challenging, the absence of a daily or home medication is of major benefit. Rituximab may be less tolerated than other therapies, with infusion reactions in up to 18% of patients. Severe or life-threatening adverse events are reported in up to 4% of patients, although this is likely an overestimate resulting from a lack of a causal relationship between rituximab and certain fatal events such as intracranial hemorrhage. 40 Recommended screening labs before infusion, monitoring, and selected adverse effects and toxicities are listed in Table 2. Other therapies Multiple other agents are used as second-line treatments for ITP, including mycophenolate mofetil, dapsone, sirolimus, vincristine, 6-mercaptopurine, azathioprine, and danazol. In addition, multiple treatment combinations have been effective and published in case reports and series. Although most of these agents have been available and used to treat ITP for decades, no research has rigorously reported on bleeding, HRQoL, and fatigue. Although these treatments may be safer or possibly equally as effective as better-studied therapies, selection of these agents is more challenging in the absence of data. Highlighted platelet response and safety data on mycophenolate mofetil and dapsone, both of which have been investigated in larger, more modern, cohorts, is outlined here. Novel treatments currently in clinical trials are shown in Table 3. Hematology

7 Mycophenolate mofetil Mycophenolate mofetil is a pro-drug that is metabolized to mycophenolic acid, a noncompetitive inhibitor of a key enzyme involved in purine biosynthesis that, when inhibited, leads to cell cycle inhibition with selective inhibition of lymphocyte proliferation. Small cohort studies of patients with refractory ITP have shown the benefit of this immunosuppressant agent. Platelet response. A study of 21 refractory patients reported a response rate of 53% with a platelet count higher than /L within 12 weeks of initiation and with continued response up to amedianof24weeks. 41 A similar-sized cohort study replicated this finding with a 69% response rate. 42 Most recently, a 46-adult-patient cohort with primary and secondary ITP was treated with a 52% response rate of a platelet count higher than /L. 43 Safety and tolerability. Although possible adverse effects include an increased risk for infection and malignancy, common adverse effects are nausea, diarrhea, and headaches. Potential risks exist to the fetus in pregnant women. In the case series of patients with ITP, it has been a reportedly well-tolerated therapy. 41,42 Dapsone Dapsone is an inexpensive antibacterial sulfonamide with poorly understood anti-inflammatory properties. Several case series of adults with refractory ITP have shown a platelet count response to this medication. The mechanism of action of effect in ITP is not clear, possibly because of hemolysis, which leads to erythrophagocytosis by the reticuloendothelial system, preventing destruction of platelets, or a result of downregulation of Mac-1 expression, leading to decreased complement-opsonized platelet clearance by macrophages. 44 Platelet response. A review of published case series in children and adults with ITP reports an overall platelet response to dapsone of 40% to 62%. 45 The median time to response is approximately 1-2 months, and response tends to be sustained if dapsone is continued. Safety and tolerability. Dapsone is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. In the absence of glucose-6-phosphate dehydrogenase deficiency, dose-dependent hemolysis is reported in up to 20% of patients, although in most cases it is mild. Methemoglobinemia, agranulocytosis, and hypersensitivity reactions can also occur. Although infrequently selected as a secondline treatment, dapsone represents one of the most cost-effective treatments available. Summary Published studies of second-line treatments for ITP are limited by varying outcome measures and definitions, efficacy endpoints, and lack of comparative trials. Ultimately, to derive a precision medicine approach to the management of ITP, we must be able to identify individual biologic profiles, which elucidate the mechanism of disease and, thereby, predict the natural history and therapy response. A personalized approach requires an understanding of the reason for treatment and, therefore, the measure of a clinically meaningful success. The effect of each treatment on that measure, including fatigue, bleeding, HRQoL, and platelet count, must then be assessed. Furthermore, these outcomes must be considered together as the posttreatment response of a patient with a platelet count of /L or higher, but debilitating fatigue should not be considered a success. Table 3. Current trials for novel second-line agents for patients with ITP Agent BMS (Bristol- Myers Squibb) PRTX-100 (Protalex, Inc.) Avatrombopag (Eisai, Inc.) Hetrombopag Olamine (Jiangsu HengRui Medicine Co., Ltd.) R788/Fostamatinib Disodium (Rigel Pharmaceuticals) Decitabine As listed on clinicaltrials.gov August 23, Mechanism of action IV administered anti-cd40l Fc-fusion protein that targets and binds CD40L expressed on T lymphocytes, which prevents T-cell-mediated proliferation and differentiation of B cells IV purified Staphylococcal protein A, an immunomodulatory protein, which binds to B lymphocytes and macrophages and modulates inflammation Oral, nonpeptide, thrombopoietin receptor agonist 52 Nonpeptide, thrombopoietin receptor agonist Oral Syk kinase inhibitor that blocks immunoglobulin G receptor signaling in macrophages and B cells 53 Demethylating agent that promotes cell differentiation and maturation Given the impracticality of randomized comparative trials resulting from significant differences in treatment approaches (surgical vs pharmacologic) and duration (ongoing vs intermittent), small patient numbers, and cost, investigators should consider additional trial designs such as noncomparative trials. Comparative effectiveness research can help account for patient preferences, various outcome measures, cost, and potential adverse effects. Until these data are available, clinicians must be mindful of the areas of insufficient data and the implications of this for their patients, and continued shared decision-making between patients and their providers will be critical to treatment selection and success. As therapies for ITP expand, research trials must be powered to detect differences among treatments and important outcomes to patients. Correspondence Rachael Grace, Dana-Farber/Boston Children s Cancer and Blood Disorder Center, 450 Brookline Ave, D3-106, Boston, MA 02215; Rachael.Grace@childrens.harvard.edu. References 1. 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;113(11): Cuker A, Neunert CE. 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