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Gene therapy found promising in patients with hemophilia B
, according to results of a recent phase 1-2a study including 10 men with hemophilia B.
The treatment, known as SPK-9001, prevented bleeding and virtually eliminated the need for exogenous factors, said authors of the study, published online Dec. 6 in the New England Journal of Medicine.
The 10 men enrolled in the study had factor IX coagulation activity 2% or less of normal value. Within a week of treatment with SPK-9001, patients exhibited vector-derived factor IX coagulant activity, according to Dr. George and her colleagues.
For all participants, the mean vector-derived factor IX coagulant activity was 33.7% of normal value, they noted in the report.
Moreover, the bleeding rate was significantly reduced over follow-up, which ranged from 28 to 78 weeks. Annualized bleeding rate was 11.1 events per year before treatment and 0.4 events per year afterward (P = .02), with 9 of 10 patients experiencing no bleeds over the follow-up period, they reported.
Factor use also dropped substantially, from a mean dose of 2,908 IU/kg before vector administration to 49.3 IU/kg afterward, the researchers said, noting that 8 of 10 patients used no factor at all.
No serious adverse events were observed during vector infusion or afterward, but the long-term safety of adeno-associated viral gene transfer will require further study, the researchers said. “However, to date, no genotoxic or gene-silencing events have been noted in human participants, including those who have been followed since the first [adeno-associated virus] trials were reported in 1998,” Dr. George and her colleagues wrote.
Spark Therapeutics and Pfizer funded the study. Dr. George reported support from Spark Therapeutics for the study, and personal fees from Pfizer outside the submitted work. Some of the authors are employees of Spark or had other financial relationships with Spark and/or Pfizer.
The positive results seen in this trial of the adeno-associated viral vector SPK-9001 represent “an important milestone for the community of patients with hemophilia B and their caregivers and advocates, who now are within touching distance of having an ideal cure for this terrible disease,” Matthew Porteus, MD, PhD, wrote in an editorial.
To reduce spontaneous bleed risk in patients with hemophilia, the current standard of care is transitioning from prophylactic intravenous infusions of clotting factor multiple times per week to longer-acting agents that can be given every 7-10 days.
However, an “ideal therapy” according to Dr. Porteus, would be one that can be delivered once with minimal toxicity and last a lifetime, and be affordable for patients anywhere in the world.
“Gene therapy in which a sufficient number of cells are modified by the delivery of a gene with prolonged or even permanent expression to produce the missing clotting factor has the potential to be such an ideal therapy for hemophilia,” he wrote.
The findings regarding SPK-9001 are “striking” but are limited due to short follow-up, he said, although investigators have started a longer-term study to better investigate safety and efficacy.
Future research on hemophilia gene therapy should focus on broadening the number of patients who could benefit from it, including children, patients with preexisting antibodies, and the 80% of hemophilia patients with hemophilia A, he added.
Dr. Porteus is with the department of pediatrics at Stanford (Calif.) University. These comments are derived from his editorial (N Engl J Med. 2017;377[23]2274-5). Dr. Porteus reported receiving personal fees from CRISPR Therapeutics outside of his submitted editorial.
The positive results seen in this trial of the adeno-associated viral vector SPK-9001 represent “an important milestone for the community of patients with hemophilia B and their caregivers and advocates, who now are within touching distance of having an ideal cure for this terrible disease,” Matthew Porteus, MD, PhD, wrote in an editorial.
To reduce spontaneous bleed risk in patients with hemophilia, the current standard of care is transitioning from prophylactic intravenous infusions of clotting factor multiple times per week to longer-acting agents that can be given every 7-10 days.
However, an “ideal therapy” according to Dr. Porteus, would be one that can be delivered once with minimal toxicity and last a lifetime, and be affordable for patients anywhere in the world.
“Gene therapy in which a sufficient number of cells are modified by the delivery of a gene with prolonged or even permanent expression to produce the missing clotting factor has the potential to be such an ideal therapy for hemophilia,” he wrote.
The findings regarding SPK-9001 are “striking” but are limited due to short follow-up, he said, although investigators have started a longer-term study to better investigate safety and efficacy.
Future research on hemophilia gene therapy should focus on broadening the number of patients who could benefit from it, including children, patients with preexisting antibodies, and the 80% of hemophilia patients with hemophilia A, he added.
Dr. Porteus is with the department of pediatrics at Stanford (Calif.) University. These comments are derived from his editorial (N Engl J Med. 2017;377[23]2274-5). Dr. Porteus reported receiving personal fees from CRISPR Therapeutics outside of his submitted editorial.
The positive results seen in this trial of the adeno-associated viral vector SPK-9001 represent “an important milestone for the community of patients with hemophilia B and their caregivers and advocates, who now are within touching distance of having an ideal cure for this terrible disease,” Matthew Porteus, MD, PhD, wrote in an editorial.
To reduce spontaneous bleed risk in patients with hemophilia, the current standard of care is transitioning from prophylactic intravenous infusions of clotting factor multiple times per week to longer-acting agents that can be given every 7-10 days.
However, an “ideal therapy” according to Dr. Porteus, would be one that can be delivered once with minimal toxicity and last a lifetime, and be affordable for patients anywhere in the world.
“Gene therapy in which a sufficient number of cells are modified by the delivery of a gene with prolonged or even permanent expression to produce the missing clotting factor has the potential to be such an ideal therapy for hemophilia,” he wrote.
The findings regarding SPK-9001 are “striking” but are limited due to short follow-up, he said, although investigators have started a longer-term study to better investigate safety and efficacy.
Future research on hemophilia gene therapy should focus on broadening the number of patients who could benefit from it, including children, patients with preexisting antibodies, and the 80% of hemophilia patients with hemophilia A, he added.
Dr. Porteus is with the department of pediatrics at Stanford (Calif.) University. These comments are derived from his editorial (N Engl J Med. 2017;377[23]2274-5). Dr. Porteus reported receiving personal fees from CRISPR Therapeutics outside of his submitted editorial.
, according to results of a recent phase 1-2a study including 10 men with hemophilia B.
The treatment, known as SPK-9001, prevented bleeding and virtually eliminated the need for exogenous factors, said authors of the study, published online Dec. 6 in the New England Journal of Medicine.
The 10 men enrolled in the study had factor IX coagulation activity 2% or less of normal value. Within a week of treatment with SPK-9001, patients exhibited vector-derived factor IX coagulant activity, according to Dr. George and her colleagues.
For all participants, the mean vector-derived factor IX coagulant activity was 33.7% of normal value, they noted in the report.
Moreover, the bleeding rate was significantly reduced over follow-up, which ranged from 28 to 78 weeks. Annualized bleeding rate was 11.1 events per year before treatment and 0.4 events per year afterward (P = .02), with 9 of 10 patients experiencing no bleeds over the follow-up period, they reported.
Factor use also dropped substantially, from a mean dose of 2,908 IU/kg before vector administration to 49.3 IU/kg afterward, the researchers said, noting that 8 of 10 patients used no factor at all.
No serious adverse events were observed during vector infusion or afterward, but the long-term safety of adeno-associated viral gene transfer will require further study, the researchers said. “However, to date, no genotoxic or gene-silencing events have been noted in human participants, including those who have been followed since the first [adeno-associated virus] trials were reported in 1998,” Dr. George and her colleagues wrote.
Spark Therapeutics and Pfizer funded the study. Dr. George reported support from Spark Therapeutics for the study, and personal fees from Pfizer outside the submitted work. Some of the authors are employees of Spark or had other financial relationships with Spark and/or Pfizer.
, according to results of a recent phase 1-2a study including 10 men with hemophilia B.
The treatment, known as SPK-9001, prevented bleeding and virtually eliminated the need for exogenous factors, said authors of the study, published online Dec. 6 in the New England Journal of Medicine.
The 10 men enrolled in the study had factor IX coagulation activity 2% or less of normal value. Within a week of treatment with SPK-9001, patients exhibited vector-derived factor IX coagulant activity, according to Dr. George and her colleagues.
For all participants, the mean vector-derived factor IX coagulant activity was 33.7% of normal value, they noted in the report.
Moreover, the bleeding rate was significantly reduced over follow-up, which ranged from 28 to 78 weeks. Annualized bleeding rate was 11.1 events per year before treatment and 0.4 events per year afterward (P = .02), with 9 of 10 patients experiencing no bleeds over the follow-up period, they reported.
Factor use also dropped substantially, from a mean dose of 2,908 IU/kg before vector administration to 49.3 IU/kg afterward, the researchers said, noting that 8 of 10 patients used no factor at all.
No serious adverse events were observed during vector infusion or afterward, but the long-term safety of adeno-associated viral gene transfer will require further study, the researchers said. “However, to date, no genotoxic or gene-silencing events have been noted in human participants, including those who have been followed since the first [adeno-associated virus] trials were reported in 1998,” Dr. George and her colleagues wrote.
Spark Therapeutics and Pfizer funded the study. Dr. George reported support from Spark Therapeutics for the study, and personal fees from Pfizer outside the submitted work. Some of the authors are employees of Spark or had other financial relationships with Spark and/or Pfizer.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: A single intravenous dose of the adeno-associated viral vector SPK-9001 produced sustained expression of factor IX coagulant activity, virtually eliminating bleeding and use of clotting factors in patients with hemophilia B.
Major finding: A mean functional clotting-factor activity of 33.7% of the normal value (median, 29.8% of the normal value) was achieved among study participants.
Data source: An open-label, nonrandomized, multicenter phase 1-2a study including 10 men with hemophilia B and factor IX coagulant activity 2% or less of normal value.
Disclosures: Spark Therapeutics and Pfizer funded the study. Lead author Lindsey A. George, MD, reported support from Spark Therapeutics for the study, and personal fees from Pfizer outside the submitted work. Full author disclosures were published on the New England Journal of Medicine website.
Empagliflozin’s heart failure benefits linked to volume drop
ANAHEIM, CALIF. – When results from the EMPA-REG OUTCOME trial came out 2 years ago and showed a dramatic decrease in heart failure hospitalizations and deaths linked to treatment with the oral diabetes drug empagliflozin, some experts suggested that a completely hypothetical effect of empagliflozin on reducing fluid volume may have largely caused these unexpected clinical benefits.
New analyses of the trial results show this hypothesis may be at least partially correct.
Results from a post hoc analysis of data collected in Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) suggest that perhaps half the heart failure benefit was attributable to what appears to have been a roughly 7% drop in plasma volume in patients treated with empagliflozin (Jardiance), which began soon after treatment started and continued through the balance of the study, David Fitchett, MD, said at the American Heart Association scientific sessions.
“Markers of change in plasma volume were important mediators of the reduction in risk of hospitalization for heart failure or death from heart failure,” said Dr Fitchett, a cardiologist at St. Michael’s Hospital in Toronto and a coinvestigator of EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
The analysis also showed that a “modest” effect from a reduction in uric acid might explain about 20%-25% of the observed heart failure benefit, he reported. In contrast, none of the traditional cardiovascular disease risk factors examined in the analysis – including lipids, blood pressure, obesity, and hemoglobin A1c – appeared to have any relationship to the heart failure effects of empagliflozin.
Dr. Fitchett and his associates assessed the possible impact of a list of potential mediators with a statistical method that performed an unadjusted, univariate analysis of the time-dependent change in each of several variables relative to the observed changes in heart failure outcomes.
This analysis showed that on-treatment changes in two markers of plasma volume, hematocrit and hemoglobin, each showed changes that appeared to mediate about half of the heart failure effects. A third marker of plasma volume, albumin level, appeared to mediate about a quarter of the heart failure effects.
The changes in both hematocrit and hemoglobin first appeared within a few weeks of treatment onset, and soon reached a plateau that remained sustained through the balance of the study. For example, during the first 12 weeks of treatment, the average hematocrit level rose from about 41% at baseline to about 44%. This 3% net rise corresponds to about a 7% drop in plasma volume, Dr. Fitchett said.
In addition to reflecting a potentially beneficial decrease in fluid volume, this effect would also boost the oxygen-carrying capacity of a patient’s blood that could be beneficial for patients with ischemic heart disease and those with reduced left ventricular function, he noted.
The EMPA-REG OUTCOME trial was sponsored by Boehringer Ingelheim and Eli Lilly, which jointly market empagliflozin (Jardiance). Dr. Fitchett has received honoraria from those companies and also from Amgen, AstraZeneca, Merck, and Sanofi.
[email protected]
On Twitter @mitchelzoler
ANAHEIM, CALIF. – When results from the EMPA-REG OUTCOME trial came out 2 years ago and showed a dramatic decrease in heart failure hospitalizations and deaths linked to treatment with the oral diabetes drug empagliflozin, some experts suggested that a completely hypothetical effect of empagliflozin on reducing fluid volume may have largely caused these unexpected clinical benefits.
New analyses of the trial results show this hypothesis may be at least partially correct.
Results from a post hoc analysis of data collected in Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) suggest that perhaps half the heart failure benefit was attributable to what appears to have been a roughly 7% drop in plasma volume in patients treated with empagliflozin (Jardiance), which began soon after treatment started and continued through the balance of the study, David Fitchett, MD, said at the American Heart Association scientific sessions.
“Markers of change in plasma volume were important mediators of the reduction in risk of hospitalization for heart failure or death from heart failure,” said Dr Fitchett, a cardiologist at St. Michael’s Hospital in Toronto and a coinvestigator of EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
The analysis also showed that a “modest” effect from a reduction in uric acid might explain about 20%-25% of the observed heart failure benefit, he reported. In contrast, none of the traditional cardiovascular disease risk factors examined in the analysis – including lipids, blood pressure, obesity, and hemoglobin A1c – appeared to have any relationship to the heart failure effects of empagliflozin.
Dr. Fitchett and his associates assessed the possible impact of a list of potential mediators with a statistical method that performed an unadjusted, univariate analysis of the time-dependent change in each of several variables relative to the observed changes in heart failure outcomes.
This analysis showed that on-treatment changes in two markers of plasma volume, hematocrit and hemoglobin, each showed changes that appeared to mediate about half of the heart failure effects. A third marker of plasma volume, albumin level, appeared to mediate about a quarter of the heart failure effects.
The changes in both hematocrit and hemoglobin first appeared within a few weeks of treatment onset, and soon reached a plateau that remained sustained through the balance of the study. For example, during the first 12 weeks of treatment, the average hematocrit level rose from about 41% at baseline to about 44%. This 3% net rise corresponds to about a 7% drop in plasma volume, Dr. Fitchett said.
In addition to reflecting a potentially beneficial decrease in fluid volume, this effect would also boost the oxygen-carrying capacity of a patient’s blood that could be beneficial for patients with ischemic heart disease and those with reduced left ventricular function, he noted.
The EMPA-REG OUTCOME trial was sponsored by Boehringer Ingelheim and Eli Lilly, which jointly market empagliflozin (Jardiance). Dr. Fitchett has received honoraria from those companies and also from Amgen, AstraZeneca, Merck, and Sanofi.
[email protected]
On Twitter @mitchelzoler
ANAHEIM, CALIF. – When results from the EMPA-REG OUTCOME trial came out 2 years ago and showed a dramatic decrease in heart failure hospitalizations and deaths linked to treatment with the oral diabetes drug empagliflozin, some experts suggested that a completely hypothetical effect of empagliflozin on reducing fluid volume may have largely caused these unexpected clinical benefits.
New analyses of the trial results show this hypothesis may be at least partially correct.
Results from a post hoc analysis of data collected in Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) suggest that perhaps half the heart failure benefit was attributable to what appears to have been a roughly 7% drop in plasma volume in patients treated with empagliflozin (Jardiance), which began soon after treatment started and continued through the balance of the study, David Fitchett, MD, said at the American Heart Association scientific sessions.
“Markers of change in plasma volume were important mediators of the reduction in risk of hospitalization for heart failure or death from heart failure,” said Dr Fitchett, a cardiologist at St. Michael’s Hospital in Toronto and a coinvestigator of EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
The analysis also showed that a “modest” effect from a reduction in uric acid might explain about 20%-25% of the observed heart failure benefit, he reported. In contrast, none of the traditional cardiovascular disease risk factors examined in the analysis – including lipids, blood pressure, obesity, and hemoglobin A1c – appeared to have any relationship to the heart failure effects of empagliflozin.
Dr. Fitchett and his associates assessed the possible impact of a list of potential mediators with a statistical method that performed an unadjusted, univariate analysis of the time-dependent change in each of several variables relative to the observed changes in heart failure outcomes.
This analysis showed that on-treatment changes in two markers of plasma volume, hematocrit and hemoglobin, each showed changes that appeared to mediate about half of the heart failure effects. A third marker of plasma volume, albumin level, appeared to mediate about a quarter of the heart failure effects.
The changes in both hematocrit and hemoglobin first appeared within a few weeks of treatment onset, and soon reached a plateau that remained sustained through the balance of the study. For example, during the first 12 weeks of treatment, the average hematocrit level rose from about 41% at baseline to about 44%. This 3% net rise corresponds to about a 7% drop in plasma volume, Dr. Fitchett said.
In addition to reflecting a potentially beneficial decrease in fluid volume, this effect would also boost the oxygen-carrying capacity of a patient’s blood that could be beneficial for patients with ischemic heart disease and those with reduced left ventricular function, he noted.
The EMPA-REG OUTCOME trial was sponsored by Boehringer Ingelheim and Eli Lilly, which jointly market empagliflozin (Jardiance). Dr. Fitchett has received honoraria from those companies and also from Amgen, AstraZeneca, Merck, and Sanofi.
[email protected]
On Twitter @mitchelzoler
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point: About according to post hoc analysis of the EMPA-REG OUTCOME study.
Major finding: About half of the observed heart failure benefit was tied to a roughly 3% rise in average hematocrit level.
Data source: Post hoc analysis of data from the 7,028 patients enrolled in the EMPA-REG OUTCOME trial.
Disclosures: The EMPA-REG OUTCOME trial was sponsored by Boehringer Ingelheim and Eli Lilly, the two companies that market empagliflozin (Jardiance). Dr. Fitchett has received honoraria from those companies and also from Amgen, AstraZeneca, Merck, and Sanofi.
Immune Thrombocytopenia
Introduction
Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.1 There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.
Pathogenesis and Epidemiology
ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.
Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.5
It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 103/µL. However, this leaves a considerable number of patients who will require chronic therapy.
Clinical Presentation
Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.10
Diagnosis
Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 103/µL as the majority of patients with counts in the 100 to 150 × 103/µL range will not develop greater thrombocytopenia.11 Also, the platelet count decreases with age (9 × 103/µL per decade in one study), and this also needs to be factored into the evaluation.12 The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.13 One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.
There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.14 Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.
Patients who present with ITP should be tested for both HIV and hepatitis C infection.15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.
The role of bone marrow examination is controversial.17 Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.
In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.4 Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.
Treatment
In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,15 as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 103/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.18 It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.19 Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.20 A suggested cut-off for treating newly diagnosed patients is 30 × 103/µL.21
Initial Therapy
The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1). 
For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.
The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.25 Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.
For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.26 The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.26 The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.27,28
Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.29 In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).30 Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.
Options for Refractory ITP
There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.
Splenectomy
In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.
Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.31 However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.31 In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.8
Method of splenectomy appears not to matter.21 Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.
Rates of splenectomy in recent years have decreased for many reasons,32 including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.
The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.
Rituximab
Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m2 weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 103/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.
Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.
There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.43 The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.
Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.40 Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.
Thrombopoietin Receptor Agonists
Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.44 Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.45 Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.
Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.46 It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.47 In a long-term extension study, the response was again high at 87%.48 These studies have also shown a reduced incidence of bleeding.
The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.
Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,49 but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.50 These trials have shown no long-term concerns for other clinical problems such as liver disease.
Eltrombopag. The other available TPO-RA is eltrombopag,51 an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.47,51
Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.
Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.53
Other Options
In the literature there are numerous options for the treatment of ITP.54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.
Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.56 Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.54
Vincristine 1.4 mg/m2 weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.54Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.54 It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.57
Cyclophosphamide 1 g/m2 intravenously repeated every 28 days has been reported to have a response rate of up to 40%.58 Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.59
Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.60 This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.
A Practical Approach to Refractory ITP
One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 103/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 103/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2). 
Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.
Special Situations
Surgery
Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 103/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.
Pregnancy
Up to 10% of pregnant women will develop low platelet counts during their pregnancy.61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 103/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.61,63
Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.64 Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 103/µL.21 Immunoglobulin is also effective,65 but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 103/µL and for an epidural greater than 50 × 103/µL.64 There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.66
Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.
Pediatric Patients
The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.1 There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.67 For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.21 For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.68 Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.69–71
Helicobacter Pylori Infection
There has been much interest in the relationship between H. pylori and ITP.16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.
Drug-Induced Thrombocytopenia
Patients with drug-induced thrombocytopenia present with very low (< 10 × 103/µL) platelet counts 1 to 3 weeks after starting a new medication.74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.77 If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).74,78,79
Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.
Evans Syndrome
Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.
The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.
In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.
Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.80 Increasingly rituximab is being used with success.84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.86 For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.
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Introduction
Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.1 There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.
Pathogenesis and Epidemiology
ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.
Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.5
It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 103/µL. However, this leaves a considerable number of patients who will require chronic therapy.
Clinical Presentation
Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.10
Diagnosis
Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 103/µL as the majority of patients with counts in the 100 to 150 × 103/µL range will not develop greater thrombocytopenia.11 Also, the platelet count decreases with age (9 × 103/µL per decade in one study), and this also needs to be factored into the evaluation.12 The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.13 One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.
There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.14 Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.
Patients who present with ITP should be tested for both HIV and hepatitis C infection.15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.
The role of bone marrow examination is controversial.17 Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.
In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.4 Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.
Treatment
In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,15 as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 103/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.18 It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.19 Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.20 A suggested cut-off for treating newly diagnosed patients is 30 × 103/µL.21
Initial Therapy
The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1).
For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.
The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.25 Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.
For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.26 The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.26 The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.27,28
Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.29 In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).30 Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.
Options for Refractory ITP
There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.
Splenectomy
In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.
Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.31 However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.31 In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.8
Method of splenectomy appears not to matter.21 Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.
Rates of splenectomy in recent years have decreased for many reasons,32 including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.
The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.
Rituximab
Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m2 weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 103/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.
Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.
There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.43 The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.
Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.40 Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.
Thrombopoietin Receptor Agonists
Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.44 Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.45 Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.
Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.46 It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.47 In a long-term extension study, the response was again high at 87%.48 These studies have also shown a reduced incidence of bleeding.
The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.
Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,49 but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.50 These trials have shown no long-term concerns for other clinical problems such as liver disease.
Eltrombopag. The other available TPO-RA is eltrombopag,51 an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.47,51
Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.
Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.53
Other Options
In the literature there are numerous options for the treatment of ITP.54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.
Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.56 Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.54
Vincristine 1.4 mg/m2 weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.54Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.54 It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.57
Cyclophosphamide 1 g/m2 intravenously repeated every 28 days has been reported to have a response rate of up to 40%.58 Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.59
Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.60 This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.
A Practical Approach to Refractory ITP
One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 103/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 103/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).
Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.
Special Situations
Surgery
Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 103/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.
Pregnancy
Up to 10% of pregnant women will develop low platelet counts during their pregnancy.61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 103/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.61,63
Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.64 Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 103/µL.21 Immunoglobulin is also effective,65 but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 103/µL and for an epidural greater than 50 × 103/µL.64 There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.66
Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.
Pediatric Patients
The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.1 There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.67 For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.21 For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.68 Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.69–71
Helicobacter Pylori Infection
There has been much interest in the relationship between H. pylori and ITP.16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.
Drug-Induced Thrombocytopenia
Patients with drug-induced thrombocytopenia present with very low (< 10 × 103/µL) platelet counts 1 to 3 weeks after starting a new medication.74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.77 If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).74,78,79
Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.
Evans Syndrome
Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.
The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.
In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.
Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.80 Increasingly rituximab is being used with success.84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.86 For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.
Introduction
Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.1 There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.
Pathogenesis and Epidemiology
ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.
Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.5
It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 103/µL. However, this leaves a considerable number of patients who will require chronic therapy.
Clinical Presentation
Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.10
Diagnosis
Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 103/µL as the majority of patients with counts in the 100 to 150 × 103/µL range will not develop greater thrombocytopenia.11 Also, the platelet count decreases with age (9 × 103/µL per decade in one study), and this also needs to be factored into the evaluation.12 The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.13 One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.
There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.14 Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.
Patients who present with ITP should be tested for both HIV and hepatitis C infection.15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.
The role of bone marrow examination is controversial.17 Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.
In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.4 Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.
Treatment
In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,15 as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 103/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.18 It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.19 Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.20 A suggested cut-off for treating newly diagnosed patients is 30 × 103/µL.21
Initial Therapy
The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1).
For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.
The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.25 Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.
For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.26 The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.26 The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.27,28
Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.29 In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).30 Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.
Options for Refractory ITP
There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.
Splenectomy
In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.
Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.31 However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.31 In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.8
Method of splenectomy appears not to matter.21 Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.
Rates of splenectomy in recent years have decreased for many reasons,32 including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.
The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.
Rituximab
Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m2 weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 103/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.
Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.
There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.43 The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.
Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.40 Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.
Thrombopoietin Receptor Agonists
Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.44 Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.45 Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.
Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.46 It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.47 In a long-term extension study, the response was again high at 87%.48 These studies have also shown a reduced incidence of bleeding.
The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.
Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,49 but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.50 These trials have shown no long-term concerns for other clinical problems such as liver disease.
Eltrombopag. The other available TPO-RA is eltrombopag,51 an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.47,51
Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.
Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.53
Other Options
In the literature there are numerous options for the treatment of ITP.54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.
Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.56 Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.54
Vincristine 1.4 mg/m2 weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.54Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.54 It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.57
Cyclophosphamide 1 g/m2 intravenously repeated every 28 days has been reported to have a response rate of up to 40%.58 Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.59
Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.60 This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.
A Practical Approach to Refractory ITP
One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 103/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 103/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).
Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.
Special Situations
Surgery
Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 103/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.
Pregnancy
Up to 10% of pregnant women will develop low platelet counts during their pregnancy.61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 103/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.61,63
Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.64 Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 103/µL.21 Immunoglobulin is also effective,65 but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 103/µL and for an epidural greater than 50 × 103/µL.64 There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.66
Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.
Pediatric Patients
The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.1 There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.67 For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.21 For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.68 Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.69–71
Helicobacter Pylori Infection
There has been much interest in the relationship between H. pylori and ITP.16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.
Drug-Induced Thrombocytopenia
Patients with drug-induced thrombocytopenia present with very low (< 10 × 103/µL) platelet counts 1 to 3 weeks after starting a new medication.74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.77 If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).74,78,79
Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.
Evans Syndrome
Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.
The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.
In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.
Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.80 Increasingly rituximab is being used with success.84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.86 For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.
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56. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al. Successful therapy with danazol in refractory autoimmune thrombocytopenia associated with rheumatic diseases. Br J Rheumatol 1997;36:1095–9.
57. 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;81:19–25.
58. Reiner A, Gernsheimer T, Slichter SJ. Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura. Blood 1995;85:351–8.
59. Figueroa M, Gehlsen J, Hammond D, et al. Combination chemotherapy in refractory immune thrombocytopenic purpura. N Engl J Med 1993;328:1226–9.
60. Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy 2 Oct 2017.
61. McCrae KR. Thrombocytopenia in pregnancy. Hematology Am Soc Hematol Educ Program 2010;2010:397–402.
62. Gernsheimer T, McCrae KR. Immune thrombocytopenic purpura in pregnancy. Curr Opin Hematol 2007;14:574–80.
63. DeLoughery TG. Critical care clotting catastrophies. Crit Care Clin 2005;21:531–62.
64. Stavrou E, McCrae KR. Immune thrombocytopenia in pregnancy. Hematol Oncol Clin North Am 2009;23:1299–316.
65. Sun D, Shehata N, Ye XY, et al. Corticosteroids compared with intravenous immunoglobulin for the treatment of immune thrombocytopenia in pregnancy. Blood 2016;128:1329–35.
66. Kong Z, Qin P, Xiao S, et al. A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy. Blood 2017;130:1097–103.
67. Psaila B, Petrovic A, Page LK, et al. Intracranial hemorrhage (ICH) in children with immune thrombocytopenia (ITP): study of 40 cases. Blood 2009;114:4777–83.
68. Journeycake JM. Childhood immune thrombocytopenia: role of rituximab, recombinant thrombopoietin, and other new therapeutics. Hematology Am Soc Hematol Educ Program 2012;2012:444–9.
69. Zhang J, Liang Y, Ai Y, et al. Thrombopoietin-receptor agonists for children with immune thrombocytopenia: a systematic review. Expert Opin Pharmacother 2017;18:1543–51.
70. Tarantino MD, Bussel JB, Blanchette VS, et al. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2016;388:45–54.71. Grainger JD, Locatelli F, Chotsampancharoen T, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet 2015;386:1649–58.
72. Stasi R, Sarpatwari A, Segal JB, et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review. Blood 2009;113:1231–40.
73. Arnold DM, Bernotas A, Nazi I, et al. Platelet count response to H. pylori treatment in patients with immune thrombocytopenic purpura with and without H. pylori infection: a systematic review. Haematologica 2009;94:850–6.
74. Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357:580–7.
75. Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 2010;116:2127–33.
76. Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis and management. J Thromb Haemost 2009;7:911–8.
77. Zondor SD, George JN, Medina PJ. Treatment of drug-induced thrombocytopenia. Expert Opin Drug Saf 2002;1:173–80.
78. George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytopenia: A systematic review of published case reports. Ann Intern Med 1998;129:886–90.
79. Green D, Hougie C, Kazmier FJ, et al. Report of the working party on acquired inhibitors of coagulation: studies of the “lupus” anticoagulant. Thromb Haemost 1983;49:144–6.
80. Michel M, Chanet V, Dechartres A, et al. The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. Blood 2009;114:3167–72.
81. Dhingra KK, Jain D, Mandal S, et al. Evans syndrome: a study of six cases with review of literature. Hematology 2008;13:356–60.
82. Notarangelo LD. Primary immunodeficiencies (PIDs) presenting with cytopenias. Hematology Am Soc Hematol Educ Program 2009:139–43.
83. Martinez-Valdez L, Deya-Martinez A, Giner MT, et al. Evans syndrome as first manifestation of primary immunodeficiency in clinical practice. J Pediatr Hematol Oncol 2017;39:490–4.
84. Shanafelt TD, Madueme HL, Wolf RC, Tefferi A. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clin Proc 2003;78:1340–6.
85. Mantadakis E, Danilatou V, Stiakaki E, Kalmanti M. Rituximab for refractory Evans syndrome and other immune-mediated hematologic diseases. Am J Hematol 2004;77:303–10.
86. Jasinski S, Weinblatt ME, Glasser CL. Sirolimus as an effective agent in the treatment of immune thrombocytopenia (ITP) and Evans syndrome (ES): a single institution’s experience. J Pediatr Hematol Oncol 2017;39:420–4.
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48. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009;113:2161–71.
49. Gernsheimer TB, George JN, Aledort LM, et al. Evaluation of bleeding and thrombotic events during long-term use of romiplostim in patients with chronic immune thrombocytopenia (ITP). J Thromb Haemost 2010;8:1372–82.
50. Severinsen MT, Engebjerg MC, Farkas DK, et al. Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Br J Haematol 2011;152:360–2.
51. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007;357:2237–47.
52. 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;377:393–402.
53. 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;90:598–601.
54. George JN, Kojouri K, Perdue JJ, Vesely SK. Management of patients with chronic, refractory idiopathic thrombocytopenic purpura. Semin Hematol 2000;37:290–8.
55. McMillan R. Therapy for adults with refractory chronic immune thrombocytopenic purpura. Ann Intern Med 1997;126:307–14.
56. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al. Successful therapy with danazol in refractory autoimmune thrombocytopenia associated with rheumatic diseases. Br J Rheumatol 1997;36:1095–9.
57. 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;81:19–25.
58. Reiner A, Gernsheimer T, Slichter SJ. Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura. Blood 1995;85:351–8.
59. Figueroa M, Gehlsen J, Hammond D, et al. Combination chemotherapy in refractory immune thrombocytopenic purpura. N Engl J Med 1993;328:1226–9.
60. Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy 2 Oct 2017.
61. McCrae KR. Thrombocytopenia in pregnancy. Hematology Am Soc Hematol Educ Program 2010;2010:397–402.
62. Gernsheimer T, McCrae KR. Immune thrombocytopenic purpura in pregnancy. Curr Opin Hematol 2007;14:574–80.
63. DeLoughery TG. Critical care clotting catastrophies. Crit Care Clin 2005;21:531–62.
64. Stavrou E, McCrae KR. Immune thrombocytopenia in pregnancy. Hematol Oncol Clin North Am 2009;23:1299–316.
65. Sun D, Shehata N, Ye XY, et al. Corticosteroids compared with intravenous immunoglobulin for the treatment of immune thrombocytopenia in pregnancy. Blood 2016;128:1329–35.
66. Kong Z, Qin P, Xiao S, et al. A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy. Blood 2017;130:1097–103.
67. Psaila B, Petrovic A, Page LK, et al. Intracranial hemorrhage (ICH) in children with immune thrombocytopenia (ITP): study of 40 cases. Blood 2009;114:4777–83.
68. Journeycake JM. Childhood immune thrombocytopenia: role of rituximab, recombinant thrombopoietin, and other new therapeutics. Hematology Am Soc Hematol Educ Program 2012;2012:444–9.
69. Zhang J, Liang Y, Ai Y, et al. Thrombopoietin-receptor agonists for children with immune thrombocytopenia: a systematic review. Expert Opin Pharmacother 2017;18:1543–51.
70. Tarantino MD, Bussel JB, Blanchette VS, et al. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2016;388:45–54.71. Grainger JD, Locatelli F, Chotsampancharoen T, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet 2015;386:1649–58.
72. Stasi R, Sarpatwari A, Segal JB, et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review. Blood 2009;113:1231–40.
73. Arnold DM, Bernotas A, Nazi I, et al. Platelet count response to H. pylori treatment in patients with immune thrombocytopenic purpura with and without H. pylori infection: a systematic review. Haematologica 2009;94:850–6.
74. Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357:580–7.
75. Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 2010;116:2127–33.
76. Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis and management. J Thromb Haemost 2009;7:911–8.
77. Zondor SD, George JN, Medina PJ. Treatment of drug-induced thrombocytopenia. Expert Opin Drug Saf 2002;1:173–80.
78. George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytopenia: A systematic review of published case reports. Ann Intern Med 1998;129:886–90.
79. Green D, Hougie C, Kazmier FJ, et al. Report of the working party on acquired inhibitors of coagulation: studies of the “lupus” anticoagulant. Thromb Haemost 1983;49:144–6.
80. Michel M, Chanet V, Dechartres A, et al. The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. Blood 2009;114:3167–72.
81. Dhingra KK, Jain D, Mandal S, et al. Evans syndrome: a study of six cases with review of literature. Hematology 2008;13:356–60.
82. Notarangelo LD. Primary immunodeficiencies (PIDs) presenting with cytopenias. Hematology Am Soc Hematol Educ Program 2009:139–43.
83. Martinez-Valdez L, Deya-Martinez A, Giner MT, et al. Evans syndrome as first manifestation of primary immunodeficiency in clinical practice. J Pediatr Hematol Oncol 2017;39:490–4.
84. Shanafelt TD, Madueme HL, Wolf RC, Tefferi A. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clin Proc 2003;78:1340–6.
85. Mantadakis E, Danilatou V, Stiakaki E, Kalmanti M. Rituximab for refractory Evans syndrome and other immune-mediated hematologic diseases. Am J Hematol 2004;77:303–10.
86. Jasinski S, Weinblatt ME, Glasser CL. Sirolimus as an effective agent in the treatment of immune thrombocytopenia (ITP) and Evans syndrome (ES): a single institution’s experience. J Pediatr Hematol Oncol 2017;39:420–4.
FDA grants priority review to NDA for avatrombopag
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population. 
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population.
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population.
FDA grants orphan drug status to rofecoxib for hemophilic arthropathy
The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).
HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.
The attempt at a reintroduction of rofecoxib specifically for the treatment of HA is being developed by Tremeau Pharmaceuticals.
Patients with hemophilia look to avoid traditional NSAIDs, as those drugs risk gastrointestinal ulcers and impair platelet aggregation. The current standard of care for HA is opioid treatment.
Rofecoxib and other NSAIDs cause an increased risk of serious cardiovascular thrombotic events and gastrointestinal adverse events.
Orphan drug status is available to treatments for rare disorders and provides a 7-year marketing exclusivity period against competition, along with tax credits and a waiver of Prescription Drug User Fee Act filing fees.
The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).
HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.
The attempt at a reintroduction of rofecoxib specifically for the treatment of HA is being developed by Tremeau Pharmaceuticals.
Patients with hemophilia look to avoid traditional NSAIDs, as those drugs risk gastrointestinal ulcers and impair platelet aggregation. The current standard of care for HA is opioid treatment.
Rofecoxib and other NSAIDs cause an increased risk of serious cardiovascular thrombotic events and gastrointestinal adverse events.
Orphan drug status is available to treatments for rare disorders and provides a 7-year marketing exclusivity period against competition, along with tax credits and a waiver of Prescription Drug User Fee Act filing fees.
The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).
HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.
The attempt at a reintroduction of rofecoxib specifically for the treatment of HA is being developed by Tremeau Pharmaceuticals.
Patients with hemophilia look to avoid traditional NSAIDs, as those drugs risk gastrointestinal ulcers and impair platelet aggregation. The current standard of care for HA is opioid treatment.
Rofecoxib and other NSAIDs cause an increased risk of serious cardiovascular thrombotic events and gastrointestinal adverse events.
Orphan drug status is available to treatments for rare disorders and provides a 7-year marketing exclusivity period against competition, along with tax credits and a waiver of Prescription Drug User Fee Act filing fees.
FDA approves first-in-class drug for hemophilia A with Factor VIII
The Food and Drug Administration has approved emicizumab-kxwh (Hemlibra) for the prevention or reduction of bleeding episodes for adult and pediatric patients with hemophilia A with Factor VIII inhibitors.
The drug received the FDA’s Priority Review, Breakthrough Therapy, and Orphan Drug designations.
It was shown to be safe and effective in two clinical trials, one of boys and men aged 12 years and older and the other of boys younger than 12 years. In the first trial, patients taking emicizumab-kxwh had an 87% reduction in the rate of treated bleeding episodes per year, compared with patients not receiving prophylactic treatment (2.9 vs. 23.3; P less than .0001).
In the second trial, 87% of the children receiving emicizumab-kxwh did not experience a bleeding episode that required treatment.
The most common adverse events were injection site reactions, headache, and arthralgia. The drug labeling includes a boxed warning about the possibility of thrombotic microangiopathy and thromboembolism in patients given an activated prothrombin complex concentrate rescue treatment for 24 hours or more while taking emicizumab-kxwh.
The Food and Drug Administration has approved emicizumab-kxwh (Hemlibra) for the prevention or reduction of bleeding episodes for adult and pediatric patients with hemophilia A with Factor VIII inhibitors.
The drug received the FDA’s Priority Review, Breakthrough Therapy, and Orphan Drug designations.
It was shown to be safe and effective in two clinical trials, one of boys and men aged 12 years and older and the other of boys younger than 12 years. In the first trial, patients taking emicizumab-kxwh had an 87% reduction in the rate of treated bleeding episodes per year, compared with patients not receiving prophylactic treatment (2.9 vs. 23.3; P less than .0001).
In the second trial, 87% of the children receiving emicizumab-kxwh did not experience a bleeding episode that required treatment.
The most common adverse events were injection site reactions, headache, and arthralgia. The drug labeling includes a boxed warning about the possibility of thrombotic microangiopathy and thromboembolism in patients given an activated prothrombin complex concentrate rescue treatment for 24 hours or more while taking emicizumab-kxwh.
The Food and Drug Administration has approved emicizumab-kxwh (Hemlibra) for the prevention or reduction of bleeding episodes for adult and pediatric patients with hemophilia A with Factor VIII inhibitors.
The drug received the FDA’s Priority Review, Breakthrough Therapy, and Orphan Drug designations.
It was shown to be safe and effective in two clinical trials, one of boys and men aged 12 years and older and the other of boys younger than 12 years. In the first trial, patients taking emicizumab-kxwh had an 87% reduction in the rate of treated bleeding episodes per year, compared with patients not receiving prophylactic treatment (2.9 vs. 23.3; P less than .0001).
In the second trial, 87% of the children receiving emicizumab-kxwh did not experience a bleeding episode that required treatment.
The most common adverse events were injection site reactions, headache, and arthralgia. The drug labeling includes a boxed warning about the possibility of thrombotic microangiopathy and thromboembolism in patients given an activated prothrombin complex concentrate rescue treatment for 24 hours or more while taking emicizumab-kxwh.
Product approved to treat patients with hemophilia A and inhibitors
The US Food and Drug Administration (FDA) has approved use of emicizumab-kxwh (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.
Emicizumab is approved as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A and factor VIII (FVIII) inhibitors.
Emicizumab can be self-administered once-weekly via subcutaneous injection.
The labeling for emicizumab contains a boxed warning noting that patients who received emicizumab in conjunction with activated prothrombin complex concentrate developed thrombotic microangiopathy (TMA) and thromboembolic events (TEs).
Therefore, patients should discontinue prophylactic use of bypassing agents (BPAs) the day before starting prophylaxis with emicizumab.
The FDA granted the approval of emicizumab to Genentech, Inc. The agency granted the application for emicizumab priority review, and the product received breakthrough therapy and orphan drug designations.
Access to emicizumab
According to Genentech, emicizumab will be available shortly.
The company said it will be offering comprehensive services to help minimize barriers to access and reimbursement. Patients can call 866-436-5427 (866-HEMLIBRA) for more information.
For people who qualify, Genentech plans to offer patient assistance programs through Genentech Access Solutions. More information is available at 866-422-2377 (866-4ACCESS) or http://www.Genentech-Access.com.
Emicizumab trials
The biologics license application for emicizumab was supported by results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July. Interim results from HAVEN 2 were presented at ISTH as well.
HAVEN 1
The study enrolled 109 patients (age 12 and older) with hemophilia A and FVIII inhibitors who were previously treated with BPAs on-demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).
Adverse events occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced TEs, and 3 had TMA while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in children younger than 12 years of age who had hemophilia A with FVIII inhibitors.
The interim efficacy analysis, after at least 12 weeks of treatment, included 23 children.
After a median observation time of 38.1 weeks, 87% (95% CI: 66.4; 97.2) of children who received emicizumab experienced 0 treated bleeds. The percentage with 0 treated or non-treated bleeds was lower, at 34.8% (95% CI: 16.4; 57.3).
The most common adverse events (observed in at least 10% of patients) were mild injection site reactions and nasopharyngitis. No TEs or TMAs were observed.
HAVEN 3 and 4
Emicizumab is now being studied in 2 additional phase 3 trials.
In HAVEN 3, researchers are evaluating emicizumab prophylaxis dosed once weekly or once every other week in patients age 12 and older with hemophilia A without FVIII inhibitors.
In HAVEN 4, researchers are evaluating emicizumab prophylaxis dosed every 4 weeks in patients age 12 and older with hemophilia A, with or without inhibitors.
The US Food and Drug Administration (FDA) has approved use of emicizumab-kxwh (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.
Emicizumab is approved as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A and factor VIII (FVIII) inhibitors.
Emicizumab can be self-administered once-weekly via subcutaneous injection.
The labeling for emicizumab contains a boxed warning noting that patients who received emicizumab in conjunction with activated prothrombin complex concentrate developed thrombotic microangiopathy (TMA) and thromboembolic events (TEs).
Therefore, patients should discontinue prophylactic use of bypassing agents (BPAs) the day before starting prophylaxis with emicizumab.
The FDA granted the approval of emicizumab to Genentech, Inc. The agency granted the application for emicizumab priority review, and the product received breakthrough therapy and orphan drug designations.
Access to emicizumab
According to Genentech, emicizumab will be available shortly.
The company said it will be offering comprehensive services to help minimize barriers to access and reimbursement. Patients can call 866-436-5427 (866-HEMLIBRA) for more information.
For people who qualify, Genentech plans to offer patient assistance programs through Genentech Access Solutions. More information is available at 866-422-2377 (866-4ACCESS) or http://www.Genentech-Access.com.
Emicizumab trials
The biologics license application for emicizumab was supported by results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July. Interim results from HAVEN 2 were presented at ISTH as well.
HAVEN 1
The study enrolled 109 patients (age 12 and older) with hemophilia A and FVIII inhibitors who were previously treated with BPAs on-demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).
Adverse events occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced TEs, and 3 had TMA while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in children younger than 12 years of age who had hemophilia A with FVIII inhibitors.
The interim efficacy analysis, after at least 12 weeks of treatment, included 23 children.
After a median observation time of 38.1 weeks, 87% (95% CI: 66.4; 97.2) of children who received emicizumab experienced 0 treated bleeds. The percentage with 0 treated or non-treated bleeds was lower, at 34.8% (95% CI: 16.4; 57.3).
The most common adverse events (observed in at least 10% of patients) were mild injection site reactions and nasopharyngitis. No TEs or TMAs were observed.
HAVEN 3 and 4
Emicizumab is now being studied in 2 additional phase 3 trials.
In HAVEN 3, researchers are evaluating emicizumab prophylaxis dosed once weekly or once every other week in patients age 12 and older with hemophilia A without FVIII inhibitors.
In HAVEN 4, researchers are evaluating emicizumab prophylaxis dosed every 4 weeks in patients age 12 and older with hemophilia A, with or without inhibitors.
The US Food and Drug Administration (FDA) has approved use of emicizumab-kxwh (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.
Emicizumab is approved as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A and factor VIII (FVIII) inhibitors.
Emicizumab can be self-administered once-weekly via subcutaneous injection.
The labeling for emicizumab contains a boxed warning noting that patients who received emicizumab in conjunction with activated prothrombin complex concentrate developed thrombotic microangiopathy (TMA) and thromboembolic events (TEs).
Therefore, patients should discontinue prophylactic use of bypassing agents (BPAs) the day before starting prophylaxis with emicizumab.
The FDA granted the approval of emicizumab to Genentech, Inc. The agency granted the application for emicizumab priority review, and the product received breakthrough therapy and orphan drug designations.
Access to emicizumab
According to Genentech, emicizumab will be available shortly.
The company said it will be offering comprehensive services to help minimize barriers to access and reimbursement. Patients can call 866-436-5427 (866-HEMLIBRA) for more information.
For people who qualify, Genentech plans to offer patient assistance programs through Genentech Access Solutions. More information is available at 866-422-2377 (866-4ACCESS) or http://www.Genentech-Access.com.
Emicizumab trials
The biologics license application for emicizumab was supported by results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July. Interim results from HAVEN 2 were presented at ISTH as well.
HAVEN 1
The study enrolled 109 patients (age 12 and older) with hemophilia A and FVIII inhibitors who were previously treated with BPAs on-demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).
Adverse events occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced TEs, and 3 had TMA while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in children younger than 12 years of age who had hemophilia A with FVIII inhibitors.
The interim efficacy analysis, after at least 12 weeks of treatment, included 23 children.
After a median observation time of 38.1 weeks, 87% (95% CI: 66.4; 97.2) of children who received emicizumab experienced 0 treated bleeds. The percentage with 0 treated or non-treated bleeds was lower, at 34.8% (95% CI: 16.4; 57.3).
The most common adverse events (observed in at least 10% of patients) were mild injection site reactions and nasopharyngitis. No TEs or TMAs were observed.
HAVEN 3 and 4
Emicizumab is now being studied in 2 additional phase 3 trials.
In HAVEN 3, researchers are evaluating emicizumab prophylaxis dosed once weekly or once every other week in patients age 12 and older with hemophilia A without FVIII inhibitors.
In HAVEN 4, researchers are evaluating emicizumab prophylaxis dosed every 4 weeks in patients age 12 and older with hemophilia A, with or without inhibitors.
CHMP backs therapy for hemophilia A
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for rurioctocog alfa pegol (Adynovi).
Rurioctocog alfa pegol (formerly BAX 855) is a pegylated, full-length, recombinant factor VIII product built on a licensed recombinant factor VIII product (Advate).
The CHMP is recommending that rurioctocog alfa pegol be approved for the treatment and prophylaxis of bleeding in patients age 12 and older with hemophilia A.
The CHMP’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
If approved, rurioctocog alfa pegol would be available as a powder and solvent for solution for injection (250 IU, 500 IU, 1000 IU, and 2000 IU).
Phase 3 trials
Rurioctocog alfa pegol has been studied in 3 phase 3 trials.
One study (phase 2/3) included 137 patients, age 12 and older, with previously treated hemophilia A. Results from this trial were published in Blood in July 2015.
Another study included 15 patients with severe hemophilia A who were undergoing surgical procedures. Results were published in Haemophilia in June 2016.
A third study included 66 patients, age 12 and younger, who had previously treated hemophilia A. Results from this trial were presented at the World Federation of Hemophilia 2016 World Congress in July 2016.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for rurioctocog alfa pegol (Adynovi).
Rurioctocog alfa pegol (formerly BAX 855) is a pegylated, full-length, recombinant factor VIII product built on a licensed recombinant factor VIII product (Advate).
The CHMP is recommending that rurioctocog alfa pegol be approved for the treatment and prophylaxis of bleeding in patients age 12 and older with hemophilia A.
The CHMP’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
If approved, rurioctocog alfa pegol would be available as a powder and solvent for solution for injection (250 IU, 500 IU, 1000 IU, and 2000 IU).
Phase 3 trials
Rurioctocog alfa pegol has been studied in 3 phase 3 trials.
One study (phase 2/3) included 137 patients, age 12 and older, with previously treated hemophilia A. Results from this trial were published in Blood in July 2015.
Another study included 15 patients with severe hemophilia A who were undergoing surgical procedures. Results were published in Haemophilia in June 2016.
A third study included 66 patients, age 12 and younger, who had previously treated hemophilia A. Results from this trial were presented at the World Federation of Hemophilia 2016 World Congress in July 2016.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for rurioctocog alfa pegol (Adynovi).
Rurioctocog alfa pegol (formerly BAX 855) is a pegylated, full-length, recombinant factor VIII product built on a licensed recombinant factor VIII product (Advate).
The CHMP is recommending that rurioctocog alfa pegol be approved for the treatment and prophylaxis of bleeding in patients age 12 and older with hemophilia A.
The CHMP’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
If approved, rurioctocog alfa pegol would be available as a powder and solvent for solution for injection (250 IU, 500 IU, 1000 IU, and 2000 IU).
Phase 3 trials
Rurioctocog alfa pegol has been studied in 3 phase 3 trials.
One study (phase 2/3) included 137 patients, age 12 and older, with previously treated hemophilia A. Results from this trial were published in Blood in July 2015.
Another study included 15 patients with severe hemophilia A who were undergoing surgical procedures. Results were published in Haemophilia in June 2016.
A third study included 66 patients, age 12 and younger, who had previously treated hemophilia A. Results from this trial were presented at the World Federation of Hemophilia 2016 World Congress in July 2016.
CHMP recommends approval of romiplostim in kids
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for romiplostim (Nplate®) to include children.
The CHMP is recommending authorization of romiplostim to treat patients age 1 and older who have chronic immune thrombocytopenia (ITP) that is refractory to other treatments.
The committee’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, a centralized marketing authorization will be granted that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
The recommendation for romiplostim was based on 5 studies of the drug in children with ITP. This includes 4 completed studies—a phase 1/2, a phase 3, and 2 long-term safety and efficacy studies—and 1 ongoing long-term study.
Results from the phase 1/2 trial were published in Blood in 2011. Phase 3 results were published in The Lancet in April of last year.
And results from 2 of the long-term trials were presented at 22nd Congress of the European Hematology Association in June (abstract P367 and abstract P727).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for romiplostim (Nplate®) to include children.
The CHMP is recommending authorization of romiplostim to treat patients age 1 and older who have chronic immune thrombocytopenia (ITP) that is refractory to other treatments.
The committee’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, a centralized marketing authorization will be granted that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
The recommendation for romiplostim was based on 5 studies of the drug in children with ITP. This includes 4 completed studies—a phase 1/2, a phase 3, and 2 long-term safety and efficacy studies—and 1 ongoing long-term study.
Results from the phase 1/2 trial were published in Blood in 2011. Phase 3 results were published in The Lancet in April of last year.
And results from 2 of the long-term trials were presented at 22nd Congress of the European Hematology Association in June (abstract P367 and abstract P727).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for romiplostim (Nplate®) to include children.
The CHMP is recommending authorization of romiplostim to treat patients age 1 and older who have chronic immune thrombocytopenia (ITP) that is refractory to other treatments.
The committee’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, a centralized marketing authorization will be granted that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
The recommendation for romiplostim was based on 5 studies of the drug in children with ITP. This includes 4 completed studies—a phase 1/2, a phase 3, and 2 long-term safety and efficacy studies—and 1 ongoing long-term study.
Results from the phase 1/2 trial were published in Blood in 2011. Phase 3 results were published in The Lancet in April of last year.
And results from 2 of the long-term trials were presented at 22nd Congress of the European Hematology Association in June (abstract P367 and abstract P727).
Drug receives orphan designation for treatment of PNH
The US Food and Drug Administration (FDA) has granted orphan drug designation to ACH-4471 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
And the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products has recommended the drug receive orphan status for the same indication in the European Economic Area.
ACH-4471 is a factor D inhibitor being developed by Achillion Pharmaceuticals, Inc.
In April, the company announced the initiation of a phase 2, three-month, dose-ranging trial with ACH-4471 for patients with untreated PNH (NCT03053102).
The primary objective of the trial is to assess the change from baseline in serum lactate dehydrogenase (LDH) levels. Secondary endpoints include changes in hemoglobin, PNH red blood cells, fatigue score (FACIT scale), changes in levels of complement pathway biomarkers such as Bb and factor D, pharmacokinetics, and safety.
The protocol allows for intra-patient dose-escalation. Patients initially receive 100 mg or 150 mg of ACH-4471 three times daily, and doses may be increased during the treatment period.
After patients complete 3 months of treatment and investigators have assessed safety and clinical benefit, patients may be enrolled in the long-term extension trial (NCT03181633).
To date, 200 mg three times daily has been the highest dose of ACH-4471 administered. And Achillion has collected data on 4 patients.
Two of the patients have completed the 3-month trial and entered the long-term extension trial. One patient continues to receive dosing in the 3-month trial, and the fourth patient voluntarily withdrew from the trial on day 41 for reasons unrelated to safety.
Thus far, ACH-4471 has produced clinically meaningful complement inhibition and demonstrated a favorable tolerability profile, with no reports of clinically meaningful increases in liver enzymes. ACH-4471 has improved LDH, hemoglobin, fatigue score, and other measures of response, including PNH clone size.
FDA’s orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
EMA’s orphan designation
The EMA’s orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. It also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.
The US Food and Drug Administration (FDA) has granted orphan drug designation to ACH-4471 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
And the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products has recommended the drug receive orphan status for the same indication in the European Economic Area.
ACH-4471 is a factor D inhibitor being developed by Achillion Pharmaceuticals, Inc.
In April, the company announced the initiation of a phase 2, three-month, dose-ranging trial with ACH-4471 for patients with untreated PNH (NCT03053102).
The primary objective of the trial is to assess the change from baseline in serum lactate dehydrogenase (LDH) levels. Secondary endpoints include changes in hemoglobin, PNH red blood cells, fatigue score (FACIT scale), changes in levels of complement pathway biomarkers such as Bb and factor D, pharmacokinetics, and safety.
The protocol allows for intra-patient dose-escalation. Patients initially receive 100 mg or 150 mg of ACH-4471 three times daily, and doses may be increased during the treatment period.
After patients complete 3 months of treatment and investigators have assessed safety and clinical benefit, patients may be enrolled in the long-term extension trial (NCT03181633).
To date, 200 mg three times daily has been the highest dose of ACH-4471 administered. And Achillion has collected data on 4 patients.
Two of the patients have completed the 3-month trial and entered the long-term extension trial. One patient continues to receive dosing in the 3-month trial, and the fourth patient voluntarily withdrew from the trial on day 41 for reasons unrelated to safety.
Thus far, ACH-4471 has produced clinically meaningful complement inhibition and demonstrated a favorable tolerability profile, with no reports of clinically meaningful increases in liver enzymes. ACH-4471 has improved LDH, hemoglobin, fatigue score, and other measures of response, including PNH clone size.
FDA’s orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
EMA’s orphan designation
The EMA’s orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. It also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.
The US Food and Drug Administration (FDA) has granted orphan drug designation to ACH-4471 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
And the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products has recommended the drug receive orphan status for the same indication in the European Economic Area.
ACH-4471 is a factor D inhibitor being developed by Achillion Pharmaceuticals, Inc.
In April, the company announced the initiation of a phase 2, three-month, dose-ranging trial with ACH-4471 for patients with untreated PNH (NCT03053102).
The primary objective of the trial is to assess the change from baseline in serum lactate dehydrogenase (LDH) levels. Secondary endpoints include changes in hemoglobin, PNH red blood cells, fatigue score (FACIT scale), changes in levels of complement pathway biomarkers such as Bb and factor D, pharmacokinetics, and safety.
The protocol allows for intra-patient dose-escalation. Patients initially receive 100 mg or 150 mg of ACH-4471 three times daily, and doses may be increased during the treatment period.
After patients complete 3 months of treatment and investigators have assessed safety and clinical benefit, patients may be enrolled in the long-term extension trial (NCT03181633).
To date, 200 mg three times daily has been the highest dose of ACH-4471 administered. And Achillion has collected data on 4 patients.
Two of the patients have completed the 3-month trial and entered the long-term extension trial. One patient continues to receive dosing in the 3-month trial, and the fourth patient voluntarily withdrew from the trial on day 41 for reasons unrelated to safety.
Thus far, ACH-4471 has produced clinically meaningful complement inhibition and demonstrated a favorable tolerability profile, with no reports of clinically meaningful increases in liver enzymes. ACH-4471 has improved LDH, hemoglobin, fatigue score, and other measures of response, including PNH clone size.
FDA’s orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
EMA’s orphan designation
The EMA’s orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. It also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.