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doi:10.1182/blood-2011-12-309153Prepublished online June 26, 2012;
Waleed Ghanima, Bertrand Godeau, Douglas B. Cines and James B. Bussel splenectomy or a medical therapy as a second-line treatmentHow I treat immune thrombocytopenia (ITP): the choice between
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How I treat immune thrombocytopenia (ITP): the choice between splenectomy or a medical therapy as a second-line treatment Waleed Ghanima 1,2, Bertrand Godeau 3, Douglas B. Cines4, James B. Bussel 1 Dept. of Pediatric Hematology/Oncology, Weill Cornell Medical College , New York, USA1,
Dept. Of Internal Medicine, Østfold Hospital Trust Fredrikstad, Fredrikstad, Norway2,Dept.
of Internal Medicine, Henri Mondor University Hospital, Assistance Publique-Hôpitaux de
Paris, UPEC, Créteil- France3, Depts. of Pathology and Laboratory Medicine and
Medicine, the Perelman School of Medicine at the University of Pennsylvania4
Corresponding Author:
Dr. James B. Bussel
Dept. of Pediatric Hematology/Oncology
Weill Cornell Medical College
New York, N.Y. 10065 USA
jbussel@med.cornell.edu
ph 212-746-3474
fax 212-746-5121
Blood First Edition Paper, prepublished online June 26, 2012; DOI 10.1182/blood-2011-12-309153
Copyright © 2012 American Society of Hematology
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Abstract
The paradigm for managing primary immune thrombocytopenia (ITP) in adults has
changed with the advent of rituximab and thrombopoietin receptor agonists (TPO-RAs)
as options for second-line therapy. Splenectomy continues to provide the highest cure
rate (60-70% at 5+ years). Nonetheless, splenectomy is invasive, irreversible, associated
with post-operative complications, and its outcome is currently unpredictable, leading
some physicians and patients towards postponement and use of alternative approaches.
An important predicament is the lack of studies comparing second-line options to
splenectomy and to each other. Furthermore, some adults will improve spontaneously
within 1-2 years. Rituximab has been given to more than 1 million patients worldwide, is
generally well tolerated and its short-term toxicity is acceptable. In adults with ITP, 40%
of patients are complete responders at one year and 20% remain responders at 3-5
years. Newer approaches to using rituximab are under study. TPO-RAs induce platelet
counts >50,000/µl in 60-90% of adults with ITP, are well-tolerated, and show relatively
little short-term toxicity. The fraction of TPO-RA-treated patients who will be treatment-
free after 12-24 months of therapy is unknown but likely to be low. As each approach has
advantages and disadvantages treatment needs to be individualized, and patient
participation in decision-making is paramount.
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Background
Consult: A 34 year-old patient presents with a platelet count of 10,000/µL accompanied
by petechiae, ecchymoses, and epistaxis. Work-up leads to the diagnosis of ITP.
Treatment with prednisone is initiated with good clinical and platelet response and the
drug is reasonably well tolerated. However, the platelet count falls and bleeding
symptoms recur when the dose is tapered below 10 mg daily. Prednisone is reinitiated at
a high dose and tapered more slowly, but the platelet count again falls to <20,000/µL
when the dose reaches 10 mg daily. It is now 5 months since diagnosis. What is the
appropriate therapy? Specifically, is splenectomy indicated or should it be reserved and
other treatments tried first?
Introduction
Splenectomy has been the standard second-line treatment for adults with ITP for
decades and remains the option that provides the highest cure rate. Careful choice of
patients, widespread adoption of a laparoscopic approach, peri-operative
thromboprophylaxis, and better approaches to prevent and mitigate sepsis have helped
reduce morbidity, costs1 and possibly mortality.2 Concurrently, important advances have
been made in understanding the pathogenesis of ITP accompanied by development of
novel treatments, including anti-CD20 antibodies3 and thrombopoietin receptor agonists
(TPO-RAs).4,5 This has led to increased uncertainty as to when splenectomy is advisable
as the standard next step. It has also become clear that some adults improve over time
either spontaneously or as a result of treatment, leading some to recommend deferring
surgery for one to several years.6 Moreover, increased clinical awareness and use of
laboratory testing now identifies concomitant illnesses in patients who otherwise meet
diagnostic criteria for ITP (“cryptic” secondary ITP), including some, e.g. hepatitis C and
common variable immune deficiency (CVID), that mitigate against splenectomy.
It is our distinct impression that information of variable validity widely available on the
Internet has increased the number of patients who wish to avoid splenectomy. The
introduction of new therapies and increased awareness of late remissions in ITP have
resulted in physicians tending to avoid or defer splenectomy, which is increasingly
viewed as the last resort, particularly in the United States and some European countries.
This is evidenced by a decrease in the rate of splenectomy for ITP from 50–60% in
previously reported cohorts to 20–25% more recently.7
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Two recent reviews of treatment for ITP have been published.8,9 The International
Consensus document used both published studies and the accumulated experience of
22 international experts, somewhat akin to the process used to develop the initial ASH
guidelines, though with less formal integration of expert opinion.8 In contrast, the revised
ASH guidelines focused on evidence-based medicine, with half of the writing group
having expertise in trial-methodology and data-analysis, the remainder in ITP.9 Both
groups considered splenectomy, and both recommended it as a second-line therapy.
However, the International Consensus gave it equal place among a number of options,
whereas the ASH guidelines gave splenectomy its highest grade of recommendation
based on its curative effects and the extensive published experience. Additional
guidelines that consider the role of splenectomy in second line treatment are summarized
in Supplemental Table 1.
This article on “How I Treat ITP” investigates the question: What is the optimal
second line treatment for adults with ITP? Splenectomy is considered in the context of
the two most commonly employed, newer approaches to second line therapy: rituximab
and TPO-RAs. Since no comparative evidence-based recommendations can be made,
our focus is to consider and balance the potential benefits and relative contraindications
of each option to help inform individualized care.
What is ITP? ITP is an autoimmune disease characterized by isolated thrombocytopenia (platelet
count <100,000/µl) resulting from accelerated clearance and destruction of antibody-
coated platelets by tissue macrophages, predominantly in the spleen.10 Anti-platelet
antibodies also target antigens on megakaryocytes and pro-platelets, variably
suppressing platelet production.11,12 Plasma thrombopoietin (TPO) is generally normal or
only minimally elevated, primarily because of accelerated clearance via megakaryocytes
and platelets.13 Activated cytotoxic CD8 positive T cells may contribute to
thrombocytopenia in certain patients.14 A potential underlying etiology giving rise to
secondary ITP, such as infection with hepatitis C, human immunodeficiency virus (HIV)
or Helicobacter pylori, and co-existence of systemic lupus erythematosus (SLE),
antiphospholipid syndrome (APS) or common variable immunodeficiency
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(hypogammaglobulinemia, CVID), is identified in approximately 20% of patients with
immune thrombocytopenia.15 Discovering an underlying cause is important since it may
impact the efficacy and safety of splenectomy and other approaches (see below).16,17
Moreover, patients such as in the case example are often not thoroughly evaluated for
secondary ITP and an underlying etiology may not be apparent on presentation.
Who should be treated?
Treatment is generally confined to patients who are bleeding or are perceived to be at
significant risk of bleeding. The risk of bleeding is multi-factorial and its assessment is
complex. For the most part, bleeding is related to a decreased platelet count, increasing
age, co-morbidities (including their treatments), risk of trauma, and previous history of
bleeding.18 Although a platelet count of <30,000/µl is often used as a surrogate
marker,4,5,9,19 lower (10-20,000/µl) or higher (50,000/µl) thresholds are pursued
depending on the risk of bleeding, the presence of co morbidities, patient’s lifestyle and
risk of trauma, all of which need to be weighed against the likely benefits and the risk of
treatment-related side effects.20 Some therapies may improve health related quality of life
(HRQoL), especially fatigue, although this issue is infrequently considered or invoked as
a reason to treat.21,22 Comparative outcome studies are lacking here as well.
When should splenectomy be considered among second-line therapies?
The frequency of complete remission23 after a course of first line therapy with
corticosteroids ranges from 10-30% with daily oral prednisone24 to as much as 60-80%
with high-dose, pulsed dexamethasone (HDD).6,25,26 However, the latter remains to be
confirmed in controlled trials and currently available evidence does not establish the
superiority of HDD.27 In the absence of such evidence, we do not routinely use multiple
cycles of HDD to induce remission in patients who have failed a course of prednisone.
Patients may develop hemostatic platelet counts by one year (Figure 1)6,28 or
occasionally after many years of severe disease without additional treatment.29,30
Accordingly, the International Consensus statement suggests deferring splenectomy until
the chronic phase (> 12 months), if possible, unless an adequate count cannot be
maintained with medical therapy, adverse reactions to medical alternatives develop, or
there is compelling patient preference, e.g. because of life-style or employment.8
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The management of patients who fail corticosteroids is challenging, as there have been
no comparative trials of treatment options in this setting. The International Consensus
report lists more than 10 second-line therapeutic options, including splenectomy, without
indicating a preference.8 The revised ASH guidelines recommend splenectomy (Grade-
1B evidence) for patients who failed corticosteroid therapy while suggesting treatment
with TPO-RAs and rituximab pre-splenectomy (Grade 2C evidence).9 What follows is our
analysis of the factors to be considered when choosing amongst the three most common
options (Table 2; Figure 2). We recognize that other approaches, including watchful
waiting may be appropriate in many patients. Also, other treatments widely used in some
countries, such as dapsone and immunosuppressive agents,8 are not commonly
employed as second line treatments in our practice.
Splenectomy
Splenectomy has been employed for decades as the primary option in patients who
require additional treatment after a course of corticosteroids.
What are the Pros of Splenectomy?
1- Splenectomy is “curative”
Splenectomy “cures” ITP by removing both the primary site of platelet destruction and an
important site of anti-platelet antibody production in an uncertain but large proportion of
patients. Platelet counts rise rapidly in 85% of patients. Relapses are encountered,
especially in the first 2 years after surgery, but 60-65% of patients remain in clinical
remission 5-10 years after splenectomy, an outcome unmatched by any other therapy
(Figure 3).2,31,32 A systematic review of 135 case-series published between 1966 to 2004
revealed a complete response rate of 66% with a median duration of follow-up of 28
months (range 1 to 153 months).2 A recent systematic review of 23 articles and 1,223
patients post-laparoscopic splenectomy recorded a success rate of 72% at 5 years.33
Responding patients require relatively little follow-up e.g. yearly platelet counts and
repeated vaccinations, except in pregnant women who are at risk for having a fetus with
thrombocytopenia.
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2- Splenectomy failure does not jeopardize response to most medical treatments
It has been thought for some time that some patients who fail splenectomy may be
managed with lower doses of corticosteroids than were required before surgery. 19
However, strong evidence is lacking. TPO-RA and rituximab are equally effective in
splenectomized and non-splenectomized patients.34,35 The only therapies known to be
less effective after splenectomy are IV anti-D,36 and probably dapsone.
3- Advantages of laparoscopic splenectomy
Laparoscopic splenectomy37 is widely used as the preferred approach because it is less
traumatic, engenders less post-operative pain, and is associated with fewer wound
infections and other complications leading to shorter hospital stays, more rapid
convalescence, and more rapid return to work, all of which contribute to lower costs.38,39
Cosmesis is improved compared with the open approach. Laparoscopy does not
increase the frequency of missing accessory spleens.40 Consequently, laparoscopic
splenectomy has been embraced as the “Gold Standard,”1,41 but should only be
performed by experienced operators.42 The conversion rate to open laparotomy ranges
from 5-15%.38,42 As with open splenectomy, it is important to elevate platelet counts
preoperatively to >20,000/µl to avoid longer hospital stay, blood transfusions, and other
complications.43
4- Splenectomy has a well-characterized safety profile and generally preventable
complications
Perioperative complications of splenectomy include bleeding, infection, and thrombosis.
Long-term complications include overwhelming sepsis by encapsulated bacteria and
vascular/thrombotic events. Most complications are infrequent and either preventable or
treatable (see Splenectomy “Cons”). Surgical expertise combined with proper patient
selection and preparation is key to reducing complication rates and involves: excluding
patients with serious co-morbidities for general surgery and “older” patients (age cut-offs
for those in otherwise excellent health is debated), optimizing platelet counts peri-
operatively, and judicious use of antibiotics and thromboprophylaxis.43 We recommend
Pneumococcal, Meningococcal, and Haemophilus influenzae vaccination prior to
splenectomy and periodically every 5 years or according to titers.1,44
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5- Splenectomy reduces cost
Prior to TPO-RA, the annual cost of treating severe chronic ITP was estimated to be
$40,00045, although comprehensive cost-effectiveness studies are lacking in adults.
However, the cost of TPO-RAs ranges from $2500-$4000 per month, and each 4-infusion
course of rituximab costs $10,000-$50,000, whereas the estimated total procedural cost
of splenectomy is not more than $20,000. These cost estimates apply only to patients
who respond. The societal cost of failed splenectomy includes the cost of surgical
complications and subsequent therapy.
6-Pregnancy
Women with ITP who contemplate pregnancy may opt for splenectomy because most
options for management of the maternal platelet count, including TPO-RA and rituximab,
may not be safe for the fetus.46,47 However, women in remission post-splenectomy may
relapse during pregnancy and the fetus/neonate may develop thrombocytopenia even if
the splenectomized mother remains in remission.48
What are the Cons?
1- Removal of a “healthy” organ
Splenectomy is irreversible and consequently leads to the loss of its multiple hematologic
and immunologic functions e.g. elimination of abnormal blood cells, cell particles and
organisms from the blood and production of antibodies to blood-borne antigens.49
2- Unpredictability of response
The response to splenectomy cannot be predicted using readily available clinical criteria,
e.g. previous response to steroids or IVIG, other than “older” age, which is ill-defined.2 In
a retrospective review of 111In-labeled autologous platelet sequestration studies, the
complete response rate after splenectomy was 87% (median 3.8 years follow up) in
patients having predominantly splenic sequestration as opposed to 35% in those with
“mixed” or hepatic sequestration (OR 5.39; 95% CI 1.3–21.6).50 Confirmatory studies are
needed. Major limitations include restricted availability and technical difficulty.51
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3- Post-Splenectomy Mortality and Morbidity
Splenectomy is an invasive procedure associated with near-term complications primarily
related to general anesthesia and surgery and long-term complications from loss of
splenic functions.
a- Overall Mortality
The 30-day mortality and complication rates after laparoscopic splenectomy (0.2% and
9.6%) are reported to be lower than after open splenectomy (1% and 12.9%).2 A Danish
cohort study compared 3,812 patients splenectomized for various indications between
1996 and 2005, 8,310 non-splenectomized patients with matched underlying conditions,
and 38,120 controls. Ninety-day mortality was elevated in the splenectomized cohort as a
whole and in the sub-cohort with ITP (n=269) (Adjusted Relative risk (RR) 33.6; 95%CI
7.9-143) compared to the general population. However, for patients with ITP, the
difference in mortality during the first year after splenectomy was not significant when
compared to the non-splenectomized cohort. Interestingly, after one year, the RR of
death in the splenectomized ITP patients was significantly lower than in the matched ITP
controls treated otherwise (RR 0.4; 95% CI 0.2-0.7).52 However, the assessment period
preceded the introduction of TPO-RAs and extensive use of rituximab; therefore data in
the non-splenectomized ITP cohort was derived from an era when patients typically
underwent prolonged exposure to high doses of corticosteroids and other
immunosuppressives not widely used and/or no longer considered safe or appropriate in
this setting.
b- Risk of infection
Since 1952, it has been evident that asplenic subjects are at increased risk of life-
threatening infections.53 The Danish cohort study identified a 14-fold higher RR of sepsis
in splenectomized ITP patients (n=269) during the first year after splenectomy and a 4-
fold higher RR after 1 year compared to the general population. Importantly, compared to
non-splenectomized ITP patients, a higher rate of sepsis was observed only during the
first 90 days.53 Interestingly, enteric organisms were the predominant cause of early and
late postsplenectomy bacteremia; encapsulated bacteria, such as pneumococci,
meningococci, and Haemophilus influenzae were rarely encountered in the
splenectomized cohort, perhaps a result of widespread vaccination and early intervention
with antibiotics (see below). No sepsis-related mortality was reported in two Italian
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studies that included 612 splenectomized ITP patients.31,54
Repeated patient education is vital because the rarity of sepsis predisposes to non-
compliance. Med-alert bracelets may be helpful. Guidelines for preventing sepsis and/or
improving the outcome, when it occurs, vary but may include: a) repeat vaccination every
5-10 years or when antibody titers (especially to pneumococcus) fall; b) measurement of
body temperature at the onset of any illness and urgent emergency room evaluation for a
fever of 101oF or higher with initiation of IV antibiotics such as ceftriaxone (absent
allergy); and c) consideration of penicillin 250-500 milligrams twice a day for life (however,
the incidence of pneumococcal penicillin resistance currently approaches 30%).
Exposure to infections with known worse outcomes in splenectomized patients, e.g.
malaria and babesiosis, should be avoided if at all possible. Table 3 summarizes pre-
and post-operative recommendations to minimize post splenectomy infectious
complications.
c- Vascular complications
Splenectomy may increase morbidity from venous thromboembolism (VT) or
atherosclerosis. Increased pro-coagulant derived microparticles,55 platelet activation,
disturbance and activation of the endothelium, altered lipid profiles and persistent
thrombocytosis have been implicated in hypercoagulability in ITP.44
VT is reported to occur in up to 10% of patients with hematologic diseases undergoing
splenectomy.2,38,42,56 The risk of VT is highest in the first year post-splenectomy, but even
thereafter the rate of VT in splenectomized ITP was 2.7-fold (95% CI 1.1-6.3) higher than
in age-matched controls.57 However, these studies did not include a non-splenectomized
ITP cohort. In a more recent French study of 275 patients given thromboprophylaxis who
underwent laparoscopic splenectomies for various hematological disorders (76% with
ITP), only 1% developed VT.42 Portal vein thrombosis is a known early complication of
open or laparoscopic splenectomy. Systematic screening for portal vein thrombosis with
doppler ultrasound or CT scan revealed a high incidence (8-37%), but symptomatic
cases are rare (<2%),57,58 making the value of routine post-operative surveillance
unproven. Secondary pulmonary arterial hypertension has been reported after
splenectomy in patients with hemolytic anemia, e.g. spherocytosis and thalassemia, but
only anecdotally after splenectomy for ITP.59 There is insufficient information to know
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whether splenectomy predisposes to other reported vascular complications, (e.g. multi-
infarct dementia and acute coronary syndrome).60
Summary. Splenectomy offers the greatest opportunity for cure and societal costs
appear favorable. There is little evidence to suggest increased long-term mortality and
morbidity compared with medical treatment options if patients are managed appropriately,
especially with regard to selection, pre- and peri-operative management, laparoscopy by
an experienced surgeon, and prophylaxis of and attention to sepsis and thrombosis.
On the other hand, data comparing splenectomized and non-splenectomized ITP patients,
which suggest little difference in adverse outcomes (e.g. sepsis), were acquired in
patients with extensive steroid exposure before the current era of TPO-RA and rituximab.
Furthermore, the long-term consequences of splenectomy remain ill defined. Delaying
the decision for 12 months or more appears to lessen the need for surgery in a
substantial proportion of patients. If this approach is adopted more widely, it may affect
subsequent analyses, because restricting splenectomy to third-line “salvage” therapy will
likely reduce not only the need but also the response rate.
Primary Alternative Therapeutic Options including Factors
Determining the Choice of Treatment
Rituximab a. Pros. Rituximab is appealing because of its curative potential and relative safety and
because hematologists are familiar with its use in treating lymphoma. Four once-weekly
IV infusions at 375 mg/m2 induce complete remission (CR) in 44% of patients. 61 In one
study, splenectomy was deferred by two years in 40% of the patients who were treated
with rituximab.62 Patients with CRs generally persist at least 1 year; those with PRs
usually relapse within 6 months.3 In adults, the CR rate falls to approximately 20% by 2-5
years after a single 4-infusion course.62,63 More durable remissions might be induced by
adding 1-3 cycles of HDD or using maintenance rituximab.64,65 First infusion reactions
induced by clearance of anti-CD20-coated B cells by macrophages and direct cytotoxicity
to B cells is generally preventable by slowing the rate of infusion and pre-administration
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of IV methylprednisolone (100 -1000 mg), IV diphenhydramine (25-50 milligrams) and
acetaminophen.
b. Cons. Toxicities primarily involve first infusion reactions, serum sickness, which is
more common (5-10%) in children, and a series of rare complications, including fulminant
hepatitis B and progressive multifocal leukoencephalopathy (primarily in the setting of
profound immunodeficiency such as when rituximab is used along with intensive
chemotherapy), delayed neutropenia (more common when rituximab is combined with
chemotherapy), hypogammaglobulinemia, and diverse idiosyncratic reactions.61,66
Persistent perturbations in the T- and B-cell repertoires and impaired response to specific
antigens have been reported in non-ITP populations and in animal models,67 but their
clinical significance is uncertain. Immunizations, such as pneumovax, should be given
prior to rituximab, as response is reduced for 4-6 months until B cells return. This may be
especially important if the patient subsequently requires splenectomy. While safety
issues exist, more than one million patients have been treated for a variety of malignant
and autoimmune indications since the 1990’s with limited long-term serious toxicity
documented to date.
c. Additional considerations. Because large randomized studies have not been
completed, Rituximab has not received FDA or EMA approval for ITP although it is
currently reimbursed for this purpose in many countries. Currently the drug is
administered IV, although subcutaneous administration has been performed with two
other anti-CD20 antibodies, one in ITP.68 The longest follow-up for which data is more
than anecdotal is 3-5 years compared with 5-20 years for splenectomy. Dosing is empiric.
Infusions of lower doses, e.g. 100 mg, showed comparable but delayed short-term
benefit.69,70 There is no mechanism or treatment effect that can be used to individualize
dose or frequency of administration, other than depletion of peripheral blood B cells.
Repeat administration has been used effectively in a few patients.71 Anecdotal
information, which suggests that Rituximab administered closer to the time of diagnosis is
more effective, needs to be formally demonstrated. Outcomes may be improved by use
in combination with HDD. The single reported study combining one cycle of HDD
followed by Rituximab in previously untreated ITP patients yielded a combined PR and
CR rate of 63% at 6 months; of those, 15-25% relapsed by 20 months.72,73 In a pilot study
of 42 previously treated patients, a combination of Rituximab with 3 cycles of HDD
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yielded a CR + PR of 71% and lasting responses in 57%.64
d. Summary. Rituximab has been used widely and appears to be relatively safe to date.
It provides long-term CR comparable to any therapy other than splenectomy. However,
the long-term outcome after 4 standard-dose infusions is somewhat disappointing.
Additional benefits from co-administering dexamethasone and maintenance therapy
appear promising and are under investigation
Thrombopoietin receptor agonists (TPO-RAs) TPO-RAs are the only second-line therapy validated by randomized, controlled trials;
however, thus far, the comparator arm was placebo.4,5,22,34,35,74 Two TPO-RAs,
Romiplostim and Eltrombopag, are approved for use in over 80 countries. In the USA,
Romiplostim is administered as subcutaneous weekly injections, which, at the time of this
writing, must be administered by a health care provider. Eltrombopag is an oral agent
given daily that must be taken at least 2 hours apart from ingestion of food and 4 hours
apart from calcium-containing products (e.g. dairy) and supplemental iron.
a. Pros.
The reported response rates to TPO-RAs range from 59-88%;22,34,35 responses are
generally sustained as long as treatment continues.22,75
The short-term safety and
tolerability of both TPO-RAs have been carefully documented and both were monitored
closely for 3 years in the US, as part of post-marketing surveillance by the FDA. In one
long-term study, 5% of the patients discontinued therapy because of side effects.75 Only
a few patients lose responsiveness once a stable platelet count has been attained.75 In
responders, doses can be individualized to attain hemostasis and in many patients the
dose can be increased temporarily to raise platelet counts further in advance of elective
surgery. Many patients are able to discontinue or reduce the dose of concomitant ITP
treatments such as corticosteroids.22,34,74,75 Decreased bleeding, less need for other
(rescue) treatments, and increased HRQoL have been seen in responders.22,34,74,75 A
number of patients, after months to years of treatment, appear able to discontinue
treatment and maintain an adequate platelet count.76
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b. Cons.
The major disadvantage of these agents compared to splenectomy and rituximab is the
indefinite duration of treatment. As TPO-RAs are potentially life-long treatments,
compliance may be a real issue. The current requirement for a healthcare professional to
administer romiplostim and the alimentary requirements to ensure effective dosing of
eltrombopag are cumbersome. TPO-RAs require at least 1-2 weeks to take effect (in
responders) and therefore play at most a supplementary role in managing urgent
conditions. Patients may experience mild-moderate headache, myalgias and
gastrointestinal disturbances.46 Eltrombopag carries a black-box warning for
hepatotoxicity. Neither should be used during pregnancy or lactation. “Rebound”
thrombocytopenia occurs infrequently after abrupt discontinuation of TPO-RAs, which
can be prevented by tapering the drugs and/or using rescue treatment, if needed.22 An
increase in bone marrow reticulin has been observed in several patients.75,77,78 However,
current evidence does not indicate progressive bone marrow fibrosis with prolonged
exposure.77 TPO-RAs have not been shown to induce malignancy or myelodysplasia in
patients with ITP thus far,77 but they are not indicated in patients with myelodysplasia due
to the potential risk of acute myeloid leukemia (romiplostim carries a warning). Although,
it seems these agents have acceptable short and intermediate term safety profiles, long-
term safety data beyond 5 years is limited.
c. Additional considerations: Relapse occurs in a large majority of patients when
treatment is interrupted.74,75,79 An increase in regulatory T-cells (Tregs) is seen and a few
patients appear to maintain adequate platelet counts off therapy.80 In contrast to
splenectomy and rituximab, TPO-RAs have only been in use for 7 years in trials and 3
years in general practice; hence experience in patients who were not eligible for inclusion
on protocols is limited.81 It is difficult to discern if there is an increase in the rate of VT
compared with other successful interventions; it is important to take the underlying risk of
arterial or venous thrombosis into consideration in patients with ITP and to consider use
of aspirin in those at risk once the platelet count has entered a safe range, e.g.
>50,000/µL. Additional detailed analyses of toxicity have been reported in primary
studies4,5,22,34,35,74,75 and in reviews.82 These agents are not approved for use pre-
splenectomy in Europe unless surgery is contraindicated.
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d. Summary: TPO-RAs are highly effective before and after splenectomy, rituximab, and
other agents. Toxicity appears limited, although surveys and studies are ongoing
involving patients treated in the United States and elsewhere to better define
complication rates (especially thrombosis and marrow fibrosis) in larger numbers of
patients followed for longer times. There is no evidence at this time that there is any
major difference in efficacy or toxicity between the two agents, although eltrombopag
requires monitoring of liver function tests every 1-2 months, which may occasionally lead
to at least temporary discontinuation, if abnormal. Anecdotal evidence suggests that
infrequently one agent will be effective when the other is not.
Factors that influence the choice of treatment
1-Patient and physician preference: The patient is a critical protagonist in the decision
to undergo or defer splenectomy. Increasing awareness of medical alternatives, input of
patient advocacy groups, impact of the internet, inability to predict with certainty the
response to a surgical procedure,83 and rare but dramatic adverse outcomes have
changed the landscape with respect to the patient’s perspective. In turn, this decreases
the breadth of experience of hematologists and surgeons with the procedure and its
relative long-term advantages. The recent demonstrations that a substantial fraction of
patients may not require treatment beyond 1-2 years after diagnosis further lessens
physician enthusiasm for splenectomy as initial second line management. “If, however,
response becomes predictable based on sequestration of labeled platelets and such
testing becomes more widely available, then there may be a resurgence in the use of
splenectomy.”
2-Co-morbidities:
Co-morbidities (e.g. serious cardiopulmonary disorders) increase the risk of general
anesthesia and post-surgical complications. A higher rate of surgical complications and a
lower response rate is reported in most studies of patients over 45-70 years of age84 2,85,86 and in those with various secondary forms of ITP15,87. Care must be taken when
considering options for patients with a history or serious risk of thrombosis,
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3-Restrictions imposed by health funding authorities
National health services in many European countries restrict the use of TPO-RA and
rituximab. After application for permission, the cost may only be covered in
splenectomized patients or if splenectomy is contraindicated, but the situation is
liberalizing rapidly in some countries.
Deciding which option to pursue
Before considering treatment options, it is important to exclude inherited
thrombocytopenias and secondary ITP that might not have been evident on presentation.
A search should be made for conditions that may contribute to or co-exist with persistent
thrombocytopenia including infections such as human immunodeficiency virus and
hepatitis C (even if initially excluded), H. Pylori and possibly cytomegalovirus, thyroid
disorders, immunodeficiency, low-grade lymphoid neoplasms or other lymphoproliferative
disorders, and systemic autoimmune conditions. The lack of clinical findings, e.g. no
history of infection, does not exclude CVID, which might nonetheless be clinically
significant in the post-splenectomy setting and which is more amenable to treatment with
rituximab.17 If a substantial, albeit transient, response has not been achieved by prior ITP
treatments, a bone marrow examination should be performed to exclude other conditions,
particularly myelodysplasia.
The patient’s prior history, anticipated course, and relevant pros and cons of each option
are discussed in a personalized way with each patient and participating family members.
The patient’s goals, fears, individual capacities (e.g. memory, frailty), family support,
proximity to medical care and likely tolerance of each approach are considered in
addition to outcomes. The appropriate therapy for two individuals with essentially
identical clinical presentations, duration of disease and response to other therapies may
differ based on these additional medical and psychosocial factors.
At one end of the spectrum, splenectomy has the highest cure rate and may therefore be
the preferred option for younger patients, who have the best response and lowest
complication rates, engage in physically challenging sports or professions, are potentially
non-compliant with protracted daily treatment, and who do not wish to continue to “deal
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with” their ITP. Recommendations would be influenced by the results of platelet isotopic
distribution studies (if confirmed and if available).51
At the other end of the spectrum, we try to avoid splenectomy in patients over 65-70
years of age (depending on their physical condition) not only because of higher
complication rates, but also lower response rates. The same considerations apply to
the very frail, those with significant surgical co-morbidities, history or risk of thrombosis,
those with obligatory exposure to malaria or babesia, or who have secondary ITP.
Questions may be raised about post-splenectomy infection in teachers, veterinarians,
healthcare providers, travelers to certain areas, or others with increased exposure to
infectious conditions.
It is far more difficult to make recommendations for or against splenectomy to the
majority of patients with ITP who do not meet these criteria and have no contraindications
to surgery. Although splenectomy is recommended after the failure of steroids, there is
an argument to be made for waiting one year or more after diagnosis before proceeding.
We generally follow the recommendations of the International consensus,8 and often lean
towards either rituximab (lower response rate, modest likelihood of cure) or TPO-RA
(higher response rate, less likelihood of cure) after considering the many factors
mentioned above based on personal clinical experience and patient preference. This
difficulty is exemplified by the responses of each of the authors to how they would advise
the patient presented in the case report:
Consult: We would proceed by excluding causes of secondary ITP and by assessing the
risk of bleeding. This patient’s course to date is consistent with the initial diagnosis of ITP,
which is best substantiated by the response to prednisone and the absence of new
evidence of an underlying cause of secondary ITP. Each of the four authors recommend
therapeutic intervention as opposed to “wait and watch”, since the patient had
experienced bleeding with a platelet count below 20,000/µl. The probability of responding
to low dose or alternate day corticosteroids was considered as remote. All authors
proceeded to second-line treatment. Three different approaches were adopted. These
were: a) 4 weekly infusions of rituximab at conventional doses (WG and BG), b) 4 weekly
infusions of rituximab combined with 3 cycles of HDD (JBB), c) a TPO-RA for a limited
period, i.e. 6 months (DC). None of the authors considered splenectomy as initial next
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step in this patient with “persistent” disease. TPO-RA was recommended as the next
option if rituximab-based therapy fails, and rituximab would be considered if treatment
with a TPO-RA failed or the patient wanted an option that might lead to cure. All authors
would consider splenectomy if an adequate response was not achieved by one year.
Conclusions
The last decade has seen the introduction of new exciting suitable second-line medical
approaches to manage adults with ITP. Each approach has unique benefits, limitations,
and risks, and none have been subjected to head-to-head comparisons. Nor have quality
of life or long-term comparative effectiveness analyses been performed to inform
decisions. It is unlikely any comparative studies will hold interest for the pharmaceutical
industry. Even consortia of major academic centers will have difficulty pursuing these
studies because of the relatively low frequency of disease, cost and reimbursement
issues, and the duration of studies needed to address critical concerns. Therefore,
optimal treatment will continue to involve a personalized approach to therapy that
combines the art of medicine with the science through close collaboration between
patients and health-care providers for the foreseeable future.
AUTHORSHIP
All 4 authors wrote and edited the article extensively.
CONFLICTS OF INTEREST
W.G. has received research grants from Roche and Amgen, consultancy and lecture
honoraria from Amgen and Glaxo Smith Kline (GSK).
B.G. has participated in advisory boards and symposia for Amgen, Roche, GSK and LFB
and has received research funding from Roche.
D.C is Ad hoc member of medical advisory board for Amgen, GSK and Eisai.
J.B. currently receives clinical research support from the following companies: Amgen,
Cangene, GSK, Genzyme, IgG of America, Immunomedics, Ligand, Eisai, Inc, Shionogi
and Sysmex. His family owns stock in Amgen and GSK. He has participated in Advisory
Boards for Amgen, GSK, Ligand, Shionogi, Symphogen and Eisai. He had a one day
consult with Potola.
For personal use only. by guest on April 4, 2013. bloodjournal.hematologylibrary.orgFrom
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References
1. Dolan JP, Sheppard BC, DeLoughery TG. Splenectomy for immune thrombocytopenic
purpura: surgery for the 21st century. Am J Hematol. 2008;83(2):93-96.
2. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with
idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet
count responses, prediction of response, and surgical complications. Blood.
2004;104(9):2623-2634.
3. Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy and safety of B-cell
depletion with anti-CD20 monoclonal antibody in adults with chronic immune
thrombocytopenic purpura. Br J Haematol. 2004;125(2):232-239.
4. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein,
for chronic ITP. N Engl J Med. 2006;355(16):1672-1681.
5. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic
idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237-2247.
6. Sailer T, Lechner K, Panzer S, Kyrle PA, Pabinger I. The course of severe autoimmune
thrombocytopenia in patients not undergoing splenectomy. Haematologica.
2006;91(8):1041-1045.
7. Rodeghiero F, Ruggeri M. Is splenectomy still the gold standard for the treatment of
chronic ITP? Am J Hematol. 2008;83(2):91.
8. Provan D, Stasi R, Newland AC, et al. International consensus report on the
investigation and management of primary immune thrombocytopenia. Blood.
2010;115(2):168-186.
9. Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Jr., Crowther MA. The American
Society of Hematology 2011 evidence-based practice guideline for immune
thrombocytopenia. Blood. 2011;117(16):4190-4207.
10. Cines DB, McMillan R. Pathogenesis of chronic immune thrombocytopenic purpura.
Curr Opin Hematol. 2007;14(5):511-514.
11. McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro
megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic
ITP. Blood. 2004;103(4):1364-1369.
12. Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows
morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with
idiopathic thrombocytopenic purpura. Blood. 2004;103(2):500-506.
13. Nugent D, McMillan R, Nichol JL, Slichter SJ. Pathogenesis of chronic immune
thrombocytopenia: increased platelet destruction and/or decreased platelet production. Br J
Haematol. 2009;146(6):585-596.
14. Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cytotoxicity toward platelets
in chronic idiopathic thrombocytopenic purpura. Nat Med. 2003;9(9):1123-1124.
15. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: pathogenic and
clinical diversity. Blood. 2009;113(26):6511-6521.
16. Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia:
clinical and laboratory characteristics compared with chronic immune thrombocytopenic
purpura. Br J Haematol. 2005;129(6):818-824.
17. Gobert D, Bussel JB, Cunningham-Rundles C, et al. Efficacy and safety of rituximab in
common variable immunodeficiency-associated immune cytopenias: a retrospective
multicentre study on 33 patients. Br J Haematol. 2011; 155(4): 498-508.
For personal use only. by guest on April 4, 2013. bloodjournal.hematologylibrary.orgFrom
20
18. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural
history of idiopathic thrombocytopenic purpura in patients with persistent low platelet
counts. Arch Intern Med. 2000;160(11):1630-1638.
19. Godeau B, Provan D, Bussel J. Immune thrombocytopenic purpura in adults. Curr Opin
Hematol. 2007;14(5):535-556.
20. George JN. Definition, diagnosis and treatment of immune thrombocytopenic purpura.
Haematologica. 2009;94(6):759-762.
21. George JN, Mathias SD, Go RS, et al. Improved quality of life for romiplostim-treated
patients with chronic immune thrombocytopenic purpura: results from two randomized,
placebo-controlled trials. Br J Haematol. 2009;144(3):409-415.
22. 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(9763):393-402.
23. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology,
definitions and outcome criteria in immune thrombocytopenic purpura of adults and
children: report from an international working group. Blood. 2009;113(11):2386-2393.
24. George JN, el-Harake MA, Raskob GE. Chronic idiopathic thrombocytopenic purpura.
N Engl J Med. 1994;331(18):1207-1211.
25. Mazzucconi MG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone
(HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic
purpura: a GIMEMA experience. Blood. 2007;109(4):1401-1407.
26. Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic
purpura with high-dose dexamethasone. N Engl J Med. 2003;349(9):831-836.
27. Bae SH, Ryoo, H.M., Lee, W. et al. High Dose Dexamethasone Vs. Conventional Dose
Prednisolone for Adults with Immune Thrombocytopenia: a Prospective Multicenter Phase
III Trial. American Society of Hematology Congress. [abstract] Blood 2010;116: Abstract
3687.
28. Cooper N, Woloski BM, Fodero EM, et al. Does treatment with intermittent infusions
of intravenous anti-D allow a proportion of adults with recently diagnosed immune
thrombocytopenic purpura to avoid splenectomy? Blood. 2002;99(6):1922-1927.
29. Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR. Clinically significant
newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a
population-based cohort of 245 patients. Br J Haematol. 2003;122(6):966-974.
30. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a
practice guideline developed by explicit methods for the American Society of Hematology.
Blood. 1996;88(1):3-40.
31. Vianelli N, Galli M, de Vivo A, et al. Efficacy and safety of splenectomy in immune
thrombocytopenic purpura: long-term results of 402 cases. Haematologica. 2005;90:72-77.
32. Schwartz J, Leber MD, Gillis S, Giunta A, Eldor A, Bussel JB. Long term follow-up after
splenectomy performed for immune thrombocytopenic purpura (ITP). Am J Hematol.
2003;72(2):94-98.
33. Mikhael J, Northridge K, Lindquist K, Kessler C, Deuson R, Danese M. Short-term and
long-term failure of laparoscopic splenectomy in adult immune thrombocytopenic purpura
patients: a systematic review. Am J Hematol. 2009;84(11):743-748.
34. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic
immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet.
2008;371(9610):395-403.
For personal use only. by guest on April 4, 2013. bloodjournal.hematologylibrary.orgFrom
21
35. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and
bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised,
double-blind, placebo-controlled trial. Lancet. 2009;373(9664):641-648.
36. Scaradavou A, Woo B, Woloski BM, et al. Intravenous anti-D treatment of immune
thrombocytopenic purpura: experience in 272 patients. Blood. 1997;89(8):2689-2700.
37. Delaitre B, Maignien B. [Splenectomy by the laparoscopic approach. Report of a case].
Presse Med. 1991;20(44):2263.
38. Mohamed SY, Abdel-Nabi I, Inam A, et al. Systemic thromboembolic complications
after laparoscopic splenectomy for idiopathic thrombocytopenic purpura in comparison to
open surgery in the absence of anticoagulant prophylaxis. Hematol Oncol Stem Cell Ther.
2010;3(2):71-77.
39. Winslow ER, Brunt LM. Perioperative outcomes of laparoscopic versus open
splenectomy: a meta-analysis with an emphasis on complications. Surgery.
2003;134(4):647-653.
40. Quah C, Ayiomamitis GD, Shah A, Ammori BJ. Computed tomography to detect
accessory spleens before laparoscopic splenectomy: is it necessary? Surg Endosc.
2011;25(1):261-265.
41. Friedman RL, Fallas MJ, Carroll BJ, Hiatt JR, Phillips EH. Laparoscopic splenectomy for
ITP. The gold standard. Surg Endosc. 1996;10(10):991-995.
42. Delaitre B, Champault G, Barrat C, et al. [Laparoscopic splenectomy for hematologic
diseases. Study of 275 cases. French Society of Laparoscopic Surgery]. Ann Chir.
2000;125(6):522-529.
43. Keidar A, Feldman M, Szold A. Analysis of outcome of laparoscopic splenectomy for
idiopathic thrombocytopenic purpura by platelet count. Am J Hematol. 2005;80(2):95-100.
44. Crary SE, Buchanan GR. Vascular complications after splenectomy for hematologic
disorders. Blood. 2009;114(14):2861-2868.
45. Khellaf M, Le Moine JG, Poitrinal P, et al. Costs of managing severe immune
thrombocytopenia in adults: a retrospective analysis. Ann Hematol. 2011; 90(4): 441-6.
46. Ghanima W, Bussel JB. Thrombopoietic agents in immune thrombocytopenia. Semin
Hematol. 2010;47(3):258-265.
47. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal
exposure to rituximab. Blood. 2011;117(5):1499-1506.
48. Valat AS, Caulier MT, Devos P, et al. Relationships between severe neonatal
thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune
thrombocytopenia. Br J Haematol. 1998;103(2):397-401.
49. Chadburn A. The spleen: anatomy and anatomical function. Semin Hematol. 2000;37(1
Suppl 1):13-21.
50. Sarpatwari A, Provan D, Erqou S, Sobnack R, David Tai FW, Newland AC. Autologous
111 In-labelled platelet sequestration studies in patients with primary immune
thrombocytopenia (ITP) prior to splenectomy: a report from the United Kingdom ITP
Registry. Br J Haematol. 2010;151(5):477-487.
51. Cuker A, Cines DB. Evidence-based mini-review: Is indium-labeled autologous platelet
scanning predictive of response to splenectomy in patients with chronic immune
thrombocytopenia? American Society of Hematology Educational Program. 2010;2010:385-
386.
52. Yong M, Thomsen RW, Schoonen WM, et al. Mortality risk in splenectomised patients:
a Danish population-based cohort study. Eur J Intern Med. 2010;21(1):12-16.
For personal use only. by guest on April 4, 2013. bloodjournal.hematologylibrary.orgFrom
22
53. Thomsen RW, Schoonen WM, Farkas DK, et al. Risk for hospital contact with infection
in patients with splenectomy: a population-based cohort study. Ann Intern Med.
2009;151(8):546-555.
54. Stasi R, Stipa E, Masi M, et al. Long-term observation of 208 adults with chronic
idiopathic thrombocytopenic purpura. Am J Med. 1995;98(5):436-442.
55. Fontana V, Jy W, Ahn ER, et al. Increased procoagulant cell-derived microparticles (C-
MP) in splenectomized patients with ITP. Thromb Res. 2008;122(5):599-603.
56. Cordera F, Long KH, Nagorney DM, et al. Open versus laparoscopic splenectomy for
idiopathic thrombocytopenic purpura: clinical and economic analysis. Surgery.
2003;134(1):45-52.
57. Thomsen RW, Schoonen WM, Farkas DK, Riis A, Fryzek JP, Sorensen HT. Risk of
venous thromboembolism in splenectomized patients compared with the general population
and appendectomized patients: a 10-year nationwide cohort study. J Thromb Haemost.
2010;8(6):1413-1416.
58. van't Riet M, Burger JW, van Muiswinkel JM, Kazemier G, Schipperus MR, Bonjer HJ.
Diagnosis and treatment of portal vein thrombosis following splenectomy. Br J Surg.
2000;87(9):1229-1233.
59. Hoeper MM, Niedermeyer J, Hoffmeyer F, Flemming P, Fabel H. Pulmonary
hypertension after splenectomy? Ann Intern Med. 1999;130(6):506-509.
60. Ahn YS, Horstman LL, Jy W, Jimenez JJ, Bowen B. Vascular dementia in patients with
immune thrombocytopenic purpura. Thromb Res. 2002;107(6):337-344.
61. Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of
rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med.
2007;146(1):25-33.
62. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy
candidates with chronic immune thrombocytopenic purpura: results of a prospective
multicenter phase 2 study. Blood. 2008;112(4):999-1004.
63. Medeot M, Zaja F, Vianelli N, et al. Rituximab therapy in adult patients with relapsed
or refractory immune thrombocytopenic purpura: long-term follow-up results. Eur J
Haematol. 2008;81(3):165-169.
64. Ghanima W, Elstrom R, Bussel JB. The Combination of Three Dexamethasone Cycles
and Rituximab Yields High Response Rate in Previously Treated Immune thrombocytopenia
(ITP). [abstract] Haematologica 2011; 96: 95 Abstract 231.
65. Mahler M, Hasan A, Bussel JB. Rituximab Maintenance Treatment In Immune
Mediated Thrombocytopenia (ITP) Including Evans Syndrome. [abstract] Blood 2010; 116:
Abstract 2523.
66. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J
Haematol. 2008;141(2):149-169.
67. Yri OE, Torfoss D, Hungnes O, et al. Rituximab blocks protective serologic response to
influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after
treatment. Blood. 2011;118(26):6769-6771.
68. Liebmann A, Saleh N, Bussel JB, et al. Subcutaneous Injections of Low-Dose Anti-CD20
Veltuzumab for Patients with Relapsed Immune Thrombocytopenia (ITP). [abstract]
Haematologica 2011; 96: 224 Abstract 0527.
69. Zaja F, Vianelli N, Volpetti S, et al. Low-dose rituximab in adult patients with primary
immune thrombocytopenia. Eur J Haematol. 2010;85:329-334.
70. Provan D, Butler T, Evangelista ML, Amadori S, Newland AC, Stasi R. Activity and
safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults.
Haematologica. 2007;92(12):1695-1698.
For personal use only. by guest on April 4, 2013. bloodjournal.hematologylibrary.orgFrom
23
71. Hasan A, Michel M, Patel V, et al. Repeated courses of rituximab in chronic ITP: Three
different regimens. Am J Hematol. 2009;84(10):661-665.
72. Zaja F, Baccarani M, Mazza P, et al. Dexamethasone plus rituximab yields higher
sustained response rates than dexamethasone monotherapy in adults with primary immune
thrombocytopenia. Blood. 2010;115(14):2755-2762.
73. Zaja F, Baccarani M, Mazza P, et al. Long Term Follow up Analysis Following Front
Line Therapy with Dexamethasone or Dexamethasone Plus Rituximab in Adults with
Primary Immune Thrombocytopenia. [abstract] Blood 2009; 114: Abstract 2415.
74. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with
immune thrombocytopenia. N Engl J Med. 2010;363(20):1889-1899.
75. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of
long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood.
2009;113(10):2161-2171.
76. Newland A, Cervinek L, Eggermann J, Lefrere F, Kreuzbauer G. Sustained hemostatic
platelet counts in adult patients with primary immune thrombocytopenia (ITP) following
cessation of romiplostim - four European case studies. [abstract] Haemtologica 2010; 96: 98
Abstract 0237
77. Ghanima W, Junker P, Hasselbalch HC, et al. Fibroproliferative activity in patients with
immune thrombocytopenia (ITP) treated with thrombopoietic agents. Br J Haematol.
2011;155(2):248-255.
78. Boiocchi L, Orazi A, Ghanima W, Arabadjief M, Bussel JB, Geyer JT. Thrombopoietin
receptor agonist therapy in primary immune thrombocytopenia is associated with bone
marrow hypercellularity and mild reticulin fibrosis but not other stromal abnormalities. Mod
Pathol. 2012;25(1):65-74.
79. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune
thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2010; 377(9763):
393-402.
80. Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with
chronic immune thrombocytopenia treated with thrombopoietic agents. Blood.
2010;116(22):4639-4645.
81. Khellaf M, Michel M, Quittet P, et al. Romiplostim safety and efficacy for immune
thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim
compassionate-use program. Blood. 2011;118(16):4338-4345.
82. Cuker A. Toxicities of the thrombopoietic growth factors. Semin Hematol.
2010;47(3):289-298.
83. Stasi R, Newland A, Thornton P, Pabinger I. Should medical treatment options be
exhausted before splenectomy is performed in adult ITP patients? A debate. Ann Hematol.
2010;89(12):1185-1195.
84. Jensen AO, Norgaard M, Engebjerg MC, et al. Predictors for splenectomy among
patients with primary chronic immune thrombocytopenia: a population-based cohort study
from Denmark. Ann Hematol. 2011;90(2):207-212.
85. Cortelazzo S, Finazzi G, Buelli M, Molteni A, Viero P, Barbui T. High risk of severe
bleeding in aged patients with chronic idiopathic thrombocytopenic purpura. Blood.
1991;77(1):31-33.
86. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in
adults with idiopathic thrombocytopenic purpura. Blood. 2001;97(9):2549-2554.
87. Arnal C, Piette JC, Leone J, et al. Treatment of severe immune thrombocytopenia
associated with systemic lupus erythematosus: 59 cases. J Rheumatol. 2002;29(1):75-83.
For personal use only. by guest on April 4, 2013. bloodjournal.hematologylibrary.orgFrom
24
88. Matzdorff A, Giagounidis A, Greinacher A, et al. [Diagnosis and therapy of
autoimmune thrombocytopenia. Recommendations of a joint Expert Group of DGHO, DGTI,
DTH]. Onkologie. 2010;33 Suppl 3:2-20.
89. Guidelines for the investigation and management of idiopathic thrombocytopenic
purpura in adults, children and in pregnancy. Br J Haematol. 2003;120(4):574-596.
For personal use only. by guest on April 4, 2013. bloodjournal.hematologylibrary.orgFrom
25
Table 1 Comparison between various national and international guidelines in regard to splenectomy in the treatment of ITP.
Guidelines Year Language Publication site Timing, indication and restrictions for splenectomy
Timing Age Stage Indication for splenectomy
ASH 2011 English Blood9 Deferred > 6 mo NG
2nd line therapy after
steroids- grade of recommendation IB.
International Consensus 2010 English Blood8 Deferred
> 6-12 mo NG
One of the second-line
therapies without preference.
French 2009 French www.has-sante.fr Deferred >12 mo NG
2nd line after steroids but
TPO-mimetics or rituximab should be considered in
some patients.
Platelet count < 30,000/µl
associated with bleeding
Norwegian 2011 Norwegian www.legeforeningen.no/hematologi Deferred > 6-12 mo NG
2nd line after failure of steroid and/or rituximab.
German 2010 German Onkologie88 Deferred >12 mo NG
2nd line after steroids but TPO-mimetics or rituximab
should be considered in some patients.
Platelet count < 30,000/µl
associated with bleeding
British 2003 English British Journal of Haematology89 NG 65?
2nd line after failure of steroids
Swedish 2010 Swedish www.sfhem.se NG NG 2nd line after failure of
steroid in the absence of contraindication
Platelet count <10 or <30,000/µl and
presence of bleeding or high
steroid requirement
NG= not given
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Table 2*: Comparison between Splenectomy, Thrombopoietic Agents and Rituximab
Therapy Efficacy and response
prediction Safety Contraindications
Mode of application and
follow-up
Grade of ASH
2011 guidelines
recommendation Splenectomy Highest cure rate; short-term
response 80% and long-term
response 60-70% at 5-10
years. Response hard to
predict (see text)
Surgery-related mortality and
morbidity (bleeding, infections,
thrombosis); lifetime risk of
overwhelming infection.
Possible AE: venous thrombosis,
pulmonary hypertension,
atherosclerosis, dementia
Patients with co-morbid conditions
that increase the risk of
complications.
Relative: elderly patients over 60-70
because high rate of complication
and lower response; patients with
immunodeficiency and secondary ITP
e.g. CVID, hepatitis C, neutropenia,
possibly SLE
Invasive procedure usually
performed laparoscopically. Requires
pre- and post-operative preparation
and care and regular vaccination
well-established
treatment for ITP
ASH- 1B after failure
of steroids/
TPO-RA
Romiplostim A maintenance treatment;
60-80% achieve platelet
elevation; sustained -
response in 70-90% in those
entering long- term treatment
studies.
Headache, rebound
thrombocytopenia, weekly injection
Possible AE: Bone marrow reticulin
fibrosis, arterial and venous
thrombosis, risk of malignancy (if
MDS)
Pregnancy and lactation, MDS
Relative: past history of venous or
arterial thrombosis
Weekly s.c injections; requires dose-
adjustment and regular CBC
Approved treatment
for ITP;
ASH- 2C after failure
of steroids before
splenectomy/
Eltrombopag A maintenance treatment;
60-80% achieve platelet
elevation; sustained response
in 70-90% in those entering
long- term treatment studies
Headache, rebound
thrombocytopenia, elevated liver
enzymes.
Possible AE: Bone marrow reticulin
fibrosis, arterial and venous
thrombosis; nausea, vomiting in
small percent; cataracts (very
infrequent if at all)
As with Romiplostim
Requires monitoring of liver tests but
used successfully in large studies of
patients with liver disease secondary
to hepatitis C
Daily ingestions; requires dose-
adjustment and regular CBC and liver
tests
same
Anti-CD20
Rituximab May be curative treatment;
initial response in 50-60%;
sustained response 3-5 years
in 20%; retreatment gives the
same pattern of response as
observed after the first
course in complete
responders. Cannot predict
response
Infusion-related side effects (chills,
fever, dyspnea), neutropenia,
Possible AE: increased risk of
infection and viral reactivation,
hypogammaglobulinemia, serum
sickness (especially in children),
multifocal leukoencephalopathy
(PML)
Active hepatitis B virus, known
clinically significant allergy including
past serum sickness with anti-CD20,
or anti-mouse antibody
Pregnancy and lactation
Weekly IV infusions for 4 weeks; CBC
required depending on the response
Not approved for ITP
– only off-label use.
ASH- 2C after failure
of steroids/
*See text for more complete description of the issues in this table.
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Table 3. Pre-and post-operative measures to reduce and/or prevent complications after
splenectomy
Prior to splenectomy
Patient education regarding risk of
overwhelming sepsis
Early administration of oral antibiotic therapy that covers S.
pneumoniae and H. influenzae in case of fever (amoxicillin-
clavulanate, cefuroxime axetil, or levofloxacin) AND immediate
travel to a hospital for assessment and IV antibiotics.
Vaccination
Vaccination against S. pneumoniae, meningococcus, and H.
influenzae type b. ideally at least 14 days prior to scheduled
splenectomy
Elevation of platelet count
Elevation of platelets to >50x109/L by steroids or IVIg or another
treatment
After splenectomy
Antibiotic prophylaxis
Post-operative antibiotics prophylaxis until the risk of infection is
abated
Thromboprophylaxis
Early mobilization, good hydration and early initiation of
prophylactic anticoagulants once hemostasis is ensured if any
risk of thrombosis
Discontinuation of other treatments
Gradual tapering of steroids, discontinuation of TPO-RA
(provided that counts are good)
Re-vaccination
Vaccination against S. pneumoniae every 5 years and annual flu
vaccine
Regular follow-up
Responding patients require platelet count every 3 months for
one year and no less than annually thereafter. Patients need to
be reminded of precautions. Pregnancy requires reevaluation.
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Figure legends Figure 1. Probability of first complete remission according to the type of onset (insidious or acute). Kaplan-Meier curves show that remissions continued to occur with or without treatment with low-dose steroids between 6 months and 3 years and that remissions occurred earlier and at higher rates in patients with an acute onset of symptoms as opposed to those with an insidious onset. Splenectomized patients were censored at time of splenectomy. Obtained from Haematologica (http://www.haematologica.org) and reprinted from Sailer et al.6 Figure 2. Suggested treatment algorithm for ITP Footnotes: *: These are overall factors that go for or against splenectomy without distinguishing between TPO-RA and rituximab. †: Based on recommendations to defer splenectomy for 1 year, if possible. ‡: Alternative option is rituximab and wait for 12 months prior to conception. §: Anticipated poor compliance is also applicable to splenectomy although post-splenectomy management, e.g. repeat vaccination, management of febrile illness, and f/u re platelet count would probably also be at risk.
Figure 3. Probability of thrombocytopenia-free survival after splenectomy. The estimated relapse-free survival for all patients during plateaus at 75% after 48 months. Obtained from Haematologica (http://www.haematologica.org) and reprinted from Vianelli et al.31
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