James B. Bussel, MD
Professor of Pediatrics and Professor of Pediatrics in Obstetrics and Gynecology and in Medicine; Director, Platelet Research & Treatment Program; Division of Pediatric Hematology Oncology, New York Presbyterian Hospital, Weill Cornell Medical College
Our approach to idiopathic thrombocytopenic purpura (ITP) has undergone a
number of changes over the past several years. A number of these have been
highlighted in three excellent reviews published in Blood in 2009. First, there
is now a standard nomenclature. ITP is now immune thrombocytopenia1;
the “i” is no longer “idiopathic” and “purpura” is no longer part of the name.
Second, categorization of the underlying mechanisms of secondary ITP has been undertaken.
2 Finally, while an official ASH guideline update is in progress, an extensive guideline
update has been provided by an international group of experts led by Provan et al.3
The most fundamental area of change has been in our understanding of pathophysiology.
The “old” concept was that thrombocytopenia resulted from antibody-mediated
platelet destruction. There are two “new” concepts; the most developed is that the same
antibodies that mediate platelet destruction also mediate impaired platelet production by
damaging megakaryocytes and/or blocking their ability to release proplatelets (Figure). A
much less well-understood area is the basis of the 10 to 20 percent of cases that are not
antibody-mediated. This number is derived from the percentage of patients who do not
respond to IVIG and splenectomy. The original pioneering studies in which infusions of
ITP plasma into normal subjects were shown to produce thrombocytopenia only reduced
the platelet count in 16 of 26 cases. Some of the 10 non-effective plasmas were probably
still from patients with antibody-mediated platelet destruction, but perhaps all or most
of the antibody was bound to the platelets and not free-floating in plasma. Other cases
may reflect myelodysplasia too early to be diagnosed. An exciting but to-be-explored area
involves the role of platelet reactive cytotoxic CD8+ cells. These cells clearly exist, but
their clinical relevance is not known. Finally, an area of intensive investigation involves
T-regulatory cells, which have been reported to be deficient in ITP in several studies.
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What about therapy? Has it been affected by these new advances? The most obvious
change in the management of ITP has been the development and licensure of two
thrombopoietic agents, romiplostim (AMG 531) and eltrombopag. There are now six
peer-reviewed published studies on the use of these agents in ITP showing that they are
unequivocally highly effective, tolerable, and not overly toxic.4-9 Even for refractory ITP, a
response rate higher than 75 percent
is anticipated. Responses are
generally not seen until at least one
to two weeks of therapy, depending
upon dosage. Usually, it would
take a minimum of four to six weeks
of therapy at the highest dose to
declare a patient “unresponsive.”
ITP patients who have failed splenectomy
are the best candidates
for a TPO-R agonist, especially if
they have also received rituximab.
However, these agents are often
used prior to splenectomy. The efficacy
of these agents in chronic,
refractory disease supports the
pathophysiologic concept that
ITP in part results from immune
mediated suppression of platelet
production. The potential toxicity
of these agents is being monitored
by the FDA-mandated Risk
Evaluation and Mitigation Strategy
(REMS) program, in which all cases
are being tracked to determine the
incidence of complications in larger
numbers of patients than the 300 to
500 on whom licensure was based.
Other new therapeutic developments
include use of more
aggressive treatment upfront in
newly diagnosed adults. This approach
is based on the hypothesis
that ITP is more likely to be “cured”
by intensive immunosuppressive therapy early in its course (i.e., the newly diagnosed
phase) than later on after the disease is well-established and patients have been exposed
to multiple courses of treatment. The first attempt at this approach was the use of a single
cycle of high-dose dexamethasone for four days.10 This was followed by further studies
using three to four cycles11 of dexamethasone which suggested durable response rates of
60 to 80 percent. A recent study combined one cycle of dexamethasone with rituximab; the
final results are not available yet. Studies comparing standard prednisone and dexamethasone
are underway to clarify the utility of this approach.
This upfront treatment would be prior to consideration of splenectomy, the place of which
is controversial at this time. It could be as early as three months from diagnosis after failure
of the initial steroid treatment or only be resorted to after essentially all other active
and safe agents have been tried. There are no clear data to inform this decision in that
long-term data on splenectomy (e.g., for 10 to 30 years after) are largely non-existent.
ITP secondary to persistent infections (HIV, hepatitis C, H. pylori, and CMV) offers the
opportunity to treat the infection as an approach to ameliorating or even curing the ITP.
While HIV is usually clinically apparent, co-existing hepatitis C, H. pylori, and even CMV
may not be in ITP patients. H. pylori is particularly confusing because it seems to be
causative of ITP in Japan and Italy but much less so in the United States; this is based on
the relative rates of improvement of ITP with eradication of the infection.12
Two important issues are fatigue and thrombophilia. Fatigue has now been shown in a
number of studies to affect a substantial number of patients with ITP.13 Previously, this had
been considered to be steroid-related, but it is clear now that it is an intrinsic part of ITP,
more evident in certain patients than in others. As such, it may be appropriate to treat patients
with minimal to no bleeding symptoms if they are substantially affected by fatigue (if
treatment will improve fatigue). It has also become clear, although it remains not well studied,
that ITP is simultaneously a pro-thrombotic disease as well as a hemorrhagic one. This
means that the optimal platelet count is sometimes 50 to 100,000 μl instead of normal (i.e.,
>150,000 μl) and that patients with stable responses may require anti-platelet therapy.
Future developments will require more study of pathophysiology and especially how to
apply emerging insights to patients. One striking example is the use of rituximab in ITP;
in certain patients, 30 percent to 40 percent, there is a great response, while in others,
no response whatsoever is seen.14 Controlled trials need to directly compare treatments
to prospectively determine the pros and cons of common approaches, to investigate
which is better, and to select treatments for individual patients.
- Rodeghiero F, Stasi R, Gernsheimer T, et
of terminology, definitions and outcome criteria in immune thrombocytopenic
purpura of adults and children: report from an international working group.
Cines DB, Bussel JB, Liebman HA, et al. The
ITP syndrome: pathogenic and clinical diversity. Blood. 2009:113;6511-21.
Provan D, Stasi R, Newland AC, et al. International
consensus report on the investigation and management of primary immune
thrombocytopenia. Blood. 2010:115;168-86.
Bussel JB, Kuter DJ, George JN, et al. AMG
531, a thrombopoeisis-stimulating protein, for chronic ITP. N Engl J Med.
Newland A, Caulier MT, Kappers-Klunne M,
et al. An
open-label, unit dose-finding study of AMG 531, a novel
thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic
purpura. Br J Haematol. 2006;135:547-53.
Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag
for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J
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;371:395-403.
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;373:641-8.
Bussel JB, Kuter JD, Pullarkat V, et al. Safety
and efficacy of long-term treatment with romiplostim in thrombocytopenic
patients with chronic ITP. Blood. 2009;113:2161-71.
Cheng Y, Wong RS, Soo YO, et al. Initial
treatment of immune thrombocytopenic purpura with high-dose dexamethasone.
N Engl J Med. 2003;349:831-36.
Mazzucconi MG, Fazi P, Bernasconi S, et
with high-dose dexamethasone (HD-DXM) in previously untreated patients affected
by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood.
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.
McMillan R, Bussel JB, George JN, et al. Self-reported
health-related quality of life in adults with chronic immune thrombocytopenic
purpura. Am J Hematol. 2008;83:150-54.
- 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.
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