H e m a t o lo g y E d u c a t io n - European Hematology Association

stemming from antibodies against PEG-rHuMgDF that
cross-reacted with endogenous TPO (eTPO), neutralizing
its biologic activity.
Despite safety concerns raised by autoantibody crossreactivity,
the success of the first-generation thrombopoietic
growth factors in stimulating platelet production
led to the development of a second generation of
thrombopoietic growth factors that had no sequence
homology with native TPO. Clinical trials with these,
the TPO peptide mimetic AMG 531 (also known as
Nplate or Romiplostim, Amgen, Thousand Oaks,
California) and the nonpeptide mimetic eltrombopag
(also known as Promacta, GlaxoSmithKline, Research
Triangle Park, North Carolina) have both resulted in
dose-dependent increases in platelets in healthy subjects
and in significant increases in platelets in patients with
chronic ITP. 50
The extensive clinical studies have shown that
platelet responses are seen in approximately 80%, a
much greater percentage than in other second line studies
and the response is maintained while the drugs continue
to be administered. They are almost as effective in
splenectomized patients as in the nonsplenectomized
ones. 51 Recent phase III studies have confirmed the efficacy
and safety following long-term usage of both of
the currently available products. 52,53 The licenses for
these agents vary throughout the world. In some (USA
and Canada) the license covers pre-splenectomy use
whereas in Europe, this is only covered for patients in
whom the surgery is contraindicated.
These agents appear to be well tolerated without the
formation of autoantibodies that were seen in the studies
with the first generation of thrombopoietins.
Increases in marrow reticulin have been reported, but
these appear to be a reversible phenomenon and not
associated with formation of collagen fibrosis. The incidence
of increase in marrow reticulin is unknown but is
likely to be higher in patients treated with high doses,
which should therefore be used with caution. There
appears to be no increased incidence of thrombotic
events in patients who achieve normal platelet counts
compared with those receiving placebo, however,
thrombotic events have been reported in patients with
other risk factors of cardiovascular disease, and a recent
report has shown an increased of venous and arterial
thrombo-embolism in any patient with ITP, suggesting
that ITP is a pro-thrombotic condition. 54
New developments
With the increasing understanding of molecular pathways
in ITP and of the aetiology of the disease, more
targeted and immune based therapies are under study.
Ongoing clinical trials in ITP involve antibodies against
the Fc receptor, such as MDX-33, a humanized anti-
FcgRI monoclonal, and GMA-161, a humanized anti-
FcgRIII monoclonal. 55 Investigation of inhibition of FcR
signaling mechanisms is currently under investigation
with R788, 56 a small molecule prodrug of the biologically
active R406. This is a potent and relatively selective
orally available inhibitor of Syk (spleen tyrosine kinase).
There are also a number of anti-CD20 monoclonal antibodies
attempting to duplicate and improve on the
results shown with Rituximab first described by Stasi in
2001. 31 Future treatment options have been recently
reviewed. 57
Conclusion
While there is general agreement over treatment of
the newly presenting adult with ITP, few evidence
based studies direct therapy in the relapsed and refractory
patient. There is an understanding that the patient
should be treated for their clinical state rather than their
platelet count but not what second line treatment
should be used and in what order. In order to develop a
rational approach, an international group produced a
consensus report on investigation and management giving
(where possible) evidence based advice on treatment
pathways. It is hoped that by following such an
approach, treatment in the future can be audited and
authoritative guidelines developed 7 and the place of the
newer treatments understood.
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