Dierickx_EU Haematology 03/03/2010 14:37 Page 13
The Use of Rituximab in Immune-mediated Anaemia
patients, of whom 11 were treated with rituximab during the course Table 1: Classification of Thrombotic Microangiopathy
of their disorder. Initial overall response rate in this series was 82%,
with long-term response rates of 64%.
21
ADAMTS13-deficiency Thrombocytopenia Thrombotic Purpura
Congenital (mutations in ADAMTS13 gene)
Rituximab in Pure Red Cell Aplasia Acquired (auto-anti-ADAMTS13 antibodies)
PRCA is another immune-mediated disorder, characterised by an Haemolytic Uraemic Syndrome (HUS)
isolated depletion of erythroid precursors in an otherwise normal Typical HUS (Shiga toxin producing Escherichia coli)
bone marrow. Like AIHA, ITP and ES, PCRA can be classified as
Atypical HUS:
‘primary’ or ‘secondary’, depending on the absence or presence of an
Congenital (mutations in complement regulatory proteins,
underlying condition. Specific PCRA-inducing conditions include
thrombomodulin)
parvovirus B19 infection, thymoma and treatment with recombinant
Acquired (auto-anti-complement regulatory proteins, antibodies)
human erythropoietin.
22
As PRCA is an extremely rare disorder,
Secondary Thrombotic Micro-angiopathy Associated with:
evidence on the use of rituximab is limited to several case reports and
Solid organ transplantation
very small series, showing both successes and failures.
23,24
Haematopoietic stem cell transplantation
Pregnancy
Medication (clopidogrel, ticlodipin, quinine, mitomycin C, gemcitabine,
Rituximab in Thrombotic Microangiopathy
calcineurin inhibitors, proliferation signalling inhibitors, etc.)
TMA is a life-threatening disorder characterised by Coombs-negative
Auto-immune disorders (antiphopsholipid syndrome, systemic lupus
micro-angiopathic haemolytic anaemia, thrombocytopenia and
erythematosus, etc.)
formation of microthrombi in different organs, especially the kidneys,
heart and central nervous system. Although anaemia in TMA is caused Figure 2: Pathogenetic Mechanisms in
by mechanical fragmentation of red blood cells, TMA is immune-
Thrombotic Microangiopathy
mediated in a substantial proportion of patients.
25,26
The term TMA comprises different entities, including thrombo-
cytopenic thrombotic purpura (TTP) and haemolytic uremic syndrome
(HUS). Broadly, TMA can be divided into three different categories:
• a disintegrin and metalloproteinase with thrombospondin type 1, 13,
the member (ADAMTS13)-deficiency TTP (congenital or acquired);
• HUS (typical and atypical); and
• secondary TMA (see A: Normal circumstances: the endothelium produces von Willebrand factor (vWF).Table 1).
27,28
Afterwards, there is a rapid proteolysis of vWF by the ADAMTS13 enzyme. B: Idiopathic
thrombocytopenic thrombotic purpura (TTP): unusually large von Willebrand factors (ULvWF)
Acquired ADAMTS13-deficiency TTP is a typical autoimmune disorder remain in a multimer form because of the inhibition of ADAMTS13 by auto-antibodies.
caused by the formation of auto-antibodies against ADAMTS13. This
C: ULvWF result in platelet aggregation; peripheral thromboembolisation develops under the
influence of increased shearing stress.
enzyme is responsible for cleavage of ultralarge von Willebrand factor
(ULvWF) multimers. Due to these antibodies, ULvWF multimers are not activity in the plasma of the patients.
32
So far the largest series has
or are insufficiently cleaved in patients with TTP, leading to profound been published by Scully et al., who described 25 patients with
platelet consumption, fragmentation of red blood cells and occlusion relapsing/refractory TMA and demonstrable auto-antibodies against
of small blood vessels in different organs (see Figure 2).
29
ADAMTS13. All 25 patients attained complete clinical and laboratory
remission within a median of 11 days after initiation of rituximab.
33
Although initial treatment of TMA consists of urgent daily therapeutic
plasma exchange,
30
treatment with rituximab is a promising approach Besides the use of rituximab as adjunctive therapy, there are a few
in immune-mediated TMA, both as an adjunctive treatment reports on the successful use of rituximab as a monotherapy in patients
to therapeutic plasma exchange and in case of relapse.
4
Currently, the with relapsing TTP. In an effort to better understand the therapeutic
experience with rituximab is limited to a few smaller case series and benefit of rituximab in relapsed/refractory TTP, the Canadian Apheresis
case reports on relapsing and refractory cases of TTP. Taken together, Group recently initiated a phase II trial incorporating anti-CD20 therapy
rituximab therapy seems to provide the most benefit in patients with together with standard therapeutic plasma exchange.
34
severe ADAMTS13 deficiency due to ADAMTS13 auto-antibodies,
which seems to be associated with a significantly higher relapse rate Rituximab may also be used in a prophylactic way in patients with
compared with patients with non-severely deficient ADAMTS13 relapsing TTP. In a multicentre, open-label, prospective trial, Fakhouri
activity levels.
31
Currently, more than 100 patients have been reported, et al. treated five patients with severe relapsing TTP and persistent
with severe ADAMTS13 deficiency being documented in about 80% of ADAMTS13 auto-antibodies during a period of clinical remission. In all
these patients. In most of these cases, rituximab was used at the patients, antibodies disappeared with the appearance of significant
moment of relapse in adjunct to therapeutic plasma exchange, ADAMTS13 activity following rituximab admission.
35
reaching response rates as high as 80–100%. Ling et al. recently
reported on 13 patients with ADAMTS13 deficiency (12 patients These promising results using rituximab in TTP have raised the
experiencing severe deficiency) treated with rituximab, leading to question of whether rituximab should be used upfront together
durable complete response rates in 92% of the patients. Besides with therapeutic plasma exchange as standard treatment for TTP. In
clinical remissions, most responses were also associated with a 2006, George et al. started a study on this specific subject, which will
decrease in ADAMTS13 antibodies and an increase in ADAMTS13 help to identify the place of rituximab in first-line therapy of TTP.
36
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