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The Management of Paroxysmal Nocturnal Haemoglobinuria
and even disappearance, of PNH cells during immunosuppression leukocyte antigen (HLA)-identical sibling transplant for PNH was 56%
have been observed.
at two years (International Bone Marrow Transplant Registry [IBMTR])
or 70% at five years (EBMT).
The substantial differences in outcome
Androgens have been successfully used to treat anaemia in PNH.
most likely represent the heterogeneity in indication, timing
Corticosteroids can be used to attenuate haemolytic exacerbations; of transplant, concurrent aplastic anaemia or complications
however, only some patients respond to steroids.
Given the (e.g. Budd-Chiari) present at the time of transplant. There is no
inconsistent response and their toxicity profile, it is debatable evidence that results with matched unrelated donors are inferior to
whether corticosteroids and androgens should be used for long-term those with HLA-matched sibling transplants. For PNH-aplastic
Careful evaluation in terms of convincing evidence for anaemia syndrome, a conditioning regimen of cyclophosphamide and
beneficial effects in the individual patient is necessary, and antithymocyte globulin (ATG) is recommended.
monitoring is essential. with classic PNH, the best regimen – in particular the role of
reduced-intensity regimens – needs to be determined.
Levels of erythropoietin and granulocyte-colony-stimulating factor
(G-CSF) are markedly elevated in PNH.
Therefore, it has been Unsatisfactory results are not due to relapse of PNH, which is a very
questioned whether there is an indication for growth factors in PNH rare event (see Tables 3 and 4). Transplant-related mortality is the
treatment at all;
however, in some patients improvement of major problem that needs to be addressed. In particular, future
anaemia could be achieved by treatment with erythropoietin.
In studies must address indications for stem cell transplantation,
anecdotal cases, the course of GPI-AP-deficient cells suggests that the optimisation of conditioning regimens and donor selection.
efficacy of erythropoietin can be due to either a preferential action on
normal cells or the GPI-deficient erythroid clone.
In particular, Disease-modifying Treatment – Eculizumab
erythropoietin may be a suitable adjunct in patients who have reduced Eculizumab (Soliris
, Alexion Pharmaceuticals) is a humanised
haemolysis during eculizumab treatment (see below), but who are still monoclonal immunoglobulin (IgG)-
antibody directed against the
terminal complement protein C5. Eculizumab contains the murine
complementary-determining regions of m5G1.1 mAb, which were
In patients with hypoplastic PNH, a combination of G-CSF and grafted onto the human framework light- and heavy-chain variable
cyclosporin can improve cytopenia and reduce the number of regions to minimise the potential for immunogenicity.
In eculizumab-treated patients with reduced binds to the complement protein C5 with high affinity and inhibits its
haemolysis who are still transfusion-dependent, promotion cleavage to C5a and C5b, thereby preventing the generation of the
of erythropoiesis by addition of erythropoiesis-stimulating factors terminal complement complex C5b–C9.
Blockade of C5 completely
may further improve haemoglobin and render patients transfusion- blocks the terminal complement cascade with formation of the
independent, in particular in PNH with underlying bone marrow membrane attack complex irrespective of the pathway of
Other approaches so far studied in animal models and not complement activation. However, it does not interfere with the
yet available for clinical treatment are the replacement of generation of components in the early steps of complement
complement inhibitory proteins in PNH cells and gene therapy. activation, which generate important mediators for immunoregulation
Alternative artificial glycolipid anchors or single-chain antibody and protection against infections.
fragments (scFv) were used to anchor CD59 into the cell membrane
(Prodaptin-CD59 and scFv-DAF), which restores resistance of PNH Eculizumab has been evaluated in three trials in PNH patients.
cells to complement in vitro.
first pilot study enrolled 11 patients with haemolytic PNH,
phase III trials enrolled another 184 patients.
The first phase III trial,
Curative Treatment – Allogeneic TRIUMPH, was a double-blind, randomised, placebo-controlled,
Stem Cell Transplantation multicentre trial that examined safety and efficacy in haemolytic PNH
Allogeneic stem cell transplantation is the only treatment with
However, due to the high transplant-related
morbidity and mortality, only a small group of PNH patients have been
For patients with classic paroxysmal
transplanted in the past.
For example, only 268 allogeneic stem cell
transplants were reported to the Registry of the European Group for
nocturnal haemoglobinuria, the best
Blood and Marrow Transplantation (EBMT) between 1978 and 2007.
regimen – in particular the role of
According to the recommendation of the IPIG criteria for
reduced-intensity regimens – needs
consideration of transplantation are bone marrow failure (fulfilling
to be determined.
criteria of severe aplastic anaemia) or major complications of PNH,
i.e. recurrent life-threatening thromboembolic disease or refractory,
transfusion-dependent haemolytic anaemia.
patients who had received at least four transfusions in the four months
prior to enrolment and a platelet count >100x10
SHEPHERD was an
Published single-centre experience using either conventional
or open-label, non-placebo-controlled trial that examined eculizumab in a
is summarised in Tables 3 and 4. more heterogenous PNH patient population.
Patients were required to
Great heterogeneity of results exists, with the probability of overall have received at least one transfusion in the previous two years. A
survival ranging from <60 to 100%. Recent studies using platelet count of ≥30x10
/l was required. In both trials, lactate
reduced-intensity conditioning reported very favourable results. In dehydrogenase (LDH) levels of 1.5 times the upper limit of normal and a
retrospective analyses of registry data, overall survival after human PNH type III RBC population of 10% or more were required.
EUROPEAN HAEMATOLOGY 15
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