Download Palifermin in allogeneic HSCT: many questions remain

Bone Marrow Transplantation (2009) 43, 85–86
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LETTER TO THE EDITOR
Palifermin in allogeneic HSCT: many questions remain
Bone Marrow Transplantation (2009) 43, 85–86;
doi:10.1038/bmt.2008.269; published online 1 September 2008
Mucositis has become the dose-limiting complication of
high-dose chemotherapy. Therefore, recombinant keratinocyte growth factor (KGF)-1, Palifermin, seems a major
breakthrough in the management of patients receiving
intensive treatment for solid tumours and haematological
malignancies.1 Palifermin reduces the incidence and severity
of oral mucositis and its clinical consequences.1 The side
effects of treatment are generally mild and transient, and
are confined to skin rashes, pruritus, mouth and tongue
disorders and altered taste.1 This led the Food and Drug
Administration (FDA) to approve palifermin for the
prevention of oral mucositis of patients with haematological malignancies and boosted the development of other
mucosa-protective growth factors, such as repifermin
(KGF-2) and velafermin (fibroblast growth factor-20).
Preclinical studies show that KGF has several other
properties besides protecting epithelial surfaces, as it lessens
apoptosis of several cell types and modulates the inflammatory and immune responses,2 which could be of benefit
in the setting of allogeneic haematopoietic SCT. Moreover,
KGF has been shown to reduce the incidence of
acute GVHD (aGVHD) in mouse models3 and to
improve immune reconstitution by thymic preservation.4
The amelioration of aGVHD has been attributed to
the preservation of gut integrity with decreased
translocation of microbial products and reduced cytokine
production, although other factors probably contribute
such as the shift of cytokine profiles from helper T cell (Th)
1 to Th2.
Therefore, with palifermin proven to reduce mucositis in
humans treated with intensive chemotherapy and radiotherapy, it is conceivable that the drug should lead to less
aGVHD after allogeneic haematopoietic SCT. This question has been addressed recently in three clinical trials of
matched-related and -unrelated allogeneic haematopoietic
SCT after myeloablative conditioning using CY plus TBI
(CY-TBI) and BU plus CY (BU-CY).5–7 Palifermin was
mostly administered at a dose of 60 mg/kg intravenously
3 days before and 3 days after conditioning. The studies
were small and consisted of heterogeneous groups of
patients and only one was a randomized double-blind trial.
None showed an impact on the occurrence of aGVHD,
despite the amelioration of oral mucositis. However, the
impact on mucositis was not consistent and seemed present
only in subgroups, with one study showing an impact on
matched-unrelated transplant recipients and another showing an effect on patients conditioned with CY-TBI and not
BU-CY.
The addition of MTX (15 mg/m2 on day þ 1, 10 mg/m2
on days þ 3, 6 and 11) to the regimen of CsA or tacrolimus
for the prophylaxis of GVHD might explain this. Importantly, MTX is cytotoxic to epithelial cells, and aGVHD
prophylaxis regimens containing the drug are associated
with significantly more moderate and severe mucositis.8
The protective effects of palifermin on epithelial barriers of
gut and mouth might, therefore, have been offset by MTX,
resulting in less impact on mucositis and failure to reduce
aGVHD. Indeed, in a mouse model, MTX-induced
mucositis of the small intestine was not reduced by
pretreatment with KGF, suggesting that MTX counteracts
the effects of KGF.9
In addition to its protective effect on epithelial barriers,
KGF also stimulates thymic epithelial cell proliferation and
function.4 When given to mice ahead of myeloablative
conditioning, KGF reduced thymic epithelial cell injury
resulting from myeloablative conditioning and thymic
GVHD resulting from alloimmune responses directed at
the thymus.4 Thymus preservation results in accelerated
post transplant immune recovery predominantly of the
T-lymphocyte compartment. Again, MTX could nullify
KGF’s beneficial effects on the toxicity of chemotherapy on
epithelial cells of the thymus. Although little is known
about the effects of MTX on the thymus, a study in mice
indeed showed MTX to reduce thymus mass even at low
dose, compared with calcineurin inhibitor tacrolimus.10
In addition, folic acid is required for normal thymus
development with drugs such as MTX interrupting this
pathway, resulting in thymic atrophy. Importantly, CsA
also negatively influences thymic regeneration and subsequent immune reconstitution, highlighting the need to
consider the effects of standard GVHD prophylaxis on the
expected protective effects of KGF. Although no clear
differences exist in the immune reconstitution after
exposure to CsA and MTX, combining the two drugs
results in more toxic complications than are seen with either
alone.8
Also the timing of palifermin is important for both the
intestinal and thymic epithelial preservation and function.
KGF was used before, during and after conditioning in
most mouse models showing a beneficial effect on aGvHD.
This contrasts with clinical trials in humans, as palifermin
was not administered in this way, because concomitant use
of the drug can paradoxically increase mucositis by
increasing the susceptibility of proliferative epithelial cells
to cytostatic drugs. The profile of KGF suggests administering the drug later on, either during mucosal and thymic
recovery or at the time of active aGvHD. However, studies
on the optimal dosing schedule for palifermin are
absolutely necessary before firm conclusions can be drawn.
In these studies, because of the clear negative effects on
Letter to the Editor
86
epithelial cells, MTX should be avoided altogether to
determine the real benefits of palifermin regarding aGVHD
and immune reconstitution.
WJFM van der Velden, AHE Herbers and NMA Blijlevens
Department of Haematology, Radboud University Nijmegen
Medical Centre, Nijmegen, The Netherlands
E-mail: [email protected]
References
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