I. Introduction
Extracorporeal photoimmune therapy (ECP) is an immunological
treatment, which is defined as the extracorporeal exposure of pathogenic
leucocytes to irradiation by ultraviolet light (UVA) in the presence of a
photosensitising drug known as 8-methoxypsoralen (8-MOP). ECP was introduced for the first time by Edelson et al,
(1987) for the treatment of Sezary's syndrome and was approved in 1988 by the
United States Food and Drug Administration (FDA) for the treatment of advanced
forms of cutaneous T-cell lymphoma (CTCL); subsequently ECP has been used in
the treatment of systemic sclerosis and other autoimmune diseases and for
complications involving transplants of organs (rejection) or allogenic bone
marrow (graft-versus-host-disease,
GVHD).
The
immunomodulating mechanism of action was described for the first time in mice
exposed to UVA in the presence of 8-MOP. Immunosuppression was accompanied by a
reduction in the number and function of the epidermoidal Langerhans cells and
by a change in the production of cytokines by the keratinocytes (Vogelsang
et al, 1987). Subsequently numerous experiments showed that
administering spleen and bone marrow cells, treated with ECP, to mice which had
undergone allogenic bone-marrow transplants, significantly reduced the
occurrence of GVHD, providing evidence of a UVA effect on the cells responsible
for alloreactivity (Ullrich, 1991).
II. The "Photopheresis"
system
Taking samples of lymphocytes from the
patient using a process of leucapheresis, and then activating them with 8-MOP
and UVA carried out ECP in an extracorporeal circulation. The drug is activated
by the presence of UVA radiation, and so only the cells exposed to this light
are modified. The half-life of photoactivated 8-MOP is extremely short;
therefore the cells can be re-infused immediately once treatment has been
completed with very few side effects for the patient. Completion of each
individual procedure normally requires between 3 and 5 hours; good patient
venous access from a peripheral vein or, alternatively, from a central venous
catheter, is essential.
There are two ECP systems:
1)
The
Therakos system, which uses UVAR XTSTM apparatus, following a
protocol of two procedures in 2 consecutive days for each treatment cycle (125
ml bowl, 6-9 fractionation cycles; 225ml bowl, 3-4 fractionated cycles); the
machine, using a single needle, allows whole blood to be taken from the patient
and centrifuged in order to produce a blood fraction enriched with leucocytes.
8-MOP in liquid form is mixed with the buffy
coat fractionated in this way, then
this fraction is exposed to the prescribed quantity of UVA rays in order to
photoactivate the drug. The red corpuscles and the remaining portion of plasma
are re-infused into the patient, without being subjected to the ultraviolet
light treatment. The advantage of this system is that the circuit is
continuous, and therefore allows blood to be taken, separated, irradiated and
then returned to the patient in a sterile and closed circuit;
2)
The
Bio-Genic system, developed by Vilber Lourmat, in which the mononucleate cells
are collected using various cell separation systems, and then processed,
irradiated and finally infused in two separate and distinct phases
("open" system).The main disadvantage of this system is the risk of
bacterial contamination correlated with the blood manipulation before the
reinfusion in the patient.
Various
treatment protocols are proposed. The basic CTCL protocol requires two
treatments, carried out on 2 successive days, every 4 weeks; more aggressive
protocols are normally applied when dealing with rejection after organ
transplant. The total duration of treatment is established by evaluating the
condition and treatment response of the individual patient. The side effect,
which occurs most frequently during the procedure, is photophobia, consequently
it is a good rule to give the patient the protection of dark goggles for the
hours immediately following treatment. In some patients a temporary rise in
temperature has been noted with an increase of the erythema, which can
accompany the pyrexial reaction. In addition it is essential to carefully
monitor blood pressure throughout the procedure, because when using
discontinuous flow apparatus in an extracorporeal circulation, there is a high
risk of hypotension.
III. Cutaneous T-cell lymphoma
The photopheresis procedure was developed
initially by Edelson et al, (1987) as a therapy for treating CTCL and Sezary's syndrome. In
the initial study responses in excess of 60% were noted in the patients
treated, with an average response time of 4-6 months when treatment was carried
out once a month for 2 consecutive days (Rook and Wolfe, 1994; Wolfe et al, 1994; Lim and Edelson, 1995).
In a retrospective analysis of 450 patients treated in the United States and in
Europe, the response percentage was 56 and 66%, respectively. Immunological
studies have shown that the subset characterised by the CD4+/CD7- pattern and
by a normal CD4/CD8 ratio had a higher likelihood of clinical response (Rook et al, 1999). The anti-tumoral effect was correlated
with the appearance of CD8+ cytotoxic T-cells in the peripheral blood and
cutaneous tumoral infiltration. The number of SŽzary cells dropped in the
majority of patients treated with ECP, while there were no significant
variations in the population of normal CD4+ lymphocytes.
Edelson et al, (1987) subsequently showed,
in the same group of patients, an increase in average survival of 60 months versus 33 months in the historical
control group not treated with ECP. Further trials confirmed the good results,
but they all presented the scientific limitation of not being randomised
studies (Fraser-Andrew et al, 1998;
Russel-Jones, 2000).
Gottlieb et al (1996) published the results of a retrospective
study involving an appreciable number of patients, evaluated over 10 years, in
which ECP was used on its own or combined with interferon (IFN) (12 patients)
and other topical or systemic drugs. In this cohort of patients, 31 underwent 6
or more cycles of ECP while 28 patients received ECP as monotherapy. 71% of
patients responded to the treatment; a further 7 patients (25%) obtained
partial remission. In this study it was very significant to observe that the
presence of SŽzary cells in the peripheral blood was associated with a
favourable clinical response, as has been confirmed in other experiments (Rook et al, 1999). Gottlieb et al, (1996) showed that
treatment with ECP is associated with an improved survival rate. In this study,
average survival was 77 months from the start of treatment and 100 months from
diagnosis.
In a similar retrospective revaluation Duvic
et al, (1996)
reported an overall response of 50% in a group of 34 patients; 6 patients (18%)
achieved complete remission (CR) and 11 (32%) partial remission (PR). It must
be emphasised that 28 of the 34 patients had an erithrodermic form of CTCL and
that the best response was obtained with a treatment schedule involving two
monthly procedures. DuvicÕs experiment involved a treatment which had been
modified in comparison with the one described by Edelson, increasing cell
separation cycles from 6 to 9 and using ACD (acid citrate dextrose) as
anti-coagulant instead of heparin; he also intensified treatment for
non-responding patients to intervals of 2 weeks. The modifications made did not
result in any advantage for the patients. One interesting fact was an increase
in type G immunoglobulin, suggesting that ECP could be associated with an
improvement of the immune function.
No clear advantages of ECP in terms of the
survival of patients suffering from CTCL emerged from one single trial (Russel-Jones et al,
1997).
Numerous publications have also shown that
combining ECP with biological response modifiers such as IFN can work in
non-responding patients (Rook et al, 1991; Gottlieb et al, 1996; Jumbou et al, 1999; Fimiani et
al,
1999).
Rook et al, (1991) had already published a work showing
that combining ECP with low doses of IFN can achieve CR with the T-cells
disappearing from the peripheral blood. Recent studies evaluated the
combination of immunomodulator drugs such as interleukin-2 (Fritz et al, 1999),
interleukin-12, or GM-CSF (Rook et al, 1997; Wood et al, 1999) with ECP.
The most important data published in
literature, concerning the therapeutic synergism of treatment schemes used in
order to improve long-term results, mainly concerned the combination of total
skin electron beam therapy (TSEBT) and ECP (Wilson et al, 1995, 2000). In an initial work Wilson et al, (1995) assessed 163 patients who had been
treated with TSEBT with a total dose of 36 Gy at 1 Gy/day for 9 weeks. All
patients obtained CR or good PR with TSEBT, and then they were randomised in
order to be treated with polichemotherapy schemes (anthracyclin +
cyclophosphamide) or with ECP. In patients treated with chemotherapy survival
after 3 years was 75% while in those treated with ECP it was 100%. In the
analysis of the overall survival curves, only the group treated with ECP
achieved a statistically significant difference (p < 0.06).
The same group subsequently
recorded its own experience of using ECP in combination with TSEBT in mycosis
fungoides, in its erythrodermic variant (Wilson et al, 2000).
In this retrospective, non-randomised study, 44 patients were evaluated, 73% of
who achieved CR and overall disease-free
survival (DFS) was 63%. After stratifying the patients, the DFS was 49% for
those treated with TSBET alone and 81% in patients treated in combination with
ECP.
From the cumulative results from numerous groups,
we conclude that conventional ECP is efficacious in a high percentage of those
CTCL patients who have circulating malignant T cells in the context of a
still-near-normal immunocompetence. However, it is equally clear that a
sizeable population of patients with extensive CTCL do not fit the profile of
good responders to conventional ECP. Given the increased understanding of the mechanism
underlying the efficacy of ECP and the improvements that have recently been
made in the treatment modality, we favor the initiation of randomized trials of
the improved ECP method, rather than the presumably antiquated conventional
method.
A. Immunomodulation of ECP in T lymphoma
The direct anti-idiotype antibody response
against the clonal T-cell population, which occurs during ECP, is probably
induced by UVA-mediated cell damage. During the procedure 8-MOP remains
biologically inert until it is activated by the specific waves of UVA energy.
The T lymphocytes seem to be the cell population which is most sensitive to
this effect, as demonstrated by Yoo et al, (1996), who pointed out that only the normal T
population and the T pattern of the SŽzary syndrome showed signs of a process
of apoptosis within 24 hours of carrying out ECP, with the appearance of
typical markers such as annexin (Bladon
and Taylor, 1999). ECP determines
a selective variation of the subpopulations of T-cells, with normalisation of
the CD4/CD8 ratio (Zouboulis et al, 1998) and maturation of the CD4+ line towards
the inflammatory line (Th1), in comparison with the adjuvant one (Th2). In
pathology such as CTCL, the increase in Th1 production in turn determines a
higher production of IL-2 by the monocytes, with a negative feedback effect
towards the Th2, which are probably the cytokines responsible for the clinical
symptoms of the lymphoma (Di Renzo et al, 1997). While the lymphocytes seem to be
resistant to the apoptotic effects of photopheresis, the induction of TNF-a secretion by the photoactivated monocytes
facilitates apoptosis of the lymphocytes (Vowels et al, 1992).
In addition, the photoactivation of the monocytes seems to stimulate their
differentiation into dendritic CD 83+ and CD 36+ cells, capable of
phagocytizing the apoptotic T-cells (Berger
et al, 2001). In the presence of coadjuvant
molecules, these dendritic cells are capable of determining an initial
immune-cellular response (Edelson, 1991). These mechanisms are not, however,
sufficient to justify the induced immunogenicity because the percentage of
lymphocytes treated during ECP constitutes 10-15% of the total lymphocyte
population. Consequently the problem of the mechanism of action of
photopheresis still leaves a wide margin for future studies.
IV. ECP and graft-versus host-disease
(GVHD)
GVHD remains a major cause of morbidity and mortality after
allogeneic stem cell transplantation. While improvements in immunosuppressive
regimens have reduced the frequency and severity of acute GVHD, the incidence
of chronic GVHD remains unchanged at 27–50% after sibling matched related
donor transplants and 42–72% after unrelated donor bone marrow or
peripheral blood stem cell transplanted (Lazarus
and Rowe, 1995; Urbano-Ispizua et al, 1997; Remberger et al, 2001). Factors associated with cGVHD have
been well described and include increased donor and recipient age,
HLA-disparate and unrelated donor transplants, prior acute GVHD, and use of
alloimmune female donors (Ratanatharathorn et
al, 2001). The onset of cGVHD has arbitrarily
been defined as occurring 100 days after allogeneic stem cell infusion, and its
clinical features are distinguished from acute GVHD in that they more closely
resemble autoimmune diseases Histopathologic changes which include
sclerodermatous skin changes resulting from collagen deposition, pulmonary
fibrosis, esophageal dysfunction, dry mouth or mucocutaneous ulcerations,
cholestasis and myositis or fasciitis are thought to be initiated, in part, by
autoantibodies to cell surface and intracellular proteins(Shulman et al, 1978).
This pathology is responsible for the
significant post-transplant morbidity and mortality, due to both direct organ
dysfunction and the significant increase in predisposition towards serious
infections. The factors mostly responsible for this phenomenon are the donorÕs
T-lymphocytes, although other types of cells are implicated, with the
consequent amplification of this process by various cytokines.
Conventional therapeutic
approaches for cGVHD, including corticosteroids and immunosuppressive agents
have demonstrated limited efficacy in patients with extensive disease.
Ultraviolet A therapy (PUVA), while effective in alleviating the symptoms of
chronic skin GVHD, has had no impact on visceral involvement. Novel strategies,
including humanized anti-CD25 antibody (dacluzimab) and and anti-TNF-antibody
(infliximab), have shown promise in limited pilot studies (Przepiorka et al, 2000; Simpson, 2000; Basara et
al, 2001).
A.
ECP and acute GVHD
The work with the highest number of
patient recruits suffering from GVHD who received treatment was published by
Greinix et al, (2000). In this trial 21 patients with a median age of 38
years who developed steroid-refractory acute GVHD grades II to IV after stem
cell grafting from sibling or unrelated donors and were referred to ECP. Three
months after initiation of ECP 60% of patients achieved a complete resolution
of GVHD manifestations. Complete responses were obtained in 100% of patients
with grade II, 67% of patients with grade III, and 12% of patients with grade
IV acute GVHD. Three months after start of ECP complete responses were achieved
in 60% of patients with cutaneous, 67% with liver, and none with gut
involvement. Adverse events observed during ECP included a decrease in
peripheral blood cell counts in the early phase after stem cell transplantation
(SCT). At the time of trial, 57% of patients were alive at a median observation
time of 25 months after SCT. Probability of survival at 4 years after SCT was
91% in patients with complete response to ECP compared to 11% in patients not
responding completely. Their findings suggested that ECP was an effective
adjunct therapy for acute steroid-refractory GVHD with cutaneous and liver
involvement, but, in patients with acute GVHD grade IV or gut involvement other
therapeutic options are warranted.
Our comment is that the experience of ECP
treatment of patients with acute GVHD is still limited. Furthermore, there are
differences in patient selection, entry criteria, additive immunosuppressive
treatment and tapering down during ECP treatment and frequency of treatment
among different centers. All these aspects stress the importance of randomized
prospective multicenter studies.
B. ECP and
chronic GVHD
Owsianowski et al, (1994) published the
first work that evaluated the association between ECP and chronic GVHD. The
author reported the experience of one individual case that showed improvement
of lichenoid lesions on the skin, muscle thickening and sicca syndrome, and
normalisation of the CD4/CD8 ratio and increase of NK cells from 8 to 20%.
Subsequently, in 1996, Rosetti et al
published a trial on 9 paediatric patients showing improvement of cutaneous,
hepatic and pulmonary GVHD. ECP was carried out for 2 consecutive days every 3
weeks for 6 months, and then monthly. The patients who responded showed
normalisation of the CD4/CD8 ratio and a reduction in the number of CD56+ and
HLA-DR+ cells after 9 months of treatment (Rosetti et al, 1996). A further
study was published by Abhvankar et al, (1998)
with a very small number of patients, who had a response in the case of
scleroderma-type skin symptoms, but not in the case of visceral involvement.
Two recent studies reported the results of
treatment in 11 and 15 patients, respectively (Greinix et al, 1998; Child et al, 1999).
None of the patients had responded to 1st and 2nd line
treatment with corticosteroids and cyclosporin. In one study ECP had been
started at a late point after the onset of GVHD (average of 510 days), while in
the other study it had been started at an early stage (average 178 days). In
the group receiving early treatment the clinical responses were 12/15 in the
case of cutaneous pathology; 11/11 in the case of muco-cutaneous involvement;
7/10 for hepatic GVHD and 5/6 in the case of ocular disease. In the group
receiving late treatment the response on the skin was also good (10/10) but not
for the other locations, confirming that the best responses are obtained if
treatment is started within 10 months of the transplant. Intensification of
treatment (twice per month for the first 4-6 months) had an impact on the
response percentage. The clinical improvement allowed the immunosuppressive
therapy to be reduced. The average time for suspending cortisone was 80 days,
the average duration of response after suspension of ECP 12 months, with 14% of
patients relapsing after suspending treatment.
A more systemic immunomodulatory
effect, however, has been achieved with ECP, where direct exposure of
peripheral blood mononuclear cells to UVA-activated 8-methoxypsoralen by
apheresis is administered. Complete responses of cutaneous chronic GvHD have
been reported in up to 80% of steroid-refractory patients, with improvement
even in sclerodermatous skin (Messina et al, 2003;.Seaton et al, 2003; Di
Venuti et al, 2002) (Table 1).
Improvement in visceral chronic GvHD has been less consistent. Reports of high
complete response rates in hepatic and gut GvHD (Messina et al, 2003) have not
been consistently observed (Seaton et al., 2003).No clinical factor predicting
response to ECP has been observed.
Ilhan et al (2004)
treated eight patients with a median age 42 (range, 17-43) with ECP (UVAR XTS)
on 2 consecutive days every 2-4 weeks until resolution of GVHD over a period of
6-15 months concomitantly with immunosuppressive agents. Beyond extensive
steroid
Four
patients with uncontrolled disease, despite prolonged courses of treatment with
high dose of prednisone in combination with cyclophosphamide or azathiopirine,
responded to ECP. All patients initially had improvement in the extent of their
skin disease that allowed for significant tapering of all treatment.
Significant reduction in serum levels of antiepidermal cell immunoglobulin
occurred in conjunction with clinical improvement. Three patients achieved CR
and halted immunosuppressive treatment; 3 suffered a relapse but CR was easily
obtained with new photopheresis treatment. ItÕs a common experience that once
clinical improvement occurs, gradual tapering of corticosteroids and
immunosuppressive medications can proceed; however, simultaneous abrupt
tapering of ECP along with the tapering of other medications may result in the
early reoccurrence of skin lesions. ECP produced no serious adverse effects in
any of the four patients during several years of follow-up.
In 1992 a multi-center randomized study
was published (Rook et al, 1992) which evaluated the results of a study on 72 patients
suffering from systemic sclerosis of recent onset with progressive involvement
of the skin, comparing ECP with treatment with D-penicillamine Substantial
skepticism has arisen regarding the use of ECP for systemic sclerosis because
it manifests primarily as a fibrosing disease with increased deposition of
collagen within the skin and involved visceral organs. Despite its status as a
fibrosing disease, recent observation have implicated the immune system as a
prime factor in the genesis of the increased collagen production. In this
study, after 6 months of treatment, an improvement was registered in the skin
in 68% of the patients treated with ECP, as opposed to 32% of those treated in
the other arm of the study. Thus, in the early phases of treatment, a
significantly higher response rate was obtained with ECP (p= 0.02). At both the
6 and 10 mo evaluation point, the mean skin severity score, mean percentage
involvement, and mean oral aperture measurements were significantly improved
from baseline among those who received ECP. Mean right- and left-hand closure
measurements had also improved significantly by 10 mo of therapy. Skin biopsy
studies demonstrated an association between clinical improvement and decreases
thickness of the dermal layer. It is noteworthy that adverse effects of ECP
were minimal during this trial and did not require discontinuation of treatment
by any patients. In contrast, 25% of patients who received D-penicillamine were
required to permanently discontinue this drug due to side-effects when used for
aggressive cases of recent onset systemic sclerosis.
In 1992 a trial was published (Knobler et al, 1992)
conducted on patients suffering from systemic lupus erythematosus (SLE) which
showed that in 5 patients treated with ECP, in combination with conventional
cures, CR was obtained and was persisting after 30 months of follow-up, even
though there was no change in the laboratory parameters characterising the
disease.
In addition to these studies, the results
of pilot trials have suggested the potential efficacy of ECP for rheumatoid
arthritis (Malawista et al, 1991), epidermolysis bullosa acquisita (Miller et
al, 1995; Gordon et al, 1997), atopic dermatitis (Prinz et al, 1994). Other
clinical indications that have been studied where efficacy has not been
demonstrated include multiple sclerosis, chronic hepatitis C, and AIDS-related
complex.
VII. Conclusions
The future prospects of ECP concern
defining the mechanism of action, its use in other pathologies and the
combination of ECP-pharmacological treatment and/or radiotherapy. Photopheresis
is a relatively safe and promising treatment. This review clearly shows that
the fields of application of the procedure could be vast, and could include
metabolic diseases, such as recently demonstrated by Ludvigsson et al, (2001) who presented a
randomised study in 49 children suffering from type 1 diabetes mellitus,
demonstrating possible control of the disease using phototherapy. It could also include pathologies of an
infectious nature (hepatitis C) (OÕBrien et al, 1999) and even diseases such as Crohn's disease (Reinisch
et al, 2001).
It is clear that all the published works
present case histories involving small numbers and, in addition, that there are
few randomised studies. Starting from these premises, national and
international studies, aimed not only at developing the clinical possibilities
of the treatment, but also at evaluating its biological aspects, are desirable,
given the potential of the treatment, which, for the time being, has many
unknown aspects.
References
Abhvankar S,
Godder K, Chiang K, et al, (1998)
Extracorporeal photopheresis with UVADEX for the treatment of chronic
graft-versus-host disease. Exp Hematol 26, 32
Abhyankar S,
Gilliland DG, Ferrara JL (1993)
Interleukin-1 is a critical effector molecule during cytokine dysregulation in
graft-versus- host disease to minor histocompatibility antigens. Transplantation 56,
1518–1523
Alcindor T,
Gorgun G, Miller KB, et al, (2001)
Immunomodulatory effects of extracorporeal photochemotherapy in patients with
extensive chronic graft-versus-host disease. Blood 98, 1622–1625.
Barr ML, Meiser BM, Eisen HJ, et al, (1998) Photopheresis for the prevention of rejection in
cardiac transplantation. Photopheresis Transplantation Study Group. New Engl J Med 339, 1744–1751
Basara N, Gunzelmann S, Willenbacher W, et al, (2001) New immunosuppressants in BMT/GVHD. Transplant Proc 33, 2220–2222.
Berger CL, Xu
AL, Hanlon D, et al, (2001)
Induction of human tumor-loaded dendritic cells. Int J Cancer
91, 438–447.
Bladon J,
Taylor PC (1999) Extracorporeal
photopheresis induces apoptosis in the lymphocytes of cutaneous T-cell lymphoma
and graft-versus-host disease patients. Br J Haematol 107, 707–711
Child FJ,
Ratnavel R, Watkins P, et al, (1999)
Extracorporeal pho-topheresis (ECP) in the treatment of chronic
graft-versus-host disease (GVHD). Bone
Marrow Transplant 23, 881–887
Di Renzo M, Rubegni P, De Aloe G, et al, (1997) Extracorporeal photochemotherapy restores
Th1/Th2 imbalance in patients with early stage cutaneous T-cell lymphoma. Immunology 92, 99–103.
DiVenuti G, Miller DF, Sprague K et al., (2002).
Phopheresis as
a treatment for chronic graft-vs-host disease after
allogeneic bone marrow transplantation. Blood;
100: 846a.
Duvic M, et al, (1996) Photopheresis therapy for
cutaneous T-cell lymphoma. J. Am. Acad
35, 573-579
Edelson R, Berger C, Gasparro F, et al, (1987) Treatment of cutaneous T-cell lymphoma by
extracorporeal photochemotherapy. Preliminary results. New Engl J Med 316, 297–303
Edelson RL (1991) Photopheresis, a clinically
relevant immunobiologic response modifier. Ann NY Acad Sci 636, 154–164.
Fimiani M, et al, (1999) Role
of extracorporeal photochemotherapy alone and in combination with interferon
alfa in the treatment of cutaneous T-cell lymphoma. Am. Acad. Dermatol. 41,
502-503
Fraser-Andrew
E, et al, (1998) Extracorporeale
photopheresis in Sezary syndrome. Arch.
Dermatol 134, 1001-1005
Fritz TM, et al, (1999)
Combination
treatment with extracorporeal photopheresis, interferon alfa and interleukin-2
in a patient with the Sezary syndrome. Br. J. Dermatol. 140, 1144-1147
Gordon K, Chan
L, Woodley D (1997) Treatment of
refractory epidermolysis bullosa acquisita with extracorporeal
photochemotherapy. Br J Dermatol
136: 415-420
Gottlieb S, et
al, (1996) Treatment of cutaneous
T-cell lymphoma with extracorporeal photopheresis momotherapy and in
combination with recombinant interferon alpha, a 10 year experience at a single
institution. J. Am. Acad. Dermatol 35, 946.957
Greinix HT, Volc-Platzer B, Kalhs P, et al, (2000) Extracorporeal photochemotherapy in the treatment of
severe steroid-refractory acute graft-versus-host disease, a pilot study. Blood 96, 2426–2431.
Greinix HT, Volc-Platzer B, Rabitsch W, et al, (1998) Successful use of extracorporeal photochemotherapy
in the treatment of severe acute and chronic graft-versus-host disease. Blood 92, 3098–3104
Heald P, et
al, (1992) Treatment of
erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J. Am. Acad. Dematol 27, 427-433
Ilhan O, Arat M, Arslan O, et al (2004) Extracorporeal
photoimmunotherapy for the treatment of steroid refractory progressive chronic
graft-versus-host disease. Transfus
Apheresis Sci. 2004 Jun;30(3):185-7.
Jumbou O, et
al, (1999) Long-term follow-up in 51
patients with mycosis fungoides and Sezary syndrome treated by interferon-alfa.
Br. J. Dermatol. 140, 427-431
Knobler RM,
Graninger W, Lindmaier A, et al, (1992)
Extracorpreal photochemotherapy for the treatment of SLE. Arthr Rheum 35, 319-324
Lazarus HM,
Rowe JM (1995) New and
experimental therapies for treating graft-versus-host disease. Blood Rev 9, 117–133
Lim HW,
Edelson RL (1995) Photopheresis for
the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9, 1117–1126.
Ludvigsson J, Samuelsson, Ernerudh J, et al, (2001) Photopheresis at onset of type 1 diabetes, a
randomised, double blind, placebo controlled trial. Arch Dis Child 85, 149-154
Malawsta S,
Trock D, Edelson R. (1991) Treatment
of rheumatoid arthritis by extracorporeal photochemotherapy: a pilot study. Arthritis Rheum 34: 646-654
Miller J,
Stricklin G, Fine J et al, (1995)
Remission of severe epidermolysis bullosa acquisita by extracorporeal
photochemotherapy. Br J
Dermatol 133; 467-471
Messina C, Locatelli F, Lanino E et al., (2003) Extracorporeal
photochemotherapy for paediatric patients with
graft-versus host disease after haematopoietic stem cell transplantation. Br J Haematol; 122: 118–127.
OÕBrien CB,
Henzel BS, Moonka DK, et al, (1999)
Extracorporeal photopheresis alone and with interferon-alpha 2a in chronic
hepatitis C patients who failed previous interferon therapy. Dig Dis Sci 44, 1020-1026
OÕHagan AR,
Stillwell PC, Arroliga A, et al, (1999)
Photopheresis in the treatment of refractory bronchiolitis obliterans
complicatinglung transplantation. Chest.
115, 1459-1462
Owsianowski M,
Gollnick H, Siegert W, et al, (1994)
Successful treatment of chronic graft-versus-host disease with extracorporeal
photopheresis. Bone Marrow Transplant
14, 845–848
PrintzB,
Nachbar F, Plewig G (1994) Treatment
of severe atopic dermatitis with extracorporeal photochemotherapy. Arch Dermatol Res 287: 48-52
Przepiorka D, Kernan NA, Ippoliti C, et al, (2000) Daclizumab, ahumanized
anti-interleukin-2 receptor alpha chain antibody, for treatment of acute
graft-versus-host disease. Blood 95, 83–89.
Ratanatharathorn
V, Ayash L, Lazarus HM, et al, (2001)
Chronic graft-versus-host disease, clinical manifestation and therapy. Bone Marrow Transplant 28,
121–129.
Reinisch W,
Nahavandi H, Santella R, et al, (2001)
Extracorporeal photochemotherapy in patients with steroid-dependent CrohnÕs
disease, a prospective pilot study. Aliment
Pharmacol Ther 15, 1313.1322
Remberger M,
Ringden O, Blau IW, et al, (2001) No
difference in graft-versus-host disease, relapse, and survival comparing
peripheral stem cells to bone marrow using unrelated donors. Blood 98, 1739–1745.
Rook A, et al, (1991)
Combined therapy
for Sezary syndrome with extracorporeal photochemotherapy and low-dose
interferon alfa therapy. Arch. Dermatol.
127, 1535.1540
Rook AH, et
al, (1997) Pathogenesis of cutaneous
T-cell lymphoma, implication for the use of recombinant cytochines and
photopheresis. Clin.
Exp. Immunol.
107 (Suppl.1), 16-20
Rook AH,
Freundich B, Jegasothy BV, et al, (1992)
Treatment of systemic sclerosis with extracorporeal photochemotherapy, results
of a multicenter trial. Arch. Dermatol.
128, 337-346
Rook AH,
Jegasothy B, Heald P, et al, (1990)
Extracorporeal photpchemotherapy for drug resistant pemphigus vulgaris. Ann Intern Med 112, 303-305
Rook AH, Suchin KR, Kao DM, et al, (1999) Photopheresis, clinical applications and mechanism
of action. J Invest Dermatol Symp Proc
4, 85–90
Rook AH, Wolfe
JT (1994) Role of extracorporeal
photopheresis in the treatment of cutaneous T-cell lymphoma, autoimmune
dis-ease, and allograft rejection. J
Clin Apheresis 9, 28–30
Rosetti F, DallÕAmico R, Crovetti G, et al, (1996) Extracorporeal photochemotherapy for the treatment
of graft-versus-host disease. Bone Marrow Transplant 18 (Suppl. 2), 175–181.
Rosetti F, Zulian F, DallÕAmico R, et al, (1995) Extracorporeal pho-tochemotherapy as single therapy
for extensive, cutaneous, chronic graft-versus-host disease. Transplantation 59, 149–151
Russel-Jones
AR, et al, (1997) Extracorporeal
photopheresis in Sezary syndrome. Lancet.
350, 886
Russel-Jones R
(2000) Extracorporeal photopheresis
in cutaneous T-cell lymphoma. Inconsistent data undrline the need for
randomised studies. Br. J. Dermatol. 142, 16-21+
Shulman HM, Sale GE, Lerner KG, et al, (1978) Chronic cutaneous
graft-versus-host disease in man. Am J
Pathol 91, 545–570.
Simpson D (2000)
Drug therapy for acute graft-versus-host disease prophylaxis. J Hematother Stem Cell Res 9,
317–325.
Seaton ED, Szydlo RM, Kanfer E, et al. (2003) Influence of
extracorporeal photopheresis on clinical and
laboratory parameters in chronic graft-versus-host disease and analysis of
predictors of response. Blood15, Vol
. 102, N.4, 12-17-1223
Tanaka J, Imamura M, Kasai M, et al, (1997) The important balance between cytokines derived from
type 1 and type 2 helper T cells in the control of graft-versus-host disease. Bone Marrow Transplant 19, 571–576
Ullrich SE (1991)
Photoinactivation of T-cell function with psoralen and UVA radiation suppresses
the induction of experimental murine graft-versus-host disease across major
histocompatibility barriers. J Invest Dermatol 96, 303–308.
Urbano-Ispizua A, Garcia-Conde J, Brunet S, et al, (1997) High incidence of chronic graft-versus-host
disease after allogeneic peripheral blood progenitor cell transplantation. The
SpanishGroup of Allo PBPCT. Haematologica 82, 683–689
Vogelsang GB, Wolff D, Altomonte V, et al, (1987) Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA). Bone Marrow Transplant 17, 1061–1067
Vowels BR, Cassin M, Boufal MH, et al, (1992) Extracorporeal photochemotherapy induces the
production of tumor necrosis factor-alpha by monocytes, implications for the
treatment of cutaneous T-cell lymphoma and systemic sclerosis. J Invest Dermatol 98, 686–692
Wilson LD, et
al, (1995) Systemic chemotherapy and
extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lumphoma
patients who have achieved a complete response to total skin electron beam
therapy. Int J.
Radiat. Oncol. Biol. Phys., 32, 987-995
Wilson LD, et al, (2000) Experience
with total skin electron beam therapy in combination with extracorporeal
photopheresis in the management of patients with erythodermic (T4) mycosis
fungoides. J.
Am. Acad. Dermatol. 43, 54-60
Wolfe JT,
Lessin SR, Singh AH, Rook AH (1994)
Review of immu-nomodulation by photopheresis, treatment of cutaneous T-cell
lymphoma, autoimmune disease, and allograft rejection. Artif Organs 18, 888–897
Wood GS, Yoo
EK, et al, (1999) Interleukin 12
induces lesion regression and cytotoxic T cell responses in cutaneous T cell
lymphomas. Blood. 94, 902-908
Yoo EK, Rook
AH, Elenitsas R, et al, (1996)
Apoptosis induction of ultraviolet light A and photochemotherapy in cutaneous
T-celllymphoma, relevance to mechanism of therapeutic action. J Invest Dermatol 107, 235–242
Zouboulis CC,
Schmuth M, Doepfmer S, et al, (1998)
Extracorporeal photopheresis of cutaneous T-cell lymphoma is associated with
reduction of peripheral CD4 T lymphocytes. Derma-tology 196, 305–308.
Dr. Massimo Martino