Extracorporeal photochemotherapy (ECP), is a form
of apheresis therapy that permits the direct targeting of
psoralen-mediated photochemotherapy to circulating
pathogenic T cells. Cutaneous T-cell lymphoma (CTCL)
is a low-grade non-Hodgkin’s lymphoma characterized
by the malignant proliferation of helper T lymphocytes
that infiltrate the skin. ECP is the treatment of choice
especially for Sezary syndrome and erythrodermic CTCL,
in which the circulating phase of the CTCL dominates
the clinical picture. First introduced for the treatment
of CTCL, ECP has since been evaluated in studies and
randomized trials as a potential treatment for autoimmune
diseases, solid organ transplant rejection, and graft-vs-host
disease. This article focuses on the current use of
ECP in CTCL, procedure and complications, possible
mechanisms of action, and predictors of clinical response.
CTCL was the first disease for which ECP was evaluated.
In the first study by Edelson et al. published in
1987 , 27 of 37 patients with otherwise resistant
CTCL responded with an average 64% decrease in
cutaneous involvement. The responding group included
8 of 10 patients with lymph-node involvement, 24 of 29
with exfoliative erythroderma, and 20 of 28 whose
disease was resistant to standard chemotherapy. One
year after this clinical study the use of ECP for the
treatment of Sezary syndrome had FDA approval. Heald
et al.  provided long-term follow-up on the original 29 erythrodermic CTCL patients reported by Edelson et
al., compared the results with historical controls and
declared that ECP may also increase survival time from
a median of 30 months to over 66 months. Even in the
view of existing controversy and statistical validity
associated with comparing results to historical controls,
the influence of ECP on the natural history of erythrodermic
CTCL by inducing remissions and prolonging
survival appeared to be of significance.
Later studies appeared to confirm the initial impressions
of efficacy. Zic et al. [3,4] described a response
rate reaching up to 75% with possible complete remissions
of up to 25% and a median survival time of 96
months. Zachariae et al.  treated 7 patients with the
red man (pre-Sezary) syndrome. Of these 7 patients, 6 had been on systemic steroids and 3 had also received steroids without sufficient effects, all were initially treated with topical nitrogen mustard but no longer tolerated this treatment. With ECP all signs of erythroderma disappeared in 6 of 7 patients.
The effectiveness of ECP for CTCL patients with
generalized patch/plaque and tumor stage has also been
evaluated. Armus et al.  published data from 8 ECP treated patients. Four of 5 patients with erythrodermic
CTCL and all 3 patients with patch/plaque or tumor
Contrasting with these results, there have also been
investigators who did not support the contention that
ECP prolongs survival. Comparing survival in patients
treated with ECP with that of patients treated conventionally,
Fraser-Andrews et al.  were unable to show
any significant difference in a retrospective study. In
another 9-year retrospective study performed by Bisaccia et al.  complete and partial response were achieved
by 14% and 41%, respectively, giving an overall response
rate of 54%, which was underscoring the potential value
of ECP in treating CTCL. Duvic et al.  reported their
experience with 34 patients, 28 of which had erythroderma
and 26 had extracutaneous disease. The overall
response rate was 50%. Although found effective, ECP
neither improved the remission rate nor shortened the
response time in this study. We believe that, a randomized
trial comparing ECP with standard therapies would
clarify the effect of ECP on the survival of patients with
ECP is likely to be more useful when combined with
other modalities. Numerous therapies have been combined
with ECP in past studies with apparent clinical
benefit [2,4,6,9-12]. Possibly because of its synergic
effects, interferon seems to be the most commonly used
combination with ECP. It was noted in one study that
interferon-2a as an adjuntive therapy to ECP almost
doubles the number of patients with a complete response
for the combined treatment versus for ECP alone [<4)].
For patients with a partial response or who does not
improve, who presented with Sezary syndrome, tumoral
stage or rapidly progressive disease at the pretreatment
evaluation, combination treatment with ECP and interferon-
should be considered .
ECP consists of placing an intravenous line into the
patients arm. Peripheral blood is drawn into the instrument
where the white cells or buffy coat and a small
amount of plasma are isolated and mixed with a steril
8-methoxypsoralen solution, a photoactivatable drug.
The buffy coat is exposed to ultraviolet light to activate
the drug and then returned to the patient. The entire
procedure takes about 4 hours depending on the hematocrit
level of the patient. This procedure is performed
on 2 consecutive days at 4-week intervals with clinical
evaluation at 6 months to determine response. Those
who show clinical improvement are maintained on this
treatment schedule until maximum clearing. Afterwards
an additional 6 months of treatment is given and the
patient is then gradually weaned off therapy.
Complications of ECP are minimal. Some patients
may have nausea or an accentuation of erythema. About
10% may experience a transient fever after reinfusion
of cells and less frequently hypovolemic hypotension
can occur . Complications associated with other
treatment modalities for CTCL such as myelosuppression,
liver toxicity, renal toxicity, neural toxicity and radiation
dermatitis have not been reported with ECP.
Mechanism of action
The mechanism of action of ECP is not well understood.
Malignant lymphocytes may be directly killed by
this approach. Marks et al.  showed that the lymphocytotoxic
effect of ECP in CTCL is appearently mediated
by DNA damage. UVA light is cytotoxic on its own, but
is potentiated by methoxsalen.
The reinfused photomodified cells may provide a
potent immunogenic stimulus leading to the onset of
CD8+ cell-mediated anticlonotypic immune responses.
It has been postulated that ECP may induce cytokine
production . In advanced CTCL and in Sezary syndrome
(perhaps through interleukin 4 and interleukin
10) a Th2 environment exists. This downregulates suppressor
cell function and thus malignant clone can
proliferate. ECP restores Th1/Th2 imbalance in CTCL
and normalizes Th2 response, which in return normalizes
CD8+ T cell response .
Alternatively there is evidence that ECP alters the
soluble interleukin-2 receptor (sIL-2R) levels. It was
known that the serum concentration of sIL-2R correlates
with tumor burden in CTCL, which is necessary for the
clonal expansion of the malignancy. Vonderheid et al.
 showed that during ECP, serum concentrations of
sIL-2R correlated with changes in clinical status.
Another possible mechanism may be induction of
apoptosis. In vitro studies demonstrated that UVAinduced
apoptosis is mediated by CD95-Fas expression
and inhibited by Bcl-2 up-regulation and that UVA
irradiation is able to down-regulate Bcl-2 expression.
Osella-Abate et al.  evaluated Bcl-2/CD95-Fas
expression on circulating clonal T cells from 7 patients
with CTCL before and during ECP, and found that a Bcl-
2 normal phenotype before ECP or a normalization in
Bcl-2 expression during ECP were related to a better
clinical response, whereas a persistent Bcl-2 high expression
was a negative prognostic factor. On the other hand,
no response was found in patients with a CD95-Fas
negative phenotype, whereas the expression of CD95-
Fas was associated with hematologic remission.
Predictors of clinical response
A normal CD4/CD8 ratio and a normal absolute count
of CD8+ cells in the peripheral blood at the start of
therapy are among the generally accepted criteria that appear to help predict a better outcome .
The presence of circulating Sezary cells seem to be
another predictor of a satisfactory clinical response to
ECP. It is reported that patients with circulating Sezary
cells had a significantly better response to ECP than
patients without circulating Sezary cells .
It is a common finding that patients with erythroderma
respond best [1,6,9]. A short interval from diagnosis to
entrance into ECP is related with a better responce. Heald
et al.  reported that patients with erythroderma who
were heavily pretreated and received ECP late in the
course of their disease did not respond as well as those
who received ECP early. Thus they suggested that ECP
should be considered the first line of therapy for erythrodermic
CTCL. Zic et al.  revealed that early response
after 6 to 8 months of ECP had a sensitivity of 100%
and a specifity of 90% for predicting long-term (>4
An increase in the serum IgG values during ECP was
also reported to be a meaningful response marker .
Still, these factors are not always sufficient for
predicting response, responders and non-responders can be found at both extremes.