TRANSFUSION MEDICINE UPDATE
Issue #1 2010
Extracorporeal Photochemotherapy (ECP)
Anand Padmanabhan MD PhD, Transfusion Medicine Fellow, Institute for Transfusion Medicine & University of Pittsburgh School of
Medicine, Department of Pathology and Joseph E. Kiss, MD, Medical Director, Hemapheresis & Blood Services, Institute for Transfusion
Medicine & Associate Professor of Medicine, University of Pittsburgh
__________________________________________________________________________
in patients at all stages of CTCL reported a combined
INTRODUCTION
Photopheresis or extracorporeal photochemotherapy
(ECP) is a leukocytapheresis-based therapy, in which
leukocytes treated with 8-methoxypsoralen (8-MOP) are
irradiated with ultraviolet-A light (UVA) ex vivo and reinfused into the patient. Notably, ECP was the first
selective immunotherapy approved by the Food and
Drug Administration (FDA) for the treatment of cancer.
Edelson et al. performed studies that formed the basis
for FDA approval for the use of ECP in the treatment of
patients with cutaneous T-cell lymphoma (CTCL)1. In
recent years, there has been a rapid broadening of
interest in the use of ECP in transplant settings, both
solid organ and hematopoietic stem cell transplantation
utilizing both prophylactic and therapeutic approaches.
This review briefly discusses various aspects of this
treatment modality including mechanism of action,
clinical applications, and technical specifications.
MECHANISM OF ACTION
Long wavelength UVA (320–400 nm) treatment of 8MOP-exposed cells induces the formation of interstrand
crosslinks in DNA and leads to T cell apoptosis2. A
number of potential mechanisms by which apoptotic
leukocytes induce immune tolerance have been
proposed. They include generation of tolerogenic
dendritic cells (DCs) after uptake of apoptotic bodies by
antigen presenting cells (APCs); decreased production of
pro-inflammatory cytokines and increased production of
anti-inflammatory cytokines; reduced ability of APCs to
stimulate T-cell responses; enhanced production and
function of regulatory T cells (Treg) and T suppressor
cells; and peripheral clonal deletion of effector T cells by
activation-induced cell death3. While the exact
mechanism of action may not be completely understood,
this has not hindered empiric use for various diseases
and conditions discussed below.
CLINICAL APPLICATIONS
CTCL refers to a group of rare lymphoproliferative
disorders such as Sezary syndrome, which are
characterized by the accumulation of malignant T-cells
that home to the skin. ECP is an established and
effective therapy for CTCL. A meta-analysis of 19 studies
overall response rate of 55.5% with 17.6% achieving a
complete response (CR)4.
Acute Graft Versus Host Disease (aGVHD), a serious and
frequent complication of allogeneic hematopoietic stem
cell transplantation contributes to post-transplant
morbidity and mortality. Established therapy consists of
corticosteroids and escalation to other immunosuppressives. A major consequence of escalation of
immunosuppressive treatment is infection and sepsis. In
one study5, after a median of 4 cycles of ECP, 82% of
patients with cutaneous involvement, 61% with liver
involvement, and 61% with gut involvement achieved a
complete resolution of aGVHD. CR rates were higher for
patients with grade II and III disease (86% and 55%,
respectively) than for grade IV disease (30%). In
another recent retrospective analysis, ECP treatment
was associated with a response rate of 61% in patients
with severe chronic GVHD (cGVHD). Responses were
seen in skin, liver, oral mucosa and eye cGVHD6. A
recent multicenter prospective phase 2 randomized
study of ECP for the treatment of cGVHD compared the
safety and efficacy of ECP and standard therapy versus
standard therapy alone in patients with cutaneous
manifestations of cGVHD that were not adequately
controlled by corticosteroid treatment7. While there were
no differences in the percent change from baseline in
total skin scores (TSS) at 12 weeks following treatment,
there was a significant difference between the two
groups in the percentage of patients whose steroid
doses were decreased by at least 50% (ECP arm-8.3%;
Standard treatment arm-0%). These results suggest that
ECP may have a steroid sparing effect within 12 weeks
of treatment. Progressive improvement in TSS and
continued reduction of steroid dose was noted in
patients in the ECP arm at 24 weeks, but most patients
in the standard arm had either discontinued participation
or had switched over to the ECP arm, precluding a
meaningful statistical analysis.
The successful use of photopheresis in human cardiac
transplant recipients was first published in 19928. Less
than a decade later, results from a multicenter,
international, randomized, double-blind study were
published9. In this study, a total of 60 recipients of
primary cardiac transplants were randomly assigned to
standard medical immunosuppressive therapy alone or
standard therapy in conjunction with photopheresis.
Significantly more patients in the photopheresis group
had no rejection or one rejection episode compared to
the standard-therapy group, and significantly fewer
patients in the photopheresis group had two or more
rejection episodes compared to the standard-therapy
group. In addition, although there were no significant
differences in the rates or types of infection,
cytomegalovirus DNA was detected significantly less
frequently in the photopheresis group than in the
standard-therapy group. Several subsequent reports
show beneficial effects of ECP in the management of
heart transplant recipients, including its use in the
prevention of coronary allograft vasculopathy, a leading
cause of mortality in cardiac transplant patients10-12.
treatment on two consecutive days separated by one or
more weeks. These protocols vary from institution to
institution and also depend upon the severity and nature
of the disease process. Recent FDA approval for a third
generation device (Cell Ex Photopheresis System,
Therakos, Exton, PA) will permit continuous separation
of blood components with the use of double needle
access, and result in abbreviated treatment times,
treatment of a greater number of leukocytes, and offer
the capability to treat younger and smaller patients by
use of a RBC prime in the set.
CONCLUSION
Groups have reported successful experience utilizing ECP
in lung transplant patients with bronchiolitis obliterans
(BOS), a manifestation of chronic lung rejection that1.
constitutes a major hurdle to long-term survival13-15. In a
recent large retrospective analysis, outcomes were2.
reported for 60 lung allograft recipients treated with ECP 3.
for progressive BOS16. This analysis showed that ECP
4.
was associated with a significant reduction in the rate of 5.
decline in lung function associated with progressive BOS.
Very limited data exists at this time for the use of this 6.
treatment modality in other transplant areas including7.
kidney, liver and pancreas17. Interestingly ECP has also8.
been introduced in the treatment of rejection in the area
of composite organ transplantation with its use in two9.
patients with face transplants18,19.
TECHNICAL SPECIFICATIONS
10.
11.
Photopheresis is now generally performed using the12.
UVAR-XTS second-generation photopheresis system
(Therakos, Exton, PA). In the first step of ECP, whole13.
blood is drawn from the patient via a large-caliber14.
needle/catheter into the centrifugation bowl of the 15.
instrument where cellular components are separated.
This is repeated three to six times depending on patient 16.
size and level of hemoglobin. At the end of each cycle,
the white blood cells (buffy coat) are added to a bag,17.
while plasma and red cells are returned to the patient. 18.
The second step of ECP involves exposure of the
leukocytes to UVA in the presence of 8-MOP injected into19.
the bag. In general, adverse effects from ECP have been20.
21.
minor and are typically related to volume shifts during
the procedure, however fatigue, low-grade fever and
abdominal discomfort have been reported20. Patients are
also counseled about the use of sunscreen/protective
clothing and dark glasses for 24 hours after the
procedure given the risk of photosensitivity. Risks related
to maintenance of vascular access include bleeding,
infection, thrombus formation and venous sclerosis21.
The typical schedule for ECP involves multiple cycles of
ECP is showing promising efficacy in a number of
disease states. It is expected that its use will expand and
that optimal treatment protocols will be developed.
Increasing our understanding of the mechanisms of
action of ECP should facilitate improvements in the use
of this therapy.
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Copyright 2010, Institute for Transfusion Medicine
Editor: Donald L. Kelley, MD, MBA: dkelley@itxm.org.
For questions about this TMU, please contact:
Joseph E. Kiss, MD at: jkiss@itxm.org 412-209-7320.
Copies of the Transfusion Medicine Update can
be found on the ITxM web page at www.itxm.org.