VALUE IN HEALTH 18 (2015) 457–466

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Comparative Effectiveness Research/HTA

Extracorporeal Photopheresis for Second-Line Treatment of
Chronic Graft-versus-Host Diseases: Results from a Health
Technology Assessment in Italy
Chiara de Waure, MD, MSc, PhD1,*, Stefano Capri, MSc1,2, Maria Assunta Veneziano, MSc, PhD1, Maria
Lucia Specchia, MD, PhD1, Chiara Cadeddu, MD1, Francesco Di Nardo, MD1, Anna Maria Ferriero, MD1,
Francesca Gennari, PhD3, Colette Hamilton, MSc, MBA3, Agostino Mancuso, MD1,
Gianluigi Quaranta, MD, MSc1, Matteo Raponi, MD1, Luca Valerio, MD1, Gianfranco Gensini, MD4,
Walter Ricciardi, MD, MSc1
1
Section of Hygiene, Institute of Public Health, Catholic University of the Sacred Heart, Rome, Italy; 2School of Economics and
Management, LIUC University, Castellanza (VA), Italy; 3Therakos, Inc., West Chester, PA, USA; 4Faculty of Medicine, Department of
Experimental and Clinical Medicine, University of Florence, Florence, Italy

AB STR A CT

Objectives: To develop a comparative, cost-effectiveness, and budget
impact analysis of Therakos online extracorporeal photopheresis
(ECP) compared with the main alternatives used for the treatment of
steroid-refractory/resistant chronic graft-versus-host disease (cGvHD)
in Italy. Methods: The current therapeutic pathway was identified by
searching medical databases and from the results of a survey of
practice in Italian clinical reference centers. A systematic review was
performed to evaluate the efficacy and safety of second-line alter-
natives. Budget impact and cost-effectiveness analyses were per-
formed from the Italian National Health Service perspective over a
7-year time horizon through the adaption of a Markov model. The
following health states were considered: complete and partial
response, stable disease, and progression. A discount rate of 3% was
applied to costs and outcomes. Results: The most common alterna-
tives used in Italy for the management of steroid-refractory/resistant
cGvHD were ECP, mycophenolate, pentostatin, and imatinib. The
literature review highlighted that complete and partial responses
are higher with ECP than with the alternatives while serious adverse
events are less common. The economic analysis showed that Ther-
akos online ECP represents the dominating alternative, in that it
delivers greater benefit at a lower cost. In fact, according to the
alternatives considered, cost saving ranged from €3237.09 to
€19,903.51 per patient with 0.04 to 0.21 quality-adjusted life-year
gained. Conclusions: Therakos online ECP should be considered an
effective, safe, and cost-effective alternative in steroid-refractory/
resistant cGvHD. There is inequality in access, and a dedicated
reimbursement tariff, however, should be introduced to overcome
these barriers.
Keywords: cost-effectiveness analysis, economic evaluation, graft-
versus-host disease, Markov model, photopheresis, technology
assessment.
Copyright & 2015, International Society for Pharmacoeconomics and
Outcomes Research (ISPOR). Published by Elsevier Inc.

lung), with no clinically significant functional impairment. Moderate

Introduction
Graft-versus-host disease (GvHD) is one of the major complications
of allogenic hematopoietic cell transplants and may present in
acute and chronic forms. It occurs when the donor’s T cells react to
nonhistocompatible antigens in the recipient’s tissues [1].
In chronic GvHD (cGvHD), the main organs affected are skin, liver,
eyes, lungs, joints and fascia, genital tract, mouth, and gastrointes-
tinal system. The classification of cGvHD is based on the number of
organs or sites involved and the severity within each affected organ.
Mild cGvHD involves only one or two organs or sites (except the
cGvHD involves at least one organ or site with clinically significant
but no major disability; or three or more organs; or sites with no
clinically significant functional impairment (maximum score of 1 in
all affected organs or sites). Severe cGvHD indicates major disability
caused by cGvHD [1]. Chronic GvHD can originate from the acute
form (progressive type), develops after resolution of the acute form
(quiescent or interrupted type), or occurs de novo [2].
Furthermore, cGvHD includes classic cGvHD without features of
acute GvHD and the overlap syndrome in which diagnostic or
distinctive features of chronic and acute GvHD appear together [1].

* Address correspondence to: Chiara de Waure, Section of Hygiene, Institute of Public Health, Catholic University of the Sacred Heart,
Rome, L.go F. Vito 1, 00168 Rome, Italy.
E-mail: chiara.dewaure@rm.unicatt.it.
1098-3015$36.00 – see front matter Copyright & 2015, International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.jval.2015.01.009
458 VALUE IN HEALTH 18 (2015) 457–466
The percentage of people developing cGvHD varies from 30%
among recipients of completely histocompatible transplants to
60% among recipients of mismatched hematopoietic cells and
70% among recipients of hematopoietic cells from unrelated
donors [3–6]. The average diagnosis time is 4.5 months after
transplant from human leukocyte antigen–identical sibling and 4
months after transplant from an unrelated donor. De novo
cGvHD almost never occurs later than 2 years after an allogenic
hematopoietic cell transplant [6].
On the basis of these data and the number of allogenic
hematopoietic cell transplants performed in Italy each year—
approximately 1700 [7]—it may be estimated that from 500 to
1200 new cases of cGvHD may occur per year.
The most important factor influencing survival among
patients with cGvHD is treatment-associated complications, par-
ticularly bacteremias and pulmonary infections due to the
patient’s immunocompromised state [8].
With regard to the management, the document released by
the Joint Working Group of the British Committee for Standards
in Hematology and the British Society for Bone Marrow Trans-
plantation [9] suggests different approaches based on disease
grade and patient’s response. The proposed first-line treatment is
corticosteroid therapy in combination with calcineurin inhibitors
[9]. Switching to second-line treatment is recommended for
patients who do not respond to first-line treatment. Options
available for second-line treatment include pentostatin, selective
mammalian target of rapamycin inhibitors, rituximab, imatinib,
and extracorporeal photopheresis (ECP) [9].
ECP is a cell-based therapy available to date in more than 200
centers worldwide [10,11]. It consists of the extracorporeal expo-
sure of mononuclear cells of peripheral blood to photoactivated
8-methoxypsoralen, followed by reinfusion of treated cells [12].
The recommended ECP schedule includes two sessions in two
consecutive days every 2 weeks for at least 3 months; patient
assessment is carried out in the third month and, subsequently,
every 3 months to determine how to continue the treatment [11].
There are two methods to perform ECP, which differ in the
way mononuclear cells are collected and irradiated with ultra-
violet A rays [13–16].
The online procedure is carried out with the integrated
THERAKOS UVAR XTS Photopheresis System or the latest THER-
AKOS CELLEX Photopheresis System. The offline procedure
requires multiple machines and consists of three separate stages:
in the first stage (collection stage), mononuclear cells are col-
lected via different separation systems; in the second stage
(irradiation stage), they are treated with 8-methoxypsoralen and
the buffy coat is transferred into a special bag permeable to
ultraviolet A rays; in the third stage (reinfusion stage), mono-
nuclear cells are reinfused into the patient after being irradi-
ated. The Therakos online procedure, in contrast to the offline
procedure, ensures sterility and reduces the risk of infection
because the circuit is closed; furthermore, the duration of the
procedure is shorter (115 minutes vs. 192 minutes) [13–18].
Also, the online procedure can be carried out safely in loca-
tions outside the transfusion center and the UVAR XTS System
and the CELLEX System are currently the only devices
Conformité Européenne-marked for ECP, whereas multiple
equipment units used for the offline procedure have author-
ization limited to their specific step.
Considering the limited health care resources available and
recent innovations in the second-line treatment options for
cGvHD, it is becoming increasingly important to allocate resour-
ces appropriately and efficiently. On this basis, the purpose of
this article was to report the results of a comparative and cost-
effectiveness analysis of Therakos online ECP in the second-line
treatment of steroid-refractory/resistant cGvHD in Italy, along
with a budget impact assessment in the context of the Italian
National Health Service (NHS). The work aims to provide decision
makers and health workers with a useful instrument to support
decision making.
Methods
The following key aspects were tackled: 1) the current therapeut-
ical approach to steroid-refractory/resistant cGvHD in Italy, 2) the
efficacy of alternatives used as second-line treatment of steroid-
refractory/resistant cGvHD, and 3) the economic profile of Ther-
akos online ECP in comparison to current alternatives.
These key aspects were addressed through the following:
1. A PubMed review using the search terms “Graft vs Host
Disease” [MESH], (treatment OR therapy), (consensus OR
recommendation OR guideline) to identify important articles
providing an overview of available treatments and recom-
mendations on the management of steroid-refractory/resist-
ant cGvHD. The search was limited to the last 10 years.
Furthermore, to identify treatment options currently used in
Italy, a questionnaire (see Questionnaire 1 in Supplemental
Materials found at http://dx.doi.org/10.1016/j.jval.2015.01.009)
was devised and submitted for validation to a board of key
opinion leaders and, subsequently, to the 26 most relevant
Italian transplant centers. The questionnaire was aimed at
investigating the most common treatment options provided
to patients with steroid-refractory/resistant cGvHD.
2. After selecting the three most common alternatives used in
the second-line treatment of steroid-refractory/resistant
cGvHD, data on their efficacy and safety were collected by
means of targeted searches on PubMed database and by
consulting current guidelines. The goal of the literature search
was to identify clinical studies on different treatment options,
according to the hierarchy of evidence. First, published sys-
tematic reviews or meta-analyses were selected; then, con-
trolled and randomized clinical trials were sought; and,
finally, as a last resort, single-arm or prospective/retrospective
clinical studies were considered. Case reports and case series
that included fewer than 10 patients were excluded.
3. A decision tree model, associated with a Markov model
developed by Oblikue consulting s.r.l. [19], was adapted to
the Italian setting over a 7-year time horizon and applied to a
hypothetical cohort of 1000 patients affected by steroid-
refractory/resistant cGvHD (see Appendix Fig. 1 in Supple-
mental Materials found at http://dx.doi.org/10.1016/j.jval.2015.
01.009). The following health states were taken into account:
complete response, partial response, stable disease, and dis-
ease progression. The duration of each Markov cycle was set
at 3 months to account for transition probabilities between
different health states. Data about transition probabilities,
survival, utility, and efficacy were obtained from the litera-
ture. In particular, data referring to transition probabilities,
treatment efficacy, and survival were collected from the
review conducted within the efficacy section. The utility
values associated with the different health states, necessary
for the calculation of quality-adjusted life-years (QALYs), were
obtained from the article by Crespo et al. [19] (see Appendix
Table 1 in Supplemental Materials found at http://dx.doi.org/
10.1016/j.jval.2015.01.009). Only direct medical costs
(expressed in terms of €2013) were considered in relation to
specialist visits (e.g., hematology, oncology, and ophthalmol-
ogy), spirometry, skin biopsy, hospitalizations, pharmacolog-
ical therapy, and Therakos online ECP sessions. In addition,
costs related to neutropenia as an adverse event were
included. The following ECP treatment schedule was consid-
ered: first month—two cycles/week for 4 weeks; second
 VALUE IN HEALTH 18 (2015) 457–466 459

month—two cycles/week every other week; from the third

month onward—two cycles/month. The unit costs were
obtained from the national tariff lists [20]. Regarding ECP, a
cost/session of €1200 (€120 related to the equipment lease,
€990 for the ECP kit, and €90 related to Uvadex) was consid-
ered on the basis of Therakos internal data. To quantify the
resources used and treatment pathways, a questionnaire (see
Questionnaire 2 in Supplemental Materials found at http://dx.
doi.org/10.1016/j.jval.2015.01.009) was developed and admin-
istered to experts in the field. From the questionnaire it
emerged that mycophenolate is generally used at an average
dose of 20 mg/d, pentostatin is provided at an average dose of
1 mg/m2 for 6 days in a 3-month period, and imatinib is given
at 200 mg/d. A discount rate of 3% was applied to both costs
and QALYs, as recommended by Italian PharmacoEconomics
guidelines [21]. A probabilistic sensitivity analysis (PSA), con-
ducted with 1000 Monte Carlo simulations, was carried out to
assess uncertainty, by varying all significant parameters
simultaneously. In particular, the following distributions were
selected for each variable: log-normal distribution for costs,
resources used, and utilities and beta distribution for mortal-
ity rates. The parameters of each distribution were estimated
according to the primary data collected [19–22]. Based on
PSA, the incremental cost and incremental effect of Therakos
online ECP versus comparators resulting by each of the 1000
simulations were plotted in the incremental cost-
effectiveness plane. Furthermore, a budget impact model
(BIM) was developed. In particular, two scenarios were com-
pared (with and without Therakos online ECP) to assess how
an increased use of Therakos online ECP in the national
setting would affect the economic burden from the viewpoint
of the Italian NHS over 4 years. With reference to the BIM,
scenario one, “immunosuppression alone,” was compared
with scenario two, mix of “Therakos online ECP and
immunosuppressive drugs.” A hypothetical cohort of 1000
patients affected by steroid-refractory/resistant cGvHD was
considered.
Results
The results of the work are reported following the three topics
described in the Methods section.
Current Therapeutical Approach to Steroid-Refractory/
Resistant cGvHD
Several consensus articles were collected through the literature
review [9,13,23–25] (see Appendix Fig. 2 in Supplemental Materi-
als found at http://dx.doi.org/10.1016/j.jval.2015.01.009). In partic-
ular, guidelines issued by the British Committee for Standards in
Hematology and the British Society for Bone Marrow Trans-
plantation [9] were considered to make an overview of alterna-
tives because this was the most up-to-date review available.
According to current evidence, there is agreement on first-line
treatment but heterogeneity exists with respect to second-line
approaches. In particular, in the case of steroid-refractory/resist-
ant cGvHD, ECP is recommended with a 1B level of evidence,
while pentostatin and rituximab with a 2B level of evidence and
mammalian target of rapamycin and imatinib with a 2C level of
evidence [9].
The survey performed at the 26 Italian centers allowed us to
identify the alternatives commonly used in Italy. At the end of
the recall period, 13 centers (50%) sent back the completed
questionnaire. The median number of patients with cGvHD
followed in Italian centers was 10 (minimum 5; maximum 40).
Table 1 includes the treatment options indicated in the first-
and second-line treatments of cGvHD. Only alternatives with
data are presented in the table.
Based on these findings, the comparative analysis was limited
to the following alternatives because they proved to be the
most commonly used in the management of steroid-refractory/
resistant cGvHD in Italy: mycophenolate, pentostatin, and
imatinib.

Table 1 – Treatment options used as first-line and second-line treatments for chronic graft-versus-host disease
in Italy.
Treatment option First-line treatment Second-line treatment

No. of No. of patients No. of No. of patients

centers (% of total) centers (% of total)

Corticosteroids 6 77 (40.3)*
Cyclosporine 1 2 (1.0)
Corticosteroids þ cyclosporine 6 39 (20.4)
Tacrolimus 1 4 (2.1) 1 1 (0.5)
Photopheresis 4 11 (5.8) 10 109 (54.8)
Corticosteroids þ photopheresis 2 13 (6.8)
High-dose corticosteroids þ photopheresis 1 20 (10.5) 1 16 (8.0)
Infliximab 1 4 (2.0)
Mycophenolate 4 21 (11.0) 6 15 (7.5)
Mycophenolate þ imatinib 1 2 (1.0)
Sirolimus 1 1 (0.5)
Pentostatin 1 14 (7.0)
Methotrexate 1 5 (2.5)
Imatinib 4 11 (5.5)
Rituximab 1 2 (1.0) 2 4 (2.0)
Azathioprine 1 1 (0.5)
Cyclophosphamide 1 6 (3.0)
Methotrexate þ rituximab þ high-dose corticosteroids 1 12 (6.0)
* The most commonly used alternatives are in bold.
460 VALUE IN HEALTH 18 (2015) 457–466

Efficacy and Safety of ECP and Its Alternatives Used in the
Second-Line Treatment of Steroid-Refractory/Resistant cGvHD
With respect to ECP, the literature review identified consensus
articles that summarize data from clinical studies (see Appendix
Fig. 3 in Supplemental Materials found at http://dx.doi.org/10.
1016/j.jval.2015.01.009). The article by Pierelli et al. [13]—the most
recent on the use of ECP—was chosen as the starting point. With
regard to cGvHD, Pierelli et al. included 23 research articles
[26–48], while two further studies were identified through our
search [49,50]. Only two studies were experimental [33,37]. Data
are presented in Table 2.
Overall, 64.2% of the patients (376 of 586) responded to ECP; a
complete response was observed in 23.7% (85 of 389) of the cases,
whereas a partial response was observed in 45.2% (176 of 389) of
the cases. Data on overall survival at 5 years were not available
for all studies and were widely heterogeneous. The possibility of
reducing corticosteroid doses was reported in 34% of the patients
enrolled in the studies reviewed by Pierelli et al. [13]. In particular,
steroid dose was reduced by more than 50% at 3 months from the
beginning of ECP in a percentage varying from 29% to 64% [27,49].
The possibility to discontinue steroid treatment was reported in
more than 20% of the patients [30,32]. As far as safety is
concerned, the review by Pierelli et al. [13] concluded that ECP
was generally well tolerated, with an incidence of adverse events
lower than 0.003%, including nausea, fever, headache, or tran-
sient arterial hypotension [13,49]. The most common adverse
event was catheter infection. In particular, a nonfatal blood-
stream infection was observed among 27 patients (3.7%) in the
study by Kanold et al. [39] and two catheter infections
were observed in 30 patients (7%) in the study by Hautmann
et al. [49].
Table 3 reports the results of clinical studies on mycophe-
nolate [51–59] (see Appendix Fig. 4 in Supplemental Materials
found at http://dx.doi.org/10.1016/j.jval.2015.01.009), pentostatin
[60–62] (see Appendix Fig. 5 in Supplemental Materials found at
http://dx.doi.org/10.1016/j.jval.2015.01.009), and imatinib [63–67]
(see Appendix Fig. 6 in Supplemental Materials found at http://
dx.doi.org/10.1016/j.jval.2015.01.009) as the most common alter-
natives for the second-line treatment of cGvHD. The most
common adverse event in patients treated with mycophenolate
was infection. Risk of severe and/or fatal infection was 25%
[51–59]. Diabetes developed in 17 subjects out of 74 (23%).
Less common adverse events included hematologic disorders
(13%) and other toxicities (10%) [51–59]. Infections were also
observed in about 24% of the patients treated with pentos-
tatin (26 of 109 patients) [60–62], being the most common
and serious adverse event. With regard to imatinib, in the
study by Magro et al. [64], four patients (29%) suspended
imatinib because of intolerance; six of the other patients
experienced mild or moderate adverse reactions. In the
study by Olivieri et al. [65], four patients (21%) developed
relevant nonhematological adverse effects, including pneu-
monia, pleural effusion, edema, and viral infection of the
central nervous system; the conditions of three of these
required suspension of treatment. A further five patients
suspended treatment for other reasons. The study by Stadler
et al. [66] reported manifestations of toxicity, mostly of mild

Table 2 – Results of clinical studies on the use of extracorporeal photopheresis as second-line treatment in
steroid-refractory/resistant chronic graft-versus-host disease.
Author (year) N Age Skin Liver Lungs Oral GIT Global 5-y
(y) mucosa response survival
(%)

Smith et al. (1998) [47] 18 5–53 4/10 12/13 0/3 2/7 NA 6 (3 CR, 3 PR) 39
Greinix et al. (1998) [37] 15 25–55 15/15 9/10 NA 11/11 NA 15 (6 CR, 9 PR) 93
Zic et al. (1999) [48] 11 NA 6/8 2/5 NA 2/10 3/3 NA 73
Child et al. (1999) [29] 11 18–47 10/10 6/6 2/5 3/4 NA NA 82
Salvaneschi et al. (2001) [45] 14 6–20 10/12 6/9 1/1 8/12 NA 9 (4 CR, 5 PR) NA
Apisarnthanarax et al. (2003) 32 470 18/32 0/17 NA 0/11 0/11 18 (7 CR, 11 PR) NA
[27]
Messina et al. (2003) [41] 44* 0–20 20/36 16/20 6/14 0/26 10/21 25 (15 CR, 10 PR)* 30
Seaton et al. (2003) [46] 28 18–51 10/21 0/15 0/9 3/14 NA NA 86
Rubegni et al. (2005) [44] 32 18–60 22/27 10/22 2/5 23/25 NA 25 NA
Kanold et al. (2005) [40] 63 NA 31/51 24/33 7/15 0/33 16/27 40 79
Foss et al. (2005) [34] 25 18–59 20/25 0/6 2/2 6/13 2/2 16 60
Garban et al. (2005) [35] 15 14–62 12/12 1/3 3/3 NA 7/9 NA NA
Bisaccia et al. (2006) [28] 14 25–57 7/14 5/5 1/3 3/7 NA NA 79
Couriel et al. (2006) [30] 71 470 33/56 15/21 6/11 7/9 2/3 43 (14 CR, 29 PR) 41
Perseghin et al. (2007) [43] 25 6–55 20/25 4/6 NA 7/9 2/2 18 (11 CR, 7 PR) 76
Kanold et al. (2007) [39] 15 5–18 9/12 6/11 0/1 6/7 5/6 11 (4 CR, 7 PR) 67
Flowers et al. (2008) [33] 48 16–67 17/48 3/14 1/9 16/30 1/2 NA 98
Jagasia et al. (2009) [38] 31 23–67 NA NA NA NA NA 20 (3 CR, 17 PR) 52
Akhtari et al. (2010) [26] 25 NA NA NA NA NA NA 14 64
Perotti et al. (2010) [42] 23 o18 22/22 4/4 2/3 4/8 5/6 11 78
Dignan et al. (2012) [32] 82 14–69 57/75 NA NA 29/39 NA NA NA
Greinix et al. (2011) [36] 29 20–67 9/29 NA NA NA NA 9 NA
Del Fante et al. (2012) [31] 102 33–54 NA NA NA NA NA 82 (16 CR, 66 PR) 78
Tsirigotis et al. (2012) [50] 42 NA NA NA NA NA NA 27 NA
Hautmann et al. (2013) [49] 32 6–67 10/17 1/1 0/5 3/5 0/1 14 (2 CR, 12 PR) 56
CR, complete response; GIT, gastrointestinal tract; NA, not available; PR, partial response.
* Only 34 patients were evaluated for global response.
 VALUE IN HEALTH 18 (2015) 457–466 461

Table 3 – Results of clinical studies on the use of treatments different from extracorporeal photopheresis for the
second-line management of steroid-refractory/resistant chronic graft-versus-host disease.
Treatment Author (year) N Patients’ Complete response, Partial response,
age (y) n (%) n (%)

Mycophenolate Baudard et al. (2002) [51] 13 Median: 36 9 (69)*

Busca et al. (2000) [52] 15 3–16 3 (20) 6 (40)
Busca et al. (2003) [53] 18 NA (adults) 5 (28) 8 (44)
Iida et al. (2011) [54] 50 Median: 41 5 (10) 21 (42)
Kim et al. (2004) [55] 13 Median: 35 1 (8) 9 (69)
Krejci et al. (2005) [56] 11 Median: 40 4 (36) 4 (36)
Lopez et al. (2005) [57] 34 Median: 32 12 (35) 15 (44)
Martin et al. (2009) [58] 74 NA (adults) 11 (15) 20 (27)
Onishi et al. (2010) [59] 11 Median: 39 7 (64)*
Pentostatin Jacobsohn et al. (2007) [60] 58 Mean: 33 32 (55)*
Jacobsohn et al. (2009) [61] 51 Mean: 10 7 (14) 20 (39)
Pidala et al. (2010) [62] 18 NA 1 (6) 9 (50)
Imatinib Magro (2008) et al. [63] 2 Mean: 30 2 (100) 0 (0)
Magro (2009) et al. [64] 14 Mean: 39 0 (0) 7 (50)
Olivieri et al. (2009) [65] 19 Mean: 29 1 (5) 11 (58)
Stadler et al. (2009) [66] 9 Mean: 45 0 (0) 2 (22)
de Masson et al. (2012) [67] 39 Mean: 42 1 (2) 9 (23)
NA, not available.
* Complete or partial response.

severity, such as hematological manifestations, nausea, fluid

retention, or, in the case of two patients (22%), reversible
dyspnea that required suspension of treatment. The study by
de Masson et al. [67] reported serious adverse events,
especially generalized fluid retention (18%) and cytopenia
(8%) that led to treatment suspension. On this basis, it is
possible to state that the frequency of serious adverse events
is higher in the case of immunosuppressive options than in
the case of ECP.
Economic Profile of Therakos Online ECP in Comparison to
Current Alternatives
As discussed in previous sections, Therakos online ECP was
compared with mycophenolate, pentostatin, and imatinib.
Results of the economic analysis showed that Therakos online
ECP is dominant, meaning that Therakos online ECP was asso-
ciated with significantly lower costs and with a gain in QALYs
when compared with all the three alternatives (Table 4). The PSA
showed that the results of the base case were robust with respect
to the comparison between Therakos online ECP and pentostatin
(Fig. 1). PSA results were more heterogeneous with regard to the
comparison between Therakos online ECP and imatinib and
mycophenolate (Fig. 1).
The BIM showed how utilization rates of online ECP and its
alternative treatments affected the budget from the third-party
payer perspective. The analysis showed how expenditure could
change with changes to the balance of utilization between each
of the alternative treatments for any given number of patients.
Accordingly, a hypothetical cohort of 1000 patients with steroid-
refractory/resistant cGvHD was considered: in scenario one,
patients were distributed among the three different alternative
treatments (mycophenolate, 30%; pentostatin, 40%; and imatinib,
30%), whereas in scenario two, the impact of the introduction of
Therakos online ECP was evaluated (ECP, 70%; mycophenolate,
10%; pentostatin, 10%; and imatinib, 10%). The BIM showed that
within 4 years from the introduction of Therakos online ECP,
significant savings could be obtained for the whole Italian NHS
(€2,244,153) (Fig. 2).
Conclusions
This article shows the results of a comparative and cost-
effectiveness analysis together with budget impact assessment
of Therakos online ECP in steroid-refractory/resistant cGvHD in
Italy. It aims to summarize the available evidence to support the
policy decision-making process at both national and regional
levels in defining the best strategy in the treatment of steroid-
refractory/resistant cGvHD. The first objective of the work was to
identify current practice in the management of steroid-refrac-
tory/resistant cGvHD. The results of the literature review and the
survey underlined heterogeneity in therapeutic management of
the condition, in part due to the lack of strong recommendations
in the field. The literature review of data on the efficacy of ECP
and alternatives currently used in the Italian context highlighted
a lack of evidence from randomized clinical trials and hetero-
geneity between studies in terms of follow-up protocols and
length. Furthermore, very few studies were available to support
the efficacy and safety of the alternatives to ECP. From the
evaluation of all the studies on ECP and alternatives, it may be
concluded that with respect to steroid-refractory/resistant
cGvHD, the percentage of complete and partial responses to the
treatment may be considered higher for ECP than for mycophe-
nolate, pentostatin, and imatinib. This is the first valuable result
of this study, although not based on head-to-head studies. As far
as safety is concerned, ECP was shown to be well tolerated. The
most common adverse event was represented by catheter-related
infections. Evidence showed that the incidence of infections was
higher in patients treated with the alternatives instead of ECP.
Furthermore, some of them, for example imatinib, were charac-
terized by intolerance and need for suspension. It is interesting to
underline also the steroid-sparing effect of ECP shown in several
studies [27,30,32,33,36,49]. The resulting reduction in steroid dose
and, in some cases, complete discontinuation of steroids may
reduce steroid-induced complications [68], such as life-
threatening infections. In fact, treatments with high-dose ste-
roids are associated with high morbidity and mortality. All these
data support the use of ECP in steroid-refractory/resistant cGvHD.
462 VALUE IN HEALTH 18 (2015) 457–466

Table 4 – Results of economic evaluation (base case).

Results ECP Pentostatin Difference

Total cost per patient (€) 95,770.36 115,673.87 19,903.51

% Improvement 51.8 29.3 22%
LYs 5.37 5.32 0.06
QALYs 4.17 3.96 0.21
ECP Mycophenolate Difference

Total cost per patient (€) 95,770.36 100,284.23 4,513.87

% Improvement 51.8 41.5 10
LYs 5.37 5.37 0.00
QALYs 4.17 4.13 0.04
ECP Imatinib Difference

Total cost per patient (€) 95,770.36 99,007.45 3,237.09

% Improvement 51.8 43.3 8
LYs 5.37 5.35 0.02
QALYs 4.17 4.10 0.07
LY, life-year; QALY, quality-adjusted life-year.

In addition, the economic evaluation supports the dominance
of Therakos online ECP in comparison to the alternatives because
it entails lower costs and higher gains in QALYs, and the PSA
confirmed the robustness of base-case results. For these reasons,
along with the results of the budget impact analysis, the diffusion
of this technology within the Italian setting would be desirable
from the viewpoint of the third-party payer. Furthermore,
Therakos online system guarantees sterility and the possibility
of reducing the duration of the procedure.
However, a deep heterogeneity between regions in terms of
reimbursement policies exists, creating barriers to access to ECP.
In fact, even though ECP is currently one of the services that is
completely excluded from essential levels of care (LEA), in that
the services that the Italian NHS must provide to all citizens, free

Fig. 1 – PSA results (scatter plots). ECP, extracorporeal photopheresis; PSA, probabilistic sensitivity analysis; QALY, quality-
adjusted lie-year.
 VALUE IN HEALTH 18 (2015) 457–466
Fig. 2 – Results of budget impact analysis.
of charge or with co-payments [69–71], ECP has been on the
Ministry tariff list for a long time, with a reimbursement cost of
€7.75 [72]. In some regions and autonomous provinces, the old
codification is still in force. For instance, in the Emilia Romagna
region, ECP is included in the tariff list for the reimbursement of
services excluded from LEA, with a reimbursement of €7.75 [73],
whereas it is excluded from the reimbursement list of ambula-
tory specialist care [73]. In contrast, in the Umbria and Lazio
regions, ECP is listed among ambulatory specialist care services
and assigned a reimbursement of €8.50 and €7.80, respectively
[74,75]. The same applies to the Autonomous Province of Bolzano,
where the reimbursement is €7.80 [76]. In most of the remaining
regions, ECP is not included in any reimbursement list. In the
Tuscany region, however, ECP is among the procedures partially
excluded from LEA that can be provided only for specific clinical
indications and it has been enclosed in the tariff list of ambula-
tory specialist care, in the section “Miscellanea of physical
procedures,” with a tariff of €665.00 [77]. A cost-based reimburse-
ment tariff of €1537.90 has been also established in the Sicily
region [78]. The depicted situation is an example of the well-
known inequalities in access to health care services across Italian
regions [79]. In this landscape of heterogeneity and autonomy,
one of the fundamental principles stated by the European Charter
of Patients’ Rights as well as by article 32 of the Italian Con-
stitution—a principle on which the Italian NHS rests—is not
fulfilled: that is, that the NHS needs to ensure “equal access to
everybody, without discrimination by financial resources, place
of residency, type of disease or moment of access to the service”
[79,80].
In light of these considerations, as well as of the evidence
coming from clinical and economic data, the need is apparent to
remove this procedure from the list of services excluded from
LEA. This would be in line with article 1 of the law decree 502/
1992, which includes in LEA all services that should be guaran-
teed by the NHS on the basis of their individual or collective
evidence-based benefit [69]. Moreover, the ECP tariff should be
reviewed to have a national tariff and to ensure the coverage of
the cost of treatment.
Other assessments carried out across the world support the
use of ECP. For example, the Health Policy Advisory Committee
on Technology (HealthPACT) of Australia and New Zealand has
submitted to the Euroscan, the International Information Net-
work on New and Emerging Health Technologies, an assessment
report on ECP for the treatment of GvHD. In fact, ECP has been
classified as an innovative treatment with significant expected
463
health benefits, in particular considering that there is no stand-
ard therapy for patients who fail steroids [81]. In 2011, the same
HealtPACT agency released a report on ECP for the treatment of
GvHD after bone marrow transplantation. In the report, ECP was
judged, according to the evidence, well tolerated and safe in
seriously ill adult and pediatric patients with limited treatment
options. Indeed, HealthPACT recommended that information on
ECP is renowned and did not ask for further research [82].
The growing acceptance of ECP in standard practice is evi-
denced by the publication of a protocol by the Cochrane Childhood
Cancer Group on the comparison between ECP and alternative
treatments in the management of cGvHD in pediatric patients [83].
ECP has already received recommendation for routine use in
many countries. For example, the Centers for Medicare & Med-
icaid Services defined ECP as a reasonable and necessary treat-
ment for patients with cGvHD whose disease is refractory to
standard immunosuppressive drug treatment [84]. Also, Cancer
Care Ontario defined ECP as an acceptable therapy for the treat-
ment of steroid-dependent/refractory acute GvHD and cGvHD in
adult and pediatric patients [85]. In the United Kingdom, ECP is
suggested for use in the second-line treatment of cGvHD, as
recommended by Dignan et al. [86]. These recommendations on
ECP [84–86], as well as those from the Italian Society of Hema-
pheresis and Cell Manipulation and the Italian Group for Bone
Marrow Transplantation [13], are made on the basis of its efficacy
and safety, even though data from randomized clinical trial are
still missing. In this respect, this work has to be considered an
advance in knowledge because it provides evidence about the
alternatives routinely used in the management of steroid-refrac-
tory/resistant cGvHD and the economic profile of Therakos online
ECP. As far as the economic evaluation is concerned, a literature
search performed on PubMed yielded a study assessing the cost-
effectiveness of ECP in comparison to rituximab and imatinib in
steroid-refractory cGvHD [19]. The study showed that, from the
Spanish NHS viewpoint, ECP is cost-effective. Furthermore,
another cost-effectiveness analysis, conducted in Poland, showed
that ECP is the most cost-effective alternative in the management
of patients affected by cGvHD, compared with no alternative [87].
These results are in line with our evaluation that takes into
consideration more alternatives. In conclusion, this comprehen-
sive work may be considered an important step in the evaluation
of the use of Therakos online ECP in steroid-refractory/resistant
cGvHD in the Italian context and, with respect to some data,
elsewhere. It showed that Therakos online ECP should be con-
sidered an effective, safe, and cost-effective alternative in
464 VALUE IN HEALTH 18 (2015) 457–466
steroid-refractory/resistant cGvHD and should be promoted and
used, avoiding regional differences.
Study Limitations
Our study has some limitations with respect to the issues that
have been addressed and the methodology. As far as the content
is concerned, the study omits to include patients’ perspective in
terms of attitudes, behaviors, and quality of life. The study,
however, is thorough with respect to the assessment of the
following domains that are reported in the European network
for Health Technology Assessment core model [88]: health prob-
lem and current use of the technology, safety and clinical
effectiveness, and costs and economic evaluation. With regard
to methodology, the main pitfalls are represented by the lack of
validation of the questionnaires used to carry out the surveys on
alternative therapies and their costs. Furthermore, it is not
certain that the data used to populate the mathematical model
could be considered reliable and Markov modeling does not
generally provide a real-world simulation because it relies on
inputs that are not real-world based. With respect to data input, it
should also be highlighted that very few studies on the safety and
efficacy of the alternatives to ECP were available; furthermore,
they had relatively small sample sizes and were not head-to-
head studies. This represents one of the main limitations that
could affect the results of the current analysis. Because of a lack
of large sample evidence-based data, however, it was necessary
to rely on available data in this field. With reference to this
aspect, it is important to point out that cGvHD is not charac-
terized by high incidence. Another limitation of the study is that
utilities were chosen according to only one study on the cost-
effectiveness of ECP and that only neutropenia was accounted for
with respect to possible adverse effects of drugs.
Acknowledgments
We thank Oblikue contact persons Carlos Crespo Palomo and
Max Brosa for the development of the model.
Source of financial support: The assessment has been carried
out with an unconditional grant from Therakos, Inc.
Supplemental Materials
Supplemental materials accompanying associated with this
article can be found in the online version as a hyperlink at
http://dx.doi.org/10.1016/j.jval.2015.01.009 or, if a hard copy of
article, at www.valueinhealthjournal.com/issues (select volume,
issue, and article).
R EF E R EN CE S
[1] Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health
consensus development project on criteria for clinical trials in chronic
graft-versus-host disease, I: diagnosis and staging working group
report. Biol Blood Marrow Transplant 2005;11:945–56.
[2] Choi SW, Levine JE, Ferrara JL. Pathogenesis and management of
graft-versus-host disease. Immunol Allergy Clin North Am
2010;30:75–101.
[3] Antin JH. Clinical practice: long-term care after hematopoietic-cell
transplantation in adults. N Engl J Med 2002;347:36–42.
[4] Gilman AL, Schultz KR. Treatment of chronic GvHD. Bone Marrow
Transplant 2000;26:460–2.
[5] Goerner M, Gooley T, Flowers ME, et al. Morbidity and mortality of
chronic GvHD after hematopoietic stem cell transplantation from HLA-
identical siblings for patients with aplastic or refractory anemias. Biol
Blood Marrow Transplant 2002;8:47–56.
[6] Lee SJ, Klein JP, Barrett AJ, et al. Severity of chronic graft-versus-host
disease: association with treatment-related mortality and relapse.
Blood 2002;100:406–14.
[7] Gruppo Italiano per il Trapianto di Midollo Osseo, cellule staminali
emopoietiche e terapia cellulare. Available from: http://www.gitmo.it/.
[Accessed October 1, 2013].
[8] Song I, Yi CA, Han J, et al. CT findings of late-onset noninfectious
pulmonary complications in patients with pathologically proven graft-
versus-host disease after allogeneic stem cell transplant. AJR Am J
Roentgenol 2012;199:581–7.
[9] Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of
chronic graft-versus-host disease. Br J Haematol 2012;158:46–61.
[10] Knobler R, Barr ML, Couriel DR, et al. Extracorporeal photopheresis:
past, present, and future. J Am Acad Dermatol 2009;61:652–65.
[11] Scarisbrick JJ, Taylor P, Holtick U, et al. U.K. consensus statement on the
use of extracorporeal photopheresis for treatment of cutaneous T-cell
lymphoma and chronic graft-versus-host disease. Br J Dermatol
2008;158:659–78.
[12] Maeda A. Extracorporeal photochemotherapy. J Dermatol Sci
2009;54:150–6.
[13] Pierelli L, Perseghin P, Marchetti M, et al. Extracorporeal photopheresis
for the treatment of acute and chronic graft-versus-host disease in
adults and children: best practice recommendations from an Italian
Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian
Group for Bone Marrow Transplantation (GITMO) consensus process.
Transfusion 2013;53:2340–52.
[14] Martino M, Console G, Pucci G, et al. Extracorporeal photoimmune
therapy: a therapeutic alternative treatment of cutaneous T cell
lymphoma and immunological diseases. Cancer Therapy
2004;2:177–86.
[15] Bisaccia E, Vonderheid EC, Geskin L. Safety of a new, single, integrated,
closed photopheresis system in patients with cutaneous T-cell
lymphoma. Br J Dermatol 2009;161:167–9.
[16] Klassen J. The role of photopheresis in the treatment of graft-versus-
host disease. Curr Oncol 2010;17:55–8.
[17] European Dermatology Forum. Guideline on extracorporeal
photopheresis. Developed by the Guideline Subcommittee
“Extracorporeal Photopheresis” of the European Dermatology Forum.
Available from: http://www.euroderm.org/images/stories/guidelines/
Guidelines_on_the_use_of_ECP-20130121.pdf. [Accessed October 1,
2013].
[18] Adorno G, Lanti A, Fiorelli E, et al. An efficiency study comparing an
open system and Therakoss CELLEX for extracorporeal photopheresis
procedure. Presented at: 39th EBMT Annual Meeting. London, April
7–10, 2013.
[19] Crespo C, Perez-Simon JA, Rodriguez JM, et al. Development of a
population-based cost-effectiveness model of chronic graft-versus-
host disease in Spain. Clin Therapeut 2012;34:1774–87.
[20] Ministero della Salute – Decreto 18 ottobre 2012 – GU n. 23. 28 gennaio
2013.
[21] AIES. Proposta di Linee-Guida per la valutazione economica degli
interventi sanitari. PharmacoEconomics Italian Res Articles
2009;11:83–93.
[22] Briggs AH. Handling uncertainty in cost-effectiveness models.
Pharmacoeconomics 2000;17:479–500.
[23] Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic
treatment of acute graft-versus-host disease: recommendations of the
American Society of Blood and Marrow Transplantation. Biol Blood
Marrow Transplant 2012;18:1150–63.
[24] Wolff D, Bertz H, Greinix H, et al. The treatment of chronic graft-versus-
host disease: consensus recommendations of experts from Germany,
Austria, and Switzerland. Dtsch Arztebl Int 2011;108:732–40.
[25] Wolff D, Schleuning M, von Harsdorf S, et al. Consensus Conference
on Clinical Practice in Chronic GVHD: Second-Line Treatment of
Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant
2011;17:1–17.
[26] Akhtari M, Giver CR, Ali Z, et al. Receiver operating characteristic curve
analysis of circulating blood dendritic cell precursors and T cells
predicts response to extracorporeal photopheresis in patients with
chronic graft-versus-host disease. Transfusion 2010;50:2424–31.
[27] Apisarnthanarax N, Donato M, Korbling M, et al. Extracorporeal
photopheresis therapy in the management of steroid-refractory or
steroid dependent cutaneous chronic graft-versus-host disease after
allogeneic stem cell transplantation: feasibility and results. Bone
Marrow Transplant 2003;31:459–65.
[28] Bisaccia E, Palangio M, Gonzalez J, et al. Treatment of extensive chronic
graft-versus-host disease with extracorporeal photochemotherapy.
J Clin Apher 2006;21:181–7.
[29] Child FJ, Ratnavel R, Watkins P, et al. Extracorporeal photopheresis
(ECP) in the treatment of chronic graft-versus-host disease (GVHD).
Bone Marrow Transplant 1999;23:881–7.
 VALUE IN HEALTH 18 (2015) 457–466
[30] Couriel DR, Hosing C, Saliba R, et al. Photochemotherapy for the
treatment of steroid-resistant chronic GVHD. Blood 2006;107:3074–80.
[31] Del Fante C, Scudeller L, Viarengo L, et al. Response and survival of
patients with chronic graft versus-host disease treated by
extracorporeal photochemotherapy: a retrospective study according to
classical and National Institutes of Health classifications. Transfusion
2012;52:2007–15.
[32] Dignan FL, Greenblatt D, Cox M, et al. Efficacy of bimonthly
extracorporeal photopheresis in refractory chronic mucocutaneous
GVHD. Bone Marrow Transplant 2012;47:824–30.
[33] Flowers ME, Apperley JF, van Besien K, et al. A multi center prospective
phase 2 randomized study of extracorporeal photopheresis for
treatment of chronic GVHD. Blood 2008;112:2667–73.
[34] Foss FM, Di Venuti GM, Chin K, et al. Prospective study of
extracorporeal photopheresis in steroid-refractory or steroid resistant
extensive chronic graft-versus-host disease: analysis of response and
survival incorporating prognostic factors. Bone Marrow Transplant
2005;35:1187–93.
[35] Garban F, Drillat P, Makowski C, et al. Extracorporeal
chemophototherapy for the treatment of graft-versus-host disease:
hematologic consequences of short-term, intensive courses.
Haematologica 2005;90:1096–101.
[36] Greinix HT, van Besien K, Elmaagacli AH, et al. Progressive
improvement in cutaneous and extracutaneous chronic graft-versus-
host disease after a 24-week course of extracorporeal photopheresis—
results of a crossover randomized study. Biol Blood Marrow Transplant
2011;17:1775–82.
[37] Greinix HT, Volc-Platzer B, Rabitsch W, et al. Successful use of
extracorporeal photochemotherapy in the treatment of severe acute
and chronic graft-versus-host disease. Blood 1998;92:3098–104.
[38] Jagasia MH, Savani BN, Stricklin G, et al. Classic and overlap chronic
graft-versus host disease (cGVHD) is associated with superior outcome
after extracorporeal photopheresis (ECP). Biol Blood Marrow Transplant
2009;15:1288–95.
[39] Kanold J, Merlin E, Halle P, et al. Photopheresis in pediatric graft-
versus-host disease after allogeneic marrow transplantation: clinical
practice guidelines based on field experience and review of the
literature. Transfusion 2007;47:2276–89.
[40] Kanold J, Messina C, Halle P, et al. Update on extracorporeal
photochemotherapy for graft-versus-host disease treatment. Bone
Marrow Transplant 2005;35(Suppl. 1):S69–71.
[41] Messina C, Locatelli F, Lanino E, et al. Extracorporeal
photochemotherapy for paediatric patients with graft-versus-host
disease after haematopoietic stem cell transplantation. Br J Haematol
2003;122:118–27.
[42] Perotti C, Del Fante C, Tinelli C, et al. Extracorporeal
photochemotherapy in graft-versus-host disease: a longitudinal study
on factors influencing the response and survival in pediatric patients.
Transfusion 2010;50:1359–69.
[43] Perseghin P, Galimberti S, Balduzzi A, et al. Extracorporeal
photochemotherapy for the treatment of chronic graft-versus-host
disease: trend for a possible cell dose-related effect? Ther Apher Dial
2007;11:85–93.
[44] Rubegni P, Cuccia A, Sbano P, et al. Role of extracorporeal
photochemotherapy in patients with refractory chronic graft-versus-
host disease. Br J Haematol 2005;130:271–5.
[45] Salvaneschi L, Perotti C, Zecca M, et al. Extracorporeal
photochemotherapy for treatment of acute and chronic GVHD in
childhood. Transfusion 2001;41:1299–305.
[46] Seaton ED, Szydlo RM, Kanfer E, et al. Influence of extracorporeal
photopheresis on clinical and laboratory parameters in chronic graft-
versus-host disease and analysis of predictors of response. Blood
2003;102:1217–23.
[47] Smith EP, Sniecinski I, Dagis AC, et al. Extracorporeal
photochemotherapy for treatment of drug-resistant graft-vs.-host
disease. Biol Blood Marrow Transplant 1998;4:27–37.
[48] Zic JA, Miller JL, Stricklin GP, et al. The North American experience with
photopheresis. Ther Apher 1999;3:50–62.
[49] Hautmann AH, Wolff D, Hahn J, et al. Extracorporeal photopheresis in
62 patients with acute and chronic GVHD: results of treatment with the
COBE Spectra System. Bone Marrow Transplant 2013;48:439–45.
[50] Tsirigotis P, Kapsimalli V, Baltadakis I, et al. Extracorporeal
photopheresis in refractory chronic graft-versus-host disease: the
influence on peripheral blood T cell subpopulations. A study by the
Hellenic Association of Hematology. Transfus Apher Sci 2012;46:181–8.
[51] Baudard M, Vincent A, Moreau P, et al. Mycophenolate mofetil for
the treatment of acute and chronic GVHD is effective and well
tolerated but induces a high risk of infectious complications: a series of
21 BM or PBSC transplant patients. Bone Marrow Transplant 2002;30:
287–95.
[52] Busca A, Saroglia EM, Lanino E, et al. Mycophenolate mofetil (MMF) as
therapy for refractory chronic GVHD (cGVHD) in children receiving
465
bone marrow transplantation. Bone Marrow Transplant
2000;25:1067–71.
[53] Busca A, Locatelli F, Marmont F, et al. Response to mycophenolate
mofetil therapy in refractory chronic graft-versus-host disease.
Haematologica 2003;88:837–9.
[54] Iida M, Fukuda T, Ikegame K, et al. Use of mycophenolate mofetil in
patients received allogeneic hematopoietic stem cell transplantation in
Japan. Int J Hematol 2011;93:523–31.
[55] Kim JG, Sohn SK, Kim DH, et al. Different efficacy of mycophenolate
mofetil as salvage treatment for acute and chronic GVHD after
allogeneic stem cell transplant. Eur J Haematol 2004;73:56–61.
[56] Krejci M, Doubek M, Buchler T, et al. Mycophenolate mofetil for the
treatment of acute and chronic steroid-refractory graft-versus-host
disease. Ann Hematol 2005;84:681–5.
[57] Lopez F, Parker P, Nademanee A, et al. Efficacy of mycophenolate
mofetil in the treatment of chronic graft-versus host disease. Biol Blood
Marrow Transplant 2005;11:307–13.
[58] Martin PJ, Storer BE, Rowley SD, et al. Evaluation of mycophenolate
mofetil for initial treatment of chronic graft-versus-host disease. Blood
2009;113:5074–82.
[59] Onishi C, Ohashi K, Sawada T, et al. A high risk of life-threatening
infectious complications in mycophenolate mofetil treatment for acute
or chronic graft-versus-host disease. Int J Hematol 2010;91:464–70.
[60] Jacobsohn DA, Chen AR, Zahurak M, et al. Phase II study of pentostatin
in patients with corticosteroid-refractory chronic graft-versus-host
disease. J Clin Oncol 2007;25:4255–61.
[61] Jacobsohn DA, Gilman AL, Rademaker A. Evaluation of pentostatin in
corticosteroid-refractory chronic graft-versus-host disease in children:
a Pediatric Blood and Marrow Transplant Consortium study. Blood
2009;114:4354–60.
[62] Pidala J, Kim J, Roman-Diaz J, et al. Pentostatin as rescue therapy for
glucocorticoid-refractory acute and chronic graft-versus-host disease.
Ann Transplant 2010;15:21–9.
[63] Magro L, Catteau B, Coiteux V, et al. Efficacy of imatinib mesylate in the
treatment of refractory sclerodermatous chronic GVHD. Bone Marrow
Transplant 2008;42:757–60.
[64] Magro L, Mohty M, Catteau B, et al. Imatinib mesylate as salvage
therapy for refractory sclerotic chronic graft-versus-host disease. Blood
2009;114:719–22.
[65] Olivieri A, Locatelli F, Zecca M, et al. Imatinib for refractory chronic
graft-versus-host disease with fibrotic features. Blood 2009;114:709–18.
[66] Stadler M, Ahlborn R, Kamal H, et al. Limited efficacy of imatinib in
severe pulmonary chronic graft-versus-host disease. Blood
2009;114:3718–9.
[67] de Masson A, Bouaziz JD, Peffault de Latour R, et al. Limited efficacy
and tolerance of imatinib mesylate in steroid-refractory
sclerodermatous chronic GVHD. Blood 2012;120:5089–90.
[68] Jagasia M, Greinix H, Robin M, et al. Extracorporeal photopheresis
versus anticytokine therapy as a second-line treatment for steroid-
refractory acute GVHD: a multicenter comparative analysis. Biol Blood
Marrow Transplant 2013;19:1129–33.
[69] Ministero della Salute. I Livelli Essenziali di Assistenza. Available from:
http://www.salute.gov.it/programmazioneSanitariaELea/
paginaInternaMenuProgrammazioneSanitariaELea.jsp?
menu=lea&id=1300&lingua=italiano. [Accessed October 1, 2013].
[70] Decreto del Presidente del Consiglio dei Ministri 29 Novembre
2001. Definizione dei Livelli Essenziali di Assistenza GU 8 Febbraio
2002, n.33.
[71] Conferenza Stato-Regioni. Seduta del 22 Novembre 2001. Repertorio
Atti n.1318 del 22 Novembre 2001.
[72] AgeNaS. Sezione monitoraggio dei costi e delle tariffe. Confronto tra le
tariffe nazionali ex DM 1996 e le tariffe regionali massime vigenti
nell’anno 2008. Available from: http://www.agenas.it/
monitoraggio_costi_tariffe/monitoraggio_costi_tariffe_prestazioni.htm.
[Accessed October 1, 2013].
[73] Nomenclatore Tariffario Regione Emilia Romagna. Prestazioni escluse
dai Livelli Essenziali di Assistenza. Available from: http://www.saluter.
it/documentazione/nomenclatore-tariffario-rer/no-lea/view. [Accessed
October 1, 2013].
[74] Regione Umbria. Supplemento ordinario n. 3 al «Bollettino
Ufficiale» - serie generale - n. 38 del 31 agosto 2011. Available from:
http://www2.regione.umbria.it/bollettini/download.aspx?doc=
110831A38SO3.pdf&t=so&p=1&show=true. [Accessed October 1, 2013].
[75] Nomenclatore Tariffario Prestazioni Specialistiche Ambulatoriali
Regione Lazio. Available from: http://www.regione.lazio.it/binary/web/
sanita_regionale_wordpress/nomenclatore_tariffario_RLazio.
1159435842.pdf. [Accessed October 1, 2013].
[76] Deliberazione della Giunta Provinciale della Provincia Autonoma di
Bolzano, n. 1988 del 19/12/2011. Available from: http://www.provinz.bz.
it/gesundheitswesen/download/DGP_n._1988_del_19.12.
2011_aggiornamento_tariffario_spec.pdf. [Accessed October 1, 2013].
[77] Regione Toscana. Delibera 1178 del 05/12/2005 e successive modifiche.
466 VALUE IN HEALTH 18 (2015) 457–466
[78] Gazzetta Ufficiale della Regione Siciliana. Palermo - Venerdì, 15 aprile
2011. Anno 651 - Numero 17.
[79] Centro Studi Assobiomedica. La disomogeneità nei livelli di assistenza
specialistica ambulatoriale tra i servizi sanitari regionali. Numero 12 –
Dicembre 2011.
[80] Specchia ML, Capizzi S, Veneziano MA, et al. Disamina degli aspetti
organizzativi relativi all’impiego di denosumab nel contesto di cura
italiano. IJPH 2011;Suppl. 2:S86–98.
[81] Extracorporeal photopheresis for the treatment of graft versus host
disease. Available from: http://euroscan.org.uk/technologies/
technology/view/1915. [Accessed October 1, 2013].
[82] HealthPACT Health Policy Advisory Committee on Technology
Australia and New Zealand. Extracorporeal photopheresis for the
treatment of graft versus host disease following bone marrow
transplantation. 2011. Available from: http://www.health.qld.gov.au/
healthpact/docs/briefs/WP044.pdf. [Accessed October 1, 2013].
[83] Weitz M, Strahm B, Meerpohl JJ, Bassler D. Extracorporeal
photopheresis versus alternative treatment for chronic graft-
versus-host disease after haematopoietic stem cell transplantation
in paediatric patients. Cochrane Database Syst Rev 2014;2:
CD009898.
[84] Decision memo for extracorporeal photopheresis (CAG-00324R).
Available from: http://www.cms.gov/medicare-coverage-database/
details/nca-decision-memo.aspx?NCAId=180&ver=14&NcaName=
ExtracorporealþPhotopheresisþ%281stþRecon%29&bc=BEAAAAAAEA
AA&&fromdb=truee. [Accessed October 1, 2013].
[85] Bredeson C, Rumble RB, Varela NP, et al. Extra-corporeal
Photopheresis in the Management of Graft-Versus-Host Disease in
Patients who Have Received Allogeneic Blood or Bone Marrow
Transplants: Recommendations. Recommendation Report SCT-5.
Toronto, ON, Canada: Cancer Care Ontario, 2013.
[86] Dignan FL, Scarisbrick JJ, Cornish J, et al. Organ-specific management
and supportive care in chronic graft-versus-host disease. Br J Haematol
2012;158:62–78.
[87] Walczak J, Wepsiec K, Lemanski T, et al. Economical aspects of the
reimbursement of extracorporeal photopheresis (ECP) in treatment of
patients with graft-versus host disease (GvHD) after allogeneic
hematopoietic cell transplantation (HCT) who are refractory to steroid
treatment. Value Health 2012;15:A349.
[88] HTA Core Models Online. Available from: https://meka.thl.fi/htacore/
ViewHandbook.aspx. [Accessed October 1, 2013].