Management of acute graft-versus-host disease

Management of acute graft-versus-host disease

Andrea Bacigalupo

Divisione Ematologia e Trapianto di Midollo, Ospedale San Martino, Genova, Italy

Summary

Acute graft-versus-host disease (GvHD) is a frequent compli-

cation of allogeneic haemopoietic stem cell transplantation

(HSCT) and donor lymphocyte infusions (DLI). Its incidence

and severity depends on several factors, such as prophylaxis

method, donor/recipient matching, intensity of the condition-

ing regimen and composition of the graft. Significant progress

has been made in recent years in understanding the pathogen-

esis of the disease, and some of these advances have been

translated into clinical trials. First-line treatment of acute GvHD

is based on corticosteroids, and produce sustained responses in

50–80% of patients depending on the initial severity. Non-

responders are offered second-line therapy, with combinations

of immunosuppressive agents, but 1-year survival is 30% in

most large trials. New strategies explored include infusion of

expanded mesenchymal stem cells (MSC), down regulation of

antigen-presenting cells (APC) and suicide gene transduced

T cells. Acute GvHD is complicated by severe immunodefi-

ciency causing life-threatening infections. To date, GvHD has

not been differentiated from the graft-versus-leukaemia effect.

The present review will discuss some of these aspects.

Keywords: graft-versus-host disease, haemopoietic stem cell

transplantation, donor lymphocyte infusion, immunosuppres-

sive therapy, mesenchymal stem cells.

Do we understand the pathogenesis of GvHD?

Although the pathogenesis of graft-versus-host disease (GvHD)

is not the aim of the present review, a few words are warranted:

indeed some of the recent advances in understanding cellular

and cytokine mechanisms leading to GvHD have been useful in

the clinic. GvHD is thought to be caused by donor T cells

reacting against host allo-antigens: this may well be the case,

but the mechanism underlying such immune reaction are quite

complex (Teshima & Ferrara, 2002a). The early work of

Ferrara and coworkers showed that inflammatory cytokines

play a crucial role in the initial, amplification and cytotoxic

phases of the disease (reviewed in Ferrara, 2002). Unfortu-

nately, it seems that inactivation of cytokines, such as tumour

necrosis factor (TNF) is not sufficient per se, and some initial

success has come at the expense of increased infectious

complications (Marty et al, 2003). More recently, the presen-

tation of target antigens by host antigen presenting cells (APC)

has been shown to be crucial for the initiation and develop-

ment of acute GvHD (Shlomchik et al, 1999): in an early

experiment, Shlomchik showed that mice with APC that were

unable to present class I-restricted peptides (grafted from b2

knock-out), but that expressed class I on target tissues, were

unable to develop acute GvHD (Shlomchik et al, 1999).

Therefore host APC participate in activating donor T cells to

kill host cells and the age of host APC seems relevant (in

keeping with the notion that older patients have more GvHD)

(Ordemann et al, 2002). The presentation of host antigens by

host APC can be further enhanced by host gamma/delta T

cells, as recently shown in the mouse (Maeda et al, 2005). The

interplay of APC, T cells and cytokines is such that, in a mouse

transplant model – with mismatch only between donor T cells

and host APC, but not between donor and host gut-donor T

cells still efficiently killed host gut cells, suggesting that tissue

destruction can be achieved with a by-stander effect (Teshima

et al, 2002b). Finally, attention has also been given to cellular

interplay leading to tolerance: Two reports merit mentioning.

Mc Donald et al (2005) dealt with cytokine-expanded myeloid

precursors regulating APC and promoting tolerance through

interleukin (IL)-10-producing regulatory T cells. Lan et al

(2001) looked directly at regulatory T cells (TREGS): mice

given lymphoid radiation and antithymocyte globulin (ATG)

were depleted of most T cells, but not of NK 1.1 T cells, and

became resistant to GvHD. The Stanford group has brought

this in to the clinic: they have shown that the combination of

total lymphoid radiation (TLI) and ATG depletes host T cells

with the exception of CD4+CD25+ TREGS: when allografted

these patients showed little or no GvHD, suggesting a

regulatory role of host TREGS on donor incoming alloreactive

T cells (Lowsky et al, 2005).

Do we understand the pathogenesis of GvHD?

Not fully: however, we have become aware of the complexity of

the disease, and we have learned to take advantage of some

developments in the lab. Further studies in the animal model

Correspondence: Dr A Bacigalupo, Divisione di Ematologia II,

Ospedale San Martino, Piazzale Rosanna Benzi, 10, Genova, Italy.

E-mail: [email protected]

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ª 2007 The AuthorJournal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 137, 87–98 doi:10.1111/j.1365-2141.2007.06533.x

will possibly bring further advances in the clinic. Tolerance

may be achieved in more than one way.

Can acute GvHD be accurately graded?

The original grading system for acute GvHD was proposed by

Glucksberg et al (1974) and identified five categories of

patients (grades 0, I, II, III, IV). It is known as the

Glucksberg-Seattle criteria (GSC) and it is based on the degree

of skin, liver and gut involvement (skin rash, total serum

bilirubin and diarrhoea volume), together with a subjective

assessment of clinical status. The GSC have been widely used

for 30 years and correlate well with transplant-related mortal-

ity (TRM): a recent analysis of 4174 human leucocyte antigen

(HLA)-identical sibling transplants for chronic myeloid leuk-

aemia (CML) in first chronic phase showed that early and

long-term outcome is influenced by severity of acute GvHD as

identified by the classic GSC (Gratwohl et al, 2002). Indeed at

3 years survival was 74%, 74%, 64%, 37% and 10% for

patients with acute GvHD grades 0, I, II, III and IV

respectively. In 1997, the International Bone Marrow Trans-

plant Registry (IBMTR) designed a staging system from a large

data set of adult patients receiving an HLA identical sibling

BMT (Rowlings et al, 1997): the IBMTR Severity Index

regroups patients into five categories (0, A, B, C, D) based

on differences in TRM with a significance level of 0Æ05. Despite

good correlation of the IBMTR index with outcome, the classic

GSC is still used in most centres. Recently, we have shown that

the GSC can be further implemented by adding platelet counts

on day+50: patients with grade II acute GvHD and a platelet

count of less than 50 · 109/l had significantly higher TRM

when compared to patients with grade II GvHD and platelets

‡50 · 109/l (Dominietto et al, 2001).

Can we score GvHD?

Not well enough: however the classic GSC is still here after

three decades, suggesting it is clinically useful. The use of

laboratory values, such as platelet counts and cholinesterase, or

other clinical parameters (Lee et al, 2005) may further improve

our ability to predict the outcome of patient undergoing an

allogeneic transplant, and perhaps to modify treatment

accordingly.

Can GvHD be prevented?

HLA matching

HLA matching between donor and recipient is one of the most

powerful predictors of GvHD, together with other factors such

as age, donor/recipient sex match. Other supportive measures,

such as a sterile environment have been shown to protect

against GvHD both in animals and humans. Therefore using

a young-HLA matched, male donor, in a protected sterile

environment, is a very effective way of having little GvHD.

However, HLA-matched related donors are less common, at

least in Europe and the USA, and there is greater use of

unrelated donors or related HLA-mismatched donors. Thus

the question really is: can GvHD be prevented in less

favourable situations?

T cell depletion ex-vivo

Removal of T cells from the stem cell suspension, referred to as

T cell depletion (TCD) ex-vivo, was very popular in the 1980s,

but its use has declined over the past decade: this is because

survival, disease-free survival and transplant mortality were

not reduced, in the setting of HLA-matched grafts, when

compared with conventional unmanipulated transplants (Mar-

mont et al, 1991). One situation in which ex vivo-TCD is

essential, is 3 loci mismatched transplants: in this setting T cell

depletion must be thorough and one should not infuse more

than 5 · 104 CD3+ cells/kg of recipients weight, as shown by

Aversa et al (1998). TCD should be performed in a centre with

a dedicated programme, where different forms of T cell

removal can be explored, including physical and immunolo-

gical TCD (Martin & Kernan, 1997; Aversa et al, 1998).

T cell depletion in vivo

Treatment of the patient with T cell antibodies before the

transplant, in vivo-TCD, has a double target: it reduces the host

immune response, favouring engraftment, and downregulates

donor T cells, because the antibody is still in circulation at the

time of transplant, and thus prevents GvHD (Hows et al, 1993;

Holler et al, 1998; Baurmann et al, 1999; Zander et al, 1999;

Byrne et al, 2000; Finke et al, 2000). In vivo-TCD is indicated

in programmes involving alternative donor transplants, and is

used in many, but not all centres performing unrelated donor

grafts (Hows et al, 1993; Hansen et al, 1998; Holler et al, 1998;

Baurmann et al, 1999; Zander et al, 1999; Byrne et al, 2000;

Finke et al, 2000). In a recent randomised trial, we showed that

rabbit anti thymocyte globulin (ATG) significantly reduced the

risk of grade III–IV acute GvHD in unrelated donor

transplants (Bacigalupo et al, 2001a). However, TRM and

survival were unchanged due to a higher risk of lethal

infections in the ATG 15 mg/kg arm (Bacigalupo et al,

2001a). An update of the same study showed that ATG

provided significant protection against acute and chronic

GvHD, shortened time to terminate immunosuppression and

improved quality of life (Bacigalupo et al, 2006). Whether

different schedules of administration of ATG or different

agents may further improve results remains to be determined.

Expanding regulatory T cells (TREGS)

CD4+CD25+ immunoregulatory T cells (TREGS) can be

administered to inhibit GVHD while preserving graft-

versus-leukaemia activity after allogeneic bone marrow

transplantation in mice. Preclinical studies suggest that it is

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ª 2007 The Author88 Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 137, 87–98

necessary to infuse as many TREGS as conventional donor

T cells to achieve a clinical effect on GVHD (Trenado et al,

2006). How do we translate this to the clinic? The Stanford

group has designed a transplant programme consisting of

fractionated TLI (800 rads delivered in 2 weeks, 80 rads/

d ·5 ·2) and ATG (5 d) followed by allogenic unmanipulated

peripheral blood transplants (Lowsky et al, 2005), resulting in

little or no acute GvHD. A recent update of that study at the

2006 meeting of the European Group for Blood and Marrow

Transplantation (EBMT) has confirmed these results of 64

patients, half of whom received grafts from unrelated donors

(R. Lowski, unpublished observations).

Post-transplant immunosuppressive therapy

This therapy is still the conventional form of GvHD prevention

both in HLA-identical as well as unrelated-donor transplants.

It is usually based on the combination of cyclosporin A (CsA)

and short course methotrexate (MTX) on days+1, +3, +6, +11

(Storb et al, 1986; Zikos et al, 1998). The CsA dose used in the

first 10 d post-transplant may have a significant impact on

leukaemia control: in two prospective randomised trials, both

in children and in adults, low-dose CsA (1 mg/kg) was shown

to protect patients from leukaemia relapse when compared

with higher doses of CsA (3 mg/kg or 5 mg/kg) (Bacigalupo

et al, 1991; Locatelli et al, 2000). This was recently confirmed

at a 10-year follow up (Bacigalupo et al, 2001b) and should be

kept in mind especially when grafting patients at high risk of

relapse. Recently tacrolimus (FK506), a calcineurin inhibitor,

has been introduced in the prophylaxis of GvHD: 180 patients

grafted from a matched unrelated donor were randomised to

receive CsA+MTX or FK506+MTX (Nash et al, 2000). Acute

GvHD II-IV was significantly lower (51%) in FK506-treated

patients when compared with the CsA patients (70%)

(P ¼ 0Æ0002), but this did not translate in a lower risk of

chronic GvHD. The adverse events, in particular nephrotox-

icity, infections or leukaemia relapses were not significantly

different (Nash et al, 2000). There was also no difference in

survival. Therefore, both CsA+MTX and FK506+MTX com-

binations offer some protection for GvHD and have signifi-

cantly reduced the risk of severe GvHD when compared to

single agent prophylaxis (MTX or CyA alone). Mycophenolate

mofetil (MMF) has been successfully introduced for GvHD

prevention, and may substitute MTX in the standard CsA

combination, mainly because of less mucositis and overall

good tolerance (Basara et al, 2000; Nash et al, 2005; Neumann

et al, 2005).

Mesenchymal stem cells

Mesenchymal stem cell (MSC) are pluripotent stem cells

capable of generating osteoblasts, myoblats, condroblasts,

tenoblasts, adipocytes and stromal cells (Pittenger et al,

1999). There have been several reports on the immunosup-

pressive effect of MSC, both in vitro (Klyushnenkova et al,

1998; Tse et al, 2000). and in vivo (Bartholomew et al, 2002).

The co-infusion of a large number of osteoblasts together with

hemopoietic stem cells, in a mismatched mouse model,

resulted in successful engraftment and immune reconstitution

(El-Badri et al, 1998), whereas control animals died of GvHD

or rejection. A recent trial has been completed in 40 patients

with haematological malignancies, using expanded MSC from

an HLA-identical sibling, and co-infusing these cells with

a conventional unmanipulated bone marrow (BM) or periph-

eral bood (PB) transplant: the infusion of MSC was safe, and

this was the primary end point of the study (El-Badri et al,

1998); in addition, hemopoietic reconstitution was prompt.

However, the study failed to show a significant reduction in

acute or chronic GvHD when these patients were compared

with a matched pair cohort of CIBMTR patients (El-Badri

et al, 1998). MSC are now being co-transplanted in different

settings, such as cord blood or unrelated marrow grafts. One

has to note that the number of MSC or osteoblasts given

to animals (El-Badri et al, 1998) exceeds the numbers given to

humans by at least 3 logs (Lazarus et al, 2005): if we want to

achieve what has been shown in the experimental models,

perhaps we will need to escalate the number of MSC we infuse.

Inactivation of antigen presenting cells

Depleting host APC before the conditioning regimen may

reduce GvHD: in keeping with this observation, patients

receiving extracorporeal photopheresis (ECP) before the

conditioning regimen have a low incidence of GvHD (Chan

et al, 2001), because ECP may downregulate host APC

(Gorgun et al, 2001). It is also understood that broad

specificity T cell antibodies (ATG and CAMPATH), commonly

used in allotransplants, significantly deplete host APC cells. An

other way of killing APC is by using natural killer (NK) cells.

Ruggeri et al (2001) showed that elimination of host APC in

the mouse, using donor incompatible NK cells, made the

recipients resistant to GvHD (they could be infused with large

numbers of mismatched T cells, without GvHD). Thus

expanding donor NK cells may be one way of reducing GvHD,

and some centres have started to investigate whether donor NK

cells can be expanded and co-infused to reduce GvHD, and

possibly also to kill tumour cells (Aversa et al, 1998). Indeed,

in the best possible donor-recipient combination, donor NK

cells would reduce GvHD (by killing host APC), reduce

rejection (by killing host T cells) and reduce relapse (by killing

leukaemia cells). Whether we will be able to use NK cells so

cleverly remains to be determined,

Reduced-intensity conditioning regimens

Reduced-intensity conditioning (RIC) regimens were intro-

duced in the late 1970s when busulfan 8 mg/kg was used

instead of the conventional 16 mg/kg, in children with inborn

errors (Hobbs et al, 1981). These regimens are usually

associated with less severe (or delayed) acute GvHD, because

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ª 2007 The AuthorJournal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 137, 87–98 89

of the persistence of host cells (mixed chimaeras), which

counteract GvHD (Mielcarek & Storb, 2005), although early

GvHD may still occur (Mielcarek et al, 2005). There may also

be a lower level of inflammatory cytokines. RIC regimens

based on low-dose TBI (2 Gy) (Storb et al, 1999), low-dose

busulfan (Slavin et al, 1998), low-dose thiotepa (Raiola et al,

2000) low-dose melphalan (Kottaridis et al, 2000) or cyclo-

phosphamide and fludarabine (Khouri et al, 1998) are being

used widely in elderly patients up to the age of 70 years, and

the overall risk of GvHD is probably less than what would be

seen in patients of the same age with conventional intensity

regimens. Acute GvHD still remains a major obstacle after RIC

HSCT, occurring in 15% of patients in its severe form (grade

III–IV), while extensive chronic GvHD is diagnosed in 50% of

all patients (Bacigalupo, 2002). Several questions need to be

answered in this context: timing and intensity of in vivo

immunosuppression, timing of CsA discontinuation, timing of

DLI, and use of T-cell antibodies. Some regimens include anti-

T cell antibodies, such as alentuzumab (CAMPATH) (Kottar-

idis et al, 2000) or ATG (Slavin et al, 1998). It is interesting

that Russell and coworkers have taken a different approach:

they used ablative doses of intravenous busulfan combined

with fludarabine and tried to maximise GvHD prevention with

rabbit ATG in the conditioning regimen and CsA MTX for

postgraft immunosuppression (Russell et al, 2002). The pro-

gramme, designated FLU-BUP, was given up to the age of

65 years, for patients with haematological malignancies, and

yields a TRM of 4% in HLA-identical siblings and 20% in

unrelated transplants.

Anti-IL2 anti-TNF antibodies

Other monoclonal antibodies (mAbs) that interact with IL2 or

TNF have been tested in the clinical setting. Anti- CD25 mAb

seemed to delay the occurrence of GvHD; in a randomised trial

the administration of a CD25 mAb (in addition to CsA+MTX)

appeared to decrease leukaemia-free survival, in comparison to

conventional GvHD prophylaxis (Blaise et al, 1995).

A humanised CD25 mAb, assessed in a double-blind,

placebo-controlled randomised study, involving a total of

210 patients, failed to prevent GvHD or improve the outcome

of unrelated HSCT recipients (Anasetti et al, 1995). A mAb

neutralising TNF-a has also been tested in 21 patients as

GvHD prophylaxis: in a prospective trial Holler et al (2002)

showed that GvHD could be delayed (by 10 d), although the

overall grading was similar to controls.

Can GvHD be prevented?

The answer is clearly yes, and there has been a progressive

decline in the severe form of acute GvHD (III–IV) in the last

decade (Bacigalupo et al, 2004). Whether reduction of GvHD

produces improved survival, is a more difficult question.

However, this should not discourage further studies on GvHD

prevention, because if survival is comparable, morbidity is

clearly lower if patients do not experience acute or chronic

GvHD.

Can acute GvHD be treated?

First-line treatment

Corticosteroids Corticosteroids are used as first-line therapy: in

a study of 443 patients who received prednisone 60 mg/m2 for

14 d as first-line therapy, followed by an 8-week taper, an

overall improvement was observed in 55% of the patients with

durable (‡28 days) complete responses in 35% (Blazar, 2002).

The probability of survival at 1 year after initiation of therapy

was 53%: favourable predictors of survival were younger

patient age, HLA-identical sibling donor and GvHD

prophylaxis other than ex-vivo T cell depletion (Blazar,

2002). The authors of this important study concluded that

steroids provide an active but inadequate therapy for acute

GvHD, especially in patients with severe GvHD, and that more

effective prophylaxis for mismatched and unrelated donor

transplants is needed. Unfortunately. There is no evidence that

more aggressive first-line therapy is beneficial: the Italian

Group for Marrow Transplantation (GITMO) could not show

an advantage of high-dose steroids (10 mg/kg of 6-MPred)

over conventional 2 mg/kg MPred, with a transplant mortality

at 1 year of 30% in both groups (Van Lint et al, 1998).

A randomised study comparing steroids + ATG versus steroids

alone came to the same conclusion (Cragg et al, 2000). Two

additional observations were made in the GITMO study: (i)

despite the very early day of randomization (median day +12

from transplant), high dose MPred did not prevent

progression towards grade III–IV GvHD and (ii) responders

to 5 d of 6MPred 2 mg/kg had a significantly lower TRM

(16%) when compared with non-responders (46%) (Van Lint

et al, 1998). We have confirmed this result in a more recent

study (Van Lint et al, 2006).

Thus, primary treatment of acute GvHD should be pred-

nisone or 6MPred 2 mg/kg/d for 5 d (Fig 1): responsive

patients should taper steroid therapy. An IBMTR survey

confirmed that a 5-d course is sufficient to identify steroid-

refractory acute GvHD (Hsu et al, 2001). There may be less

agreement on criteria to define response on day+5 or day+7: it

is unlikely that patients will be free of GvHD. The most

common situation will be reduction of clinical signs of acute

GvHD, which may allow reduction of the 6MPred dose

(Fig 1): indeed in two consecutive studies we found it very

useful to identify day+5 responders as those patients who were

considered eligible for MPred dose tapering (Cragg et al, 2000;

Van Lint et al, 2006). The probability of response will be

higher for patients who have limited acute GvHD on day 0 of

treatment (Van Lint et al, 2006). Patients not responding on

day+5 or day+7 could not reduce their dose of steroidsand

were eligible for second-line treatment (Fig 1). Transplant

mortality is higher (as expected) in non-responders as

compared to day+5 responders, and this indicates that

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strategies for second-line therapy can be designed very early in

the course of the disease.

Second-line treatment

A large number of studies have been performed for patients

not responding to 2 mg/kg of MPred (Fig 1). Most of these

were phase II uncontrolled studies, showing some degree of

response with the use of a large variety of agents. Very few were

prospective randomised trials, and these have failed to show

any advantage of experimental treatment over standard steroid

therapy.

Anti-thymocyte globulin (ATG) Anti-thymocyte globulin is one

treatment option for steroid-refractory patients, and some

encouraging results have come from phase II trials (Roy et al,

1992; Aschan, 1994), especially when ATG was given early after

the diagnosis of GvHD (MacMillan et al, 2002). However, we

are lacking evidence that ATG improves survival. In a recent

prospective randomised trial the Italian group GITMO has

been unable to confirm that ATG is beneficial as a second-line

therapy of steroid-refractory acute GvHD (Van Lint et al,

2006): 61 patients not responding to 5 d of MPred 2 mg/kg,

were randomised to receive MPred 5 mg/kg/d for 10 d, alone

(n ¼ 34) or in combination with rabbit ATG (n ¼ 27). The

two groups were balanced for clinical and GvHD characteristic.

One-month after randomisation 26% had a complete

response, 25% a partial response, 33% stable GvHD, 10%

worsened and 8% had died: there was no significant difference

in response, TRM and survival between the non-ATG and

ATG group (Van Lint et al, 2006). Five-year actuarial survival

was 36% and 34% for controls and ATG patients.

Therefore, although ATG can induce a significant response

in GvHD patients, survival is unchanged when compared with

patients not receiving ATG: clinical response of GvHD does

not mean improved survival, and responders may still die of

infections and other complications, as suggested in a recent

review (Antin et al, 2004).

Interleukin 2 receptor antibodies

There are several monoclonal antibodies to IL2 (reviewed in

Antin et al (2004): denileukin difitox (Ontac), inolinomab

(Leukotac), Basiliximab (Simulect), Daclizumab (zenapax).

They have all shown efficacy in steroid-resistant acute GvHD

(Antin et al, 2004). Nevertheless, infections remain a serious

problem: is this due to the fact that patients come to

monoclonal antibody therapy after failing several lines of

treatment? Perhaps early administration of IL2R antibodies

would prove more effective. A large prospective randomised

trial is ongoing within the National Marrow Donor Program,

testing, among other agents, an IL2 receptor antibody.

Anti -CD147 monoclonal antibody

Deeg et al (2001) have reported a pilot study on the use of

anti-CD147 (a neurothelin member of the immunoglobulin

superfamily which is upregulated on activated T and B cells):

27 patients with GvHD entered this study and 51% were

considered as responders, including 25% complete responses.

Survival at 6 months was 44% (Deeg et al, 2001).

TNF antibodies

Tumour necrosis factor is of one the inflammatory cytokines

mediating cellular cytotoxicity. TNF can be downregulated by

steroids, pentoxifilline, transforming-growth factor beta

(TGFB) and IL4. Antibodies to TNF (infliximab) or to the

TNFreceptor (etanercept) have been developed and used both

in first- and second-line treatment of acute GvHD (Marty et al,

2003; Couriel et al, 2004; Uberti et al, 2005). Responses are

seen, some patients clear their symptoms rapidly, but infections

remain an issue (Marty et al, 2003).

Other agents

Other agents, such as MMF are being tested with some success:

MMF has a good efficacy profile, is well tolerated in general

and may prove useful in sparing steroids and steroid-associ-

ated complications (Antin et al, 2004).

Pre-emptive treatment

We have previously shown that patients at high risk of GvHD

and TRM can be identified on day +7 following an allogeneic

Methylprednisolone2 mg/kg/dx5 or 7 d

Response

1st line treatmentDay 0

Day 7

2nd line treatment

Taper MPred

No response

Diagnosis ofAcute GvHD

MPred 2–5 mg/kgATG, anti-IL2, anti-CD147TNF antibodiesMMF, ECPMesenchymal Stem CellsOther

Fig 1. Flow chart of events after the diagnosis of acute GvHD is made

(day 0). First-line treatment consists of methylprednisolone (Mpred)

2 mg/kg/d i.v. for 5 or 7 d. On day 7, responders are assigned to

a steroid-taper programme. Non-responders receive second-line

therapy: there are a number of options. Continue MPred alone; add

antithymocyte globulin (ATG), monoclonal antibodies to interleukin

2 (IL2), tumour necrosis factor (TNF), CD147, add extracorporeal

photopheresis (ECP). The most promising option today seems the

addition of mesenchymal stem cells (MSC).

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bone marrow transplant (BMT), based on serum bilirubin and

blood urea nitrogen levels (Bacigalupo et al, 1999): we have

recently revised the scoring system with the inclusion of day+7

cholinesterase, gammaglutamyltransferase, total protein to-

gether with cell dose and donor type (Sormani et al, 2003).

One possible approach to reduce the risk of GvHD and TRM,

is pre-emptive treatment before the disease develops. In a pilot

study, we tested the feasibility of this approach in patients

undergoing an alternative donor HSCT: the risk of severe

GvHD and the actuarial 1 year TRM was reduced in the ATG

treated patients (Bacigalupo et al, 2001c). This is in keeping

with a previous randomised trial, published some years ago,

showing that early administration of ATG after an HLA-

identical sibling transplant, could significantly reduce the risk

of acute GvHD (Ramsay et al, 1982). Whether this will

translate in survival advantage is being now tested in

a prospective multicenter trial by GITMO.

Cellular therapy of GvHD

This section includes the use of MSC, ECP directed against

APC, and suicide gene transduced T cells

Suicide gene transduction of T cells This approach is based on

transducing T cells with a gene, such as herpes simplex virus

thymidine kinase (HSV-TK) which renders them susceptible to

killing by ganciclovir, provided the cell is also dividing. The

T cells are infused into the host and when GvHD develops,

ganciclovir is given, killing only transduced T cells. This system

requires efficient gene transduction and the ability to select

transduced cells. It has been implemented in humans and

animals models with some positive results, although anectotal

(Bonini et al, 1997). The model is based on the hypothesis,

that established GvHD can be turned off by killing alloreactive

T cells, although there is scanty evidence that this can be

achieved: the activation system is very complex, and by the

time it is established there are many cell types (both of donor

and recipient origin) and many cytokines involved, often with

opposite actions. During induction phase the administration

of IL12 inhibits GvHD (Sykes et al, 1995). If, in the same

mouse model, IL12 was given later after transplant, there was

enhancement of GvHD by induction of host-derived

interferon-c (IFNc) (Sykes et al, 1999). T cells from IFNcknock-out mice, surprisingly, caused a more virulent GvHD,

suggesting a protective effect of IFNc (Murphy et al, 1998). In

a different mouse P¤ F1 model, the lack of IFNc T cells

delayed GvHD (Minasi et al, 1993). These results outline the

complex pathogenesis of GvHD and the multiple effectors

involved, which may vary according to the animal model

chosen. If this is the case, can GvHD be turned off by killing

T cells, and if so, which T cells need to be killed? Although

suicide gene transduction was reported almost 10 years ago,

and despite some pilot phase I/II studies, it has not been used

in the clinic as a standard approach for acute GvHD

prevention and treatment: it faces numerous problems,

including logistic, technical and conceptual. For the time

being, it remains an interesting investigational tool.

Mesenchymal stem cells There has been great interest in the use

of MSC for treatment of acute GvHD in the past few years

(Ringden et al, 2006): at the EBMT meeting 2006 we presented

a cooperative report on patients treated in Huddinge, Genova

and Pavia, and we further updated this report at the 2006 ASH

meeting (Le Blanc et al, 2006): 40 patients with grades III–IV

acute GvHD receiving MSC were evaluated. The median MSC

dose was 1Æ0 (range 0Æ4–9) 106 cells/kg body weight of the

recipient. No side-effects were seen after MSC infusions.

Nineteen patients received one dose, 19 patients received two

doses, two patients received three and five doses, respectively.

MSC donors were HLA-identical siblings in five cases,

haploidentical in 19 cases and third-party HLA-mismatched

in 41 cases. Among the 40 patients treated for severe acute

GvHD, 19 had complete responses, nine showed improvement,

seven patients did not respond, four had stable disease and one

patient was not evaluated due to short follow-up. Twenty-one

patients were alive between 6,weeks up to 3Æ5 years after

transplantation, Nine of whom had extensive chronic GvHD.

These results suggest that immunomodulatory and tissue

repairing effects of MSC should be further explored as

treatment of severe acute GvHD in prospective randomised

trials, especially as there have been negative reports in the

experimental model (Sudres et al, 2006).

Extracorporeal photopheresis

Extracorporeal photopheresis has been mostly used in patients

with chronic GvHD, and significant responses have been seen

in a proportion of patients (Couriel et al, 2006). A randomised

study has been completed in chronic GvHD patients, and

should be available for definitive analysis this year (Greinix

et al, 2006a). Recent reports have been published, of ECP used

for acute GvHD: the procedure is invasive, requires a dedicated

team at the Blood Bank and responses are not seen before

12 weeks, therefore requiring long-term supportive care (Gar-

ban et al, 2005; Greinix et al, 2006b). However, given the

current poor results with second-line therapy, waiting

12 weeks for a response would not be the greatest of problems.

Greinix et al (2006b)) reported an 82% complete response rate

for patients with severe skin acute GvHD treated with ECP and

steroids, 61% for gut involvement and 61% for liver involve-

ment. A randomised trial comparing prednisone + ECP versus

prednisone alone has been activated this year.

Can GvHD be treated ?

The answer is a cautious ‘Yes’. Most events occur very early in

the course of the transplant. First-line therapy with conven-

tional dose steroids (1–2 mg/kg/d) can be successfully given to

over half of affected patients. Response depends on the severity

of GvHD and organ involvement. If patients respond, their

Review


transplant mortality is relatively low; if they don’t respond to

first-line treatment, their transplant mortality is high (possibly

exceeding 60%). Mortality after second-line therapy has not

been reduced in the last three decades: patients do respond to

second-line therapy and GvHD severity is diminished, but the

patients may still succumb to infectious complications. New

agents, antibodies or intensified immunosuppression have not

changed GvHD-related mortality, cellular therapy holds

promise. The important take-home message is: whatever you

decide to do, please enter your patients in to a clinical trial

(Bolanos-Meade & Vogelsang, 2005): this is the only way we

can expect to make progress in the near future.

Can we improve immune-reconstitution ?

Immune reconstitution remains a significant problem follow-

ing allogeneic stem cell transplantation and several studies

have analysed this. The number of NK cells, as monitored by

CD56 or CD16 expression on peripheral blood lymphocytes,

rose rapidly after transplant, and returned quickly to the

normal range while CD8+ cells frequently remained high

(Dokhelar et al, 1981). There is a strong imbalance of helper/

suppressor cells, first described many years ago (Bacigalupo

et al, 1981), which still needs to be fully understood. It may be

associated with immune reconstitution or with alloreactivity

(Noel et al, 1978; Paulin et al, 1987; Barrett et al, 2003): the

former seems more probable, since the CD4/CD8 ratio is not

a good indicator of acute GvHD. Other factors associated with

poor immune recovery also predict GvHD: older age (Seddik

et al, 1984), unrelated donors (Small et al, 1999) and of course

steroid therapy given to treat GvHD (Douek et al, 2000). The

thymus plays an important role in reconstitution of T-cell

immunity and increasing patient age has an adverse effect on

the regeneration of naive CD4+ T cells, probably due to age-

related thymic involution: these observations were confirmed

by TCR rearrangement excision circlet (TREC) assay to

measure thymic output (Douek et al, 1998, 2000; ). Attempts

to boost immune reconstitution by IL7 or IL7-engeneered cells

have been reported (Li et al, 2006), but we have not yet seen

these studies translated in the clinic. Recently, keratinocyte

growth factor (KGF) has been shown to promote immune

reconstitution after HSCT in the animal model (Min et al,

2002): trials using KGF are underway in clinical allograft

programs.

Immune reconstitution is inversely correlated with the

severity of GvHD: the more severe the disease the worse the

immune recovery (Sale et al, 1992). The situation is worsened

by treatment of GvHD with steroids, antibodies and other

suppressive manoeuvres. Attempts to manipulate immune

recovery with cytokines have failed so far, although IL7 holds

promise. Infections are a frequent and often lethal complica-

tion: they include viral, fungal and bacterial infections in

patients with GvHD. Discussing these complications is outside

the scope of the present review, however, monitoring and early

treatment of infections should be a major part of standard

protocols or prospective trials. This is also relevant because of

the many old and new agents available to treat cytomegalovirus

(CMV), Epstein–Barr virus (EBV), aspergillus and vancomy-

cin-resistant enterococci.

We can not leave this section without mentioning the

elegant studies, pursued by several groups, in expanding

antigen-specific T cells (Peggs et al, 2001; Rauser et al, 2004;

Perruccio et al, 2005; Bollard et al, 2006; Riddell et al, 2006):

immunity to CMV, EBV and aspergillus has been successfully

transferred with expanded antigen-specific T cells, with no

GvHD, and with clearance of the infection. A very powerful

proof-of-principle indeed. Thus the technology is now estab-

lished, but is the cost and the laboratory resources affordable

for most transplant centres? Possibly not, but developing this

technology should advance our ability to manipulate the

immune system, and this is important for the management of

transplants, and possibly also for the treatment of tumours.

Is acute GVHD influenced by stem cell source?

What about the three stem cell sources: PB, BM, cord blood

(CB). They are listed here in the order of current ‘preference’,

because numbers do represent what happens every day in our

centres. The last EBMT survey told us that allogeneic PB is the

preferred source, followed by BM and CB. The influence on

acute and chronic GvHD is probably also falls in the same

order; PB, BM, CB.

There are four large international randomised studies that

used BM or PB as the source of stem cells (Blaise et al, 2000;

Bensinger et al, 2001; Couban et al, 2002; Schmitz et al, 2002).

Acute GvHD grade III–IV was similar in three studies, and

significantly increased in PB recipients in one study (Schmitz

et al, 2002). It is therefore reasonable to say that acute GvHD

was rather comparable in patients receiving allogeneic BM or

PB cells, although chronic GvHD was significantly increased in

almost all studies. Three recent publications have set the stage

for HLA-identical sibling CB transplants (Rocha et al, 2000)

and for unrelated CB transplants in children (Rocha et al,

2001) and in adults (Laughlin et al, 2001). Common to these

three publications is the low risk of acute and chronic GvHD

for patients receiving CB transplants: in the HLA-identical

study, the risk of acute GvHD was 0Æ41 for CB when compared

with BM (P ¼ 0Æ001) and for chronic GvHD the risk was 0Æ35

(P ¼ 0Æ02).

But, perhaps comparing unmanipulated PB, BM and CB is

not the right question at present: efforts should be made to

optimise programs involving each of these stem cell sources:

we will then find patients who might benefit from the different

impact these stem cell sources have on GvHD and outcome.

Conclusions

Treatment of established GvHD is complex and has not made

major advances in the last decade. Possibly we treat our

patients too late, when tissue damage has already taken place

Review


and cytokine production by activated donor T cells and

autologous macrophages can proceed undisturbed. It would

seem that acute GvHD is, to a certain extent, self-programmed,

since very early treatment with high dose corticosteroids and/

or ATG does not modify the natural course of the disease. Over

the last three decades we have considerably reduced the risk of

acute GvHD and understood how to prevent it by modifying

the transplant program and the stem cell source: we now need

to improve our ability to predict GvHD and develop new

strategies of early treatment.

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Review


Management of acute graft-versus-host disease

Technology

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