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hematology Board Review Manual
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Editorial Purpose
The Hospital Physician Hematology Board Review
Manual is a study guide for fellows and prac­
ticing physicians preparing for board exami­
nations in hematology. Each manual reviews
a topic essential to the current practice of
hematology.
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Acute and Chronic GraftVersus-Host Disease
Series Editor:
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Instructor of Medicine
Harvard Medical School
Attending Physician
Dana-Farber Cancer Institute
Boston, MA
editorial director
Debra Dreger
Associate EDITOR
Rita E. Gould
assistant EDITOR
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Contributor:
Corey Cutler, MD, MPH, FRCP(C)
Assistant Professor of Medicine
Harvard Medical School
Boston, MA
executive vice president
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executive director
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Table of Contents
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sales & marketing manager
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Acute GVHD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Chronic GVHD. . . . . . . . . . . . . . . . . . . . . . . . . . . 6
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Internal Medicine.
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Cover Illustration by Kathryn K. Johnson
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Acute and Chronic Graft-Versus-Host Disease
Corey Cutler, MD, MPH, FRCP(C)
INTRODUCTION
Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT) that occurs when donor T cells
attack the tissues of an immunocompromised host.
There are 2 distinct syndromes of GVHD: acute GVHD
and chronic GVHD. Acute GVHD remains one of the
most significant barriers to successful allogeneic HSCT,
accounting for a substantial portion of early transplantrelated morbidity and mortality. Clinically relevant acute
GVHD occurs in 35% to 40% of patients transplanted
from a matched sibling donor1 and in 40% to more than
50% of recipients of unrelated donor grafts.2,3 Severe
acute GVHD occurs in up to 20% of recipients of related
donors1 and up to 35% of unrelated donors.2,3 Likewise,
chronic GVHD has become increasingly more common
as the proportion of patients who become long-term survivors of HSCT increases. It is estimated that up to 50% to
70% of long-term survivors of allogeneic HSCT will have
some manifestations of chronic GVHD. Chronic GVHD
and its complications are the most frequent cause of late
(> 2 yr) death after transplantation, underscoring its
importance.4,5 Although there is an association between
chronic GVHD and a protective graft-versus-tumor effect, the morbidity and mortality associated with chronic
GVHD remains substantial. Chronic GVHD is also associated with important limitations on patient quality of
life. Using an illustrative case, this review discusses the
pathophysiology, risk factors, clinical features, and management of both acute and chronic GVHD.
ACUTE GVHD
CASE PRESENTATION
A 43-year-old man is referred for allogeneic HSCT.
He was previously diagnosed with acute myelogenous
leukemia with normal cytogenetics. He received induction chemotherapy followed by consolidation and
attained a complete remission. Fifteen months after
the initial diagnosis, the patient suffers a relapse. He re-
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ceives reinduction chemotherapy and attains a second
remission. The patient has a healthy, human leukocyte
antigen (HLA)-matched sibling who will donate stem
cells, but he is concerned about the risk of developing
acute GVHD.
• What is the pathophysiology of acute GVHD?
Acute GVHD results from the complex interaction of
donor T cells and host tissues that involves recognition
of major and minor histocompatibility antigens in an
inflammatory milieu. Critical factors that modulate the
alloreactivity seen in acute GVHD include donor–host
tolerance mechanisms and the judicious use of immune
suppression. The pathophysiology of acute GVHD involves both the innate and adaptive immune systems and
is thought to follow a reproducible pattern of (1) tissue
damage from conditioning regimen, (2) donor T-cell
activation, and (3) an inflammatory effector phase.6
• What are the risks for developing acute GVHD?
Several risk factors can predict the occurrence of
acute GVHD (Table 1). These factors can be separated
into distinct categories, of which only some may be selectively modulated by clinical decision making. For example, many of the donor-recipient factors often cannot be
altered, particularly when only a single donor is available
for stem cell donation (eg, sex matching). However, risk
factors related to the graft composition and the choice
of the conditioning regimen often can be selected by the
transplant team at the time of transplantation.
• How is acute GVHD prevented?
ACUTE GVHD PROPHYLAXIS
Without prophylaxis, acute GVHD would be nearly
universal; therefore, some form of prophylaxis is always
employed in the peritransplant period. Two main strategies are used in preventing GVHD: graft manipulation
and pharmacologic prophylaxis.
Graft Manipulation
Consistent with the notion that GVHD is induced by
donor T cells coinfused with the stem cell graft, graft manipulation to remove T cells (T-cell depletion [TCD]) is
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one effective method available for preventing GVHD.7
Graft manipulation can be accomplished using either in
vivo or ex vivo approaches. Either approach can reduce
T-cell numbers in the stem cell graft by several logfold.
In vivo TCD methods use horse- or rabbit-derived antithymocyte globulin or alemtuzumab to immunologically
purge T cells. In vivo TCD simultaneously eliminates both
recipient T cells that could mediate graft rejection and
donor T cells that could mediate acute GVHD. However,
other cellular components such as B cells, natural killer
cells, and dendritic cells of both donor and host origin
are likely to be affected by these polyspecific antibodies.
The specific depletion of these cellular components may
or may not influence the risk of acute GVHD.
Ex vivo TCD can be accomplished via several methods. Physical separation of T cells from the stem cells
can be performed using methods such as lectin agglutination (using sheep red blood cell rosetting) or counterflow centrifugal elutriation in a closed ex vivo system.
An alternative strategy is the use of magnetic bead
columns coated with monoclonal antibodies. With this
method, either positive selection of CD34+ progenitors,
with subsequent elutriation of the captured cells from
the column for transplantation, or negative selection
of T cells using monoclonal T-cell antibodies can be
performed. The resulting eluate that passes through
the column is then used for transplantation.2
Studies in both matched related and unrelated transplantation have demonstrated that TCD can be an effective strategy to prevent acute GVHD, with rates of acute
GVHD as low as 10% in matched related transplantation8
and 34% to 38% in matched unrelated donor transplantation.9 In a recent prospective, multicenter, randomized phase II/III trial that enrolled 405 patients who
underwent unrelated donor marrow transplantation,
the incidence of acute GVHD was significantly lower in
the ex vivo TCD arm as compared with the conventional
(pharmacologic) GVHD prophylaxis arm (39% versus
63%; P < 0.0001). However, overall disease-free survival
at 3 years was 30%, with no difference between the TCD
and non-TCD arms (27% versus 34%; P = 0.16).10 The
lack of a survival advantage seen in this and other trials
has been explained by impaired posttransplant immune
reconstitution, which causes an increased incidence of
infections as well as an increased risk of graft failure, an
increase in the risk of posttransplant Epstein-Barr virus–
associated lymphoproliferative disorders, and a reduction in graft-versus-tumor activity, leading to increased
relapse rates.2,5 Despite these limitations and the lack of
contemporary randomized evidence supporting their
use, in vivo TCD strategies are commonly used as GVHD
prophylaxis. However, the continued use of these agents
Table 1. Risk Factors for Acute GVHD
Factor
Condition That Increases
Risk of Acute GVHD
Donor-recipient factors
Major HLA disparity
(HLA class I, II)
HLA mismatched donor > matched
donor
Minor HLA disparity
(mHA)
Unrelated donor > related donor
Sex matching
Mismatch > match
Donor parity
Multiparity > nulliparity
Donor age
Older donor > younger donor
ABO type
ABO mismatch > ABO match
Donor CMV serostatus
CMV positive > CMV negative
Cytokine gene poly­
morphisms
Numerous associated with acute GVHD
Stem cell graft factors
Stem cell source
PBSC > BM > UCB
Graft composition
Higher CD34+ cell count > lower
CD34+ cell count*
Higher T-cell dose > lower T-cell dose*
Transplantation factors
Conditioning intensity Myeloablative > reduced-intensity regimens
BM = bone marrow; CMV = cytomegalovirus; GVHD = graft-versushost disease; HLA = human leukocyte antigen; mHA = minor histocom­
patibility antigens that are expressed in the context of HLA by antigen
presenting cells; PBSC = peripheral blood stem cell; UCB = umbilical
cord blood. *Controversial.
relates more to their role in preventing chronic GVHD,
particularly in alternative donor transplantation, rather
than as prophylaxis of acute GVHD.11,12
Pharmacologic Prophylaxis
Pharmacologic prevention of acute GVHD is practiced more commonly in North America than prophylaxis with TCD. Immunosuppressive drugs are used
to reduce the alloimmune activation of donor T cells.
Methotrexate, which impairs purine synthesis in T cells
and thus prevents T-cell expansion in response to neo­
antigen, was the first agent used to prevent GVHD.
Single-agent methotrexate was supplanted by cyclosporine when it became widely available. Cyclosporine
inhibits interleukin-2–mediated T-cell expansion via inhibition of calcineurin. Studies comparing cyclosporine
monotherapy with the combination of cyclosporine and
methotrexate demonstrated superiority of the 2-drug
regimen over monotherapy, and the current standard
was established.13
Newer agents have been developed to prevent
acute GVHD. The most prominent of these is tacrolimus, which is used interchangeably with cyclosporine. In
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contrast to cyclosporine, tacrolimus does not interact
with calcineurin or its downstream effectors, but both
compounds share a final common pathway of T-cell inhibition. Large phase III studies comparing tacrolimus and
methotrexate with cyclosporine and methotrexate after
matched related and unrelated transplantation have
been performed. In the matched related donor setting,
329 patients were randomized to receive either tacrolimus with methotrexate or cyclosporine and methotrexate.
The incidence of grade II through grade IV acute GVHD
was 31.9% in the tacrolimus arm and 44.4% in the
cyclosporine arm.14 Similarly, the incidence of grade II
through grade IV acute GVHD was 56% among 46 patients randomized to tacrolimus versus 74% among 63
patients randomized to receive cyclosporine in the unrelated donor study.15 Other investigational but promising
strategies to prevent acute GVHD involve newer immunosuppressants, such as sirolimus16 or mycophenolate
mofetil,17 as well as agents with activity in the treatment
of advanced established acute GVHD.
CASE CONTINUED
The patient undergoes transplantation from his
HLA-matched sibling. He receives cyclophosphamide
and total body irradiation as conditioning therapy, and
tacrolimus with methotrexate as GVHD prophylaxis.
Twenty-three days after successful transplantation, the
patient presents to his physician complaining of a new
rash and profuse watery diarrhea. A complete metabolic panel also reveals significant elevation of alanine
aminotransferase, aspartate aminotransferase, and total
bilirubin levels.
• What are the clinical features of acute GVHD?
CLINICAL FEATURES OF ACUTE GVHD
Acute GVHD is a clinicopathologic syndrome involving the skin, liver, and gut. The median time to the
diagnosis of acute GVHD varies with conditioning, with
recipients of high-dose therapy and transplantation
being diagnosed at a median of 17 days,18 as compared
with recipients of reduced-intensity conditioning transplantation being diagnosed at a median of 3 months.19
The skin is the most commonly affected organ in acute
GVHD. In a representative study that enrolled 160 pa­
tients who underwent HLA-matched HSCT, over 75%
of patients who developed acute GVHD had some cutaneous involvement and 44% had skin involvement as
their only manifestation of acute GVHD.20 The initial
manifestation of acute GVHD is most commonly a maculopapular exanthema. The rash may be pruritic or
painful and red to violaceous in color. Typically, a rash
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that involves the palms and soles suggests acute GVHD,
most likely due to the concentration of hematopoietic
stem cells in the rete ridges. The presence of rash at
these locations helps differentiate the rash caused by
acute GVHD from a rash caused by drug eruption,
as the latter generally spares these areas. As the rash
intensifies, confluent involvement of the cheeks, ears,
neck, and trunk is noted. In its most severe form, bullae formation may occur with epidermal necrosis and
desquamation, mimicking toxic epidermal necrolysis.
The gastrointestinal (GI) tract is the second most
commonly involved organ in acute GVHD, with up to
half of individuals being affected in 1 study.20 In general, signs of enteric GVHD develop as the chemoradiotherapy effects resolve following the first several weeks
after transplantation; however, these syndromes may
overlap, making an early diagnosis difficult. Symptoms
of acute GVHD of the small bowel and colon include
profuse watery diarrhea, intestinal bleeding, crampy
abdominal pain, and, in its most severe form, paralytic
ileus. The diarrhea is often green, mucoid, watery, and
mixed with exfoliated cells, forming fecal casts. Some
patients may develop a variant of GVHD that involves
the upper GI tract and is associated with anorexia,
nausea, and dyspepsia; these patients may not manifest
lower tract involvement. Endoscopic findings of enteric
GVHD range from normal to extensive edema and
mucosal sloughing. Lesions may be most prominent in
the cecum, ileum, and ascending colon but may also
involve the stomach, duodenum, and rectum. Endoscopy and biopsy are recommended for the diagnosis of
lower GI tract in order to exclude other diagnoses.
The liver is the least commonly affected organ in
acute GVHD, with less than 20% of patients with acute
GVHD having some degree of hepatic involvement.20
Cholestatic jaundice is the most common manifestation; however, a concomitant or isolated transaminitis
is not uncommon. In severe cases, hepatic failure with
encephalopathy may occur. Percutaneous or transjugular liver biopsy is recommended for the diagnosis of
hepatic GVHD, when feasible, as there are no imaging
studies that reliably can differentiate hepatic GVHD
from other causes of liver dysfunction, such as drug
toxicity or veno-occlusive disease of the liver.
In general, biopsies of the target organs are often
obtained to confirm the diagnosis of acute GVHD.
However, the diagnosis remains largely clinical and
therapy often must be initiated before the results of
biopsies are known. Once the diagnosis is obtained, the
severity of acute GVHD can be staged (Table 2). The
modified Seattle-Glucksberg criteria, also called the
Consensus criteria, are used to stage acute GVHD.21,22
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Table 2. Grading and Staging of Acute Graft-Versus-Host Disease
Individual Organ Staging
Organ
Skin
Liver
Gut
Stage
BSA (%)*
Bilirubin (mg/dL)
Diarrhea (mL/day)
1
Rash < 25
2–2.9
500–1000 or biopsy-proven upper GI involvement
2
Rash 25–50
3–6
1000–1500
3
Rash > 50
6.1–15
1500–2000
4
Generalized erythroderma with bullae 15
> 2000 or severe abdominal pain with or without ileus
Overall Grade
Skin
Liver
Gut
I
Stage 1–2
None
None
II
Stage 3
Stage 1
Stage 1
II
—
Stage 2–3
Stage 2–4
IV
Stage 4
Stage 4
—
Overall Grade
Skin
Liver
Gut
A
Stage 1
None
None
B
Stage 2
Stage 1 or 2
Stage 1 or 2
C
Stage 3
Stage 3
Stage 3
D
Stage 4
Stage 4
Stage 4
Consensus Grading
IBMTR Grading
BSA = body surface area; GI = gastrointestinal; IBMTR = International Bone Marrow Transplant Registry. *Use “Rule-of-Nines” to determine BSA. (Data
from Glucksberg et al,21 Przepiorka et al,22 and Rowlings et al.23)
In this system, each individual organ is given a stage,
and a composite grade is calculated. A more recent
staging system proposed by the International Bone
Marrow Transplant Registry uses the same individual
organ staging but modifies the overall grading scheme
slightly.23 Both systems predict overall survival from
acute GVHD equally well.
• How is acute GVHD treated and what are the outcomes of this treatment?
TREATMENT AND OUTCOME OF ACUTE GVHD
Once established, acute GVHD must be treated aggressively, unless it is limited to a low-surface area skin
rash alone (stage I or II skin disease). If left untreated,
some of these rashes will resolve spontaneously or will
resolve with local application of corticosteroid creams.
Corticosteroids are lympholytic and inhibit inflammatory cytokine cascades; this class of drugs is considered
standard primary systemic therapy for acute GVHD.
The dose and route of administration of corticosteroids
may vary slightly among transplant centers, but the recommended initial dose of corticosteroids for moderate
to severe (grade II–IV) acute GVHD is 2 mg/kg/day of
methylprednisolone; randomized trials have not demonstrated an advantage for using higher doses.24 Large
retrospective reviews have shown that the response rate
to single-agent corticosteroid therapy is approximately
50%.18 It is important to note that the pace of response
to primary therapy varies with the organs involved
with GVHD. Although erythematous cutaneous acute
GVHD may show improvement within 24 hours after
initiating therapy, it is unlikely that GI or hepatic GVHD
would respond within the same timeframe.
Systemic therapy for acute GVHD is continued for at
least 1 to 2 weeks after a complete remission is attained
and then a gradual taper is initiated. The pace of the
steroid taper should generally be no greater than a
10% reduction per week, but this recommendation is
affected by factors such as the durability of the response
to corticosteroids and the toxicity of high-dose steroid
administration. Despite an initial response, many patients will experience a flare of their acute GVHD upon
steroid taper, requiring reinstitution of higher doses
of corticosteroids or the addition of other agents. In
acute GVHD developing after matched unrelated and
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Table 3. Therapeutic Agents Used for Steroid-Refractory
Acute GVHD
T-cell immunosuppression
IL-2 mediated
Cyclosporine, tacrolimus
mTOR mediated
Sirolimus
Antimetabolite/
chemotherapy
Mycophenolate mofetil, methotrexate,
pentostatin
Biologic anti–T-cell therapy
Polyclonal antibodies
Antithymocyte globulin
Monoclonal antibodies
Muromonab-CD3, visilizumab,*
ABX-CBL,* daclizumab, inolimomab,
basiliximab, alemtuzumab, alefacept
Immunotoxin/conjugate
Denileukin diftitox
TNF-α blockade
Infliximab, etanercept
Phototherapy
PUVA, extracorporeal photopheresis
Cellular therapy
Mesenchymal stem cells
Topical/directed therapy
Oral beclomethasone diproprionate
or budesonide for intestinal GVHD;
intra-arterial steroid or methotrex­
ate infusion
GVHD = graft-versus-host disease; IL = interleukin; mTOR = mam­
malian target of rapamycin; PUVA = psoralen plus ultraviolet A; TNF = tumor necrosis factor. *Not commercially available.
related donor transplantation, durable remission of
acute GVHD with steroid alone were reported in only
21% and 40% of patients, respectively.25,26
The suboptimal response and long-term survival associated with acute GVHD treated with corticosteroids
alone has prompted the investigation of additional systemic immunosuppressive agents in the initial therapy
of acute GVHD. Unfortunately, this strategy has generally been unsuccessful, as the benefit of more effective
initial GVHD control is often offset by a greater risk of
infection and other side effects, thus resulting in no net
survival benefit.27,28
Currently, there is no established consensus for de­
fining failure of primary therapy in acute GVHD. A
set of criteria common to some clinical trials define
steroid-refractory acute GVHD as (1) progression after
3 days, (2) no change after 5 to 7 days, or (3) incomplete
response after 14 days of steroid treatment with methylprednisolone at a dose of 2 mg/kg/day or equivalent.29
For patients with steroid-refractory GVHD, there is no
clear standard for salvage or second-line treatment, and
survival remains poor despite seemingly high response
rates to certain second-line therapeutic agents. Table 3
provides a summary of therapeutic agents available for
the treatment of steroid-refractory acute GVHD.
In addition to immunosuppressive therapy, supportive
care is critical for achieving a favorable outcome in steroidrefractory acute GVHD. Organ-specific supportive mea-
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sures for the skin involve using a topical emollient and
meticulous wound care, which may include admission to
a burn unit. For the GI tract, bowel rest and intravenous
hyperalimentation are required. Antimotility agents are
employed but may not be clinically useful, as GI GVHD
is a secretory process. Octreotide or other somatostatin
analogues may be of benefit in controlling the secretory component of GI GVHD.30,31 Ursodeoxycholic acid
may be considered as a supportive measure for hepatic
GVHD. Given that most patients with steroid-refractory
GVHD will succumb to infection, systematic monitoring and judicious use of antibiotic prophylaxis is paramount. Standard infection prophylaxis in patients with
GVHD should include trimethoprim-sulfamethoxazole
or equivalent agents to prevent Pneumocystis jirovecii pneumonia, acyclovir to pre­vent herpesvirus reactivation, and
prophylaxis against inva­sive fungal infections. Monitoring
for viral pathogens such as cytomegalovirus and fungal
pathogens using serum assays for β-glucan and galactomannan is required.
CASE CONTINUED
A presumptive diagnosis of acute GVHD is made,
the patient is rehospitalized, and corticosteroids
(2 mg/kg/day) are instituted. Bowel rest is prescribed.
After 3 days of therapy, the patient’s skin rash improves.
At 10 days of therapy, his liver function tests have normalized and his diarrhea is resolved. The patient is
discharged on a tapering course of corticosteroids.
CHRONIC GVHD
CASE CONTINUED
Eight months after transplantation, the patient returns
for routine follow-up. He has been successfully weaned off
all immunosuppressive therapy, and there is no evidence
of leukemic relapse. He now notes the progressive onset
of dry and itchy eyes, oral ulcers, and a new rash over his
torso. His complete blood count reveals eosinophilia and
thrombocytopenia with a platelet count of 80,000/µL
(normal, 150,000–350,000/µL). A presumptive diagnosis
of extensive chronic GVHD is made, and corticosteroids
and a calcineurin inhibitor are initiated.
• What are the risk factors for developing chronic
GVHD?
Risk factors for chronic GVHD are similar to those
for acute GVHD, with the contribution of the stem cell
source and disparities among major and minor HLA
disparities being the most prominent risks. The recent
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administration of a donor lymphocyte infusion is a risk
factor, and the prior occurrence of acute GVHD is also
a well-established risk factor.
• What is the pathophysiology of chronic GVHD?
Unlike acute GVHD, the pathophysiology of chronic
GVHD is poorly understood. Human chronic GVHD
shares several characteristics with systemic autoimmune
diseases such as scleroderma, Sjögren’s syndrome, primary biliary cirrhosis, and systemic lupus erythematosus,
which helps relate the pathophysiology of this disorder
to other autoimmune (or in the case of chronic GVHD,
alloimmune) disorders. T cells play a critical role in
GVHD and graft-versus-leukemia immune responses
after allogeneic HSCT. Depending on the model system
utilized, both CD4+ and CD8+ T cells have been implicated as primary mediators of chronic GVHD, and there
are data supporting the role of other subsets of T cells,
including CD4+CD25+FoxP3+ regulatory T cells, as well as
the subcategories of central and effector memory T cells.
Dendritic cells certainly play a role as antigen presenting
cells, and most recently, B cells have been implicated in
the pathophysiology of chronic GVHD.32
• What are the clinical features of chronic GVHD?
• How is chronic GVHD diagnosed?
CLINICAL FEATURES
The diagnosis of chronic GVHD is largely clinical.
The signs and symptoms of chronic GVHD are detailed
in Table 4. A detailed physical examination with clinical
testing of potentially affected organs is crucial. Laboratory and radiologic testing of affected organs may also provide diagnostic utility. Common supplemental clinical
tests that readily can be performed include Schirmer’s
test for ocular dryness, portable spirometry for the diagnosis of bronchiolitis, and hand-held dynamometry for
musculoskeletal involvement. These tests are also useful
for monitoring patient with active chronic GVHD.
Traditionally, only GVHD features that occurred
beyond 100 days from transplantation were considered
part of the spectrum of chronic GVHD. It is now clear
that chronic GVHD may present prior to day 100, and
features of late acute GVHD may present well after day
100. Thus, it is the syndrome’s clinical features, not its
timing, that determines the diagnosis.
Recently, a National Institutes of Health (NIH) Con­
sensus Project outlined the clinical features seen in
chronic GVHD. The diagnosis of chronic GVHD is currently based on satisfying a number of clinical criteria as
set forth by the Consensus committee (Table 4).29 The
diagnosis of chronic GVHD requires (1) the distinction
of the clinical syndrome from acute GVHD; (2) the
presence of at least 1 diagnostic clinical sign of chronic
GVHD or presence of at least 1 distinctive manifestation
confirmed by pertinent biopsy or other relevant tests;
and (3) exclusion of other possible diagnoses.33
• How is chronic GVHD staged?
STAGING CHRONIC GVHD
Traditionally, chronic GVHD was staged using a method initially developed from a small cohort of patients
treated in Seattle.34 In this system, chronic GVHD patients are divided into 2 categories—clinically limited
or clinically extensive disease. Limited chronic GVHD
is comprised of patients with localized skin dysfunction
or hepatic dysfunction. All others are then considered
to have clinically extensive chronic GVHD. Although
easy to remember, this system simply groups patients
by their requirement for systemic therapy and is of little
clinical utility today. As such, the NIH Consensus committee proposed a more complicated but more clinically
meaningful scoring system, with the goal of standardizing
patient staging for clinical trial design and interpretation. This new system incorporates both the number of
target organs involved as well as the severity of the organ
involvement.33 The utility of this new system in predicting response to therapy or long-term outcome has not
yet been validated in prospective clinical trials. The individual organ scoring system is found in the Figure. The
summation of the individual organ scores is then used to
place the chronic GVHD patient into 1 of 3 categories:
mild, moderate, or severe (Table 5).
• How is chronic GVHD treated?
TREATMENT
Single-agent corticosteroids are the mainstay of therapy for chronic GVHD, and other agents such as cyclosporine, while active, are associated with a low response
rate when used alone. Instituting combination therapy as
initial therapy for chronic GVHD has not been shown to
be beneficial, with the exception of a reduction in steroidassociated side effects. In a trial that compared combination cyclosporine and prednisone with single-agent
prednisone as initial therapy for chronic GVHD, the
requirement for secondary immunosuppressive therapy
due to a lack of response or an insufficient response was
no different between study arms. In addition, no differences in transplant-related mortality, relapse rate, or overall mortality were noted. The median duration of therapy
with corticosteroids and cyclosporine for chronic GVHD
was 1.6 years, and despite dual immunosuppressive
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Table 4. Signs and Symptoms of Chronic Graft-Versus-Host Disease (GVHD)
Organ
or Site
Skin
Diagnostic
(Sufficient to Establish
the Diagnosis of
Chronic GVHD)
Distinctive (Seen in Chronic
GVHD, but Insufficient Alone
to Establish a Diagnosis of
Chronic GVHD)
Other Features*
Poikiloderma
Lichen planus-like features
Sclerotic features
Morphea-like features
Lichen sclerosis-like fea­
tures
Depigmentation
Nails
Dystrophy
Longitudinal ridging, splitting, or
brittle features
Onycholysis
Pterygium unguis
Nail loss (usually symmetric;
affects most nails)†
Scalp and body
hair
New onset of scarring or non­
scarring scalp alopecia (after
recovery from chemoradio­
therapy)
Scaling, papulosquamous lesions
Mouth
Lichen-type features
Hyperkeratotic plaques
Restriction of mouth open­
ing from sclerosis
Eyes
Lichen planus-like features
Vaginal scarring or stenosis
GI tract
Esophageal web
Strictures or stenosis in the
upper to mid third of the
esophagus†
Sweat impairment
Ichthyosis
Keratosis pilaris
Hypopigmentation
Hyperpigmentation
Thinning scalp hair, typically
patchy, coarse, or dull (not
explained by endocrine or
other causes)
Premature gray hair
Gingivitis
Mucositis
Erythema
Pain
Photophobia
Periorbital hyperpigmentation
Blepharitis (erythema of the
eyelids with edema)
Confluent areas of punctate kera­
topathy
Erosions†
Fissures†
Ulcers†
Exocrine pancreatic insuf­
ficiency
Liver
Lung
Muscles, fascia,
joints
Erythema
Maculopapular rash
Pruritus
Xerostomia
Mucocele
Mucosal atrophy
Pseudomembranes†
Ulcers†
New onset of dry, gritty, or pain­
ful eyes‡
Cicatricial conjunctivitis
Keratoconjunctivitis sicca‡
Genitalia
Common
(Seen with Both Acute
and Chronic GVHD)
Anorexia
Nausea
Vomiting
Diarrhea
Weight loss
Failure to thrive (infants and
children)
Total bilirubin, alkaline phos­
phatase > 2× ULN†
ALT or AST > 2× ULN†
Bronchiolitis obliterans diag­ Bronchiolitis obliterans diagnosed
nosed with lung biopsy
with PFTs and radiology‡
Fasciitis
Myositis or polymyositis‡
Edema
Joint stiffness or con­
Muscle cramps
tractures secondary to
Arthralgia or arthritis
sclerosis
Bronchiolitis obliterans
organizing pneumonia
(continued)
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Table 4. Signs and Symptoms of Chronic GVHD (continued)
Organ
or Site
Diagnostic
(Sufficient to Establish
the Diagnosis of
Chronic GVHD)
Distinctive (Seen in Chronic
GVHD, but Insufficient Alone
to Establish a Diagnosis of
Chronic GVHD)
Other Features*
Hematopoietic
and immune
Thrombocytopenia
Eosinophilia
Lymphopenia
Hypo- or hypergammaglobu­
linemia
Autoantibodies (AIHA and ITP)
Other
Pericardial or pleural effusions
Ascites
Peripheral neuropathy
Nephrotic syndrome
Myasthenia gravis
Cardiac conduction abnormal­
ity or cardiomyopathy
Common
(Seen with Both Acute
and Chronic GVHD)
AIHA = autoimmune hemolytic anemia; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; ITP = idiopathic
thrombocytopenic purpura; PFTs = pulmonary function tests; ULN = upper limit of normal. *Can be acknowledged as part of the chronic GVHD
symptomatology if the diagnosis is confirmed. †In all cases, infection, drug effects, malignancy, or other causes must be excluded. ‡Diagnosis of
chronic GVHD requires biopsy or radiology confirmation (or Schirmer’s test for eyes). (Adapted from 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;11:948–9. Copyright 2005, with permission from Elsevier.)
therapy, only 54% of patients were successfully weaned
from immunosuppressive medications at 5 years. Mortality directly attributable to chronic GVHD was 17% in
the combination immunosuppressive arm.35 Trials that
included additional agents (eg, thalidomide) as part of
initial therapy for chronic GVHD also did not demonstrate an advantage.35,36 Typical doses of corticosteroids
used in the initial management of chronic GVHD
range from 0.5 to 1.0 mg/kg/day of prednisone. Some
investigators prefer to administer corticosteroids on
alternate days to reduce the incidence of steroid-related
side effects, since therapy with corticosteroids is often
very prolonged. In contrast to the tapering of steroids
in acute GVHD, most investigators prefer to maintain
steroid doses at therapeutic levels for up to 3 months
once a complete remission has been attained before
initiating a taper.
Currently, there is no standard second-line therapy
for chronic GVHD when primary therapy is insufficient. As a result, therapy often consists of prolonged
administration of corticosteroids in conjunction with
other immunosuppressive medications. The interested
reader is referred to these recent publication for a detailed discussion of regimens used in chronic GVHD.37,38
Response rates to individual agents vary, with responses
noted in up to 75% of patients treated with mycophenolate mofetil. Up to 20% of these patients will attain a
complete response to this agent. Use of novel agents (eg,
sirolimus, thalidomide) as well as newer approaches to
treating chronic GVHD (eg, rituximab, extracorporeal
phototherapy) has also been explored.
In addition to systemic therapy for chronic GVHD,
organ-specific therapy is required. This organ-specific
therapy can be vital and includes the topical administration of immunosuppressants to individual organs (ie,
corticosteroid-containing oral rinses, calcineurin inhibitor ocular preparations) and other supportive care measures to maintain the integrity of the affected organ. A
complete guide to supportive care of individual organs
for patients with chronic GVHD was also produced by the
NIH Consensus Group.39
• What is the prognosis for patients with chronic
GVHD?
PROGNOSIS
There have been numerous attempts to define the
prognosis of chronic GVHD. Several factors have repeatedly demonstrated adverse prognostic importance,
such as a progressive onset of chronic GVHD arising
out of acute GVHD and thrombocytopenia at the time
of diagnosis. Others, such as poor performance status
at the time of diagnosis, hyperbilirubinemia, and extensive skin involvement, have not retained prognostic
significance across studies.4,40
CASE CONCLUSION
Nine months after initiating corticosteroids and
www.turner-white.comHematology Volume 3, Part 1 A c u t e a n d C h ro n i c G r a f t - Ve r s u s - H o s t D i s e a s e
SCORE 0
PERFORMANCE
SCORE:
KPS
ECOG
LPS
❑A
symptomatic
and fully active
(ECOG 0; KPS
or LPS 100%)
SCORE 1
❑ Symptomatic, fully
ambulatory, restricted
only in physically stren­
uous activity (ECOG 1,
KPS or LPS 80%–90%)
SCORE 2
SCORE 3
❑ Symptomatic, ambulato­ ❑ Symptomatic, limited self-care,
ry, capable of self-care,
> 50% of waking hours in bed
> 50% of waking hours
(ECOG 3–4, KPS or LPS < 60%)
out of bed (ECOG 2,
KPS or LPS 60%–70%)
SKIN
❑ No symptoms
Clinical features:
❑ Maculopapular rash
❑ Lichen planus-like features
❑P
apulosquamous lesions
or ichthyosis
❑ Hyperpigmentation
❑ Hypopigmentation
❑ Keratosis pilaris
❑ Erythema
❑ Erythroderma
❑ Poikiloderma
❑ Sclerotic features
❑ Pruritus
❑ Hair involvement
❑ Nail involvement
% BSA involved
❑ < 18% BSA with disease ❑ 19%–50% BSA OR
❑ > 50% BSA OR deep sclerotic
signs but NO sclerotic
involvement with super­
features “hidebound” (unable
features
ficial sclerotic features
to pinch) OR impaired mobility,
“not hidebound” (able
ulceration, or severe pruritus
to pinch)
MOUTH
❑ No symptoms
❑ Mild symptoms with
disease signs but not
limiting oral intake sig­
nificantly
❑ Moderate symptoms
with disease signs with
partial limitation of oral
intake
❑ Severe symptoms with disease
signs on examination with major
limitation of oral intake
EYES
Mean tear test (mm):
❑ >10
❑ 6–10
❑≤5
❑ Not done
❑ No symptoms
❑ Mild dry eye symptoms
not affecting ADL
(requiring eyedrops
≤ 3× daily) OR asymp­
tomatic signs of kerato­
conjunctivitis sicca
❑ Moderate dry eye
symptoms partially
affecting ADL (requir­
ing drops > 3× daily
or punctal plugs),
WITHOUT vision
impairment
❑ Severe dry eye symptoms signifi­
cantly affecting ADL (special eye­
ware to relieve pain) OR unable
to work because of ocular symp­
toms OR loss of vision caused
by keratoconjunctivitis sicca
GI TRACT
❑ No symptoms
❑ Symptoms such as dys­ ❑ Symptoms associated
phagia, anorexia, nausea,
with mild to moderate
vomiting, abdominal pain
weight loss (5%–15%)
or diarrhea without
significant weight loss
(< 5%)
❑ Symptoms associated with signifi­
cant weight loss > 15%, requires
nutritional supplement for most
calorie needs OR esophageal
dilation
LIVER
❑ Normal LFT
❑ Elevated bilirubin, AP,*
AST or ALT < 2× ULN
❑B
ilirubin > 3 mg/dL or
bilirubin, enzymes 2–
5× ULN
❑ Bilirubin or enzymes > 5× ULN
LUNGS†
❑N
o symptoms
❑ Mild symptoms (short­
ness of breath after
climbing 1 flight of
steps)
❑ Moderate symptoms
(shortness of breath
after walking on flat
ground)
❑ Severe symptoms (shortness of
breath at rest; requiring 02)
❑ F EV1 > 80% OR
LFS = 2
❑ FEV1 60%–79% OR
LFS 3–5
❑ FEV1 40%–59% OR
LFS 6–9
❑ FEV1 ≤ 39% OR
LFS 10–12
FEV1
DLCO
(continued)
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SCORE 0
SCORE 1
SCORE 2
SCORE 3
JOINTS AND FASCIA
❑N
o symptoms
❑ Mild tightness of arms
or legs, normal or mild
decreased ROM AND
not affecting ADL
GENITAL TRACT
❑N
o symptoms
❑ Symptomatic with mild ❑ Symptomatic with mod­ ❑ Symptomatic WITH advanced
signs on exam AND
erate signs on exam
signs (stricture, labial agglutina­
no effect on coitus and
AND with mild dys­
tion or severe ulceration) AND
minimal discomfort with
pareunia or discomfort
severe pain with coitus or inabil­
gynecologic exam
with gynecologic exam
ity to insert vaginal speculum
❑ Tightness of arms or
❑ Contractures WITH significant
legs OR joint contrac­
decrease of ROM AND signifi­
tures, erythema thought
cant limitation of ADL (unable
due to fasciitis, moder­
to tie shoes, button shirts, dress
ate decrease ROM
self etc.)
AND mild to moderate
limitation of ADL
Other indicators, clinical manifestations or complications related to chronic GVHD (check all that apply and assign a score to
its severity (0–3) based on its functional impact where applicable (none = 0; mild –1; moderate –2; severe –3)
Esophageal stricture or web___
Ascites (serositis)___
Myasthenia gravis___
Polymyositis___
Platelets < 100,000/µL ___
Pericardial effusion___
Nephrotic syndrome___
Cardiomyopathy___
Cardiac conduction defects___
Progressive onset___
Pleural effusion(s)___
Peripheral neuropathy___
Eosinophilia > 500 µL___
Coronary artery involvement___
OTHERS: Specify: _____________________________________________________________________________________________________
Figure. Individual Organ Scoring Criteria for Chronic GVHD. ADL = activities of daily living; ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; BSA = body surface area; DLCO = diffusion capacity of carbon
monoxide; ECOG = Eastern Cooperative Oncology Group; FEV1 = forced expiratory volume in 1 second; GI = gastrointestinal;
GVHD = graft-versus-host disease; KPS = Karnofsky Performance Status; LFS = Lung Function Score; LFT = liver function test;
LPS = Lansky Performance Status; PFT = pulmonary function testing; ROM = range of motion; ULN = upper limit of normal. *AP
may be elevated in growing children and is not reflective of liver dysfunction. †Pulmonary scoring should be performed using both
the symptom and PFT scale whenever possible. When discrepancy exists between pulmonary symptom and the PFT scores, the
higher value should be used for final scoring. Scoring using the LFS is preferred, but if DLCO is not available, grading using FEV1
should be used. The percent predicted FEV1 and DLCO (adjusted for hematocrit but not alveolar volume) should be converted
to a numeric score as follows: ≥ 80% = 1; 70%–79% = 2; 60%–69% = 3; 50%–59% = 4; 40%–49% = 5; < 40% = 6. The LFS + FEV1
score = DLCO score, with a possible range of 2–12. (Adapted from 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;11:952–3. Copyright 2005, with permission from Elsevier.)
tacrolimus, all signs and symptoms of chronic GVHD
have resolved. The patient remains on a tapering
course of corticosteroids and a therapeutic dose of
tacrolimus. He has developed glucose intolerance and
requires oral hypoglycemic medications. His hematologic parameters have returned to normal, and routine
staging with bone marrow examination has revealed no
evidence of recurrence of leukemia.
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Table 5. Definitions of Mild, Moderate, or Severe Chronic
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Mild chronic GVHD
Up to 2 organ (excluding lung) scores = 1
Moderate chronic
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Lung score = 1
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www.turner-white.comHematology Volume 3, Part 1 11
A c u t e a n d C h ro n i c G r a f t - Ve r s u s - H o s t D i s e a s e
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test yourself with board-type questions
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