12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

Official reprint from UpToDate®

www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Treatment of chronic graft-versus-host disease

Author: Nelson J Chao, MD
Section Editor: Robert S Negrin, MD
Deputy Editor: Alan G Rosmarin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2020. | This topic last updated: Apr 20, 2020.

INTRODUCTION

Acute and chronic graft-versus-host disease (GVHD) are multisystem disorders that are common
complications of allogeneic hematopoietic cell transplant (HCT). GVHD occurs when immune cells
transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign,
thereby initiating an immune reaction that causes disease in the transplant recipient. (See "Pathogenesis of
graft-versus-host disease (GVHD)".)

GVHD has been classically divided into acute and chronic variants based on the time of onset using a cutoff
of 100 days. However, this conventional division has been challenged by the recognition that signs of acute
and chronic GVHD may occur outside of these designated periods. This observation has led to the increased
use of clinical findings, rather than a set time period, to differentiate between acute and chronic GVHD. The
widely accepted National Institutes of Health (NIH) consensus criteria for the diagnosis of GVHD include an
overlap syndrome in which diagnostic or distinctive features of chronic GVHD and acute GVHD appear
together [1].

Clinical manifestations of chronic GVHD include skin involvement resembling lichen planus or the cutaneous
manifestations of scleroderma; dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract;
and a rising serum bilirubin concentration. In contrast, patients with acute GVHD commonly demonstrate a
classic maculopapular rash; abdominal cramps with diarrhea; and a rising serum bilirubin concentration.
(See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Clinical
and histological manifestations'.)

Chronic GVHD is the single major factor determining long-term quality of life following HCT. Because of the
profound immunosuppression observed with this disorder, recurrent infections occur in almost all affected
patients. These complications account for most of the morbidity and mortality associated with chronic
GVHD. (See "Outcomes and late complications after hematopoietic cell transplantation in adults".)

This topic review will discuss the treatment of chronic GVHD. The diagnosis of chronic GVHD and the
prevention and treatment of acute GVHD are discussed separately. (See "Clinical manifestations, diagnosis,
and grading of chronic graft-versus-host disease" and "Prevention of acute graft-versus-host disease" and
"Treatment of acute graft-versus-host disease".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 1/23
12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the
risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social
distancing during care delivery, and appropriately and fairly allocating limited health care resources. These
issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See
"Coronavirus disease 2019 (COVID-19): Cancer screening, diagnosis, treatment, and posttreatment
surveillance in uninfected patients during the pandemic".)

OVERVIEW

Prevention — Prophylaxis of acute GVHD centers on immunosuppression of the donor cells, either

pharmacologically or via T cell depletion. There is no agreed upon standard regimen, and clinical practice
varies by institution. However, each institution must have guidelines for the prevention and management of
GVHD in order to be acknowledged by international accrediting organizations.

Multiple different regimens (eg, glucocorticoids, cyclosporine, intravenous immune globulin) have been
used in an attempt to prevent the development of chronic GVHD; most have been ineffective [2-9]. Two
potential exceptions are the use of antithymocyte globulin (ATG) as part of the preparative regimen and the
use of rituximab in the post-transplant period. ATG is commonly incorporated into the prophylactic regimen
for patients with an unrelated donor or haploidentical donor undergoing either myeloablative or reduced
intensity conditioning. (See "Prevention of acute graft-versus-host disease", section on 'Antithymocyte
globulin'.)

The following randomized trials suggest that ATG decreases the cumulative incidence of chronic GVHD and
allows more patients to discontinue GVHD prophylaxis, without increasing relapse:

● A randomized trial assigned 202 patients undergoing allogeneic hematopoietic cell transplantation
(HCT) from matched unrelated donors to receive GVHD prophylaxis with cyclosporine plus
methotrexate, with or without rabbit ATG [10]. The addition of ATG significantly reduced the overall
incidence of acute and chronic GVHD, without an increase in relapse or non-relapse mortality, and
without compromising overall survival. However, addition of ATG did not significantly reduce the
incidence of grade III to IV acute GVHD or death within 100 days, the primary endpoints of the study. A
subsequent report of this study demonstrated a lower incidence and severity of chronic GVHD without
increasing the risk of relapse [11]. Patients treated with ATG were more likely to have undergone
successful taper of other immunosuppressants.

● In a multicenter, open-label, phase 3 trial, 161 patients with acute leukemia undergoing myeloablative
allogeneic HCT were randomly assigned to receive their conditioning regimen with or without the
addition of antilymphocyte globulin [12]. All patients received cyclosporine and methotrexate for GVHD
prophylaxis. After a median follow-up of 24 months, the addition of antilymphocyte globulin resulted in
a lower cumulative incidence of chronic GVHD (32 versus 69 percent) and a higher percentage of
patients able to discontinue cyclosporine (91 versus 39 percent). Rates of acute GVHD, relapse-free
survival, and overall survival at two years were similar between the two groups. The two groups also had
similar rates of CMV reactivation and EBV reactivation, and no cases of post-transplant
lymphoproliferative disorder.

Nonrandomized trials have evaluated the use of rituximab in the post-transplant period:

● In a phase II trial of 65 adults who had received a nonmyeloablative or myeloablative peripheral blood
stem cell transplantation from an 8/8 HLA-matched donor or single antigen/allele-mismatched donor,
https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 2/23
12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

rituximab (375 mg/m2 given on day 100 and at 6, 9, and 12 months) resulted in two-year rates of chronic
GVHD and systemic corticosteroid-requiring chronic GVHD of 48 and 31 percent, respectively [13].
Corresponding rates from a concurrent control group were 60 and 49 percent, respectively. Rituximab
was also associated with a lower rate of treatment-related mortality (5 versus 19 percent) and improved
overall survival (71 versus 56 percent) at four years.

● In another phase II trial of 35 adults who had received a reduced-intensity conditioning (total lymphoid
irradiation plus antithymocyte globulin) transplantation from a 10/10 HLA-matched or single
antigen/allele-mismatched donor followed by rituximab (375 mg/m2 infused weekly on days 56, 63, 70,
and 77 after transplantation), the cumulative incidence of chronic GVHD was 20 percent [14].
Nonrelapse mortality was 3 percent.

Randomized trials are required to confirm these results. (See "Prevention of acute graft-versus-host disease"
and "Treatment of acute graft-versus-host disease".)

Diagnosis — The diagnosis of chronic GVHD should be considered in any patient who has undergone
allogeneic HCT. Chronic GVHD can occur at any time point in the post-HCT setting, and screening for signs
and symptoms of chronic GVHD should be incorporated into the long-term follow-up of transplant survivors.
Chronic GVHD can be readily made on clinical grounds in the patient who presents with the classic features
of skin involvement, manifestations of gastrointestinal involvement, and a rising serum bilirubin
concentration. In many cases, however, the diagnosis is less straightforward, and competing causes for
isolated abnormalities must be considered and excluded. This is discussed in more detail separately. (See
"Clinical manifestations, diagnosis, and grading of chronic graft-versus-host disease".)

PRETREATMENT EVALUATION

Grading — Several systems for grading chronic GVHD have been developed. For treatment purposes,
disease severity can be documented using the National Institutes of Health (NIH) GVHD scoring system. This
system includes information on the number of organs or sites involved and the severity within each affected
organ (eg, skin, mouth, eyes, gastrointestinal tract, liver, lungs, joints/fascia, and genital tract) (form 1) [1].
Organ-specific severity is scored from 0 to 3 with higher scores reflecting more severe disease. (See "Clinical
manifestations, diagnosis, and grading of chronic graft-versus-host disease", section on 'NIH consensus
criteria for GVHD severity'.)

Impact of acute GVHD — The administration of immunosuppressive medications as prophylaxis against

and/or treatment of acute GVHD affects the choice of therapy for chronic GVHD. Prophylaxis of acute GVHD
centers on immunosuppression of the donor cells, either pharmacologically or via T cell depletion. There is
no agreed upon standard regimen, and clinical practice varies by institution. Commonly employed regimens
include the use of methotrexate plus a calcineurin inhibitor (cyclosporin or tacrolimus) and the use of
mycophenolate mofetil plus a calcineurin inhibitor. Antithymocyte globulin may be added, especially for
those with an unrelated or haploidentical donor. (See "Prevention of acute graft-versus-host disease".)

While prophylaxis for acute GVHD is usually administered for a limited period of time, there are a number of
exceptions to this general course:

● In mismatched related sibling or matched unrelated donor transplants, cyclosporine may need to be
continued for a prolonged period of time, sometimes even years.

● A slower taper of immunosuppression may be preferable in older patients to prevent chronic GVHD.

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 3/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

● Some patients with chronic GVHD have unresolved acute GVHD, which is being treated with prednisone
and/or other immunosuppressive agents.

As a result, the patient who develops chronic GVHD may or may not already be taking an
immunosuppressive agent, such as prednisone, cyclosporine, tacrolimus, or mycophenolate mofetil. (See
"Prevention of acute graft-versus-host disease".)

INITIAL MANAGEMENT

Choice of therapy — The choice of initial therapy for patients with chronic GVHD depends on the organs
involved, the severity of symptoms, the prophylactic regimen used, and, to some extent, the importance of a
graft-versus-tumor (GVT) effect. Most treatment options are based on the immunosuppression of donor T
cells, which are responsible for the clinical manifestations of GVHD. However, the same cells are likely
responsible for an immunologic effect on the tumor. As such, treatment must aim to balance the benefit of
reducing GVHD with the potential harm of decreasing a GVT effect. (See "Prevention of acute graft-versus-
host disease", section on 'Balancing GVHD and GVT effect'.)  

The severity of chronic GVHD is determined by an assessment of the degree of organ involvement. Mild
disease involves two or fewer organs/sites with no clinically significant functional impairment. Mild disease
can be managed with adjunct treatment to specific sites alone. (See 'Adjunct treatment of specific sites'
below.)

In contrast, the following features are associated with a high risk of chronic GVHD-related morbidity and
mortality and are indications for systemic therapy:

● Involvement of three or more organs [1]

● Any single organ with severity score >2 (form 1) [1]
● Persistent thrombocytopenia (platelet count less than 100,000/microL) [15,16]
● Chronic GVHD that has evolved from acute GVHD [17]

In addition to ancillary therapy and supportive care to specific sites, patients with one or more of these
features require systemic therapy, usually with systemic glucocorticoids. All patients with chronic GVHD
requiring systemic therapy should be encouraged to enroll on clinical trials. (See 'Clinical trials' below.)

For those who are not eligible for a clinical trial or who do not wish to participate in one, we offer the
following guidance. While there is no agreed upon standard approach to the treatment of GVHD,
corticosteroids remain the mainstay of initial treatment. Patients who develop chronic GVHD while receiving
systemic glucocorticoids are treated with additional agents, such as those used for resistant disease. (See
'Treatment of resistant disease' below.)

Each institution must have guidelines for the management of GVHD in order to be acknowledged by the
international accrediting organizations for transplant centers (Joint Accreditation Committee for ISCT Europe
and EBMT [JACIE] and Foundation for the Accreditation of Cell Therapy [FACT]). Guidelines for the treatment
of chronic GVHD have been proposed by the American Society of Blood and Marrow Transplantation [18];
the British Committee for Standards in Hematology and the British Society for Bone Marrow Transplantation
[19,20]; and the European Group for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet
[21]. Our approach is generally consistent with these guidelines.

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 4/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

Prednisone — Corticosteroids are the initial systemic therapy of choice for patients with moderate to severe
chronic GVHD. Patients may require extended courses of corticosteroids with treatment durations of two to
three years and in some instances lifelong use of the lowest acceptable dose. The goal is to use the
minimum amount of corticosteroid necessary to control symptoms. Prednisone is usually started at a dose
of 1 mg/kg/day [22]. If symptoms are stable or improving after two weeks, prednisone may be tapered by 25
percent per week to a target dose of 1 mg/kg every other day. Prednisone is tapered further once symptoms
are fully resolved. If symptoms progress at two weeks or improvement is not apparent by four to six weeks,
therapy is escalated. (See 'Adding a calcineurin inhibitor' below.)

Randomized trials have evaluated the addition of other agents (azathioprine, cyclosporine, thalidomide,
mycophenolate mofetil, hydroxychloroquine) to prednisone for the initial treatment of chronic GVHD [15,23-
27]. Of these, only the addition of cyclosporine demonstrated a potential clinical benefit by decreasing
prednisone exposure. In this study, patients with newly diagnosed clinical extensive chronic GVHD and
platelet counts >100,000/microL were randomly assigned to treatment with prednisone (starting dose 1
mg/kg per day) with or without cyclosporine (12 mg/kg every other day) [23]. While treatment with the two-
drug combination reduced some of the risks associated with steroids (eg, avascular necrosis), there were no
significant differences between the two treatment arms in terms of overall mortality, transplantation-related
mortality, recurrent malignancy, or discontinuation of all immunosuppressive therapy.

We generally reserve the use of cyclosporine for patients who have persistent disease despite prednisone.
When chronic GVHD develops in a patient receiving prophylaxis for acute GVHD (eg, cyclosporine,
tacrolimus), the prophylactic regimen should be optimized to ensure a therapeutic level. (See 'Adding a
calcineurin inhibitor' below and "Treatment of acute graft-versus-host disease", section on 'Optimizing
prophylactic agents'.)

Prevention of infection — Patients who undergo hematopoietic cell transplantation (HCT) are at risk for
bacterial, viral, and fungal infections, the time course of which varies in the post-transplant period,
according to the degree of immune deficiency and cytopenias induced by the transplantation procedure.
Organ damage related to chronic GVHD, as well as the immunosuppressive regimen used to treat GVHD,
further increase the risk of infection. (See "Overview of infections following hematopoietic cell
transplantation".)

As a result, prophylactic therapies are used to prevent infections. Strategies to prevent infections in HCT
recipients with GVHD include the use of neutropenic (and HCT) precautions, antibacterial drugs, antiviral
drugs, antifungal drugs, immunoglobulin infusions, and vaccinations. Recommendations for use of these
strategies differ from one institution to another; the approach to prophylaxis in HCT recipients is discussed
in greater detail separately. (See "Prophylaxis of invasive fungal infections in adult hematopoietic cell
transplant recipients" and "Prevention of infections in hematopoietic cell transplant recipients" and
"Immunizations in hematopoietic cell transplant candidates and recipients".)

Adjunct treatment of specific sites — Patients with specific organs affected by chronic GVHD may benefit
from supportive care targeting these organs. Often, this requires a multidisciplinary approach. Detailed
suggestions regarding ancillary therapy have been provided by the American Society for Blood and Marrow
Transplantation, the British Committee for Standards in Hematology and the British Society for Bone Marrow
Transplantation, and the German-Austrian-Swiss Consensus Conference [18,20,28-30]. Underlying all these
sites is the concern of possible second malignancy, and special attention needs to be paid so that new
lesions are investigated.

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 5/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

● Skin – Dryness and flaking of the skin are a common manifestation of the disease. The thinning of the
skin may also make it prone to ulceration, which combined with the sclerosis may impair healing.
Emollients (ointments and creams) are frequently used, and a sauna suite may be especially helpful for
those with very dry skin. Topical steroids, when used sparingly, are also helpful, as is topical tacrolimus.
Attention to areas of skin breakdown is very important to ensure that these sites do not become
secondarily infected with microbes. Patients should be encouraged to use sun protection and to have an
annual skin examination by a dermatologist with a low threshold for biopsy of suspicious lesions. (See
"Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Ancillary measures in
chronic graft-versus-host disease'.)

● Mouth – Good oral and dental hygiene is very important [31]. Topical fluorides should be offered to
prevent caries. Infection with herpes simplex virus, human papilloma virus, Candida, and other fungal
organisms should be ruled out before initiating therapy. Topical steroids (eg, clobetasol) can be helpful
in areas that have ulceration or leukoplakia due to GVHD. Artificial saliva has also been used but, in our
experience, most patients prefer to carry a bottle of water and drink frequently. Stretching exercises
may increase the range of motion of the mouth. Patients with persistent or new oral lesions that occur
greater than three months after HCT should be evaluated for secondary cancer involving the oral cavity,
as discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor",
section on 'Oral health'.)

● Eyes – Dry eyes are very irritating, resulting in photophobia and significant pain [32]. Sunglasses can be
helpful. For patients who produce tears, options include tear duct plugs and duct closure with laser
treatment. The former tend to fall out frequently while the latter may be more permanent. Preservative-
free artificial tears are often used for hydration, with steroids and topical tacrolimus [33]. Gas permeable
scleral lenses have been developed to decrease symptoms in severe cases. Clinicians should have a high
degree of suspicion for infections (eg, infectious keratitis). Initial evaluation and periodic follow up by an
ophthalmologist knowledgeable in the potential complications of transplantation is described
separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on
'Ocular complications'.)

● Vagina – Vaginal dryness can be a common problem, especially in the setting of estrogen insufficiency.
Sexual function should be addressed with specific questions aimed towards resolving issues. Vaginal
stenosis is common and may require dilators. Early consultation with a gynecologist is warranted as
early intervention with topical steroids and estrogen can minimize progression [30,34].

● Gastrointestinal – Patients may have difficulty swallowing and esophageal strictures can occur.
Mechanical dilation (eg, bougienage) may be used to break apart the strictures. Patients with diarrhea
should have a standard evaluation including cultures, testing for Clostridioides difficile toxin,
cytomegalovirus cultures, and endoscopy. Occasionally, patients may have persistent diarrhea
(steatorrhea) due to pancreatic insufficiency from chronic GVHD. Pancreatic replacement is beneficial in
this setting. Consultation with a nutritionist should be considered for the malnourished patient. (See
"Treatment of chronic pancreatitis", section on 'Steatorrhea'.)

● Pulmonary – Oxygen, bronchodilators, inhaled corticosteroids, and pulmonary rehabilitation programs

may be beneficial to patients with pulmonary involvement [28]. (See "Pulmonary complications after
allogeneic hematopoietic cell transplantation".)

● Musculoskeletal – Patients with chronic GVHD often develop joint contractures, limb swelling, muscle
atrophy, and weakness [29]. Patients with chronic GVHD require screening for glucocorticoid-induced

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 6/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

myopathy and sclerotic changes in the skin and fascia that can limit joint mobility. Physical and
occupational therapy should be considered for patients with a decreased ability to perform activities of
daily living. Repeated evaluation may be needed by a physical therapist to assess muscular weakness
and range of motion. Patients with chronic GVHD should be evaluated for accelerated bone loss, as
discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor",
section on 'Bone and joint health'.)

● Endocrine – Patients with chronic GVHD have an increased risk of diabetes mellitus, hypothyroidism,
hypogonadism, and hypoadrenalism, as discussed separately. (See "Long-term care of the adult
hematopoietic cell transplantation survivor", section on 'Diabetes' and "Long-term care of the adult
hematopoietic cell transplantation survivor", section on 'Other endocrine'.)

● Immunological – Chronic GVHD is associated with impaired immune function. Therefore, close
attention should be paid to potential infections. Those with functional asplenia should be on penicillin
for prophylaxis against encapsulated organisms. Immunization should proceed as per guidelines, and
empiric antibiotics need to be started if the patient develops fevers. (See "Overview of infections
following hematopoietic cell transplantation".)

ASSESSMENT OF RESPONSE

Patients must be evaluated periodically to ensure that their disease is responding to treatment. The
frequency of these assessments depends on the comfort of the physician and patient and on the severity of
disease. In general, we expect patients to have stable or improving disease within two weeks of therapy. For
those with progression at two weeks or lack of response by four to six weeks, we consider the disease
resistant and switch therapy.

The National Institutes of Health (NIH) Consensus Criteria for Clinical Trials in Chronic Graft-versus-Host
Disease have proposed comprehensive diagnostic, staging, and response criteria for chronic GVHD [35].
These measures are practical for use both by transplantation and non-transplantation medical providers,
adaptable for use in adults and children, and focus on the most important chronic GVHD manifestations.

Based on these criteria, a proposed set of measures to be considered for use in clinical trials, as well as
forms for data collection, have been provided and are available on the ASBMT website [36]. Measures should
be made at three-month intervals and whenever major changes are made in treatment. Provisional
definitions of complete response, partial response, and progression are proposed for each organ system
and for overall outcomes. These response criteria have been validated in a prospective chronic GVHD
observational trial [37].

TREATMENT OF RESISTANT DISEASE

Adding a calcineurin inhibitor — As described above, prednisone (1 mg/kg daily) is our initial treatment of
choice for patients requiring systemic therapy for chronic GVHD. Additional therapy is warranted for patients
with progression after two weeks of prednisone or lack of response by four to six weeks. The ideal therapy in
this situation is not known, and patients should be encouraged to participate in a clinical trial. For those
unable or unwilling to participate in a trial, we suggest the addition of a calcineurin inhibitor (eg,
cyclosporin, tacrolimus). (See 'Clinical trials' below.)

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 7/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

The calcineurin inhibitors cyclosporine and tacrolimus have similar mechanisms of action, expected clinical
effectiveness, and toxic effects, including hypomagnesemia, hyperkalemia, hypertension, and
nephrotoxicity. Serious side effects include transplant-associated thrombotic microangiopathy and
neurotoxic effects that can lead to premature discontinuation. Cyclosporine and tacrolimus are nephrotoxic.
As a result, other nephrotoxic drugs should be avoided, if possible, so that the agent can be delivered at the
target doses. (See "Pharmacology of cyclosporine and tacrolimus".)

One option in this setting is the combination of prednisone (1 mg/kg every other day) and cyclosporine (6
mg/kg twice daily alternating every other day with prednisone). This combination was evaluated in a trial of
61 patients with high risk chronic GVHD [16]. Forty patients received this regimen as primary therapy for
chronic GVHD associated with thrombocytopenia, while the remaining patients received this combination as
salvage therapy after having failed prednisone plus azathioprine. At four years, actuarial survival was 51 and
67 percent for those administered prednisone plus cyclosporine as primary and salvage therapy,
respectively. Deaths resulted from interstitial pneumonia, relapse of the original disease, GVHD, infection,
organ failure, and hemorrhage.

In another study, patients with newly diagnosed clinical extensive chronic GVHD and platelet counts
>100,000/microL were randomly assigned to treatment with prednisone (starting dose 1 mg/kg per day) with
or without cyclosporine (12 mg/kg every other day) [23]. While treatment with the two-drug combination
reduced some of the risks associated with steroids (eg, avascular necrosis), there were no significant
differences between the two treatment arms in terms of overall mortality, transplantation-related mortality,
recurrent malignancy, or discontinuation of all immunosuppressive therapy.

We expect to attain stable disease within two weeks of starting therapy and wait four to six weeks prior to
changing to a new regimen.

Other therapeutic options — The best treatment for patients with progressive or persistent disease
despite prednisone and a calcineurin inhibitor (cyclosporine or tacrolimus) is not known, and clinical practice
varies. Patients should be encouraged to enroll on a clinical trial. (See 'Clinical trials' below.)

For those ineligible or unwilling to enroll on a clinical trial, the main treatment options are
nonpharmacologic therapies, such as extracorporeal photopheresis and psoralen ultraviolet irradiation
(PUVA) therapy, and the use of additional immunosuppressive drugs. A choice among these agents must
take into consideration the organs involved, patient comorbidities, physician experience, and available
resources.

In this setting, we often consider the use of extracorporeal photopheresis in addition to prednisone and a
calcineurin inhibitor since it allows for relatively high response rates without the addition of drugs with
potential side effects. However, extracorporeal photopheresis is only available at specialized centers and
requires the placement of a central venous catheter.

Nonpharmacologic therapies

Extracorporeal photopheresis — Extracorporeal photopheresis (ECP) consists of re-infusion of

ultraviolet-irradiated autologous peripheral lymphocytes that have been collected by apheresis and
incubated with 8-methoxypsoralen [38-44].

A literature review identified 735 patients with steroid-resistant, steroid-intolerant, or steroid-dependent

chronic GVHD treated with ECP [45]. ECP resulted in overall response rates of 50 to 65 percent
(approximately 30 to 35 percent complete) and approximately 25 to 35 percent of patients were able to

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 8/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

significantly taper steroid use. Responses were less likely in patients with more extensive disease, those with
a history of acute GVHD, and patients with thrombocytopenia.

ECP is contraindicated in patients with severe cardiovascular or renal impairment. Immunosuppression

results from a decrease in the number and function of circulating lymphocytes due primarily to the
inhibition of DNA transcription and mitosis. (See "Treatment of acute graft-versus-host disease", section on
'Extracorporeal photopheresis'.)

Psoralen ultraviolet irradiation — Psoralen ultraviolet irradiation (PUVA) combines the administration

of psoralens, a class of phototoxic plant-derived compounds, with an exposure to ultraviolet A radiation
(UVA) [46-54]. When used in patients with chronic GVHD and extensive skin involvement, PUVA is usually
begun at 25 percent of the normal dose; those with chronic GVHD and extensive skin involvement may be
very sensitive to burning with this modality. One study, for example, found that approximately 30 percent of
patients administered PUVA therapy achieved a complete remission [51]. In some, but not all studies [52],
the efficacy of PUVA seemed to be limited to the skin complications of chronic GVHD such as a steroid-
sparing effect on skin lesions [55]. This modality may therefore be most effective if used earlier in the course
of the disease when GVHD is limited to the skin. (See "Psoralen plus ultraviolet A (PUVA)
photochemotherapy".)

Mycophenolate mofetil — Mycophenolate mofetil (MMF) has antibacterial, antifungal, antiviral,

antitumor and immunosuppressive properties.

The use of MMF (2 g daily) in combination with cyclosporine and prednisolone was evaluated in a single
center trial of 24 patients with GVHD, including seven patients with chronic GVHD [56]. Moderate
improvement in symptoms was seen in three of six patients with limited stage chronic GVHD. The most
common toxicities were leukopenia, anemia, and thrombocytopenia.

A double-blind randomized trial to determine whether the addition of mycophenolate mofetil improves the
efficacy of initial systemic therapy of chronic GVHD was closed because an interim analysis indicated a low
probability of a positive result [24].

Side effects of MMF at commonly employed doses have been low. The major effect has been suppression of
the hematopoietic system with neutropenia as an important side effect. Gastrointestinal side effects have
also been reported. While the optimal dose of MMF has not been determined, doses of 15 mg/kg twice daily
are most commonly employed.

Sirolimus — Sirolimus (rapamycin) has been used for the treatment of refractory chronic GVHD [57].
While there is no standard dose, a reasonable regimen would be to use a loading dose of 6 mg followed by a
daily dose of 2 mg aiming for a target level of 10 ng/microL. Myelosuppression is common; other potential
side effects include seizures and hemolytic uremic syndrome. The use of sirolimus has also been associated
with sinusoidal obstruction syndrome (SOS) following myeloablative conditioning regimens, especially when
myeloablative doses busulfan were employed. (See "Prevention of acute graft-versus-host disease", section
on 'Tacrolimus plus sirolimus'.)

In a phase II trial of sirolimus plus tacrolimus and methylprednisolone in 35 patients with steroid-refractory
chronic GVHD, the overall response rate was 63 percent (17 percent complete) [57]. Common toxicities
included hyperlipidemia, renal dysfunction, and cytopenias. Thrombotic microangiopathies and infectious
complications were also seen.

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle… 9/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

Ruxolitinib — Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor that is used in the treatment of
primary myelofibrosis and polycythemia vera, has activity against chronic GVHD. JAK signaling contributes to
inflammation and tissue damage in GVHD. (See "Overview of immunosuppressive agents used for
prevention and treatment of graft-versus-host disease", section on 'Ruxolitinib'.)

Dose adjustments of ruxolitinib may be required for cytopenias and for renal or hepatic impairment. Toxicity
includes cytopenias, liver dysfunction, neurologic complaints, reactivation of viral infections, and bacterial or
fungal infections.

A "withdrawal syndrome" that resembles systemic inflammatory response syndrome may be seen when
ruxolitinib is discontinued in myelofibrosis [58]. Dose reduction should be gradual rather than abrupt,
caution is advised to monitor for a withdrawal-like syndrome, and resumption of ruxolitinib (and other
medical management) may be required in the setting of severe symptoms. As an example, among four
patients treated with ruxolitinib for acute and/or chronic GVHD following allogeneic hematopoietic cell
transplantation (HCT) for myelofibrosis, one of two patients who received a higher dose (10 mg/day) of
ruxolitinib developed severe cytopenias and died with recurrence of GVHD shortly after discontinuation of
the medication; treatment of two patients with 5 mg/day was safe and effective [59]. (See "Management of
primary myelofibrosis", section on 'Ruxolitinib treatment and cautions'.)

Ruxolitinib has not been directly compared in prospective trials to other immunosuppressive agents for
treatment of chronic GVHD.

A multicenter retrospective study included patients with steroid-refractory, moderate/severe chronic GVHD
who were treated with ruxolitinib (5 to 10 mg orally twice daily); patients had received a median of three
prior treatments for chronic GVHD (range 1 to 10) [60]. Results included the following:

● Responses were seen in 35 of 41 patients (85 percent).

● Relapses occurred in 2 of 35 patients (6 percent), and the estimated survival rate at six months was 97
percent (95% CI 92-100 percent).

● Adverse events included cytopenias (17 percent) and reactivation of cytomegalovirus (15 percent).

Further study is necessary to determine the efficacy and long-term toxicity of this agent in the treatment of
GVHD.

Ibrutinib — Ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that is used to treat certain lymphoid
malignancies (eg, chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma,
marginal zone lymphoma) has activity against chronic GVHD. Ibrutinib is approved by the US Food and Drug
Administration for treatment of chronic GVHD [61].

Reported in abstract form only, a phase II trial of ibrutinib in 42 patients with steroid-dependent or steroid-
resistant chronic GVHD reported responses in two-thirds (one-third of which were complete responses);
responses lasted ≥5 months in one-half of all patients [62]. Improvement occurred in multiple organ systems
(eg, skin, mouth, gastrointestinal tract, liver). Response to ibrutinib permitted reduction of glucocorticoid
dose to ≤0.15 mg/kg/day in nearly two-thirds of patients, and was associated with improved quality of life.
Common side effects of ibrutinib in patients with chronic GVHD included fatigue, bruising, stomatitis,
nausea, diarrhea, thrombocytopenia, and anemia; more serious side effects included hemorrhage,
infections, atrial fibrillation, hypertension, and tumor lysis syndrome.

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 10/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

Rituximab — Reports on the successful use of the anti-CD20 monoclonal antibody rituximab in patients
with refractory chronic GVHD suggest the potential use of agents directed at B cells [63-67]. Rituximab is also
being evaluated for chronic GVHD prophylaxis. In this setting, rituximab 375 mg/m2 is administered weekly
for four weeks. If there is a partial response, up to two more four-week courses may be administered.

Uncontrolled studies have suggested high response rates, especially among patients with skin or
musculoskeletal involvement:

● In another phase II trial of rituximab in 37 patients with steroid-refractory chronic GVHD, clinical
responses were seen in 32 patients (86 percent) [67]. Responses were maintained at one year, resulting
in corticosteroid dose reductions in 21 patients. Responses were more commonly seen in the skin, oral
cavity, and musculoskeletal system.

● In another study of rituximab in 21 patients with steroid-refractory chronic GVHD, clinical responses
were seen in 70 percent [65]. Responses were limited to patients with cutaneous and musculoskeletal
manifestations and were durable through one year of therapy.

● In a retrospective analysis of rituximab in the treatment of 18 patients with steroid-refractory chronic

GVHD, responses were seen in 11 patients (55 percent) with one achieving a complete response [68]. Ten
patients were able to reduce or discontinue corticosteroid therapy.

● In a phase 2 randomized study of agents for sclerotic chronic GVHD, improvement in skin sclerosis or
joint range of motion was seen in 10 of 37 (27 percent) treated with rituximab and 9 of 35 (36 percent)
patients randomized to imatinib [69].

Tyrosine kinase inhibitors — Small prospective and retrospective studies have evaluated the use of
imatinib for patients with chronic GVHD [70-73]. In three prospective studies performed in patients with
steroid-refractory chronic GVHD, responses were seen in 7 of 14 patients, 15 of 19 patients, and 20 of 39
patients, respectively [70,71,73]. While complete responses are not seen, many patients are able to decrease
their steroid requirements. This agent has also had some effectiveness in patients with chronic GVHD
involving the lungs [74].

In a randomized phase 2 study evaluating agents for sclerotic chronic GVHD, improvement in skin sclerosis
or joint range of motion was seen in 9 of 35 (36 percent) patients randomized to imatinib and 10 of 37 (27
percent) patients randomized to rituximab [69].

Ursodeoxycholic acid — The rationale for the use of ursodeoxycholic acid (UDCA), a relatively nontoxic
hydrophilic bile acid with a striking choleretic effect, is that chronic GVHD affecting the liver shares many
features with primary biliary cirrhosis, a disorder known to respond to this agent. (See "Overview of the
management of primary biliary cholangitis".)

One study evaluated the effectiveness of 6 to 12 weeks of UDCA in 12 patients with refractory chronic GVHD
of the liver [75]. Compared with baseline values, treatment resulted in decreases in the serum
concentrations of bilirubin, alkaline phosphatase, and AST by approximately one-third each. Drug
discontinuation quickly resulted in a rise in the serum levels of all three markers. Long-term efficacy of this
treatment has not been determined.

The mechanism of action of UDCA in chronic GVHD is unclear. One possibility is that the agent simply
replaces the more hydrophobic detergent and toxic bile acids. A more intriguing mode of action may be
altered expression of HLA class I antigens on hepatocytes, thereby diminishing the immune attack [76].

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 11/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

Interleukin-2 — Interleukin-2 (IL-2) is a T cell derived cytokine that plays a central role in immune
responses. IL-2 is also important for the development and function of regulatory T cells (Tregs). Interest in
the use of IL-2 in the management of GVHD was initially based on mouse studies that suggested that Treg
cells could control GVHD. (See "Pathogenesis of graft-versus-host disease (GVHD)", section on 'Overview of
GVHD'.)

In a phase I dose escalation study, 28 patients with glucocorticoid refractory chronic GVHD were treated with
eight weeks of daily low-dose subcutaneous IL-2 [77]. At enrollment, patients were on a median of three
concurrent agents for the management of GVHD. They had a median of three areas of GVHD involvement.
The maximum tolerated dose of IL-2 was 1x106 international units/m2. Higher doses produced persistent
constitutional symptoms (eg, fever, malaise, and arthralgia). Severe (grade 3/4/5) toxicities included
thrombotic microangiopathy (two patients), infection (three patients), and myocardial infarction (two
patients). None of the patients experienced a relapse of the underlying malignancy. Of the 23 patients who
could be evaluated for response, 12 had a partial response and 11 had stable disease. Prolonged responses
were seen in a subset of patients who chose to continue IL-2 for an extended period, many of whom were
able to taper glucocorticoid dose.

A phase 2 trial of the same regimen in 35 adults with glucocorticoid refractory chronic GVHD reported
clinical responses in 20 of 33 evaluable patients (61 percent, none complete) by week 12 [78]. Ten patients
had stable disease and three had progressive disease. Following a mandatory four-week hiatus, 35 patients
elected to resume injections and extended IL-2 therapy was continued long-term, allowing for glucocorticoid
taper in some. Adverse events resulted in dose reduction in five patients and early withdrawal in two. The
use of low-dose IL-2 was associated with an increase in regulatory T cells.

These results suggest that IL-2 administration is safe and may produce responses in chronic refractory
GVHD. We await further study of this agent prior to incorporating it into routine care.

Other agents and modalities — Newer agents have continued to be introduced and patients should be
encouraged to participate in clinical trials. (See 'Clinical trials' below.)

Differences in the overall response rates may be related to the characteristics of enrolled patients, such as
the presence or absence of high-risk features, or whether chronic GVHD had developed de novo or occurred
despite the administration of immunosuppressive medications.

● In initial studies, etanercept has been used as salvage therapy with some success [79].

● Studies of thalidomide have reported overall response rates ranging from 20 to 65 percent [80,81].

● Pentostatin (initial dose: 4 mg/m2 IV every two weeks for 12 doses, continued as long as benefit was
documented) was given to heavily pretreated (median of four prior regimens) patients with chronic
GVHD [82]. An objective response was seen in 32 of the 58 patients (55 percent), with a one-year overall
survival of 78 percent. Similar response rates were noted in a phase II trial of this agent in 51 children
with corticosteroid-refractory chronic GVHD [83].

CLINICAL TRIALS

Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid,
peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate
research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 12/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

PROGNOSIS

Patients with mild (limited) chronic GVHD have a favorable prognosis even without therapy, while those who
have more extensive (moderate to severe) GVHD, particularly with multiorgan involvement, have poor long-
term outcomes. Several patient-, transplant-, and disease-related prognostic factors have been identified.
These are described in more detail separately. (See "Clinical manifestations, diagnosis, and grading of
chronic graft-versus-host disease", section on 'Prognosis and grading'.)

Hematopoietic cell transplantation survivors are at risk of developing therapy-related complications that
may present years after treatment. These complications have surfaced as significant causes of increased
mortality, and screening for some of these entities is advised in the hope that early detection may lead to
better management. This is discussed in more detail separately. (See "Long-term care of the adult
hematopoietic cell transplantation survivor".)

SUMMARY AND RECOMMENDATIONS

● Chronic graft-versus-host disease (GVHD) is the single major factor determining long-term outcome and
quality of life following allogeneic hematopoietic cell transplantation.

● The addition of antithymocyte globulin (ATG) to preparative regimens reduces the rate of chronic GVHD.
The choice of preparative regimen is individualized taking into account details regarding the recipient
comorbidities, underlying condition and disease status, donor, and graft source. ATG is commonly
incorporated into the prophylactic regimen for patients with an unrelated donor or haploidentical donor
undergoing either myeloablative or reduced intensity conditioning. (See 'Prevention' above and
"Preparative regimens for hematopoietic cell transplantation", section on 'Choice of regimen'.)

● The treatment of chronic GVHD may be complicated by the current administration of

immunosuppressive agents for active prophylaxis against and/or treatment of acute GVHD. (See 'Impact
of acute GVHD' above.)

● The treatment of chronic GVHD is determined in part by the severity of the disease. Disease severity can
be documented using the National Institutes of Health (NIH) GVHD scoring system (form 1). (See
'Grading' above.)

● Mild disease involves two or fewer organs/sites with no clinically significant functional impairment. Mild
disease can be managed with adjunct treatment to specific sites alone. Patients with mild chronic GVHD
that does not respond to local measures or who are not candidates for localized therapy are candidates
for systemic treatment. (See 'Adjunct treatment of specific sites' above.)

● The following features are associated with a high risk of chronic GVHD-related morbidity and mortality
and are indications for systemic therapy (see 'Choice of therapy' above):

• Involvement of three or more organs

• Any single organ with severity score >2 (form 1)
• Persistent thrombocytopenia (platelet count less than 100,000/microL)
• Chronic GVHD that has evolved from acute GVHD

● In addition to ancillary therapy and supportive care to specific sites, patients with one or more of these
features require systemic therapy, usually with systemic glucocorticoids. All patients with chronic GVHD

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 13/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

requiring systemic therapy should be encouraged to enroll on clinical trials. (See 'Clinical trials' above.)

● For patients who are ineligible or unwilling to participate in a clinical trial, we offer the following
suggestions. For patients requiring systemic therapy, we suggest single agent prednisone rather than
prednisone plus other agents (Grade 2B). The goal is to use the minimum amount of corticosteroid
necessary to control symptoms. Prednisone is usually started at a dose of 1 mg/kg/day. (See
'Prednisone' above.)

● Additional therapy is warranted for patients with progression after two weeks of prednisone or lack of
response by four to six weeks. For such patients, we suggest the addition of a calcineurin inhibitor (eg,
cyclosporin, tacrolimus) (Grade 2C). The best treatment for patients with progressive or persistent
disease despite prednisone and a calcineurin inhibitor (cyclosporine or tacrolimus) is not known and
clinical practice varies. Patients should again be encouraged to enroll on a clinical trial. (See 'Clinical
trials' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
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.

2. Lee SJ. New approaches for preventing and treating chronic graft-versus-host disease. Blood 2005;
105:4200.

3. Pavletic SZ, Carter SL, Kernan NA, et al. Influence of T-cell depletion on chronic graft-versus-host
disease: results of a multicenter randomized trial in unrelated marrow donor transplantation. Blood
2005; 106:3308.

4. Fraser CJ, Scott Baker K. The management and outcome of chronic graft-versus-host disease. Br J
Haematol 2007; 138:131.

5. Chao NJ, Parker PM, Niland JC, et al. Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-
host disease. Biol Blood Marrow Transplant 1996; 2:86.

6. Witherspoon RP, Sullivan KM, Lum LG, et al. Use of thymic grafts or thymic factors to augment
immunologic recovery after bone marrow transplantation: brief report with 2 to 12 years' follow-up.
Bone Marrow Transplant 1988; 3:425.

7. Deeg HJ, Lin D, Leisenring W, et al. Cyclosporine or cyclosporine plus methylprednisolone for
prophylaxis of graft-versus-host disease: a prospective, randomized trial. Blood 1997; 89:3880.

8. Deeg HJ, Flowers ME, Leisenring W, et al. Cyclosporine (CSP)or CSP plus methylprednisolone for graft-
versus-host disease prophylaxis in patients with high-risk lymphohemopoietic malignancies: long-term
follow-up of a randomized trial. Blood 2000; 96:1194.

9. Kansu E, Gooley T, Flowers ME, et al. Administration of cyclosporine for 24 months compared with 6
months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial.
Blood 2001; 98:3868.
https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 14/23
12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

10. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or without
anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a
randomised, open-label, multicentre phase 3 trial. Lancet Oncol 2009; 10:855.

11. Socié G, Schmoor C, Bethge WA, et al. Chronic graft-versus-host disease: long-term results from a
randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-
Fresenius. Blood 2011; 117:6375.

12. Kröger N, Solano C, Wolschke C, et al. Antilymphocyte Globulin for Prevention of Chronic Graft-versus-
Host Disease. N Engl J Med 2016; 374:43.

13. Cutler C, Kim HT, Bindra B, et al. Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD
after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial. Blood 2013;
122:1510.

14. Arai S, Sahaf B, Narasimhan B, et al. Prophylactic rituximab after allogeneic transplantation decreases
B-cell alloimmunity with low chronic GVHD incidence. Blood 2012; 119:6145.

15. Sullivan KM, Witherspoon RP, Storb R, et al. Prednisone and azathioprine compared with prednisone
and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged
thrombocytopenia after allogeneic marrow transplantation. Blood 1988; 72:546.

16. Sullivan KM, Witherspoon RP, Storb R, et al. Alternating-day cyclosporine and prednisone for treatment
of high-risk chronic graft-v-host disease. Blood 1988; 72:555.

17. Wingard JR, Piantadosi S, Vogelsang GB, et al. Predictors of death from chronic graft-versus-host
disease after bone marrow transplantation. Blood 1989; 74:1428.

18. Couriel D, Carpenter PA, Cutler C, et al. Ancillary therapy and supportive care of chronic graft-versus-
host disease: national institutes of health consensus development project on criteria for clinical trials in
chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol
Blood Marrow Transplant 2006; 12:375.

19. Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft-versus-host disease. Br
J Haematol 2012; 158:46.

20. 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.

21. Ruutu T, Gratwohl A, de Witte T, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group
recommendations for a standardized practice. Bone Marrow Transplant 2014; 49:168.

22. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003;
9:215.

23. Koc S, Leisenring W, Flowers ME, et al. Therapy for chronic graft-versus-host disease: a randomized trial
comparing cyclosporine plus prednisone versus prednisone alone. Blood 2002; 100:48.

24. 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.

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 15/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

25. Arora M, Wagner JE, Davies SM, et al. Randomized clinical trial of thalidomide, cyclosporine, and
prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease.
Biol Blood Marrow Transplant 2001; 7:265.

26. Koc S, Leisenring W, Flowers ME, et al. Thalidomide for treatment of patients with chronic graft-versus-
host disease. Blood 2000; 96:3995.

27. Gilman AL, Schultz KR, Goldman FD, et al. Randomized trial of hydroxychloroquine for newly diagnosed
chronic graft-versus-host disease in children: a Children's Oncology Group study. Biol Blood Marrow
Transplant 2012; 18:84.

28. Hildebrandt GC, Fazekas T, Lawitschka A, et al. Diagnosis and treatment of pulmonary chronic GVHD:
report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant
2011; 46:1283.

29. Marks C, Stadler M, Häusermann P, et al. German-Austrian-Swiss Consensus Conference on clinical

practice in chronic graft-versus-host disease (GVHD): guidance for supportive therapy of chronic
cutaneous and musculoskeletal GVHD. Br J Dermatol 2011; 165:18.

30. Frey Tirri B, Häusermann P, Bertz H, et al. Clinical guidelines for gynecologic care after hematopoietic
SCT. Report from the international consensus project on clinical practice in chronic GVHD. Bone Marrow
Transplant 2015; 50:3.

31. Mays JW, Fassil H, Edwards DA, et al. Oral chronic graft-versus-host disease: current pathogenesis,
therapy, and research. Oral Dis 2013; 19:327.

32. Dietrich-Ntoukas T, Cursiefen C, Westekemper H, et al. Diagnosis and treatment of ocular chronic graft-
versus-host disease: report from the German-Austrian-Swiss Consensus Conference on Clinical Practice
in chronic GVHD. Cornea 2012; 31:299.

33. Jung JW, Lee YJ, Yoon SC, et al. Long-term result of maintenance treatment with tacrolimus ointment in
chronic ocular graft-versus-host disease. Am J Ophthalmol 2015; 159:519.

34. Hirsch P, Leclerc M, Rybojad M, et al. Female genital chronic graft-versus-host disease: importance of
early diagnosis to avoid severe complications. Transplantation 2012; 93:1265.

35. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-versus-host disease:
National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic
Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant
2006; 12:252.

36. http://c.ymcdn.com/sites/asbmt.site-ym.com/resource/resmgr/Docs/ResponseCriteriaAPPENDIXAFor.p
df (Accessed on June 26, 2014).

37. Palmer J, Chai X, Pidala J, et al. Predictors of survival, nonrelapse mortality, and failure-free survival in
patients treated for chronic graft-versus-host disease. Blood 2016; 127:160.

38. 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.

39. Alcindor T, Gorgun G, Miller KB, et al. Immunomodulatory effects of extracorporeal

photochemotherapy in patients with extensive chronic graft-versus-host disease. Blood 2001; 98:1622.
https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 16/23
12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

40. Dall'Amico R, Messina C. Extracorporeal photochemotherapy for the treatment of graft-versus-host

disease. Ther Apher 2002; 6:296.

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.

42. 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.

43. 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.

44. Dignan FL, Aguilar S, Scarisbrick JJ, et al. Impact of extracorporeal photopheresis on skin scores and
quality of life in patients with steroid-refractory chronic GVHD. Bone Marrow Transplant 2014; 49:704.

45. 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.

46. Hymes SR, Morison WL, Farmer ER, et al. Methoxsalen and ultraviolet A radiation in treatment of
chronic cutaneous graft-versus-host reaction. J Am Acad Dermatol 1985; 12:30.

47. Atkinson K, Weller P, Ryman W, Biggs J. PUVA therapy for drug-resistant graft-versus-host disease. Bone
Marrow Transplant 1986; 1:227.

48. Deeg HJ. Ultraviolet irradiation in transplantation biology. Manipulation of immunity and
immunogenicity. Transplantation 1988; 45:845.

49. Eppinger T, Ehninger G, Steinert M, et al. 8-Methoxypsoralen and ultraviolet A therapy for cutaneous
manifestations of graft-versus-host disease. Transplantation 1990; 50:807.

50. Kripke ML. Immunological unresponsiveness induced by ultraviolet radiation. Immunol Rev 1984;
80:87.

51. Kapoor N, Pelligrini AE, Copelan EA, et al. Psoralen plus ultraviolet A (PUVA) in the treatment of chronic
graft versus host disease: preliminary experience in standard treatment resistant patients. Semin
Hematol 1992; 29:108.

52. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-
resistant chronic GVHD. Blood 2006; 107:3074.

53. Marshall SR. Technology insight: ECP for the treatment of GvHD--can we offer selective immune control
without generalized immunosuppression? Nat Clin Pract Oncol 2006; 3:302.

54. Knobler R, Barr ML, Couriel DR, et al. Extracorporeal photopheresis: past, present, and future. J Am
Acad Dermatol 2009; 61:652.

55. Flowers ME, Apperley JF, van Besien K, et al. A multicenter prospective phase 2 randomized study of
extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood 2008; 112:2667.

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 17/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

56. Basara N, Blau WI, Römer E, et al. Mycophenolate mofetil for the treatment of acute and chronic GVHD
in bone marrow transplant patients. Bone Marrow Transplant 1998; 22:61.

57. Couriel DR, Saliba R, Escalón MP, et al. Sirolimus in combination with tacrolimus and corticosteroids for
the treatment of resistant chronic graft-versus-host disease. Br J Haematol 2005; 130:409.

58. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients
with myelofibrosis. Mayo Clin Proc 2011; 86:1188.

59. Mori Y, Ikeda K, Inomata T, et al. Ruxolitinib treatment for GvHD in patients with myelofibrosis. Bone
Marrow Transplant 2016; 51:1584.

60. Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease

after allogeneic stem cell transplantation: a multicenter survey. Leukemia 2015; 29:2062.

61. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205552s017lbl.pdf.

62. Miklos D, Cutler CS, Arora M, et al. Multicenter Open-Label Phase 2 Study of Ibrutinib in Chronic Graft
Versus Host Disease (cGVHD) after Failure of Corticosteroids (late breaking abstract-3). Blood 2016.

63. Ratanatharathorn V, Carson E, Reynolds C, et al. Anti-CD20 chimeric monoclonal antibody treatment of
refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease.
Ann Intern Med 2000; 133:275.

64. Canninga-van Dijk MR, van der Straaten HM, Fijnheer R, et al. Anti-CD20 monoclonal antibody
treatment in 6 patients with therapy-refractory chronic graft-versus-host disease. Blood 2004;
104:2603.

65. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease.
Blood 2006; 108:756.

66. Alousi AM, Uberti J, Ratanatharathorn V. The role of B cell depleting therapy in graft versus host disease
after allogeneic hematopoietic cell transplant. Leuk Lymphoma 2010; 51:376.

67. Kim SJ, Lee JW, Jung CW, et al. Weekly rituximab followed by monthly rituximab treatment for steroid-
refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study.
Haematologica 2010; 95:1935.

68. Clavert A, Chevallier P, Guillaume T, et al. Safety and efficacy of rituximab in steroid-refractory chronic
GVHD. Bone Marrow Transplant 2013; 48:734.

69. Arai S, Pidala J, Pusic I, et al. A Randomized Phase II Crossover Study of Imatinib or Rituximab for
Cutaneous Sclerosis after Hematopoietic Cell Transplantation. Clin Cancer Res 2016; 22:319.

70. 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.

71. Olivieri A, Locatelli F, Zecca M, et al. Imatinib for refractory chronic graft-versus-host disease with
fibrotic features. Blood 2009; 114:709.

72. 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.

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 18/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

73. Olivieri A, Cimminiello M, Corradini P, et al. Long-term outcome and prospective validation of NIH
response criteria in 39 patients receiving imatinib for steroid-refractory chronic GVHD. Blood 2013;
122:4111.

74. Stadler M, Ahlborn R, Kamal H, et al. Limited efficacy of imatinib in severe pulmonary chronic graft-
versus-host disease. Blood 2009; 114:3718.

75. Fried RH, Murakami CS, Fisher LD, et al. Ursodeoxycholic acid treatment of refractory chronic graft-
versus-host disease of the liver. Ann Intern Med 1992; 116:624.

76. Hillaire S, Boucher E, Calmus Y, et al. Effects of bile acids and cholestasis on major histocompatibility
complex class I in human and rat hepatocytes. Gastroenterology 1994; 107:781.

77. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N
Engl J Med 2011; 365:2055.

78. Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-2
therapy for chronic graft-versus-host disease. Blood 2016; 128:130.

79. Chiang KY, Abhyankar S, Bridges K, et al. Recombinant human tumor necrosis factor receptor fusion
protein as complementary treatment for chronic graft-versus-host disease. Transplantation 2002;
73:665.

80. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for the treatment of chronic graft-versus-host
disease. N Engl J Med 1992; 326:1055.

81. Parker PM, Chao N, Nademanee A, et al. Thalidomide as salvage therapy for chronic graft-versus-host
disease. Blood 1995; 86:3604.

82. 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.

83. Jacobsohn DA, Gilman AL, Rademaker A, et al. 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.

Topic 3550 Version 42.0

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 19/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

GRAPHICS

NIH consensus criteria for organ scoring of chronic GVHD

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 20/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 21/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate

GVHD: graft-versus-host disease; KPS: Karnofsky Performance Status; ECOG: Eastern Cooperative Oncology Group; LPS: Lansky Performance Status; BSA: body
surface area; ADL: activities of daily living; LFTs: liver function tests; AP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase;
ULN: upper limit of normal.
* Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the
percentage of total body surface (BSA) score and the skin feature score, OR if superficial sclerotic features are present (score 2), but there is impaired mobility or
ulceration (score 3), the higher level should be used for the final skin scoring.
¶ Weight loss within three months.
Δ Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 22/23

12/10/2020 Treatment of chronic graft-versus-host disease - UpToDate
discrepancy between symptoms and FEV1 scores.
◊ To be completed by specialist or trained medical providers.

Reproduced from: Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-
versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015; 21:389. Illustration used with the permission of
Elsevier Inc. All rights reserved.

Graphic 69017 Version 5.0

https://www.uptodate.com/contents/treatment-of-chronic-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitl… 23/23