Treatment of Acute Graft-Versus-Host Disease

12/10/2020 Treatment of acute graft-versus-host disease - UpToDate
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Treatment of acute 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: May 15, 2020.
INTRODUCTION
Acute graft-versus-host disease (GVHD) is a common complication of allogeneic

hematopoietic cell transplant (HCT) that classically presents in the early post-transplantation
period. It is thought to be primarily a T cell-mediated disease that 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. The skin, gastrointestinal tract, and liver are the principal target organs in patients
with acute GVHD.
Clinically significant acute GVHD occurs in 9 to 50 percent of patients who receive an

allogeneic HCT from a genotypically HLA-identical sibling, despite intensive prophylaxis with
immunosuppressive agents, such as methotrexate, cyclosporine, corticosteroids,
mycophenolate mofetil, or antithymocyte globulin. Acute GVHD is more common following
HCT from matched unrelated donors and haploidentical donors. (See "Donor selection for
hematopoietic cell transplantation".)
The management of acute GVHD will be reviewed here. Specific recommendations for the
prevention and diagnosis of GVHD are discussed separately. (See "Prevention of acute graft-
versus-host disease" and "Clinical manifestations, diagnosis, and grading of acute graft-
versus-host disease".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC
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
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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 of 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. However, each institution must
have guidelines for the prevention and management of GVHD in order to be acknowledged
by international accrediting organizations. This is discussed in more detail separately. (See
"Prevention of acute graft-versus-host disease", section on 'Choice of prophylaxis'.)
Diagnosis of GVHD — Acute GVHD can involve the skin, gastrointestinal tract, and liver. The
diagnosis can be made readily on clinical grounds in the patient who presents with a classic
rash, abdominal cramps with diarrhea, and a rising serum bilirubin concentration within the
first 100 days following hematopoietic cell transplantation (HCT), most often within two to
three weeks following HCT. (See "Clinical manifestations, diagnosis, and grading of acute
graft-versus-host disease".)
In many cases, however, the diagnosis is less straightforward, and competing causes for
isolated abnormalities must be considered and excluded. A skin rash alone may be caused by
antibiotics or a myriad of other drugs with which these patients are often treated including
the preparative regimen; diarrhea may be infectious in nature; and hyperbilirubinemia may
be related to biliary sludge or a side effect of multiple drugs or parenteral nutrition. This is
discussed in more detail separately. (See "Diagnostic approach to the adult with jaundice or
asymptomatic hyperbilirubinemia" and "Drug-induced liver injury".)
Prevention of infection — Patients who undergo 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 and immune suppression due to damage to lymph nodes and the thymus
related to acute 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, immune globulin 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".)
INITIAL MANAGEMENT
Choice of therapy — The choice of initial therapy for patients with acute 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 acute GVHD is determined by an assessment of the degree of involvement of

the skin, liver, and gastrointestinal tract (table 1). Grade I GVHD describes cutaneous GVHD
over ≤50 percent body surface area without liver or gastrointestinal tract involvement. All
other manifestations of acute GVHD and more severe cutaneous disease are considered
grade II or higher.
● Grade I GVHD – Management of mild cutaneous GVHD centers on the use of topical
treatments (eg, topical steroids) and the optimization of prophylactic measures (eg,
cyclosporine levels). (See 'Skin-directed therapy' below.)
● Grade II or higher GVHD – In addition to the care outlined for grade I GVHD, patients
with more severe disease are treated with systemic glucocorticoids (eg,
methylprednisolone). Nonabsorbable oral steroids are added as local therapy for most
patients with gastrointestinal involvement. Nonabsorbable oral steroids should not be
used in patients with suspected gastrointestinal infection (eg, cytomegalovirus colitis).
(See 'Gastrointestinal tract-directed therapy' below.)
While there is no agreed-upon standard approach to the treatment of GVHD, corticosteroids

remain the mainstay of initial treatment and 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 acute GVHD have been proposed by the American Society of
Blood and Marrow Transplantation [1]; the British Committee for Standards in Hematology
and the British Society for Bone Marrow Transplantation [2]; and the European Group for
Blood and Marrow Transplantation (EBMT) and European LeukemiaNet [3]. Our approach is
generally consistent with these guidelines.
Grade I GVHD — Grade I acute GVHD includes patients with a maculopapular rash over ≤50
percent of their body surface area without evidence of liver or gastrointestinal tract
involvement. The management of grade I GVHD is directed toward the control of local
symptoms and maximizing prophylactic agents.
Skin-directed therapy — In most patients, the first (and most common) clinical
manifestation of acute GVHD is a maculopapular rash, usually occurring at or near the time
of the white blood cell engraftment. Topical steroids are the most commonly used skin-
directed therapy for acute GVHD. Antihistamines may be used as adjuvant therapy for
patients with pruritus.
Topical steroids differ in their strength, vehicle (eg, ointments, creams, lotions), and method
of application. In general, for cutaneous GVHD, mid- to high-potency topical steroids are
applied twice daily to moist skin and covered with warm wet towels as an occlusive measure
("wet wrap"). The choice of topical steroid and duration of therapy must take into account the
location of disease. (See "Topical corticosteroids: Use and adverse effects".)
General measures for the management of pruritus include moisturizers, nonirritating

creams, topical corticosteroids, and antihistamines. (See "Pruritus: Overview of
management" and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section
on 'Ancillary measures in chronic graft-versus-host disease'.)
There is no agreed-upon second-line therapy for cutaneous disease that is resistant to topical
steroids, and clinical practice varies [4]. One approach is to use topical tacrolimus [2]. Topical
tacrolimus (0.1 percent for adults) is applied twice daily until resolution of symptoms. If the
disease flares upon discontinuation, topical tacrolimus can be restarted at a lower dose (0.03
percent) and then discontinued upon resolution of symptoms.
Optimizing prophylactic agents — All patients undergoing allogeneic hematopoietic cell

transplant (HCT) with T cell-replete grafts should receive prophylaxis for GVHD. When acute
GVHD of any grade develops, the prophylactic regimen should be optimized to ensure a
therapeutic level. For those no longer receiving prophylaxis, the prior prophylactic agent (eg,
cyclosporine) should be restarted to achieve therapeutic levels.
While practice varies, the most common prophylaxis regimen is the combination of
cyclosporine and methotrexate [3]. The cyclosporine is administered to reach a therapeutic
target concentration, which varies according to the time from transplantation. A target
concentration of 200 to 300 mcg/L is used during the first three to four weeks post-
transplant; then, if there is no GVHD, the target concentration is decreased to 100 to 200
mcg/L until three months after transplantation, and then tapered further. Patients who
develop GVHD of any grade should have their cyclosporine dose adjusted to ensure a
therapeutic level (eg, 200 to 300 mcg/L).
Although tacrolimus and cyclosporine are closely related, several anecdotal reports suggest
that tacrolimus may be used to treat patients who have failed prophylaxis with cyclosporine.
Currently, however, these are only case reports and abstracts; there are no prospective
studies to suggest the actual salvage rate with tacrolimus for those who have failed
prophylaxis with cyclosporine. In a retrospective study, 2 of 20 evaluable patients had a
complete resolution of GVHD after changing treatment to tacrolimus [5].
Grade II to IV GVHD — As described above, grade I GVHD describes cutaneous GVHD over
≤50 percent body surface area without liver or gastrointestinal tract involvement. All other
manifestations of acute GVHD and more severe cutaneous disease are considered grade II or
higher. Patients with grade II or higher acute GVHD are treated with glucocorticoids (eg,
methylprednisolone). Oral beclomethasone, a nonabsorbable glucocorticoid, is added for
most patients with gastrointestinal involvement. Oral beclomethasone should not be
administered if a gastrointestinal infection, such as cytomegalovirus (CMV) colitis, is
suspected. Topical steroids can be added for further control of cutaneous lesions. In
addition, the prophylactic regimen should be optimized to ensure a therapeutic level. (See
'Optimizing prophylactic agents' above and "Epidemiology, clinical manifestations, and
treatment of cytomegalovirus infection in immunocompetent adults", section on
'Gastrointestinal manifestations'.)
Studies evaluating the addition of other agents to glucocorticoids have had mixed results.
The largest was a randomized phase II trial that evaluated the relative effectiveness of
glucocorticoids plus one of four agents (ie, etanercept, mycophenolate, denileukin,
pentostatin) for the initial treatment of acute GVHD [6]. Results included:
● Day 28 post-initiation of treatment complete response (CR) rates for methylprednisolone

plus either etanercept, or mycophenolate, or denileukin, or pentostatin were 26, 60, 53,
and 38 percent, respectively.
● Nine-month overall survival (OS) rates for these four treatment regimens were 47, 64, 49,
and 47 percent, respectively.
● Cumulative incidences of severe infection were 48, 44, 62, and 57 percent, respectively.
● An exploratory subgroup analysis suggested that a panel of six biomarkers for GVHD
measured at the initiation of therapy predicted for response to therapy and survival at
six months [7].
These efficacy and toxicity data suggested the use of mycophenolate plus glucocorticoids as
the most promising combination. However, a multicenter, randomized, double blind, phase

III trial comparing glucocorticoids to glucocorticoids plus mycophenolate was closed early
due to futility (CTN 0802, NCT01002742). Therefore, although mycophenolate appeared
promising, corticosteroids remain as the standard initial treatment for clinically significant
acute GVHD.
Glucocorticoids — Glucocorticoids are the standard initial therapy for patients with grade
II or higher acute GVHD [1-4]. The most commonly used glucocorticoid is
methylprednisolone. Although different doses and schedules have been used, the most
widely used is methylprednisolone 2 mg/kg per day in divided doses. Steroids are continued
for several weeks in responders and then gradually tapered over a period of several months
[8]. Gradual tapering is important to prevent a flare of GVHD. Patients who demonstrate
progression of disease by day 5 or nonresponse by day 7 are considered to have
corticosteroid resistance. Treatment of acute GVHD with glucocorticoids results in CR rates
ranging from 25 to 40 percent [9-12].
A variety of different glucocorticoid regimens have been evaluated for the management of
acute GVHD. Initial studies used high doses (eg, 10 to 20 mg/kg) of intravenous bolus
methylprednisolone [13,14]. These studies showed a high response rate, but were
complicated by opportunistic infections, interstitial pneumonitis, and recrudescence of GVHD
with dose reduction. Subsequent studies evaluating more moderate doses of
methylprednisolone (1.5 to 2 mg/kg) reported good response rates overall, but poor
outcomes for those with severe GVHD [15,16].
In an attempt to compare these different approaches, a multicenter trial randomly assigned

95 patients with acute GVHD to receive early treatment with either low (2 mg/kg per day) or
high (10 mg/kg per day) dose methylprednisolone [17]. On day 5 of therapy, almost one-half
of patients in the low dose group were switched to a higher dose because of lack of response
or progression. With this strategy, there were no differences in mean response rates or
actuarial survival at three years (63 versus 62 percent).
It is unknown whether even lower doses can be used for less severe GVHD (eg, grade II). A
retrospective study analyzed transplant outcomes among 733 patients who received initial
treatment for acute GVHD with either standard dose (prednisone-equivalent dose of 2 mg/kg
per day) or low dose (1 mg/kg per day) glucocorticoids [18]. It was concluded that initial
treatment with low dose glucocorticoids for patients with grades I to II acute GVHD did not
compromise disease control or mortality and was associated with decreased length of
hospitalization, as well as reductions in the incidence of invasive fungal infection and Gram-
negative bacteremia.
However, this was a retrospective study and the reasons why certain patients began at a
lower glucocorticoid dose compared with others likely reflect many different aspects of their
GVHD, including physician preference as well as the pace of onset of signs and symptoms. A

subsequent prospective, randomized trial comparing 1 mg/kg versus 2 mg/kg in 150 patients
with newly diagnosed acute GVHD did not show any difference in nonrelapse mortality,
relapse, OS, or toxicities [19]. A lack of difference may have been due to the rapid taper of
steroids in those responding to standard dose steroids.
Gastrointestinal tract-directed therapy — Acute GVHD frequently involves both the

upper and lower gastrointestinal tract. Gastrointestinal involvement usually presents with
diarrhea and abdominal pain, but may also manifest as nausea, vomiting, and anorexia.
Confirmation of the diagnosis is recommended by pathologic evaluation of tissue obtained
by upper endoscopy, rectal biopsy, or colonoscopy. (See "Clinical manifestations, diagnosis,
and grading of acute graft-versus-host disease", section on 'Gastrointestinal tract'.)
Diarrhea and intestinal inflammation after allogeneic HCT can be caused by pathogenic
bacteria and viruses or by GVHD. Bacterial cultures, viral polymerase chain reaction (PCR)
assays, and histologic analyses of intestinal biopsy specimens are imperfect at distinguishing
infection from GVHD, in part because the list of potential gut pathogens after transplantation
is incomplete. Further, it is relatively common for patients to have both GVHD and viral
infection (eg, CMV colitis). Thus, the cause of transplantation-associated diarrhea and
enterocolitis can remain unclear, and decisions to increase immunosuppression to
ameliorate GVHD must be balanced against the potential risks of exacerbating an
undiagnosed infection.
For patients with GVHD with gastrointestinal involvement without gastrointestinal infection,
we suggest the use of systemic glucocorticoids plus oral nonabsorbable steroids rather than
systemic therapy alone [3,20]. Most patients will require supplemental nutrition. Octreotide
may reduce the amount of diarrhea, but should be discontinued within 24 hours after the
resolution of diarrhea to avoid the development of ileus [21-23].
Oral nonabsorbable steroids, such a budesonide and beclomethasone, can increase

response rates and allow for lower doses of systemic steroids.
● In one randomized study, 60 patients with anorexia and poor oral intake because of
intestinal GVHD were treated with prednisone (1 mg/kg per day) plus either placebo or
oral beclomethasone (8 mg/day) [24]. Beclomethasone therapy was associated with a
higher likelihood of both an initial treatment response at day 10 (71 versus 55 percent)
and a durable treatment response at day 30 (71 versus 41 percent).
● In a second trial, 129 patients were treated for 10 days with prednisone (with tapering
after 10 days) and then randomly assigned to receive either placebo or oral
beclomethasone (8 mg/day orally) [25]. On an intent-to-treat basis, patients assigned to
beclomethasone therapy had a significantly lower risk of GVHD treatment failure and

reduced mortality, especially among those receiving unrelated and HLA-mismatched

transplants.
Our preference to add oral nonabsorbable steroids to the treatment of those with
gastrointestinal involvement is largely based on the ability to decrease systemic
glucocorticoid exposure. Although the term "nonabsorbable" is widely used, it is possible
that a small amount of the drug may be systemically absorbed.
Patients with gastrointestinal involvement should be evaluated by a nutritionist. Such

patients often have malnutrition, protein-losing enteropathy, and abnormalities in
magnesium, zinc, vitamin B12, and vitamin D [26]. Most patients will require
supplementation with enteral or parenteral nutritional support. The enteral route is
preferred, if tolerated. Patients with diarrhea exceeding 500 mL/day should be considered
for parenteral nutrition, with a stepwise reintroduction of an oral diet once the diarrhea
decreases to <500 mL/day. (See "The role of parenteral and enteral/oral nutritional support in
patients with cancer", section on 'Hematopoietic cell transplantation'.)
ASSESSMENT OF RESPONSE
Patients with acute GVHD should be assessed daily for evidence of disease-related
complications (eg, infection) and symptoms (eg, pruritus, diarrhea). A more formal
assessment should be undertaken on days 5 and 7 after the initiation of therapy. At this time,
the severity (grade) of acute GVHD is determined by the degree of involvement of the skin,
liver, and gastrointestinal tract (table 1). Patients who demonstrate progression of disease by
day 5 or nonresponse by day 7 are considered to have glucocorticoid resistance. (See
'Treatment of resistant disease' below.)
TREATMENT OF RESISTANT DISEASE
Choice of agent — For patients with glucocorticoid-resistant acute GVHD, we favor

participation in a clinical trial.
Outside of a clinical trial, we suggest treatment with ruxolitinib rather than mycophenolate
mofetil, etanercept, extracorporeal photopheresis, antithymocyte globulin, alpha-1
antitrypsin, mesenchymal stromal cells, everolimus, sirolimus, or other agents. This
suggestion is based on superior efficacy and modest toxicities associated with ruxolitinib,
compared with other agents.
Second-line agents

Ruxolitinib — Ruxolitinib is a selective inhibitor of Janus kinase (JAK)1 and JAK2. Signaling

through JAKs and signal transducers and activators of transcription (STAT) contributes to
inflammation and tissue damage in GVHD. (See "Pathogenesis of graft-versus-host disease
(GVHD)", section on 'Acute GVHD'.)
Ruxolitinib is administered twice daily by mouth; the usual dose is 10 mg twice daily, but
some experts suggest starting at 5 mg twice daily and increasing to 10 mg twice daily after
≥3 to 7 days of treatment, if the absolute neutrophil count (ANC) and platelet count have not
declined by ≥50 percent relative to the first day of treatment [27]. 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.
For patients who have a response, ruxolitinib may be tapered gradually after eight weeks. It
is important that ruxolitinib is tapered gradually rather than discontinued abruptly or
reduced rapidly, because a "withdrawal syndrome" that resembles systemic inflammatory
response syndrome may be seen when ruxolitinib is discontinued in myelofibrosis [28].
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 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 [29]. (See "Management of primary myelofibrosis", section on 'Ruxolitinib
treatment and cautions'.)
A multicenter trial reported that ruxolitinib was superior to standard care for glucocorticoid-
refractory acute GVHD (grades II to IV) [30]. In this trial, 309 patients ≥12 years old were
randomly assigned (1:1) to ruxolitinib (10 mg by mouth, twice daily) versus the investigator’s
choice of therapy; control therapy was chosen by the investigator at the time of
randomization from one of the following: antithymocyte globulin, extracorporeal
photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil,
everolimus, sirolimus, etanercept, or infliximab. At day 28, compared with the control group,
ruxolitinib achieved superior rates of overall response (62 versus 39 percent; odds ratio 2.64;
95% CI 1.65-4.22) and complete response (CR; 34 versus 19 percent). Superiority of ruxolitinib
was maintained at day 56 (40 versus 22 percent) and its benefits were seen with all grades of
disease and affected organs, but the duration of follow-up was not sufficient to draw
conclusions about an impact on survival. By day 56, 21 percent of patients in the ruxolitinib
group had discontinued glucocorticoids, compared with 14 percent in the control group.
Treatment was discontinued in 72 percent of patients receiving ruxolitinib and in 85 percent
of patients in the control group; most discontinuation was due to lack of efficacy. The most

common grade ≥3 toxicity with ruxolitinib was thrombocytopenia, anemia, and

cytomegalovirus infection; there was no difference between groups regarding the frequency
of infections (approximately one fifth in both groups).
Other studies report similar benefits and toxicity of ruxolitinib for acute GVHD in adults and
children [27,31-33]. Further study is necessary to determine the efficacy and long-term
toxicity of ruxolitinib in the treatment of GVHD.
Ruxolitinib is approved by the US Food and Drug Administration for treatment of acute GVHD
[27].
Mycophenolate mofetil — Mycophenolate mofetil (MMF) has antibacterial, antifungal,

antiviral, antitumor and immunosuppressive properties. MMF has been evaluated for the
treatment of glucocorticoid-resistant acute GVHD in small prospective trials, including the
randomized phase II trial described above [6,34,35].
A multicenter, randomized, double blind, phase III trial comparing glucocorticoids to

glucocorticoids plus mycophenolate as the initial management of acute GVHD was closed
early due to futility (CTN 0802, NCT01002742) [36]. In this trial, 235 patients with newly
diagnosed acute GVHD requiring systemic therapy were randomly assigned to receive
corticosteroids plus MMF or corticosteroids plus placebo. The addition of MMF did not
significantly improve GVHD-free survival (60 versus 50 percent) or cumulative incidence of
chronic GVHD at 12 months (42 versus 43 percent). Exploratory subset analysis also failed to
demonstrate a benefit in higher risk cohorts (grade II/IV or visceral GVHD). MMF was
associated with a higher incidence of leukopenia.
Etanercept — Etanercept, a recombinant human TNF-alpha receptor fusion protein, has

been used alone or in combination to treat chronic and acute GVHD [37-40]. (See 'Choice of
agent' above.)
In one set of studies, the combination of etanercept (0.4 mg/kg per dose given
subcutaneously twice per week) and methylprednisolone (initial dose 2 mg/kg per day) was
used in 61 patients with new onset GVHD [11]. Infection prophylaxis included norfloxacin or
levofloxacin plus either fluconazole or voriconazole. Results, which were compared with a
contemporaneous group of 99 patients treated with methylprednisolone alone, included the
following:
● Patients treated with etanercept plus steroids were significantly more likely to attain
complete response (CR) after 28 days than those treated with steroids alone (69 versus
33 percent). This difference was observed in hematopoietic cell transplant (HCT)
recipients of related donors (79 versus 39 percent) as well as unrelated donors (53 versus
26 percent).
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● Plasma TNFR1 levels, a biomarker for GVHD activity, were elevated at GVHD onset and
decreased significantly only in patients achieving CR.
● The higher CR rate seen in those receiving etanercept translated into significantly
superior survival at 100 days following initiation of treatment (82 versus 66 percent).
● Infection rates during the first 100 days of treatment for bacterial, viral, or invasive
fungal infection were similar for the two treatment groups.
Pentostatin — Pentostatin, a purine analog, inhibits T cell proliferation and function, and

has been used to prevent GVHD. Studies are limited to single arm trials and the randomized
phase II trial described above. (See 'Choice of agent' above.)
A phase I trial has explored the efficacy of pentostatin in the treatment of acute GVHD [41].
CRs were noted in 14 of 22 patients with steroid-refractory acute GVHD at a maximal
tolerated dose of 1.5 mg/m2 intravenously per day for three days. Lymphopenia was
universal; the drug was otherwise well tolerated.
Pentostatin should be used with caution in patients with renal insufficiency. A 50 percent
dose reduction has been suggested for patients with an estimated creatinine clearance of 30
to 50 mL/min/1.73 m2 [42].
Alpha-1 antitrypsin — Alpha-1 antitrypsin (AAT), an abundant, circulating protease

inhibitor, protects tissues from proteolytic degradation, suppresses proinflammatory
cytokines, and alters ratios of effector to regulatory T lymphocytes [43]. Phase I and phase II
studies have examined human plasma-derived AAT in refractory acute GVHD [44,45].
A multicenter phase II study treated 40 patients with steroid-resistant acute GVHD (median
age 59 years) with intravenous AAT (60 mg/kg per day twice weekly for up to four weeks)
alone, and reported rates of overall response (OR) and CR of 65 and 35 percent, respectively
[45]. At day 60, responses were sustained without intervening immunosuppression in nearly
three-quarters of responding patients. Treatment was well tolerated, there were no drug-
related adverse events, and infectious mortality was 10 percent at six months.
Sirolimus — Sirolimus has been used for the treatment of refractory acute GVHD. A phase
I/II study of 21 patients with grade III/IV acute GVHD demonstrated that 12 patients
responded to the use of sirolimus with five CR and seven partial responses (PR) [46].
Sirolimus was given as a loading dose of 15 mg/m2 followed by a daily dose of 5 mg/m2 daily
for 13 days or at a dose of 4 to 5 mg/m2 without a loading dose for 14 days.
Myelosuppression was common; two patients also developed seizures. Five patients
developed hemolytic uremic syndrome. The use of sirolimus has also been associated with
sinusoidal obstruction syndrome (SOS) following myeloablative conditioning regimens,

especially when myeloablative doses of busulfan were employed. (See "Prevention of acute
graft-versus-host disease", section on 'Tacrolimus plus sirolimus'.)
Extracorporeal photopheresis — Extracorporeal photopheresis (ECP) consists of infusion

of ultraviolet-A irradiated autologous peripheral lymphocytes that have been collected by
apheresis and incubated with 8-methoxypsoralen. This approach is used for the treatment of
cutaneous T cell lymphoma and several autoimmune diseases and has been used to treat
rejection after organ transplantation. The mechanism of its action is unclear, although it
appears to downregulate activated T cell clones and possibly increase regulatory T cells in
murine modeling [47-49]. (See "Treatment of Sézary syndrome", section on 'Extracorporeal
photopheresis (ECP)' and "Treatment of chronic graft-versus-host disease", section on
'Psoralen ultraviolet irradiation'.)
Several studies have suggested that ECP may have a role in the treatment of acute and
chronic GVHD [50]; both poor [51,52] and encouraging results have been obtained [53-55]. As
examples:
● A multicenter retrospective analysis of 98 patients with steroid-refractory acute GVHD

treated with ECP (57 patients) or anticytokine therapy (etanercept or inolimomab, 41
patients) reported that ECP resulted in superior rates of CR (54 versus 20 percent) and
survival (hazard ratio 2.12; 95% CI 1.13-3.96) [56].
● Another retrospective analysis of 30 patients with acute GVHD treated with ECP reported
complete and partial remissions in nine (28 percent) and six (20 percent) patients,
respectively at three months [57].
● In another study, 21 patients with steroid-refractory acute GVHD were treated with ECP
[58]. CRs were noted in 100, 67, and 12 percent of patients with grades II, III, and IV
acute GVHD, respectively. The probability of survival at four years was 91 and 11 percent
in complete responders or non-responders to ECP, respectively.
● In a review of 11 studies employing ECP in a total of 76 patients with acute GVHD, CRs to
skin, gut, and liver involvement were noted in 67, 54, and 38 percent of patients,
respectively [59].
Consensus recommendations regarding the use of ECP for the treatment of glucocorticoid
refractory acute GVHD have been proposed by the Italian Group for Bone Marrow
Transplantation and the United Kingdom [60,61]. Better results are expected in patients with
disease limited to the skin.
Antithymocyte globulin — Antithymocyte globulin (ATG) has been used for the

prevention of acute GVHD in patients with an unrelated donor or haploidentical donor
undergoing either myeloablative or reduced intensity conditioning. For those who did not

receive ATG as part of their prophylactic regimen, ATG can be considered for the
management of patients with glucocorticoid refractory acute GVHD. (See "Prevention of
acute graft-versus-host disease", section on 'Antithymocyte globulin'.)
The primary role of T cells in the pathogenesis of GVHD provides the rationale for the use of
ATG and other anti-T cell antibodies. An initial report from Seattle evaluated the efficacy of
ATG among 60 patients with grade II GVHD: 36 improved, 12 did not improve, and 12 had
progressive disease [62]. These observations provided the rationale for a subsequent
randomized trial that compared ATG (given on alternate days for six doses) and prednisolone
(2 mg/kg per day for 10 days) [63]. More responses were seen in the steroid group, although
the difference was not significant. All organ systems appeared to respond to steroid therapy
whereas ATG produced only a few, incomplete responses in the gastrointestinal tract and
liver.
Another study investigated the combination of ATG and cyclosporine; some of the patients
also received methylprednisolone [64]. Patients receiving triple therapy had a lower survival
rate, mostly due to infectious complications. Untoward effects of ATG included hemolytic
anemia, severe thrombocytopenia, neutropenia, fever, chills, polyarthritis, myalgias, nausea,
vomiting, urticaria, and serum sickness.
Monoclonal antibodies — Monoclonal antibodies directed against T cells, activated T

cells, the IL-2 receptor (CD25 antigen), adhesion molecules, and TNF-alpha have been
evaluated in the treatment of acute GVHD [65]. The usefulness of these antibodies can be
difficult to assess due to a number of factors. In almost all trials, the antibodies were used as
second-line therapy in patients who did not respond to glucocorticoids. In addition,
monoclonal antibodies are selective, acting on specific sites in the immunologic cascade, and
it may be that combination therapy at an earlier stage will provide superior results.
Interleukin-2 receptor (CD25alpha) antibodies — Therapeutic antibodies against the

IL-2 receptor (CD25) include the humanized monoclonal antibodies, daclizumab and
basiliximab, and the mouse monoclonal antibody, inolimomab. Blockade of the IL-2 receptor
prevents T cell proliferation and may reduce GVHD; however, T regulatory cells are important
in modulating GVHD and their removal may contribute to poorer outcomes. (See "Liver
transplantation in adults: Overview of immunosuppression", section on 'Basiliximab' and
"Pathogenesis of graft-versus-host disease (GVHD)".)
Therapeutic antibodies directed against IL-2 receptor have not shown greater efficacy or
safety compared with other treatments for glucocorticoid-resistant acute GVHD. Examples of
such studies include:
● In an open-label multicenter trial, 100 patients were randomly assigned to inolimomab

versus ATG for steroid-resistant acute GVHD [66]. With a minimum follow-up of one year,

overall survival, time to treatment failure, and adverse events were similar in the two
arms.
● Treatment of 62 patients with daclizumab reported complete resolution of acute GVHD

in 69 percent, with higher response rates in those with fewer involved organs and less
extensive skin involvement, but most of the patients went on to develop extensive
chronic GVHD [67].
● A double-blinded randomized trial was initiated to determine whether addition of

daclizumab to initial corticosteroid therapy for acute GVHD improved outcome [10]. This
study was terminated when an interim analysis showed significantly worse survival at
both 100 days and one year for those subjects receiving the combined therapy.
● Basiliximab, with a shorter terminal half-life than daclizumab, was used in 23 patients
with steroid-refractory acute GVHD, with an 18 percent CR and 65 percent PR rate [68].
Further study is needed to determine the efficacy of these monoclonal antibodies in this
population. Daclizumab has been withdrawn from the market worldwide because of safety
concerns.
Brentuximab vedotin — Brentuximab vedotin (BV) is a monoclonal antibody-drug

conjugate that is directed against CD30 which is expressed on T cells. A multicenter, phase 1
trial that included 28 patients with steroid-refractory acute GVHD reported 15 percent CR and
24 percent PRs to treatment with biweekly dosing of BV [69]. Treatment with a weekly dosing
schedule was associated with profound neutropenia, including two deaths.
Alemtuzumab — Treatment with the humanized monoclonal anti-CD52 antibody

alemtuzumab was evaluated in 20 patients with severe (grade III/IV) steroid-resistant acute
intestinal GVHD [70]. CR and OR rates were 35 and 70 percent, respectively. Cytomegalovirus
reactivation, bacterial infection, and invasive aspergillosis were frequent complications,
requiring careful monitoring and anti-infectious supportive care.
Importantly, the manufacturer of alemtuzumab withdrew this product from the United States
market in September 2012. These actions were not related to safety concerns, but instead
were to prepare for the planned marketing of this drug under a different name for multiple
sclerosis.
Tocilizumab — Tocilizumab is an anti-IL-6 receptor antibody that has been used in the

treatment of steroid-refractory GVHD. In one study of tocilizumab, responses were seen in
four of six patients with refractory acute GVHD and in one of two patients with chronic GVHD
[71]. The second patient with chronic GVHD had stabilization of disease that allowed for
modest reduction in immunosuppressive mediations. Therapy was well tolerated. Infections
were the most common adverse event. Several patients had transient elevations in serum

transaminase levels and one patient discontinued treatment due to worsened pre-existing
hyperbilirubinemia. Further study is necessary to determine the efficacy and long-term
toxicity of this agent in the treatment of GVHD.
Mesenchymal stromal cells — The bone marrow contains small numbers of

mesenchymal stromal cells (MSCs), which are able to differentiate in vitro and in vivo into
cells of mesenchymal origin (eg, fibroblasts, adipocytes, osteoblasts, chondrocytes) and are
pivotal for the supply of growth factors supporting hematopoiesis. The immunosuppressive
potential of these cells, including their ability to induce CD4+/CD25+/FOXP3+ regulatory T
cells [72], has set the stage for their testing as cellular immunosuppressants, to promote
hematopoietic recovery after autologous and allogeneic HCT, and to treat acute, severe
GVHD [73-76].
The therapeutic efficacy of ex vivo expanded MSCs was tested in 55 patients with steroid-
resistant acute GVHD [76]. MSCs from HLA-identical sibling donors, haploidentical donors,
and third-party HLA-mismatched donors were given at a median dose of 1.4 x 106 cells/kg for
a total of one to five intravenous infusions per subject. Results included [76]:
● CRs and ORs were noted in 54 and 71 percent, respectively.
● Transplantation-related mortality at one year was significantly lower (37 versus 72

percent) and overall survival at two years significantly higher (53 versus 16 percent) in
those achieving CR as compared with those with lesser responses.
● The response rate to MSC infusion was not related to the degree of HLA matching
between donor and recipient. No patient had side effects during or immediately after
these infusions.
A phase II multi-institutional study evaluated the use of two different doses of third-party,
unmatched MSCs in addition to standard glucocorticoid therapy in 31 evaluable patients with
de novo grade II to IV acute GVHD [77]. OR and CR rates were 94 and 77 percent,
respectively. Of the 24 patients achieving CR, 21 (88 percent) were alive at day 90. Of the
seven patients not achieving CR, only one (14 percent) was alive at day 90. No infusional
toxicities or ectopic tissue formations were reported. There was no difference with respect to
safety or efficacy between the low and high doses of MSCs.
A phase III trial has been completed using MSCs generated by Osiris Therapeutics
(Prochymal); however, the trial failed to meet its primary endpoint [78,79]:
● There was no statistical difference between MSCs and placebo on the primary endpoints
for either the steroid-refractory (35 versus 30 percent, n = 260) or the first-line (45 versus
46 percent, n = 192) GVHD trials.

● The primary endpoint for the steroid-refractory GVHD trial (durable CR) for the per-
protocol population did not reach statistical significance (40 versus 28 percent, p = 0.087,
n = 179).
● In patients with steroid-refractory liver GVHD, treatment with MSCs significantly

improved both response (76 versus 47 percent, n = 61) and durable CR (29 versus 5
percent).
● MSCs significantly improved response rates in patients with steroid-refractory

gastrointestinal GVHD (88 versus 64 percent, n = 71).
● In pediatric patients, Prochymal showed a trend of improvement in response rates (86

versus 57 percent, p = 0.094, n = 28).
Additional studies using this modality are ongoing at international centers.
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). Novel therapies being investigated
include agents that target T cells (eg, ruxolitinib [80]), and the use of suicide gene strategies
to allow for the rapid reversal of GVHD when it occurs following T cell infusion [81].
PATIENT OUTCOMES
General — There are limited data regarding the outcomes of patients who develop acute
GVHD following allogeneic hematopoietic cell transplant (HCT). The largest studies are
reports from Minnesota and Seattle that have evaluated the outcomes in different groups of
patients with acute GVHD. However, patients included in these studies did not receive
modern prophylaxis for GVHD. It is not known whether the same results will be seen in
patients who develop acute GVHD despite prophylaxis that contains a calcineurin inhibitor
(eg, cyclosporine).
The Minnesota study evaluated 469 patients receiving histocompatible allogeneic HCT, 197 of
whom (42 percent) were treated for grade II to IV acute GVHD [82]. The following results
were noted:
● Forty-one percent achieved a complete and continued resolution of acute GVHD after a
median of 21 days of therapy. Treatment in these responders consisted primarily of

corticosteroids or, in a small number of patients, other immunosuppressive therapies

including cyclosporine, anti-T cell antibodies, or antilymphocyte globulin.
● Sixty-one patients not responding to initial therapy received high dose

methylprednisolone, ATG plus methylprednisolone, or other therapies. Only seven of
these patients (11 percent) eventually obtained a complete continued remission.
● The clinical features associated with a complete response (CR) to therapy for acute GVHD
included the absence of liver or skin involvement, acute lymphoblastic leukemia as the
underlying disease, and donor/recipient pairs other than male recipients with female
donors.
● The overall rate of chronic GVHD was 70 percent. In a later report from the same group,
a response to primary therapy for acute GVHD was the most important factor predicting
a lower risk of subsequent chronic GVHD [9].
Although these results are good (30 percent cure of moderate to severe acute GVHD), many
of these patients were transplanted before the availability of cyclosporine. GVHD prophylaxis
at that time consisted predominantly of methotrexate-based regimens either alone or in
conjunction with antithymocyte globulin (ATG) and prednisone or ex vivo T cell depletion. The
more recent patients transplanted with cyclosporine-based prophylactic regimens who
developed GVHD did not respond as well to the various treatments.
The report from the Seattle group was a retrospective analysis of 427 patients who did not
have a durable response to primary therapy for acute GVHD [83]. The most common
manifestations were rash (75 percent), liver disease (59 percent), and gastrointestinal
dysfunction (53 percent). Secondary treatments consisted of glucocorticoids in the majority
of the patients (n = 249), ATG (n = 214), cyclosporine (n = 80), or a monoclonal antibody (n =
19). Most of the patients received single agent therapy. The following findings were noted:
● Some response to therapy was seen in 40 percent. Improvement in or resolution of

GVHD in the respective organs was seen in 45 percent of patients with skin disease, 25
percent with liver disease, and 35 percent with gut disease.
● The highest CR rate was seen when GVHD recurred during the taper phase of primary
glucocorticoid therapy. Increasing the dose of glucocorticoids in such patients often
resulted in a second CR.
● Severe dysfunction in the skin, liver, or gut at the beginning of treatment was associated
with lower incidence of response or improvement in outcome.
● Less than one-half of patients showed a durable overall improvement.

These results indicate that the potential efficacy of immunosuppressive agents can be
assessed meaningfully in patients who have not responded adequately to primary treatment
and that more effective treatments are needed.
Matched unrelated donor transplantation — The preceding observations were almost

entirely derived from HLA-identical sibling transplants. Studies of patients with acute GVHD
following matched unrelated donor marrow transplantation suggest that more aggressive
therapies are warranted since standard treatment with prednisone and ATG is less effective.
In a series of 42 such patients from Minnesota, only 9 of 42 patients (21 percent) achieved a
complete and continuing response by day +100 after therapy with prednisone and ATG [84];
this is one-half of the response seen in patients with HLA-identical sibling donors from the
same institution [82].
The increase in GVHD following unrelated donor HCT is due to the greater histocompatibility
differences between the donor and recipient. Although in the past such patients were often
serologically matched, molecular testing reveals that approximately 45 percent of serologic
matches are actually mismatched and that the incidence of severe GVHD is higher in the
mismatched patients [85,86]. With the advent of molecular typing now commonly used,
GVHD rates appear more similar to matched sibling donors when a fully 10/10 matched
unrelated donor is used. (See "Donor selection for hematopoietic cell transplantation".)
SUMMARY AND RECOMMENDATIONS
● Graft-versus-host disease (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.
The pathogenesis of GVHD is a complex, multistep process, but is primarily a T cell-
mediated process. (See "Pathogenesis of graft-versus-host disease (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. However, each institution must have guidelines
for the prevention and management of GVHD in order to be acknowledged by
international accrediting organizations. (See "Prevention of acute graft-versus-host
disease".)
● The choice of initial therapy for patients with acute GVHD despite prophylaxis depends
on the organs involved, the severity of symptoms, the prophylactic regimen used, and,
to some extent, the importance of a graft-versus-tumor effect. The severity of acute
GVHD is determined by an assessment of the degree of involvement of the skin, liver,
and gastrointestinal tract (table 1).

• For patients with mild cutaneous (grade I) GVHD, we treat symptomatic sites with
topical steroids while optimizing prophylactic measures (eg, cyclosporine levels).
(See 'Skin-directed therapy' above.)
• For patients with grade II or higher GVHD, we recommend the use of systemic
glucocorticoids in addition to the optimization of prophylactic measures with or
without the use of topical steroids for cutaneous lesions (Grade 1B). The most
widely used regimen is methylprednisolone 2 mg/kg per day in divided doses.
Steroids are continued for several weeks in responders and then gradually tapered
over a period of several months. (See 'Glucocorticoids' above.)
• For patients with GVHD with gastrointestinal involvement, we suggest the use of
systemic glucocorticoids plus oral nonabsorbable steroids rather than systemic
therapy alone (Grade 2B). Most patients will require supplemental nutrition.
Octreotide may reduce the amount of diarrhea. (See 'Gastrointestinal tract-directed
therapy' above.)
• Patients who undergo hematopoietic cell transplant (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 cytopenia induced by the
transplantation procedure. Organ damage related to acute 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".)
● Patients with acute GVHD should be assessed daily for evidence of disease-related
complications (eg, infection) and symptoms (eg, pruritus, diarrhea). A more formal
assessment should be undertaken on days 5 and 7 after the initiation of therapy to
assess severity. Patients who demonstrate progression of disease by day 5 or
nonresponse by day 7 are considered to have glucocorticoid resistance. (See 'Assessment
of response' above.)
● For steroid-refractory GVHD, we encourage enrollment in a clinical trial, if available.

Outside of a clinical trial, we suggest treatment with ruxolitinib rather than other agents,
based on its superior balance of outcomes and toxicities (Grade 2C); examples of other
agents include mycophenolate mofetil, etanercept, extracorporeal photopheresis,
antithymocyte globulin, alpha-1 antitrypsin, mesenchymal stromal cells, everolimus, and
sirolimus. (See 'Choice of agent' above.)
● There are limited data regarding the outcomes of patients who develop acute GVHD
following allogeneic HCT. The largest studies suggest 30 percent cure of moderate to
severe acute GVHD. However, patients included in these studies did not receive modern
prophylaxis for GVHD. It is not known whether the same results will be seen in patients

who develop acute GVHD despite prophylaxis that contains a calcineurin inhibitor (eg,
cyclosporine). (See 'Patient outcomes' above.)
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Topic 3543 Version 29.0

GRAPHICS
Grading of acute graft-versus-host disease
Organ Stage Description
Skin 1 Maculopapular rash over <25% of body area
2 Maculopapular rash over 25 to 50% of body area
3 Generalized erythroderma
4 Generalized erythroderma with bullous formation and often with desquamation
Liver 1 Bilirubin 2.0 to 3.0 mg/dL; SGOT 150 to 750 international units
2 Bilirubin 3.1 to 6.0 mg/dL
3 Bilirubin 6.1 to 15.0 mg/dL
4 Bilirubin >15.0 mg/dL
Gut 1 Diarrhea >30 mL/kg or >500 mL/day
2 Diarrhea >60 mL/kg or >1000 mL/day
3 Diarrhea >90 mL/kg or >1500 mL/day
4 Diarrhea >90 mL/kg or >2000 mL/day; or severe abdominal pain with or without ileus
Glucksberg grade
I – Stage 1 or 2 skin involvement; no liver or gut involvement; ECOG PS 0
II – Stage 1 to 3 skin involvement; Grade 1 liver or gut involvement; ECOG PS 1
III – Stage 2 or 3 skin, liver, or gut involvement; ECOG PS 2
IV – Stage 1 to 4 skin involvement; Stage 2 to 4 liver or gut involvement; ECOG PS 3
International Bone Marrow Transplant Registry Severity Index
A – Stage 1 skin involvement; no liver or gut involvement
B – Stage 2 skin involvement; Stage 1 to 2 gut or liver involvement
C – Stage 3 skin, liver, or gut involvement
D – Stage 4 skin, liver, or gut involvement
SGOT: serum glutamic oxaloacetic transaminase; ECOG: Eastern Cooperative Oncology Group; PS: performance status.
Graphic 68233 Version 7.0

Treatment of Acute Graft-Versus-Host Disease - UpToDate

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Treatment of Acute Graft-Versus-Host Disease - UpToDate

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

Official reprint from UpToDate®

Acute graft-versus-host disease (GVHD) is a common complication of allogeneic

Clinically significant acute GVHD occurs in 9 to 50 percent of patients who receive an

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC

Prevention of GVHD — Prophylaxis of acute GVHD centers on immunosuppression of the

As a result, prophylactic therapies are used to prevent infections. Strategies to prevent

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=1… 2/28

another; the approach to prophylaxis in HCT recipients is discussed in greater detail

The severity of acute GVHD is determined by an assessment of the degree of involvement of

While there is no agreed-upon standard approach to the treatment of GVHD, corticosteroids

General measures for the management of pruritus include moisturizers, nonirritating

Optimizing prophylactic agents — All patients undergoing allogeneic hematopoietic cell

● Day 28 post-initiation of treatment complete response (CR) rates for methylprednisolone

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=1… 5/28

In an attempt to compare these different approaches, a multicenter trial randomly assigned

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=1… 6/28

Gastrointestinal tract-directed therapy — Acute GVHD frequently involves both the

Oral nonabsorbable steroids, such a budesonide and beclomethasone, can increase

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=1… 7/28

reduced mortality, especially among those receiving unrelated and HLA-mismatched

Patients with gastrointestinal involvement should be evaluated by a nutritionist. Such

TREATMENT OF RESISTANT DISEASE

Choice of agent — For patients with glucocorticoid-resistant acute GVHD, we favor

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=1… 8/28

Ruxolitinib — Ruxolitinib is a selective inhibitor of Janus kinase (JAK)1 and JAK2. Signaling

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=1… 9/28

common grade ≥3 toxicity with ruxolitinib was thrombocytopenia, anemia, and

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

A multicenter, randomized, double blind, phase III trial comparing glucocorticoids to

Etanercept — Etanercept, a recombinant human TNF-alpha receptor fusion protein, has

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=… 10/28

Pentostatin — Pentostatin, a purine analog, inhibits T cell proliferation and function, and

Alpha-1 antitrypsin — Alpha-1 antitrypsin (AAT), an abundant, circulating protease

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=… 11/28

Extracorporeal photopheresis — Extracorporeal photopheresis (ECP) consists of infusion

● A multicenter retrospective analysis of 98 patients with steroid-refractory acute GVHD

Antithymocyte globulin — Antithymocyte globulin (ATG) has been used for the

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=… 12/28

Monoclonal antibodies — Monoclonal antibodies directed against T cells, activated T

Interleukin-2 receptor (CD25alpha) antibodies — Therapeutic antibodies against the

● In an open-label multicenter trial, 100 patients were randomly assigned to inolimomab

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=… 13/28

● Treatment of 62 patients with daclizumab reported complete resolution of acute GVHD

● A double-blinded randomized trial was initiated to determine whether addition of

Brentuximab vedotin — Brentuximab vedotin (BV) is a monoclonal antibody-drug

Alemtuzumab — Treatment with the humanized monoclonal anti-CD52 antibody

Tocilizumab — Tocilizumab is an anti-IL-6 receptor antibody that has been used in the

https://www.uptodate.com/contents/treatment-of-acute-graft-versus-host-disease/print?search=graft versus host desease&source=search_result&selectedTitle=… 14/28

Mesenchymal stromal cells — The bone marrow contains small numbers of

● CRs and ORs were noted in 54 and 71 percent, respectively.

● Transplantation-related mortality at one year was significantly lower (37 versus 72

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● In patients with steroid-refractory liver GVHD, treatment with MSCs significantly

● MSCs significantly improved response rates in patients with steroid-refractory

● In pediatric patients, Prochymal showed a trend of improvement in response rates (86

Additional studies using this modality are ongoing at international centers.

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corticosteroids or, in a small number of patients, other immunosuppressive therapies

● Sixty-one patients not responding to initial therapy received high dose

● Some response to therapy was seen in 40 percent. Improvement in or resolution of

● Less than one-half of patients showed a durable overall improvement.