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Treatment of acute graft-versus-host disease

Treatment of acute graft-versus-host disease
Literature review current through: Jan 2024.
This topic last updated: Jun 16, 2022.

INTRODUCTION — Acute graft-versus-host disease (aGVHD) is an adverse effect of allogeneic hematopoietic cell transplantation (HCT) that classically presents in the early post-transplantation period. It is primarily a T cell-mediated process that occurs when immune cells transplanted from a donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction in the recipient. Skin, gastrointestinal (GI) tract, and liver are the principal target organs in patients with aGVHD.

The incidence of clinically significant aGVHD varies with the immunologic match between the recipient and the graft, transplant conditioning regimen, method of GVHD prophylaxis, and other factors. Treatment of aGVHD is determined by the affected organs, severity (ie, grade), and involvement of the GI tract.

Management of aGVHD is reviewed here.

Evaluation and diagnosis of aGVHD and prophylaxis are discussed separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Prevention of graft-versus-host disease".)

DIAGNOSIS AND GRADING

Diagnosis — Skin, gastrointestinal (GI) tract, and liver are the principal organs affected by aGVHD. The central nervous system, ovaries, testis, thymus, bone marrow, and kidney may also be affected, but clinical manifestations are less apparent and can be difficult to distinguish from drug toxicity and other conditions [1-3].

The diagnosis of skin and liver aGVHD can be made clinically in patients with a classical presentation, but for intestinal GVHD and all other cases, the diagnosis should be confirmed by tissue biopsy. Clinical presentation and diagnostic criteria for aGVHD are discussed in detail separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Classical presentation – The most common clinical manifestation of aGVHD is a maculopapular rash, usually occurring two to three weeks after allogeneic hematopoietic cell transplantation (HCT), around the time of the white blood cell engraftment. The diagnosis can be made clinically when aGVHD presents with a classic rash, abdominal cramps with diarrhea, and a rising serum bilirubin concentration within 100 days after allogeneic HCT.

Other presentations – When the presentation varies from the classic description, the diagnosis of aGVHD should be confirmed histologically so that alternative causes can be excluded. As examples, a skin rash alone may be caused by antibiotics or other drugs, diarrhea may be infectious in nature, and hyperbilirubinemia may be related to biliary sludge or as an adverse effect of drugs or parenteral nutrition. In some cases, aGVHD can also begin >100 days after transplantation; aGVHD can also occur after donor lymphocyte infusion (DLI). (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Evaluation of diarrhea and abdominal pain that may be related to aGVHD is discussed below and in greater detail separately. (See 'GI aGVHD' below and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Gastrointestinal tract'.)

Grading — The grade of aGVHD and determining if there is GI tract involvement informs the approach to therapy. Details of grading aGVHD (table 1) are presented separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Grading'.)

For treatment stratification, salient aspects of grading can be summarized as follows:

Grade 1 aGVHD – Grade 1 aGVHD describes limited skin involvement (ie, stage 1 or 2 cutaneous aGVHD (table 1)), without liver or GI tract involvement. All other manifestations of aGVHD and more severe cutaneous disease are considered grade 2 or higher.

Grade ≥2 aGVHD – Grade ≥2 aGVHD refers to any involvement beyond grade 1 (ie, >50 percent cutaneous involvement or GI, liver, or other organ involvement).

GI aGVHD – Grading of GI involvement is based on the extent of diarrhea and abdominal pain.

MANAGEMENT — Most treatments for aGVHD are based on suppression of donor T cells, which are primarily responsible for the syndrome. However, the same cells also mediate the immunologic reaction against the tumor (graft-versus-tumor [GVT] effect). As such, treatment should aim to balance the benefit of reducing GVHD with the potential harm of decreasing the GVT effect.

We encourage participation in a clinical trial for management of aGVHD. Examples of relevant trials in the United States are available at: www.clinicaltrials.gov.

Our approach to management of aGVHD is consistent with guidelines proposed by the American Society of Blood and Marrow Transplantation [4]; the British Committee for Standards in Hematology and the British Society for Bone Marrow Transplantation [5]; and the European Group for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet [6]. Each institution that performs hematopoietic cell transplantation (HCT) must have guidelines for GVHD management that are approved by the Joint Accreditation Committee for ISCT Europe and EBMT (JACIE) or the Foundation for the Accreditation of Cell Therapy (FACT).  

Optimizing prophylaxis — For all patients who develop GVHD, the prophylaxis regimen should be reviewed and optimized.

For patients who develop aGVHD when they are no longer receiving prophylaxis, the regimen should be restarted. Prophylaxis of GVHD is discussed separately. (See "Prevention of graft-versus-host disease".)

The calcineurin inhibitors (CNI), cyclosporine (CsA) and tacrolimus (Tac), are key components of most aGVHD prophylaxis regimens. Optimal prophylaxis involves monitoring blood level of the CNI [7].

Target trough levels of the CNIs are:

CsA – The target concentration of CsA varies according to the time from transplantation.

A trough concentration of 200 to 300 ng/mL is targeted during the first three to four weeks after transplantation. If aGVHD does not develop, the target concentration is decreased to 100 to 200 ng/mL until three months after transplantation and then tapered further.

For patients who develop aGVHD of any grade, the CsA dose should be adjusted to achieve a therapeutic level of 200 to 300 ng/mL.

Tac – The target trough range for Tac is 15 ng/mL.

Anecdotal reports suggest that Tac may be effective in patients who developed aGVHD while receiving CsA prophylaxis. No prospective studies have reported the rate of salvage with Tac, but a retrospective study reported that 2 of 20 evaluable patients had a complete resolution of aGVHD after changing from CsA to Tac [8].

Choice of initial therapy — The choice of initial therapy for aGVHD depends on the extent and severity of symptoms (ie, grade) and whether the gastrointestinal tract (GI) (table 1) is involved:

Grade 1 aGVHD — For grade 1 aGVHD, we suggest initial treatment with a topical steroid rather than systemic therapy, to limit the toxicity of systemic agents.

Selection of a topical corticosteroid is discussed below. (See 'Topical therapy' below.)

The GVHD prophylaxis regimen should also be optimized, as described above. (See 'Optimizing prophylaxis' above.)

Vigilance for disease progression during treatment is important, to enable a rapid change to systemic therapy, if needed.

Grade ≥2 aGVHD — For grade ≥2 aGVHD, we suggest treatment with a systemic glucocorticoid (GC; eg, methylprednisolone), rather than an alternative approach. Systemic GCs have been widely adopted for treatment of grade ≥2 aGVHD and no other regimen has been proven superior for treatment of grade 2-4 aGVHD.

Studies that compared initial treatment of aGVHD using a GC versus other regimens as front-line therapy for aGVHD include:

GC plus MMF – A double-blind, phase 3 trial of a GC plus mycophenolate mofetil (MMF) versus a GC plus placebo (CTN 0802, NCT01002742) was closed for futility after accrual of 235 patients (of 372 planned participants) [9]. There was no difference in day 56 GVHD-free survival (60 percent with GC plus MMF versus 54 percent with GC plus placebo), 12 month treatment-related mortality (TRM), 12 month chronic GVHD (cGVHD), grade ≥3 adverse events (AE), or incidence of severe infections or cytomegalovirus (CMV) reactivation [10].

GC plus itacitinib – A phase 3 trial (GRAVITAS-301) reported that GC plus itacitinib (JAK1 inhibitor) was not superior to GC plus placebo [11]. The trial of 439 patients reported that GC/itacitinib was associated with 74 percent day 28 overall response rate (ORR), including 53 percent complete responses (CR), while GC/placebo was associated with 66 percent ORR and 40 percent CR. The incidence of grade ≥3 AEs (mostly cytopenias) was similar between trial arms (86 versus 82 percent, respectively), and TRM was 1 percent with itacitinib and 2 percent with placebo.

GC plus etanercept – Treatment of 61 patients with a GC plus etanercept (recombinant human tumor necrosis factor [TNF]-alpha receptor fusion protein) was compared with treatment of a contemporaneous group of 99 patients who received methylprednisolone alone [12]. GC/etanercept treatment was associated with superior day 100 overall survival (OS; 82 versus 66 percent) and a higher rate of day 28 CR (69 versus 33 percent); this effect was observed in recipients of related donor grafts (79 versus 39 percent) and recipients of unrelated donor grafts (53 versus 26 percent).

GC plus various agents – A phase 2 study randomly assigned 180 patients to treatment with methylprednisolone plus either MMF, etanercept, denileukin diftitox (human interleukin-2 [IL-2] attached to diphtheria toxin), or pentostatin (purine analog) [13]. MMF was associated with superior day 28 CR (60 percent) and nine month OS (64 percent), compared with etanercept (26 percent CR; 47 percent OS), denileukin diftitox (53 percent CR; 49 percent OS), or pentostatin (38 percent CR; 47 percent OS). Severe infections were reported in 44 percent of patients treated with MMF, 48 percent with etanercept, 62 percent with denileukin diftitox, and 57 percent with pentostatin.

Administration, AEs, and outcomes with systemic GCs are discussed below. (See 'Systemic glucocorticoids' below.)

GI aGVHD — For aGVHD that affects the GI tract, we treat with a nonabsorbable oral steroid plus a systemic GC, rather than a systemic GC alone; the systemic GC should initially be given intravenously to avoid impaired absorption due to GI aGVHD. Addition of a nonabsorbable steroid to a systemic GC can decrease the dose and/or shorten the course of the systemic GC and was shown to improve survival and reduce aGVHD relapses in phase 3 trials [14,15].

Importantly, nonabsorbable oral steroids should not be used in patients with a suspected GI infection (eg, CMV colitis).

Evaluation – We evaluate the cause of diarrhea/enterocolitis before treating with an oral nonabsorbable steroid. The cause can remain unclear, even with careful investigation and GI symptoms may be due to concurrent aGVHD and infection. A decision to add a nonabsorbable oral steroid must be balanced against the potential risks of exacerbating an undiagnosed infection.

We generally evaluate diarrhea in this setting with bacterial cultures and viral testing (eg, polymerase chain reaction [PCR] assays for CMV in peripheral blood, testing of stool specimens for adenovirus or rotavirus); we consider an intestinal biopsy for histologic analysis on a case-by-case basis.

Administration – The most commonly used nonabsorbable steroids are oral beclomethasone dipropionate (BDP) or budesonide [16,17]; these agents have not been compared directly in this setting. We generally begin a slow taper of the systemic GC after one week of treatment with the oral nonabsorbable steroid. Although these agents are described as "nonabsorbable" steroids, a small amount may be systemically absorbed.

Supportive care for GI aGVHD – Patients with GI aGVHD may have malnutrition, protein-losing enteropathy, and/or abnormalities in magnesium, zinc, vitamin B12, and vitamin D [18]. We generally request an evaluation by a nutritionist.

Most patients with GI aGVHD require supplementary nutritional support. We favor the enteral route, if tolerated, rather than parenteral nutrition support. However, patients with diarrhea ≥500 mL/day should receive parenteral nutrition, with 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'.)

Octreotide can reduce the amount of diarrhea, but it should be discontinued within 24 hours after the resolution of diarrhea to avoid the development of ileus [19-21].

Adverse events – Oral nonabsorbable steroids are well-tolerated, but they must be used with caution in patients who may have an underlying GI infection. Patients who received prolonged BDP treatment (seven weeks) often developed biochemical evidence of abnormal hypothalamic-pituitary axis suppression, but no other toxicity was reported [15].

Outcomes – Oral nonabsorbable steroids can increase the rate of response and enable lower doses of systemic GCs:

A phase 3 trial reported that, compared with placebo, oral BDP achieved superior survival and more effectively prevented relapse of GI GVHD [15]. The trial enrolled 129 patients with anorexia, vomiting, and diarrhea, but it excluded patients with severe aGVHD (eg, abdominal pain, secretory diarrhea >1 L/day, intestinal bleeding, or liver and skin GVHD). Patients were treated with systemic prednisone for 10 days, followed by a rapid taper of prednisone and random assignment to 50 days of treatment with either oral BDP or an oral placebo. The risk of treatment failure at day 80 was lower with BDP (hazard ratio [HR] 0.37 [95% CI 0.20-0.69]) compared with placebo. By day 200, 5 patients treated with BDP had died, compared with 16 deaths on placebo (HR 0.33 [95% CI 0.12-0.89]); the HR for death at 12 months was 0.54 (95% CI 0.30-0.99). Among the 47 recipients of unrelated and HLA-mismatched grafts, 4 percent of patients treated with BDP died, compared with 42 percent of patients who received placebo (HR 0.09 [95% CI 0.01-0.70]).

An earlier phase 3 trial that randomly assigned 60 patients to BDP versus placebo (for 30 days) also reported that BDP was associated with improved of survival and response [14]. Treatment response at day 30 was 71 percent with BDP versus 41 percent with placebo.

RESPONSE ASSESSMENT — Response to treatment is monitored to enable dose adjustment and to limit toxicity.

On days 5 and 7 of treatment, a formal assessment of skin, liver, and gastrointestinal tract aGVHD severity (grade) (table 1) is performed. In addition, the patient is evaluated daily for symptoms, infections, and disease- or treatment-related complications.

Patients with progression of disease by day 5 or no response by day 7 are considered to have glucocorticoid-resistant aGVHD [22-26]. (See 'Glucocorticoid-resistant aGVHD' below.)

TREATMENTS

Topical therapy — Topical steroids are the mainstay of treatment for mild cutaneous aGVHD (ie, grade 1). (See "Cutaneous manifestations of graft-versus-host disease (GVHD)".)

Topical steroids differ in strength, vehicle (eg, ointments, creams, lotions), and method of application (table 2). We generally apply a mid- or high-potency topical steroid twice daily to moist skin and cover the area with warm, wet towels ("wet wrap"). Selection of a topical steroid should consider whether the affected skin is predominantly moist versus dry and hairy versus non-hairy. (See "Topical corticosteroids: Use and adverse effects", section on 'Corticosteroid selection and administration'.)

Skin moisturizers, nonirritating creams, and antihistamines can help to relieve pruritus. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Ancillary measures in chronic graft-versus-host disease'.)

For grade 1 aGVHD that has not responded adequately to topical steroids (see 'Response assessment' above), we favor treatment with topical tacrolimus or oral ruxolitinib, rather than a systemic glucocorticoid (GC). Clinical practice varies [5,27], but options include:

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.

Ruxolitinib – Oral ruxolitinib has shown efficacy for therapy-resistant grade ≥2 aGVHD of skin [22]. Important cautions with ruxolitinib therapy are described below. (See 'Ruxolitinib' below.)

Systemic glucocorticoids — Systemic GCs are standard initial therapy for patients with grade ≥2 aGVHD [4,5,16,27].

AdministrationMethylprednisolone is often used to treat aGVHD, but the preferred agent, dose, and schedule vary among institutions.

We generally begin treatment with methylprednisolone 2 mg/kg/day in divided doses and continue it for several weeks in patients whose aGVHD is responding (table 3) [28]. It is then tapered gradually over several months to prevent a disease flare.

Patients whose aGVHD progresses by day 5 or with no response by day 7 are considered to have GC-resistant GVHD and are treated as described below. (See 'Glucocorticoid-resistant aGVHD' below.)

Adverse effects (AE) – Systemic GCs are associated with immunosuppression, increased infections, metabolic, neuropsychiatric, and other AEs, as described separately. (See "Major adverse effects of systemic glucocorticoids".)

Outcomes – Systemic GCs are generally associated with 25 to 40 percent complete response (CR) of aGVHD.

A phase 3 trial reported that, compared with higher doses, lower-dose systemic prednisone achieved comparable survival but was associated with increased need for secondary immunosuppressive therapy [29]. Treatment in this trial was stratified according to the stage of aGVHD:

-Grade 2b-4 – There was no difference in overall survival (OS) at six weeks or cumulative prednisone dose for patients who were randomly assigned to prednisone 2 mg/kg/day versus 1 mg/kg/day. For the 53 patients with skin-predominant grade 2b disease, there was no significant difference in progression to grade 3-4 aGVHD (19 percent with the lower dose versus 7 percent with the higher dose), but lower-dose prednisone was associated with greater need for secondary immunosuppressive therapy (41 versus 7 percent). For gut-predominant aGVHD, there was no difference in need for secondary immunosuppressive therapy between trial arms.

-Grade 2a – Patients with grade 2a disease (ie, rash involving <50 percent of body surface area [BSA], stool <1 L/day, no hepatic dysfunction) were randomly assigned to prednisone 1 mg/kg/day versus 0.5 mg/kg/day. For these 102 patients, there was no difference in OS, mean prednisone dose, disease progression, or the likelihood of requiring secondary systemic immunosuppressive therapy.

A multicenter trial randomly assigned 95 patients with aGVHD to either low (2 mg/kg per day) or high (10 mg/kg per day) dose methylprednisolone [30]. There were no differences in three-year OS or overall response rate, but nearly half of patients in the low-dose group were switched to a higher dose because of lack of response by day 5 or disease progression.

A retrospective study analyzed transplant outcomes among 733 patients who received initial treatment with standard-dose GC (prednisone-equivalent dose of 2 mg/kg per day) versus low-dose (1 mg/kg per day) [31]. Lower-dose treatment for patients with grade 1-2 aGVHD was not associated with increased mortality or decreased disease control, but it was associated with shorter hospitalizations and fewer invasive fungal infections and Gram-negative bacteremia. However, the pace of disease and physician preference likely affected the choice of initial GC dose.

Studies that used high doses of intravenous methylprednisolone (eg, 10 to 20 mg/kg/day) showed a high response rate but were complicated by opportunistic infections, interstitial pneumonitis, and recrudescence of GVHD upon dose reduction [32,33]. Subsequent studies using intermediate doses of methylprednisolone (1.5 to 2 mg/kg) reported good response rates but poor outcomes for those with severe GVHD [34,35].

GLUCOCORTICOID-RESISTANT aGVHD — Glucocorticoid (GC)-resistant aGVHD is defined as disease that progresses by day 5 or no response to treatment by day 7. (See 'Response assessment' above.)

Choice of treatment for GC-resistant aGVHD — For GC-resistant aGVHD, we suggest treatment with ruxolitinib, rather than other agents, based on superior efficacy and modest toxicity in a phase 3 trial that compared ruxolitinib with best available therapy (BAT) [22].

A multicenter phase 3 trial reported that ruxolitinib was superior to standard care for grade 2-4 GC-refractory aGVHD [22]. 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 the following: anti-thymocyte 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 overall response rate (ORR; 62 versus 39 percent; odds ratio 2.64 [95% CI 1.65-4.22]) and complete response (CR; 34 versus 19 percent) [22]. Superiority of ruxolitinib was maintained at day 56 (40 versus 22 percent) with all grades of disease and affected organs, but the duration of follow-up was not sufficient to assess an impact on survival. By day 56, more patients who were treated with ruxolitinib had discontinued GCs (21 versus 14 percent) and fewer patients discontinued therapy for lack of efficacy (72 versus 85 percent). The most common grade ≥3 adverse effects (AEs) with ruxolitinib were thrombocytopenia, anemia, and cytomegalovirus (CMV) infection; there was no difference in the frequency of infections (approximately one-fifth for both groups). Other studies report similar benefits and toxicity of ruxolitinib for aGVHD in adults and children [23-26].

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'.)

AdministrationRuxolitinib is administered by mouth (10 mg twice daily) [23]. Dose adjustments may be required for cytopenias and for renal or hepatic impairment.

For patients who respond within eight weeks of therapy, ruxolitinib may be tapered gradually (eg, 5 mg every three weeks). The taper must be gradual, because a "withdrawal syndrome" that resembles systemic inflammatory response syndrome can occur when ruxolitinib is discontinued abruptly or tapered too quickly [36,37]. Patients should be monitored for a withdrawal-like syndrome and ruxolitinib should be resumed in patients with significant withdrawal symptoms or recrudescence of aGVHD.

Adverse effects – Toxicity includes cytopenias, liver dysfunction, neurologic complaints, reactivation of viral infections, and bacterial or fungal infections.

Ruxolitinib is approved by the US Food and Drug Administration [23] and the European Medicines Agency for treatment of GC-refractory aGVHD in patients ≥12 years.

Other second-line treatments — There is no consensus treatment for GC-resistant aGVHD beyond ruxolitinib. The preferred treatment varies among institutions and is influenced by availability, cost, and patient preference.

Mycophenolate mofetil (MMF) — MMF is a selective inhibitor of purine synthesis in lymphocytes.

MMF was associated with 31 percent ORR of 13 patients with GC-refractory aGVHD, including 31 percent ORR with skin involvement, 44 percent of nine patients with liver involvement, and 23 percent of nine patients with gastrointestinal (GI) tract involvement [38]. In a prospective study, oral MMF was associated with 47 percent ORR (including 31 percent CR) in 19 patients with GC-refractory aGVHD; similar outcomes were seen in a retrospective analysis of 29 additional patients [39]. MMF was associated with a response in 60 percent of 10 patients with GC-refractory aGVHD [40]. Four of six patients with GC-refractory aGVHD responded to MMF in a small prospective study; AEs included infections, diarrhea, and neutropenia [41].

A phase 3 trial that evaluated MMF for initial treatment of aGVHD is described above. (See 'Grade ≥2 aGVHD' above.)

Details of MMF administration and AEs are discussed separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Etanercept — Etanercept is a recombinant human tumor necrosis factor (TNF)-alpha receptor fusion protein.

Etanercept for GC-refractory aGVHD is associated with infections and relapse of the underlying malignancy. AEs associated with etanercept are described separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

A study that included 13 patients with GC-refractory aGVHD reported that etanercept (25 mg given subcutaneously twice weekly for four weeks, followed by 25 mg weekly for four weeks) resulted in 46 percent ORR (including 31 percent CR); responses were more common with gut involvement [42]. CMV reactivation occurred in one-half and bacterial and fungal infections were also seen.

A retrospective, single-institution study reported 81 percent ORR in 16 patients with predominantly visceral GC-refractory aGVHD who were treated with etanercept, anti-thymocyte globulin (ATG), and tacrolimus (Tac), with or without MMF [43]. Progressive GVHD occurred in two patients, infection in five, and relapse of the underlying malignancy in one.

A phase 2 study of etanercept plus daclizumab (IL-2 receptor antibody) in 21 patients with GC-refractory aGVHD reported 67 percent ORR (including 38 percent CR) [44]. Treatment-related mortality (TRM) due to infectious complications occurred in 53 percent, aGVHD-associated organ failure in 14 percent, and relapse of the underlying malignancy in 14 percent; progression to chronic GVHD was seen in 57 percent.

Studies that included etanercept for initial treatment of aGVHD are described above. (See 'Grade ≥2 aGVHD' above.)

Pentostatin — Pentostatin is a purine analog that inhibits T cell proliferation and function.

The standard dose of pentostatin is 1.5 mg/m2/day intravenously on days 1 to 3 of each 14-day cycle. Pentostatin should be used with caution in patients with renal insufficiency; 50 percent dose reduction has been suggested for patients with an estimated creatinine clearance of 30 to 50 mL/min [45]. Administration and AEs associated with pentostatin are discussed separately. (See "Treatment of hairy cell leukemia", section on 'Pentostatin'.)

A phase 1 study explored the efficacy of pentostatin for treatment of aGVHD [46]. CR was noted in 14 of 22 patients with GC-refractory aGVHD at a maximal tolerated dose of 1.5 mg/m2 intravenously per day for three days. Lymphopenia was universal, but pentostatin was otherwise well tolerated.

A study that included pentostatin for initial treatment of aGVHD is described above. (See 'Grade ≥2 aGVHD' above.)

Alpha-1 antitrypsin — Alpha-1 antitrypsin (AAT) is a circulating protease inhibitor that protects tissues from proteolytic degradation, suppresses proinflammatory cytokines, and alters ratios of effector T cells to regulatory T cells [47].

A multicenter phase 2 study that treated 40 patients with GC-resistant aGVHD using intravenous AAT (60 mg/kg per day twice weekly, for up to four weeks) reported 65 percent ORR (including 35 percent CR) [48]. Nearly three-quarters of responding patients sustained their responses at day 60 without intervening immunosuppression. Infection-related TRM was 10 percent at six months and there were no drug-related AEs. A phase 1 study of 12 patients reported similar responses to AAT with no significant AEs [49].

Sirolimus — Sirolimus is a lipophilic macrolide that inhibits mammalian targets of rapamycin (mTOR).

Importantly, sirolimus has been associated with hepatic sinusoidal obstruction syndrome (SOS; also called veno-occlusive disease) following myeloablative conditioning regimens, especially when myeloablative doses of busulfan were employed. (See "Prevention of graft-versus-host disease", section on 'Sirolimus'.)

A study of 21 patients with grade 3-4 aGVHD reported 57 percent ORR (including 33 percent CR) [50]. 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 developed seizures, and five patients developed hemolytic-uremic syndrome.

Extracorporeal photopheresis — Extracorporeal photopheresis (ECP) uses autologous peripheral lymphocytes that are collected by apheresis, incubated with 8-methoxypsoralen, and irradiated with ultraviolet A. Better results are expected in patients with aGVHD limited to the skin. Treatment with ECP is discussed separately. (See "Treatment of Sézary syndrome", section on 'Extracorporeal photopheresis (ECP)'.)

Studies of ECP for aGVHD include:

A review of 11 studies employing ECP (76 patients total) for aGVHD reported CR to skin, gut, and liver involvement in 67, 54, and 38 percent of patients, respectively [51].

A retrospective analysis of 98 patients with GC-refractory aGVHD treated with ECP (57 patients) or anticytokine therapy (etanercept or inolimomab, 41 patients) reported that ECP was associated with superior rates of CR (54 versus 20 percent) and OS (hazard ratio 2.12 [95% CI 1.13-3.96]) [52].

A retrospective study reported 50 percent ORR (including 28 percent CR) at three months in 30 patients treated with ECP [53]. Treatment of 21 patients reported CR in 100, 67, and 12 percent of patients with grades 2, 3, and 4 aGVHD, respectively [54]. Other studies have reported similar outcomes with ECP for GC-refractory aGVHD [55-60].

Italian and British experts have created consensus statements for use of ECP with GVHD [61,62].

Anti-thymocyte globulin (ATG) — For patients who did not receive ATG as part of their prophylaxis regimen, ATG can be considered for management of GC-refractory aGVHD. (See "Prevention of graft-versus-host disease", section on 'Antithymocyte globulin (ATG)'.)

A study that included ATG plus etanercept is described above. (See 'Etanercept' above.)

Brentuximab vedotin — Brentuximab vedotin (BV) is a CD30-directed monoclonal antibody-drug conjugate. A multicenter, phase 1 study reported 39 percent ORR (including 15 percent CR) using biweekly BV treatment in 28 patients with GC-refractory aGVHD [63]. Treatment with a weekly dosing schedule of BV was associated with profound neutropenia, including two deaths.

Monoclonal antibodies — Monoclonal antibodies (Mabs) that have been evaluated for GC-resistant aGVHD include:

Interleukin-2 receptor (CD25 alpha) antibodies – Therapeutic antibodies against the IL-2 receptor (IL-2R; CD25) include the humanized Mabs, daclizumab and basiliximab, and the mouse Mab, inolimomab. IL-2R blockade prevents T cell proliferation and may reduce GVHD, but T regulatory cells (Tregs) are important in modulating GVHD and their removal may contribute to inferior outcomes. (See "Pathogenesis of graft-versus-host disease (GVHD)", section on 'Histocompatibility' and "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Initial therapy'.)

Therapeutic antibodies directed against IL-2R have not shown greater efficacy or safety compared with other treatments for GC-resistant acute GVHD. Examples of such studies include:

Basiliximab was associated with 83 percent ORR (including 18 percent CR) in 23 patients with GC-refractory acute GVHD, with an 18 percent CR and 65 percent partial response (PR) rate [64].

In an open-label multicenter trial, OS, time to treatment failure, and AEs were similar among 100 patients who were randomly assigned to inolimomab versus ATG for GC-resistant aGVHD [65].

Treatment of 62 patients with daclizumab reported 69 percent CR of aGVHD, with higher response rates in those with fewer involved organs and less extensive skin involvement; nevertheless, most patients went on to develop extensive cGVHD [66].

A phase 3 trial that compared GC alone versus GC plus daclizumab for initial treatment of aGVHD was terminated when an interim analysis showed significantly worse OS at day 100 and at one year for patients treated with the combination [67].

Daclizumab was withdrawn from market worldwide because of safety concerns.

TocilizumabTocilizumab is an anti-interleukin-6 receptor antibody. Administration and AEs with tocilizumab are presented separately. (See "Overview of biologic agents in the rheumatic diseases", section on 'Tocilizumab'.)

Responses were seen in four of six patients treated with tocilizumab for GC-refractory aGVHD [68]. Infections were the most common AE, but some patients had transient elevations in liver function tests.

Alemtuzumab – The humanized CD52-directed monoclonal antibody, alemtuzumab was associated with 70 percent ORR (including 35 percent CR) in 20 patients with grade 3-4 GC-resistant aGVHD involving the gut [69]. CMV reactivation, bacterial infection, and invasive aspergillosis were frequent AEs.

Mesenchymal stromal cells (MSCs) — MSCs that are present in bone marrow provide growth factors that are needed for hematopoiesis; can differentiate to fibroblasts, adipocytes, osteoblasts, and/or chondrocytes in vitro and in vivo; and induce CD4+/CD25+/FOXP3+ regulatory T cells (Tregs) [70-74].

A phase 3 trial that compared standard care plus either MSCs versus placebo in 244 patients with GC-refractory GVHD reported no significant difference in CR at four weeks (40 versus 28 percent, respectively) or infections [75]. However, treatment with MSCs was superior for GC-refractory GVHD that affected all three organs (skin, liver, and gut; 63 versus 0 percent ORR), liver (76 versus 47 percent ORR and 29 versus 5 percent CR at four weeks), and gut (82 versus 68 percent); there was also less progression of liver GVHD at two and four weeks.

A phase 2 study of ex vivo expanded MSCs (one to five doses with median 1.4 x 106 cells/kg from a matched sibling donor, haploidentical donor, or third-party human leukocyte antigen [HLA]-mismatched donor) reported 71 percent ORR (including 54 percent CR) in 55 patients with GC-resistant aGVHD [74]. There were no AEs during or immediately after MSC infusions and responses were not related to the degree of immunologic match.

ORR and CR were 94 and 77 percent, respectively, in 31 evaluable patients with de novo grade 2-4 aGVHD who were treated with systemic GC plus third-party, unmatched MSCs [76]. There were no infusional AEs and there was no difference in safety or efficacy using treatment with low versus high doses of MSCs.

MSCs derived from placenta also show promise for treating aGVHD, based on small, preliminary studies [77,78].

SUMMARY AND RECOMMENDATIONS

Graft-versus-host disease (GVHD) – GVHD occurs after allogeneic hematopoietic cell transplantation (HCT), when donor immune cells in the graft recognize the transplant recipient (host) as foreign. Acute GVHD (aGVHD), which principally affects skin, gastrointestinal (GI) tract, and liver, is primarily a T cell-mediated process. (See "Pathogenesis of graft-versus-host disease (GVHD)".)

Management – Preferred treatments for aGVHD vary according to the affected organs and the extent and severity of signs and symptoms (table 1).

Optimize prophylaxis – For treatment of any grade of aGVHD, the prophylaxis regimen should be optimized by measuring blood levels of the calcineurin inhibitor (ie, cyclosporine or tacrolimus). (See 'Optimizing prophylaxis' above.)

Grade 1 – For patients with mild cutaneous (grade 1) aGVHD, we suggest treatment of symptomatic sites with topical steroids, rather than systemic therapy (Grade 2C). (See 'Grade 1 aGVHD' above.)

Grade ≥2 – For grade ≥2 GVHD, we suggest treatment with a systemic glucocorticoid (GC), rather than other agents or regimens (Grade 2C). (See 'Grade ≥2 aGVHD' above.)

GI involvement – For patients with aGVHD that involves the GI tract, we suggest a systemic GC plus an oral nonabsorbable steroid, rather than systemic therapy alone (Grade 2B). Most patients will require supplemental nutrition and they may need octreotide to control diarrhea. (See 'GI aGVHD' above.)

Treatment response – Response of aGVHD is assessed on days 5 and 7 of treatment (table 1); in addition, the patient is evaluated daily for symptoms, infections, and disease-related complications. (See 'Response assessment' above.)

Systemic therapy – The most widely used systemic GC is methylprednisolone. For patients who are responding, the GC is continued for several weeks and then gradually tapered over months. (See 'Systemic glucocorticoids' above.)

GC-refractory GVHD – Patients with progression of aGVHD by day 5 or no response by day 7 are considered to have GC-resistant aGVHD. (See 'Glucocorticoid-resistant aGVHD' above.)

For treatment of GC-refractory aGVHD, we suggest ruxolitinib, rather than other treatments (Grade 2C).

For GC-refractory aGVHD does not respond or progresses after ruxolitinib, there is no consensus treatment; options include:

-Mycophenolate mofetil – (See 'Mycophenolate mofetil (MMF)' above.)

-Etanercept – (See 'Etanercept' above.)

-Pentostatin – (See 'Pentostatin' above.)

-Alpha-1 antitrypsin – (See 'Alpha-1 antitrypsin' above.)

-Sirolimus – (See 'Sirolimus' above.)

-Extracorporeal photopheresis – (See 'Extracorporeal photopheresis' above.)

-Other agents – (See 'Anti-thymocyte globulin (ATG)' above and 'Brentuximab vedotin' above and 'Monoclonal antibodies' above and 'Mesenchymal stromal cells (MSCs)' above.)

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Topic 3543 Version 41.0

References

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