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Treatment of chronic graft-versus-host disease

Treatment of chronic graft-versus-host disease
Literature review current through: Jan 2024.
This topic last updated: Jan 17, 2023.

INTRODUCTION — Graft-versus-host disease (GVHD) can develop after allogeneic hematopoietic cell transplant (HCT), when immune cells from a non-identical donor (the graft) initiate an immune reaction against a transplant recipient (the host). Acute GVHD (aGVHD) and chronic GVHD (cGVHD) are multisystem disorders that are distinguished by their clinical findings, according to the widely-accepted National Institutes of Health (NIH) consensus criteria; an overlap syndrome with features of both aGVHD and cGVHD is also recognized [1]. Formerly, aGVHD and cGVHD were distinguished by onset before or after 100 days from transplantation, but these syndromes may occur outside of those time periods.

Clinical manifestations of cGVHD may be widespread or they may be restricted to a single organ or site. The primary manifestations of cGVHD are skin involvement resembling lichen planus or cutaneous scleroderma, dry oral mucosa, ulcerations and sclerosis of the gastrointestinal tract, elevated serum bilirubin, and bronchiolitis obliterans. By contrast, patients with aGVHD commonly demonstrate a maculopapular rash, abdominal cramps with diarrhea, and elevated serum bilirubin.

cGVHD is a major cause of morbidity and mortality after allogeneic HCT, which worsen with disease severity. Patients have impaired physical, social, and psychological well-being and impaired quality of life. More than one-third of patients who undergo allogeneic HCT require systemic treatment for severe cGVHD [2]. Treatment should aim to balance the benefit of reducing cGVHD against treatment-related adverse effects and potential diminution of a graft-versus-tumor effect.  

This topic discusses the treatment of cGVHD.

Clinical manifestations, diagnosis, and grading of cGVHD are discussed separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

Related topics include:

(See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

(See "Treatment of acute graft-versus-host disease".)

(See "Prevention of graft-versus-host disease".)

(See "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults".)

(See "Pathogenesis of graft-versus-host disease (GVHD)".)

PRETREATMENT EVALUATION — Pretreatment evaluation of cGVHD includes assessing which organ systems are affected and documenting the extent and severity of involvement. We use the National Institutes of Health (NIH) criteria for diagnosing and scoring the severity of cGVHD [3], as described separately. Overall severity of cGVHD should be recorded.

Details of clinical manifestations, evaluation, diagnosis, grading, and differential diagnosis of cGVHD are described separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

Clinical and laboratory studies

Clinical – History and physical examination should evaluate manifestations of cGVHD and the extent and severity of involvement (form 1). Comorbid conditions and medications taken for GVHD prophylaxis and treatment should be documented.

Clinical evaluation should assess:

Skin – Specific cutaneous features (eg, sclerosis, plaques, altered pigmentation) and the extent of involvement (ie, estimated body surface area [BSA])

Mouth – Lichen planus-like features

Eyes, hair, nails – Dry eyes, alopecia, brittle nails

Lungs – Dyspnea, fatigue, cough

Gastrointestinal (GI) tract – Anorexia, nausea, ulceration, diarrhea

Musculoskeletal – Weakness, arthralgias, arthritis, muscle cramps, joint contractures

Clinical manifestations are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Clinical manifestations'.)

Performance status (PS) – We score patients according to the Eastern Cooperative Oncology Group (ECOG) PS or Karnofsky PS (table 1)

Laboratory

Complete blood count (CBC) with differential

Chemistries – Serum electrolytes, glucose, renal function tests

Liver function tests – Serum alkaline phosphatase, bilirubin, transaminases

Imaging – Imaging should include a chest radiograph and other imaging studies, as guided by clinical manifestations.

Other testing – Patients with cough, dyspnea, or other respiratory manifestations should undergo pulmonary function testing.

Diagnosis — Importantly, cGVHD must be distinguished from the late onset of acute GVHD (aGVHD) and from overlap syndrome (simultaneous presence of aGVHD with diagnostic or distinctive features of cGVHD).

Diagnostic criteria for cGVHD and distinctive features that distinguish it from aGVHD are presented separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Diagnostic criteria'.)

Grading — The severity of cGVHD should be graded to assess prognosis and guide management.

We use a modification of the National Institutes of Health (NIH) scoring system, which includes assessment of skin, mouth, eyes, GI tract, liver, lungs, joints/fascia, and genital tract and grades the severity of affected organs from 0 to 3 (higher scores reflecting more severe disease) (form 1) [3]. Our grading differs in that we include <100,000 platelets/microL as an additional criterion for severe disease.

Mild disease – Involvement of one or two organs with score ≤1 plus lung score 0 and no significant functional impairment (eg, ECOG PS ≤2)

Moderate disease (any of the following):

Involvement of ≥3 organs with score ≤1

Lung score 1

Any non-lung organ score 2

Functional impairment (eg, ECOG PS ≥3)

Severe disease (any of the following):

Lung score ≥2

Any non-lung score 3

Platelet count <100,000/microL

Details of the NIH scoring system and other grading systems are described separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Prognosis'.)

GOALS OF TREATMENT — The goals of treatment are to produce a sustained reduction or elimination of symptom burden, disability, and disease activity, while limiting treatment-related adverse effects and enabling withdrawal of therapy without recurrence of cGVHD.

INITIAL MANAGEMENT — Initial treatment is guided by the classification of cGVHD as mild, moderate, or severe disease (algorithm 1). (See 'Grading' above.)

Optimal management requires a multidisciplinary team that includes transplant specialists, a primary care provider, organ-specific consultants, nurses, and ancillary services (eg, social services, vocational specialists, patient/family support groups).

Our approach to management of cGVHD is consistent with guidelines from the American Society of Transplantation and Cell Therapy (ASTCT; formerly ASBMT) [4], the British Committee for Standards in Hematology and the British Society for Bone Marrow Transplantation [5,6], and the European Group for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet [7]. We encourage enrollment in a clinical trial, when possible.

Mild cGVHD — For patients with mild cGVHD, we suggest localized/topical treatment rather than systemic therapy, to avoid the adverse effects and complications of systemic glucocorticoids and/or other immunosuppressive agents.

Localized/topical treatments for affected organs are described below. (See 'Localized/topical treatments' below.)

In some cases of very widespread mild cGVHD (eg, skin involvement involving >50 percent body surface area), systemic therapy may be favored by the clinician or patient, despite the toxicity and potential complications of oral glucocorticoids or other immunosuppressive agents. (See 'Moderate cGVHD' below.)

Moderate cGVHD — For initial treatment of moderate cGVHD, we recommend systemic prednisone, rather than an alternative immunosuppressive agent, either alone or together with prednisone. Prednisone has been the standard of care for moderate or severe cGVHD for decades, based on observational studies that showed improved survival and performance status compared with outcomes prior to the routine use of prednisone [8-11]. Prednisone has not been directly compared with other immunosuppressive agents, but addition of azathioprine, mycophenolate mofetil, cyclosporine, thalidomide, or hydroxychloroquine to prednisone did not improve the response rate, shorten the duration of therapy, or substantially reduce toxicity compared with prednisone alone, based on randomized trials [8,11-15]. (See 'Prednisone' below.)

Prednisone is effective in nearly half of patients with moderate or severe cGVHD. However, treatment is typically protracted and associated with significant adverse effects. We seek to adjust the dose to avoid complications of chronic prednisone therapy, as described below. (See 'Dose adjustment' below.)

Topical therapy can be added to systemic prednisone, if needed, to ameliorate localized symptoms. (See 'Localized/topical treatments' below.)

Severe cGVHD — For patients with severe cGVHD, we suggest initial treatment with prednisone plus ruxolitinib, rather than prednisone alone or prednisone plus an alternative second agent. This suggestion is based on expert opinion according to outcomes with prednisone plus ruxolitinib for patients with steroid-refractory (SR)-cGVHD. Some experts favor prednisone alone, as it has not been proven that ruxolitinib or any other second agent improves the response of severe cGVHD or substantially reduces adverse effects of prednisone, compared with prednisone alone, as described below. (See 'Steroid-refractory (SR) cGVHD' below.)

Ruxolitinib is not approved for initial treatment of cGVHD by the US Food and Drug Administration (FDA) or European Medicines Agency.

Prednisone plus ibrutinib was not more effective than prednisone plus placebo in a double-blind, phase 3 trial (iNTEGRATE) of 193 patients (≥12 years) with previously-untreated moderate or severe cGVHD [16]. Response rates were similar at 48 weeks (41 percent with prednisone-ibrutinib versus 37 percent with prednisone-placebo) and at 96 weeks (27 versus 22 percent, respectively); complete responses at 48 weeks (9 versus 6 percent) and at 96 weeks (14 versus 9 percent) were also similar. Overall survival, event-free survival, duration of response, and symptomatic improvement (based on Lee Symptom Scale [17]) also did not differ significantly, but there was a trend toward greater withdrawal of all immunosuppressants in the prednisone-ibrutinib group than the prednisone-placebo group (47 percent versus 39 percent, respectively). Grade ≥3 adverse events occurred in approximately one-half of patients in both trial arms and no new safety signals emerged.

If ruxolitinib is not available, contraindicated (eg, for platelets <10,000/microL), not tolerated, or not available, we favor extracorporeal photopheresis (ECP; where available) as an effective non-pharmacologic approach to limit additional adverse effects. Otherwise, no second agent (other than ruxolitinib) is proven better than others. Selection of an alternative second agent is informed by current medications, toxicity, comorbid conditions, availability, and preferences of the clinician and patient.

Overlap syndrome — Patients with overlap syndrome have cGVHD with pre-existent acute GVHD (aGVHD). As a result, patients with overlap syndrome may already be receiving prednisone therapy, with or without a calcineurin inhibitor (CI), for the aGVHD.

Treatment of overlap syndrome is informed by the severity of the cGVHD, as described above (see 'Initial management' above):

Mild manifestations of GVHD – (See 'Mild cGVHD' above.)

Moderate cGVHD:

No current systemic prednisone – Treat with systemic prednisone. (See 'Moderate cGVHD' above.)

Current systemic prednisone – Adjust the prednisone dose (if lower than the suggested initial dose) (see 'Dose adjustment' below) or add a second agent to prednisone, as per severe cGVHD. (See 'Severe cGVHD' above.)

Current prednisone plus a second agent – Treat as SR-cGVHD. (See 'Treatment of SR-cGVHD' below.)

Severe cGVHD – Treat with prednisone plus a second agent, as per SR-cGVHD. (See 'Treatment of SR-cGVHD' below.)

TREATMENTS

Localized/topical treatments — Management is guided by the involved organs, severity of findings, and response to treatment.

Mild cGVHD – Localized or topical treatments are usually sufficient for treatment of mild cGVHD. We adjust the treatment, as guided by the response and consider systemic therapy if there is progression to moderate of severe disease.

Moderate or severe cGVHD – Adding localized treatments to systemic therapy for patients who present with moderate or severe cGVHD can accelerate the response, improve local control, and/or reduce the dose and duration of prednisone and other systemic agents with little or no additional toxicity.

Detailed suggestions regarding organ-specific treatments have been provided by the American Society for Blood and Marrow Transplantation, the British Committee for Standards in Hematology, the British Society for Bone Marrow Transplantation, and the German-Austrian-Swiss Consensus Conference, and the European Society for Blood and Marrow Transplantation [4,6,7,18-20].

Skin — Skin is affected in two-thirds of patients with cGVHD. Maculopapular rash/erythema, dryness, and flaking are common with mild cutaneous involvement, while lichen planus and/or sclerosis are characteristic manifestations of grade ≥3 skin involvement. Thinning of the skin can make it prone to ulceration, while sclerosis can impair healing of the skin. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Ancillary measures in chronic graft-versus-host disease'.)

Symptom relief

Emollients – Ointments and creams are frequently used for relief with mild skin involvement.

Topical therapy – Topical glucocorticoids or calcineurin inhibitors should be used as first-line therapy for drying and flaking skin [7]. Attention to areas of skin breakdown is important to ensure that these sites do not become secondarily infected.

Extracorporeal photopheresis (ECP) can be used for treatment of very extensive (eg, >50 percent body surface area) skin involvement or when topical agents are not sufficient. (See 'Extracorporeal photopheresis' below.)

Physical therapy may be useful for patients with sclerodermatous disease to prevent contractures.

Surveillance

Referral to a dermatologist with experience in transplant dermatology is useful for patients with moderate or severe cutaneous GVHD.

Because of the increased risk of cutaneous malignancy, all patients on prolonged immunosuppression should have an annual skin check by a dermatologist.

All growing/non-healing skin lesions should be referred to a dermatologist within two to four weeks.

Mouth — Symptoms include inflammation, ulceration, and lichen planus-like lesions; when severe, symptoms may limit oral intake. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Oral health'.)

Symptom relief

Hydration – Patients may carry a bottle of water and drink frequently; some may find relief with artificial saliva.

Topical therapies – Steroid mouthwashes can be helpful in areas of ulceration or leukoplakia. Infection with Herpes simplex, human papilloma virus, and Candida and other fungal organisms should be ruled out before initiating topical steroids.

For oral lesions that do not respond adequately to topical agents, ECP can be used as systemic therapy. (See 'Extracorporeal photopheresis' below.)

Prevention/surveillance

Hygiene – Good oral/dental hygiene and topical fluorides to prevent caries are important [21].

Stretching exercises may increase the range of motion of the mouth.

Persistent or new oral lesions that occur >3 months after transplantation should be evaluated for a secondary cancer.

Eyes — Dry eyes are irritating and may progress to photophobia, pain, or impaired vision with severe disease [22].

Initial evaluation and periodic follow-up by an ophthalmologist knowledgeable in the potential complications of transplantation is described separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Ocular complications'.)

Symptom relief

Hydration – Preservative-free artificial tears, steroid eyedrops, and/or topical tacrolimus can improve eye hydration [23].

Sunglasses can be helpful for photophobia.

In severe cases, gas-permeable scleral lenses may decrease symptoms. For patients who produce tears, tear duct plugs or permanent duct closure with laser treatment may lessen symptoms.

Prevention/surveillance

Symptoms suggestive of significant ocular involvement should be evaluated and managed by an ophthalmologist experienced with ocular GVHD. Clinicians should have a high degree of suspicion for infections (eg, infectious keratitis).

Patients on prolonged systemic steroids for cGVHD are at increased risk for developing cataracts.

Vagina — Vulvovaginal dryness and/or dyspareunia is a common problem, especially in the setting of estrogen insufficiency; ulcers, lichen planus-like features, vaginal stenosis, or complete obliteration may occur with progressive GVHD. All patients should be asked about sexual function. Additional discussion of the management of vulvovaginal atrophy, pain, and stenosis is presented separately. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Vaginal estrogen therapy' and "Vulvar lichen sclerosus: Management".)

Symptom relief

Topical therapy to the vaginal epithelium, using a dilator, if needed, include one or more of the following [20,24,25]:

-Estrogen – Topical estrogens (table 2) can increase epithelial thickness and are typically prescribed daily for two weeks, followed by twice-weekly maintenance therapy.

-Corticosteroids – Topical steroids (eg, a pea-sized amount of clobetasol 0.05% ointment) can be applied to the affected area twice daily for 6 to 12 weeks, followed by two to three times per week. Alternatively, 10 percent hydrocortisone rectal foam, inserted vaginally, can be used.

-Antibiotics – Topical antibiotics (eg, clindamycin 2% gel applied intravaginally for two weeks, then twice-weekly as maintenance therapy) can decrease inflammation.

-Topical immunomodulators – Calcineurin inhibitors (eg, tacrolimus, pimecrolimus) can be applied twice daily, with tapering over six weeks to achieve twice-weekly maintenance.

Prevention – Early consultation with a gynecologist experienced in GVHD is helpful for management and to minimize disease progression.

-Hygiene – Avoidance of lotions, soaps, and tight clothing should be encouraged.

-We perform gynecologic exams every three to six months for the first two years, and then as clinically indicated; photodocumentation may be useful to objectively monitor response.

Gastrointestinal — Nausea, vomiting, and dysphagia can progress to diarrhea with weight loss and/or esophageal web or stricture, when severe.

Referral to a gastroenterologist should be considered for patients with suspected gastrointestinal (GI) cGVHD. All patients with GI GVHD or malnutrition should be assessed by a dietician.

Symptom relief

Diarrhea – Evaluation should include cultures, testing for Clostridioides difficile toxin, and cytomegalovirus. Diarrhea without associated jaundice or rash suggestive of GVHD should be investigated by upper endoscopy (with duodenal aspirate and biopsies) and flexible sigmoidoscopy or colonoscopy (with biopsy).

Occasionally, patients may have persistent diarrhea/steatorrhea due to pancreatic insufficiency from cGVHD.

Mechanical dilation (eg, bougienage) may be used to break apart the strictures.

Prevention

Nutritional supplements can prevent weight loss.

Pancreatic replacement is beneficial in this setting. (See "Chronic pancreatitis: Management", section on 'Management of pancreatic insufficiency'.)

Lungs — Evaluation and management of pulmonary manifestations of cGVHD, including supplemental oxygen, bronchodilators, inhaled corticosteroids, and pulmonary rehabilitation programs [18] is discussed separately. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

Musculoskeletal — Erythema from myositis may be accompanied by limb swelling, muscle atrophy, weakness, and joint contractures [19]. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Musculoskeletal'.)

Symptom relief

Physical and/or occupational therapy may be helpful for patients with impaired activities of daily living. Repeated evaluation may be needed to assess muscular weakness and range of motion.

Prevention

Patients require screening for glucocorticoid-induced myopathy and sclerotic changes in the skin and fascia that can limit joint mobility.

Evaluation and management of accelerated bone loss is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Bone and joint health'.)

Endocrine — There is increased risk of diabetes mellitus, hypothyroidism, hypogonadism, and hypoadrenalism in cGVHD, as discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Diabetes' and "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Other endocrine'.)

PREDNISONE — Prednisone (or an equivalent systemic glucocorticoid) has long been preferred as initial systemic therapy for moderate or severe cGVHD. Because of adverse effects and complications of prolonged prednisone therapy, attention should be paid to adjusting the dose to the minimum amount needed to control symptoms (table 3).

Initial dose — Prednisone is usually started at 1 mg/kg/day. Use of higher doses of prednisone did not improve outcomes [26] and no studies have directly tested whether every other day dosing would achieve comparable efficacy or reduce toxicity in this setting [27].

The prednisone dose should be adjusted according to symptomatic response and objective measures of GVHD [28], as described below. (See 'Dose adjustment' below.)

Toxicity

Adverse effects – Long-term prednisone therapy is associated with infections, myopathy, avascular necrosis, osteoporosis, glucose intolerance, weight gain/altered body habitus, hypertension, cutaneous atrophy and striae, cataracts, emotional lability, sleep interference, and growth retardation in children. (See "Major adverse effects of systemic glucocorticoids".)

Prevention of infections – Patients who undergo allogeneic hematopoietic cell transplantation (HCT) are at risk for bacterial, viral, and fungal infections, which may be exacerbated by cytopenias, glucocorticoid therapy, and organ damage related to cGVHD. The time course of infections varies according to the degree of immune deficiency, cytopenias, time after transplantation, and prednisone treatment, as discussed separately. (See "Overview of infections following hematopoietic cell transplantation".)

-Infection prophylaxis may include neutropenic precautions; antibacterial, antiviral, and antifungal drugs; and immunoglobulin infusions, as discussed separately. (See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prevention of infections in hematopoietic cell transplant recipients".)

-Vaccination – All patients should be vaccinated against pneumococcus, influenza and Haemophilus influenzae. Importantly, live vaccines must not be administered to patients with cGVHD. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

Outcomes – Approximately half of patients with cGVHD treated with systemic prednisone have resolution of disease manifestations that enables tapering and later discontinuation of systemic therapy. Prednisone and methylprednisolone yield similar outcomes with cGVHD, based on phase 3 trials and various prospective and retrospective studies [11,27,29-31].

Outcomes with prednisone plus a second agent are presented below. (See 'Treatment of SR-cGVHD' below.)

Dose adjustment — We promptly adjust the dose of prednisone to the minimum amount needed to control symptoms. We evaluate the patient after the first two weeks of prednisone and adjust the dose as follows:

Improving cGVHD – For patients with a complete response (CR) or a good partial response (PR) after two weeks of therapy, prednisone can be tapered by 25 percent per week. The taper should continue until the dose reaches 0.10 mg/kg every other day; it can be discontinued after ≥4 weeks of treatment at that dose. For patients who have recurrent symptoms at this dose, treatment with very low prednisone doses may be required for a year or more.

If there is an exacerbation or recurrence of cGVHD at any step of the taper, the dose of prednisone should be increased promptly. It should be increased by two levels or returned to full-dose for two to four weeks, followed by resumption of alternate-day administration. Treatment should then be continued for at least three months before attempting to resume the taper.

Stable or worsening findings – If there is no improvement after two weeks of full initial dose, we add a second agent, as described for steroid-refractory (SR)-cGVHD below. (See 'Treatment of SR-cGVHD' below.)

RESPONSE ASSESSMENT — We assess response to localized and systemic treatment using the National Institutes of Health (NIH) Consensus Criteria for Clinical Trials in cGVHD [32]. The NIH criteria can be applied to both adults and children and are practical for use by transplantation and non-transplantation clinicians. Forms for data collection are available on the ASBMT website [33]. Provisional definitions of complete response (CR), partial response (PR), and disease progression are described for each organ system and for overall outcomes. There are no generally-accepted biomarkers for response in cGVHD.

Schedule – The schedule for response assessment is individualized according to disease severity, treatment(s), and concerns of the clinician and patient:

We initially assess the response to prednisone after two weeks of therapy to determine if dose reduction is possible, as described above. (See 'Dose adjustment' above.)

We reassess response at three-month intervals, when there are major changes in symptoms or treatment, and according to concerns by the patient or clinicians.

Evaluation of response should include:

Interval history and examination

Laboratory studies:

-Complete blood count (CBC) with differential

-Serum electrolytes, glucose, and liver and renal function tests

The NIH response criteria have been validated in a prospective cGVHD observational study [34].

STEROID-REFRACTORY (SR) cGVHD — Approximately half of patients with cGVHD become steroid-refractory (SR), which greatly increases the risk of poor outcomes [29].

Definition of SR-cGVHD — SR-cGVHD includes patients who do not respond adequately to full-dose prednisone and those who are intolerant or have unacceptable complications with prednisone. We consider any of the following to be SR-cGVHD:

Progressive disease despite prednisone 1 mg/kg/day for two weeks

Stable disease after four to six weeks of prednisone ≥0.5 mg/kg/day

Inability to taper prednisone to <0.5 mg/kg/day

The definition of SR-cGVHD can vary with the affected organ and clinical manifestations. As an example, skin sclerosis generally requires longer than other cutaneous findings and a shorter period of treatment is warranted if there is significant steroid-associated toxicity [27,35].

Treatment of SR-cGVHD — When SR-cGVHD is diagnosed in a patient who is already receiving cyclosporine or tacrolimus (eg, as prophylaxis for acute GVHD or for treatment of a patient with concurrent acute GVHD/overlap syndrome), we first optimize the dose of the calcineurin inhibitor to ensure a therapeutic level and then reassess the clinical response (table 3). (See "Treatment of acute graft-versus-host disease", section on 'Optimizing prophylaxis'.)

For patients with SR-cGVHD, we suggest adding ruxolitinib to prednisone, rather than treating with higher doses of prednisone or adding an alternative second agent (eg, extracorporeal photopheresis [ECP], cyclosporine, tacrolimus, belumosudil) to prednisone. Ruxolitinib is generally well-tolerated, and it can achieve a response and reduce steroid use in more than half of patients with SR-cGVHD; a meta-analysis of 329 patients [36] and a phase 3 trial [37] reported that addition of ruxolitinib was superior to addition of best available treatment to prednisone. (See 'Ruxolitinib' below.)

If ruxolitinib is not available or is not tolerated, we favor addition of a non-pharmacologic approach, such as ECP or psoralen ultraviolet irradiation (PUVA), where available; these non-pharmacologic treatments can limit or avoid additional adverse effects, but they may be expensive, inconvenient (ie, requiring a large-bore intravenous catheter), or have limited availability.

Otherwise, we choose a second agent according to current medications, toxicity, comorbid conditions, availability, and preferences of the clinician and patient. Alternative second agents are described in the sections that follow.

Patients should be encouraged to enroll on a clinical trial, when possible.

Ruxolitinib — Ruxolitinib is a selective Janus kinase (JAK) 1/2 inhibitor that interferes with signaling downstream of cytokine receptors. JAK signaling contributes to inflammation and tissue damage in GVHD and ruxolitinib was shown to reduce collagen deposition in preclinical models of pulmonary cGVHD [38].

AdministrationRuxolitinib is administered at a dose of 10 mg by mouth, twice daily. For patients with platelets <50,000/microL, the dose of ruxolitinib should be reduced to 5 mg twice daily. Ruxolitinib is contraindicated in patients with platelets <10,000/microL.

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

A "withdrawal syndrome" that resembles systemic inflammatory response syndrome may be seen when ruxolitinib is discontinued in myelofibrosis [39]. Dose reduction should be gradual rather than abrupt, caution is advised to monitor for a withdrawal-like syndrome; resumption of ruxolitinib (and other medical management) may be required in the setting of severe symptoms.

OutcomesRuxolitinib is effective in achieving an objective response more than half of patients with SR-cGVHD, reducing steroid use, and is generally well-tolerated, based on a systematic review and meta-analysis of 16 cohort studies (414 adults) [36].

A phase 3 trial of 329 patients with SR-cGVHD reported that ruxolitinib achieved superior outcomes and acceptable toxicity, compared with the investigator's choice of best available treatment (BAT) [37]. At week 24, compared with BAT, ruxolitinib achieved superior overall response rate (ORR; 50 versus 26 percent, respectively), improved symptom response (modified Lee symptom score responder rate; 24 versus 11 percent), complete response (CR; 7 versus 3 percent), and median failure-free survival (FFS; 19 versus 6 percent). Ruxolitinib and BAT were associated with comparable rates of grade ≥3 adverse events (AEs) up to week 24 (57 versus 58 percent), including thrombocytopenia (15 versus 10 percent), neutropenia (13 versus 8 percent), and infections: fungal (12 versus 6 percent), viral (34 versus 29 percent), and bacterial (28 versus 26 percent).

Another study reported that treatment with ruxolitinib was associated with reduction of steroid dose in 57 percent and 81 percent one-year overall survival (OS) [40]. Other studies reported similar outcomes [41,42].

There is no difference in ORR, OS, and toxicity between adults and children in one study [43]. In another study, 80 percent of children with moderate-severe cGVHD had at least a partial response (PR), including five of seven patients with bronchiolitis obliterans [44]. A retrospective study also reported effectiveness of ruxolitinib in children with cGVHD [45].

Non-pharmacologic therapies — Non-pharmacologic therapies can be associated with improvements in cGVHD without adding AEs of additional drugs.

Extracorporeal photopheresis — ECP consists of re-infusion of ultraviolet-irradiated autologous peripheral lymphocytes that have been collected by apheresis and incubated with 8-methoxypsoralen [46-52].

A literature review identified 735 patients with steroid-resistant, steroid-intolerant, or steroid-dependent cGVHD treated with ECP [53]. ECP resulted in ORRs of 50 to 65 percent (approximately 30 to 35 percent complete) and approximately 25 to 35 percent of patients were able to significantly taper steroid use. Responses were less likely in patients with more extensive disease, those with a history of acute GVHD, and patients with thrombocytopenia.

ECP is contraindicated in patients with severe cardiovascular or renal impairment. Immunosuppression results from a decrease in the number and function of circulating lymphocytes due primarily to the inhibition of DNA transcription and mitosis. (See "Treatment of acute graft-versus-host disease", section on 'Extracorporeal photopheresis'.)

PUVA (psoralen ultraviolet irradiation) — PUVA combines the administration of psoralens, a class of phototoxic plant-derived compounds, with an exposure to ultraviolet A radiation (UVA) [54-62]. When used in patients with cGVHD and extensive skin involvement, PUVA is usually begun at 25 percent of the normal dose; those with cGVHD and extensive skin involvement may be very sensitive to burning with this modality.

In one study, approximately one-third of patients treated with PUVA therapy achieved CR [59]. In some, but not all studies [60], the efficacy of PUVA seemed to be limited to the skin complications of cGVHD, such as a steroid-sparing effect on skin lesions [63]. PUVA may be most effective if used earlier in the course of the disease when GVHD is limited to the skin. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)

Calcineurin inhibitors — Cyclosporine (CsA) and tacrolimus are chemically distinct calcineurin inhibitors that have similar mechanisms of action, clinical efficacy, and AEs. (See "Pharmacology of cyclosporine and tacrolimus".)

Administration – We generally treat with prednisone 1 mg/kg/day plus CsA 6 mg/kg twice daily every other day. We consider tacrolimus (eg, 0.1 mg/kg/day) equally acceptable.

Adverse effects – Both CsA and tacrolimus are associated with hypomagnesemia, hyperkalemia, hypertension, and nephrotoxicity. Other nephrotoxic drugs should be avoided, if possible, so that the agent can be delivered at the target doses. Both agents may cause transplant-associated thrombotic microangiopathy or neurotoxic effects that can necessitate premature discontinuation. (See "Pharmacology of cyclosporine and tacrolimus".)

Monitoring – We adjust dosing based on serum levels. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Drug monitoring'.)

Outcomes – In a trial that randomly assigned 287 patients with severe cGVHD to prednisone plus CsA versus prednisone alone, there was no difference in five-year transplant-related mortality (17 versus 13 percent, respectively), OS, recurrent malignancy, need for additional cGVHD therapy, or discontinuation of all immunosuppressive agents [11]. However, patients who received prednisone plus CsA has fewer episodes of avascular necrosis than those treated with prednisone alone (13 versus 22 percent).

Treatment of 61 patients with severe cGVHD using CsA on alternate days with prednisone was associated with three-year OS was 52 percent, which was superior to historical control patients who were treated with alternate-day prednisone alone (three-year OS 26 percent) [9]. None of the patients treated with CsA/prednisone developed renal failure or required dialysis and most had an excellent performance status (KPS ≥90).

Belumosudil — Belumosudil is an oral inhibitor of ROCK2 (Rho-associated coiled-coil–containing protein kinase 2) that reduces type 17 and follicular helper T cells (by downregulating STAT3) and enhances regulatory T cells (by upregulation of STAT5) [64].

AdministrationBelumosudil is taken 200 mg orally once daily with food. For patients taking a strong CYP3A inducer (table 4) or a proton pump inhibitor, the dose of belumosudil should be increased to 200 mg twice daily.

Toxicity – The most common AEs are fatigue, diarrhea, nausea, cough/dyspnea, headache, and elevated liver function tests. Belumosudil can cause fetal harm.

Outcomes – A study randomly assigned patients who had two to five prior lines of therapy for cGVHD to belumosudil 200 mg, either once daily (66 patients) or twice daily (66 patients); outcomes and adverse effects were similar with both doses [65]. ORR was 76 percent (including 2 percent CR) and 70 percent had symptomatic improvement (measured by ≥7 point reduction in the Lee Symptom Scale [LSS]). Belumosudil was well tolerated; the most common grade ≥3 AEs were pneumonia (7 percent), hypertension (6 percent), and hyperglycemia (5 percent).

Belumosudil is approved by the US Food and Drug Administration (FDA) for patients ≥12 years with cGVHD after failure of ≥2 prior lines of systemic therapy.

Ibrutinib — Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK) that has activity against cGVHD.

A phase 2 study of ibrutinib in 42 patients with SR-cGVHD reported responses in two-thirds (one-third with CR) [66]. Improvement occurred in multiple organ systems (eg, skin, mouth, gastrointestinal tract, liver) and responses lasted ≥5 months in half of patients. Response to ibrutinib permitted reduction of glucocorticoid dose to ≤0.15 mg/kg/day in nearly two-thirds and was associated with improved quality of life. Common AEs in patients with cGVHD included fatigue, bruising, stomatitis, nausea, diarrhea, thrombocytopenia, and anemia; more serious AEs included hemorrhage, infections, atrial fibrillation, hypertension, and tumor lysis syndrome.

Ibrutinib is approved by the US FDA for treatment of cGVHD [67].

Other second agents — The following agents can be considered when cGVHD has proven refractory to prednisone plus an agent described above. Selection is based on toxicity, adverse effects, and availability, as there are no direct comparisons of efficacy.

Mycophenolate mofetil (MMF) is an immunosuppressive agent that has antibacterial, antifungal, antiviral, and antitumor properties.

Administration – We generally treat with MMF 1 to 1.5 g (15 mg/kg) twice daily in combination with cyclosporin or tacrolimus.

Toxicity – AEs at commonly employed doses have been low; neutropenia is the most common AE, but gastrointestinal side effects have also been reported.

Outcomes – Addition of MMF (2 g daily) to cyclosporine and prednisolone was evaluated in a single center trial of 24 patients with GVHD, including seven patients with chronic GVHD [68]. Moderate improvement in symptoms was seen in three of six patients with limited stage chronic GVHD. The most common toxicities were leukopenia, anemia, and thrombocytopenia.

A phase 3 trial of 230 patients was terminated after four years because an interim analysis indicated a low probability that prednisone plus MMF was better than prednisone plus placebo for controlling cGVHD and enabling withdrawal of all systemic treatment [12]. Addition of MMF had no effect on the amount of prednisone treatment or the proportion of patients with CRs.

Sirolimus (rapamycin) has been used for the treatment of SR-cGVHD [69].

There is no standard dose, but a reasonable regimen is a loading dose of 6 mg followed by a daily dose of 2 mg, aiming for a target serum level of 10 ng/microL. Common toxicities include hyperlipidemia, renal dysfunction, and cytopenias; thrombotic microangiopathies, infectious complications, and seizures are also reported.

Sirolimus has also been associated with sinusoidal obstruction syndrome (SOS; also called hepatic veno-occlusive disease [VOD]) following myeloablative conditioning regimens (especially with busulfan conditioning). (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Aspects of transplantation'.)

Treatment of 35 patients with SR-cGVHD with sirolimus plus tacrolimus and methylprednisolone was associated with 63 percent overall response (17 percent CR) [69].

Rituximab

AdministrationRituximab (375 mg/m2 intravenously) is administered weekly for four weeks; if there is at least a PR, up to two more four-week courses may be administered.

ToxicityRituximab can be associated with re-activation of hepatitis B. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)  

OutcomesRituximab appears to be especially beneficial for patients with skin, oral, or musculoskeletal involvement.

Clinical responses were reported in 86 percent of 37 patients with SR-cGVHD and most responses were maintained at one year, with reductions of glucocorticoid dose in 57 percent of patients [70]. Other studies also report comparable patterns of response [70-76].

Tyrosine kinase inhibitors – Small prospective and retrospective studies have evaluated the use of imatinib, a tyrosine kinase inhibitor (TKI), for patients with cGVHD [77-80]. In three prospective studies performed in patients with SR-cGVHD, responses were seen in 7 of 14 patients, 15 of 19 patients, and 20 of 39 patients, respectively [77,78,80]. While CRs were not seen, many patients are able to decrease their steroid requirements. This agent has also had some effectiveness in patients with cGVHD involving the lungs [81].

A phase 2 study reported improvement in skin sclerosis or joint range of motion in one-third of 35 patients treated with imatinib [76].

Bortezomib is a proteasome inhibitor that has activity in cGVHD. A phase 2 study of bortezomib (1.3 mg/m2 intravenously on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles) plus prednisone (0.5 to 1 mg/kg/day, with taper after cycle 1) as initial treatment for cGVHD in 22 patients reported 80 percent ORR at 15 weeks (10 percent CR) [82]. Organ-specific CR was 73 percent for skin, 53 percent for liver, 75 percent for gastrointestinal tract, and 33 percent for joint, muscle, or fascia involvement [82]. Treatment was well-tolerated, with one occurrence of grade 3 sensory peripheral neuropathy.

Interleukin-2 (IL-2) may produce responses in SR-cGVHD, but we await further study before incorporating it into routine care. IL-2 is a T cell-derived cytokine that plays a central role in immune responses and the development and function of regulatory T cells (Tregs). Animal studies that suggested that Treg cells could control GVHD and that IL-2 depletion by calcineurin inhibition reduced Treg activity [83]. (See "Pathogenesis of graft-versus-host disease (GVHD)", section on 'Overview of GVHD'.)

A phase 2 study of IL-2 (1x106 international units/m2) in 35 adults with SR-cGVHD reported clinical responses in 20 of 33 evaluable patients (none complete) by week 12; 10 patients had stable disease and three had progressive disease [84]. AEs resulted in dose reduction in five patients and early withdrawal in two.

Other agents that have been used to treat SR-cGVHD include etanercept [85], thalidomide [86,87], and pentostatin [88].

PROGNOSIS — The presence of severe cGVHD, overlap syndrome, and extensive skin disease are associated with adverse outcomes; thrombocytopenia was also associated with inferior outcomes in some studies [89].

Moderate/severe cGVHD – Involvement of ≥3 organs or involvement of any single organ with severity score >2 (form 1) is associated with greater morbidity and inferior survival, compared with mild disease [1].

Overlap syndrome – The prognostic importance of overlap syndrome is uncertain. A study using the National Institutes of Health (NIH) severity grading criteria reported that outcomes with overlap syndrome were inferior to classic cGVHD [90]; older studies also identified "progressive onset" (which largely comprised overlap syndrome) as associated with adverse outcomes [91-93]. In contrast, a retrospective study found no difference in overall survival (OS) between overlap syndrome and cGVHD [94].

Extensive skin involvement – Skin involvement >50 percent body surface area (BSA) has been associated with poor outcomes [89].

Thrombocytopenia – In some studies, thrombocytopenia (<100,000/microL) was associated with inferior outcomes, but this may be limited to patients who were transplanted using myeloablative conditioning and peripheral blood stem cells as a graft source [8,9,89].

CLINICAL TRIALS — We strongly encourage participation in a clinical trial, when available. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (clinicaltrials.gov).

SUMMARY AND RECOMMENDATIONS

Chronic graft-versus-host disease (cGVHD) is the major determinant of long-term outcome and quality of life following allogeneic hematopoietic cell transplantation (HCT). The primary manifestations of cGVHD are sclerotic cutaneous effects, dry oral mucosa, ulcerations and sclerosis of the gastrointestinal tract, and elevated serum bilirubin.

Clinical manifestations, diagnosis, and grading of cGVHD are discussed separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

Grading is according to our modification of the National Institutes of Health (NIH) GVHD scoring system (form 1), which surveys symptoms, affected organ systems, and severity and extent of involvement (graded 0 to 3). There are no validated biomarkers for cGVHD severity. We classify cGVHD as:

Mild – ≤2 affected organs, no pulmonary manifestations, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 (see 'Mild cGVHD' above)

Moderate – Involvement of ≥3 organs with score ≤1, lung score 1, any non-lung organ score 2, or ECOG PS ≥3 (see 'Moderate cGVHD' above)

Severe – Lung score ≥2, any non-lung score 3, or <100,000 platelets/microL (see 'Severe cGVHD' above):

Treatment is based on disease severity, scored with the modified NIH scale (algorithm 1):

Mild cGVHD – For patients with mild cGVHD, we suggest localized or topical treatment rather than systemic therapy (Grade 2C), to avoid adverse effects (AEs)/complications of systemic prednisone and other systemic immunosuppressive agents. (See 'Mild cGVHD' above.)

Localized or topical therapy varies according to the affected organ, as described above. (See 'Localized/topical treatments' above.)

Moderate cGVHD – For initial treatment of moderate cGVHD, we recommend systemic prednisone, rather than an alternative immunosuppressive agent, either alone or together with prednisone (Grade 2C). (See 'Moderate cGVHD' above.)

Topical therapy can be added to systemic prednisone, if needed, to ameliorate localized symptoms.

Severe cGVHD – For initial treatment of severe cGVHD, we suggest prednisone plus ruxolitinib, rather than prednisone alone or prednisone plus another second agent (Grade 2C). (See 'Severe cGVHD' above.)

Response assessment is performed according to the NIH Consensus Criteria for Clinical Trials in cGVHD. (See 'Response assessment' above.)

Steroid-refractory (SR) cGVHD – For patients with SR-cGVHD, we recommend addition of ruxolitinib to prednisone, rather than addition of other systemic medications (eg, cyclosporine, tacrolimus, ibrutinib) or non-pharmacologic approaches (eg, extracorporeal photopheresis, psoralen ultraviolet irradiation therapy) to prednisone (Grade 2B).

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Topic 3550 Version 53.0

References

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