Approach

Optimal management of graft versus host disease (GVHD) requires a multidisciplinary team approach, comprising infectious disease specialists, dermatologists, gastroenterologists, nutritionists, physical therapists, cardiologists, pulmonologists, ophthalmologists, dentists, gynecologists, rheumatologists, and urologists. Appropriate specialists should be involved at diagnosis and throughout treatment and follow-up.

Optimal prophylaxis, prompt treatment, appropriate monitoring of treatment response, and supportive care reduce risk of complications and disability.[63][92]​​​ Other factors that may influence the management of GVHD include local practices and guidelines, availability of therapies, and the preferences and experience of treating physicians.

GVHD prophylaxis

Prophylaxis with immunosuppressants is the main preventive strategy for patients undergoing allogeneic hematopoietic cell transplantation (HCT).[62][63]​​​ Standard prophylactic regimens are calcineurin inhibitor-based. Corticosteroids are not routinely recommended for GVHD prophylaxis.

Standard GVHD prophylactic regimens

The standard regimens for GVHD prophylaxis in patients undergoing matched related or unrelated donor HCT comprise a calcineurin inhibitor (e.g., cyclosporine or tacrolimus) plus low-dose methotrexate or mycophenolate.​[63][105][106]​​

A therapeutic regimen comprising calcineurin inhibitor plus methotrexate has been shown to be superior to either agent alone in the reduction of GVHD incidence and improvement in survival.[65][107]​​​ One meta-analysis found no difference in all-cause mortality between tacrolimus plus methotrexate and cyclosporine plus methotrexate.[106] However, the former regimen was superior with respect to reducing acute GVHD incidence.[106]

One Cochrane review examining the effect of mycophenolate versus methotrexate for acute GVHD prevention found no significant differences in overall survival, median time to neutrophil engraftment, or the incidence of acute GVHD, relapse, nonrelapse mortality, and chronic GVHD.[105] However, mycophenolate was associated with less mucositis, less use of parenteral nutrition, and less use of analgesia, suggesting a more favorable toxicity profile.[105]

Tacrolimus plus sirolimus has been suggested as an alternative regimen for GVHD prophylaxis.[75][76][77][78]​​​ Incidence of acute GVHD (by day +114) is similar between tacrolimus plus sirolimus and tacrolimus plus methotrexate in patients who have undergone allogeneic HCT from a matched related donor.[78]

Evidence continues to influence the management of GVHD prophylaxis, and alternative prophylactic treatment strategies may be considered for specific patient populations.

Abatacept

A selective T-cell costimulation modulator, abatacept is approved by the Food and Drug Administration (FDA), in combination with a calcineurin inhibitor and methotrexate, for the prevention of acute GVHD in patients undergoing allogeneic HCT from a matched or 1 allele-mismatched unrelated donor.

In one phase 2 randomized trial, the addition of abatacept to standard prophylaxis (calcineurin inhibitor plus methotrexate) numerically reduced rates of severe (grade III or IV) acute GVHD (6.8% vs. 14.8%), and significantly improved severe acute GVHD-free survival (93.2% vs. 82.0%), in patients with hematologic malignancies who had undergone HCT from an HLA-matched (8/8) unrelated donor.[66]

Posttransplant cyclophosphamide (combined with standard prophylaxis of tacrolimus plus mycophenolate)

Increasingly favored for primary GVHD prevention based on results from large-scale, multisite clinical trials.[63][67]​​​​[68]​ In one phase 3 trial of patients undergoing allogeneic HLA-matched HCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common in patients randomized to cyclophosphamide-based prophylaxis (cyclophosphamide, tacrolimus, and mycophenolate) than those assigned to standard prophylaxis (52.7% vs. 34.9%).[67]​ Posttransplant cyclophosphamide-based prophylaxis is commonly used in patients who have undergone allogeneic HCT from an HLA-haploidentical (i.e., half-matched) donor or unrelated donor.[69][70]

Rabbit anti-thymocyte globulin

A polyclonal immunoglobulin G, rabbit anti-thymocyte globulin reduces the cumulative incidence of both acute and chronic GVHD in patients undergoing HCT from unrelated donors. In one randomized phase 3 trial, the addition of rabbit anti-thymocyte globulin to standard prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) reduced acute GVHD incidence at 30 and 100 days compared with standard prophylaxis (30 days: 22% vs. 37%; 100 days: 50% vs. 65%).[71]​ At 24 months, this regimen reduced incidence of chronic GVHD (26.3% vs. 41.3%), and led to improved survival (70.6% vs. 53.3%) and reduced use of immunosuppressive therapy.[72]​ Rabbit anti-thymocyte globulin effectively reduces GVHD incidence after HLA-matched sibling donor HCT.[73]​

Sirolimus combined with standard prophylaxis (cyclosporine plus mycophenolate)

Lowers the incidence of grade II to IV acute GVHD (at day 100) compared with standard cyclosporine plus and mycophenolate alone in patients who have undergone allogeneic HCT from an HLA-matched unrelated donor with non-myeloablative conditioning.[74]​

Treatment of acute GVHD

Treatment of acute GVHD is complex and multiple factors (e.g., risk of relapse, organ function, performance status, and presence or risk of infections) play an important role in treatment decisions. Furthermore, the optimal drug combination is not well defined.

Mild skin GVHD (grade I) is primarily treated with topical corticosteroids.[63]​ If the patient is asymptomatic or if the rash is stable, a period of observation without any interventional treatment may be appropriate.[92]

Systemic corticosteroids are initiated for more severe and/or symptomatic skin GVHD and/or any visceral GVHD involvement (grade II-IV).[63][92][103]​​​​​​​[108]​​​ Methylprednisolone is the standard initial treatment, given in combination with therapeutic dosing of the calcineurin inhibitor used for GVHD prophylaxis (i.e., tacrolimus or cyclosporine).[92] Patients with grade II-IV acute GVHD should be considered for enrollment in a clinical trial wherever available.[92]

With clinical response, immunosuppressive drugs should be tapered as appropriate.[63][92]​​ ​ Generally, taper schedules are influenced by the patient's clinical response and circumstances (e.g., risk for relapse, presence or absence of infection, or other corticosteroid-related complications). A commonly reported taper schedule is over 8-12 weeks.

Acute gastrointestinal GVHD: oral-topical corticosteroids

Topically active corticosteroids taken orally (oral-topical corticosteroids, e.g., budesonide, beclomethasone) may be used for confirmed cases of acute gastrointestinal GVHD in combination with a systemic corticosteroid.[92][109][110][111]​​​​ The systemic corticosteroid can be tapered in patients who show a clinical response.

Oral-topical corticosteroid formulations have high first-pass metabolism, facilitating local effects whil reducing systemic absorption. However, some systemic effects do occur.

An oral proprietary formulation of beclomethasone is not currently available in the US. However, selected pharmacies may be able to compound this formulation. Budesonide may be less effective at treating the GVHD of the upper GI tract.[92]

Corticosteroid-refractory acute GVHD

If there is disease progression or lack of response following 3-7 days treatment, additional immunosuppressive therapy is required.[92] Further immunosuppression will, however, increase the risk of life-threatening infections (due to immunosuppression and lymphopenia) and/or multiorgan dysfunction. 

There is no standard approach for the treatment of corticosteroid-refractory acute GVHD.[108]​ A variety of agents have been used, and varying response rates have been reported.[112]​ Entry into a clinical trial may be appropriate.[92]

Alternative immunosuppressive agents should be considered if a patient develops an unacceptable level of toxicity (i.e., corticosteroid intolerance).[92][108]​​ 

Acute GVHD: alternative or additional immunosuppressive treatments

Consideration should be given to an alternative or additional immunosuppressive agent in the presence of corticosteroid-refractory acute GVHD or corticosteroid intolerance, respectively.[63][92]​​​

Ruxolitinib

Approved by the FDA and European Medicines Agency (EMA) for patients with corticosteroid-refractory acute GVHD.[113]​ Ruxolitinib is recommended as a primary treatment option for corticosteroid-refractory acute GVHD by the National Comprehensive Cancer Network (NCCN) and the European Society for Blood and Marrow Transplantation (ESBMT).[63][92]​​​

Day-28 overall response rate was 54.9% among 39 patients treated with ruxolitinib for corticosteroid-refractory acute GVHD grades II-IV (occurring after allogeneic hematopoietic stem cell transplantation) in an open-label, phase 2 multicenter study (REACH 1).[114]​ The median duration of response was 345 days.

In the REACH 2 open-label phase 3 trial of patients with corticosteroid-refractory acute GVHD after allogeneic stem cell transplantation, day 28 overall response rate was 62% in patients randomized to ruxolitinib compared with 39% in the control group (investigator's choice of commonly used therapy).[115]

Anti-thymocyte globulin (ATG)

ATG is an infusion of horse- or rabbit-derived antibodies against human T cells that can lead to prolonged immunosuppression. The response rates following ATG have been reported to be highest in patients with skin involvement and lowest in those with liver involvement.[116][117]​​​​ Its use has been limited primarily due to severe life-threatening opportunistic infections from prolonged immunosuppression.[116]

There are many different horse- and rabbit-derived ATG antisera available. To date, a standard dose and schedule for ATG in the treatment for GVHD has not been established.[118]

Sirolimus

Sirolimus is efficacious in the treatment of acute and chronic GVHD.[119][120]​​​ However, in these studies, significant toxicity was observed, including thrombocytopenia, hypertriglyceridemia, neutropenia, hemolytic uremic syndrome, and hypercholesterolemia.

Etanercept

One trial reported that the combination of etanercept plus a corticosteroid (as initial treatment for grade II-IV acute GVHD) resulted in significantly better complete response rates 4 weeks following treatment compared with a historical control group of corticosteroids alone.[121]

Alemtuzumab

Alemtuzumab lowered incidence of acute GVHD in case report series.[122][123]​​​​ However, the delayed immune reconstitution has led to higher incidences of life-threatening infections.[124][125]

Pentostatin

In a four-arm, phase 2 trial (BMT CTN 0302) investigating etanercept, mycophenolate, denileukin diftitox, and pentostatin (all combined with corticosteroids) as initial therapy for acute GVHD, the day 28 complete response rate for pentostatin was 38%, and 9-month overall survival was 47%.[126] Infectious complications remain one of the most significant toxicities with this agent.

Extracorporeal photopheresis (ECP)

ECP exposes peripheral blood mononuclear cells to photoactivated methoxsalen and ultraviolet A (UV-A) radiation. Upon photoactivation, methoxsalen covalently binds and cross links DNA, initiating apoptosis. ECP has become an increasingly common adjunct therapy in efforts to minimise corticosteroid exposure and allow for more rapid corticosteroid tapers.[127]

One systematic review of prospective studies concluded that ECP demonstrated encouraging responses in corticosteroid-refractory acute GVHD, and is more likely to be beneficial in patients with skin involvement.[128] Further studies are required to evaluate the efficacy of ECP in children and adolescents.[129]

Acute GVHD: withdrawal of corticosteroid therapy

The prognosis for patients who develop severe acute GVHD, especially those not responding to corticosteroids, is generally poor.[130]

Withdrawal of corticosteroid therapy can lead to a flare of acute GVHD and/or the onset of chronic GVHD. There is no standard taper schedule; it will depend on the patient, clinical picture, and physician preference and experience.

Enrollment in a clinical trial is encouraged for patients with corticosteroid-refractory disease.[92]

Treatment of chronic GVHD

The recommended first-line therapy for patients with chronic GVHD is a systemic corticosteroid (methylprednisolone).[92]​ National Institutes of Health (NIH) guidelines recommend systemic corticosteroid therapy if three or more organs are involved, or any single organ with a severity score of more than 2.[1]​ Alternative immunosuppressive agents should be considered if a patient develops an unacceptable level of toxicity (i.e., corticosteroid intolerance).[92]

Therapeutic choice is informed by agents used for prophylaxis and/or treatment of acute GVHD, specific patient characteristics, and preference of the treating physician and center. Treatment for chronic GVHD is generally less intense and less aggressive than for acute GVHD. It may, however, require prolonged duration of therapy.

Patients should be considered for enrollment in a clinical trial whenever available.[92]

Chronic GVHD: inadequate response to initial therapy

If there is an inadequate response to initial therapy with a systemic corticosteroid, additional immunosuppressants may be required.[92]​ The NIH working group define failure of initial therapy or requirement of additional secondary therapy as:[1][131]​​​​​​

  • progression of chronic GVHD despite optimal first line therapy, or

  • no improvement after 4-8 weeks of sustained therapy, or

  • inability to taper corticosteroid dose.

Alternative or additional immunosuppressive treatments for the management of chronic GVHD have been described.​[63][92]

Ruxolitinib

FDA-approved for chronic GVHD after failure of one or two lines of systemic therapy.[132]​ Ruxolitinib is recommended as a primary treatment option for corticosteroid-refractory chronic GVHD by the NCCN and the European Society for Blood and Marrow Transplantation ESBMT.[63][92]​​

In one phase 3 open-label randomized trial of patients aged 12 years or older with moderate or severe corticosteroid-refractory or corticosteroid-dependent chronic GVHD (REACH3 trial), ruxolitinib improved overall response rate compared with best available therapy (investigator choice) at 24 weeks.[133]

Ibrutinib

A Bruton tyrosine kinase inhibitor approved by the FDA for second-line therapy of chronic GVHD (after failure of one or more lines of systemic therapy).[134]

Ibrutinib is associated with an increased risk for serious cardiac events including arrhythmias and heart failure. Recommended risk minimization measures include performing a clinical evaluation of cardiac history and function prior to starting treatment, careful monitoring for signs of cardiac deterioration during treatment, and treatment interruption and/or dose modification if any new-onset or worsening cardiac events are observed.[135][136]

Belumosudil

Approved by the FDA for chronic GVHD after failure of at least two prior lines of systemic therapy. In one phase 2 open-label randomized trial of patients with chronic GVHD who had received between 2 and 5 prior lines of therapy, the overall response rate with belumosudil was 77% (median follow-up of 14 months).[137]​ Pneumonia was the most commonly reported serious adverse event.

Axatilimab

Approved by the FDA for chronic GVHD after failure with at least two prior lines of systemic therapy. One phase 2 multinational randomized trial of patients with recurrent or refractory chronic GVHD reported an overall response rate (ORR) of 74% in the lower axatilimab dose group; an ORR of 67% and 50% was reported for higher-dose groups.[138]

Calcineurin inhibitors (cyclosporine or tacrolimus)

May be combined with systemic corticosteroids in patients with corticosteroid-refractory chronic GVHD, particularly if calcineurin inhibitors have not been used previously (e.g., for GVHD prophylaxis).[92]

Rituximab

An anti-CD20 chimeric monoclonal antibody. One retrospective study reported on 38 patients (a median age of 48 years) who received rituximab for refractory chronic GVHD. The overall response rate was 65%.[139] These findings were similar to those from a phase 1/2 study, where the clinical response rate was 70%.[140] Rituximab was well-tolerated in the latter study, and toxicity was limited primarily to infectious events.[140]

Sirolimus

In one phase 2/3 trial, sirolimus plus prednisone demonstrated similar long-term outcomes to sirolimus plus a calcineurin inhibitor plus prednisone in patients with chronic GVHD (treatment-naive or early inadequate responders).[141] Sirolimus plus prednisone was easier to administer and was better tolerated.[141]

Pentostatin

Pentostatin has been studied in a phase 2 trial of patients with corticosteroid-refractory chronic GVHD. Of the 58 heavily pretreated patients enrolled, 32 (55 %) had an objective response.[142] Infectious complications remain one of the most significant toxicities with this agent.

ECP

An increasingly common adjunct therapy to minimize corticosteroid exposure and allow for more rapid corticosteroid taper.[127]​ One systematic review of prospective studies reported an overall response rate of 69% (pooled data from six studies of patients with corticosteroid-refractory or corticosteroid-dependent acute or chronic GVHD).[128]​ ECP is more likely to be beneficial in patients with skin involvement.[128] Further studies are required to evaluate the efficacy of ECP in children and adolescents.[143]​ 

Organ systems affected by chronic GVHD: monitoring and treatment

Close serial monitoring of all organ systems is recommended to promote early detection and intervention directed toward reversing or preventing progression of chronic GVHD manifestations.[144]

Ancillary therapies are commonly employed in addition to systemic GVHD treatment, and in some cases their use may circumvent the need for systemic treatment or allow doses of systemic agents to be decreased.

Immunologic and infectious diseases

  • Immunizations and prophylaxis against Pneumocystis carinii, varicella zoster virus, and encapsulated bacteria should be guideline-based.[145]

  • Antibacterial prophylaxis is given to all patients with chronic GVHD as long as systemic immunosuppressives are being administered. Pneumocystis pneumonia <6 months after HCT is strongly associated with chronic GVHD. All patients who receive immunosuppression after allogeneic HCT should receive Pneumocystis prophylaxis.

  • Most experts advocate the use of Haemophilus influenzae type b vaccine and influenza vaccine (not live-attenuated). No live virus, including the live attenuated influenza vaccine and measles-mumps-rubella (MMR), should be given.

  • Consider intravenous immune globulin (IVIG) replacement based on levels and recurrent infections. Universal administration of IVIG after HCT has not been shown to confer clinical benefit and should be avoided.

  • No current evidence supports the use of mold-active agents

  • Surveillance for infection (viral, bacterial, fungal, atypical)

  • Empiric parenteral broad-spectrum antibacterial coverage for fever

  • Organism-specific antimicrobial agents.

Skin and appendages

  • Photoprotection

  • Surveillance for malignancy

  • For intact skin

    • Emollients

    • Topical corticosteroids. Nonsclerotic skin lesions without erosions or ulcerations (e.g., lichen planus-like or papulosquamous plaques) may respond well to topical corticosteroids and emollients. Long-term use of topical corticosteroids may be complicated by local skin atrophy and development of striae.

    • Antipruritic agents

    • PUVA (psoralen-UV-A)

    • Calcineurin inhibitors

  • For erosions/ulcerations

    • Microbiologic cultures

    • Topical antimicrobials

    • Protective films or other dressings

    • Debridement

    • Hyperbaric oxygen

    • Wound care specialist consultation

Mouth and oral cavity[146]

  • Maintain good oral/dental hygiene

  • Consider routine dental cleaning and endocarditis prophylaxis

  • Surveillance for infection and malignancy

  • Topical high and ultra-high potency corticosteroids and analgesics

  • Systemic and intralesional corticosteroid in sclerotic disease

  • Stretching exercises

  • Therapy for oral dryness

Salivary gland involvement

  • Frequent water sipping

  • Salivary gland substitute and/or stimulant

  • Home fluoride therapy

Eyes

  • Photoprotection

  • Surveillance for infection, cataract formation, and increased intraocular pressure

  • Artificial tears

  • Ocular ointments

  • Topical corticosteroids or cyclosporine

  • Punctal occlusion

  • Humidified environment

  • Occlusive or moisture chamber eyewear

  • Cevimeline or pilocarpine

  • Tarsorrhaphy

  • Gas-permeable scleral contact lens

  • Autologous serum, microbiologic cultures

  • Topical antimicrobials

Vulva and vagina

  • Surveillance for estrogen deficiency, infection (e.g., herpes simplex virus, human papillomavirus, yeast, bacteria), malignancy

  • Water-based lubricants

  • Topical estrogens

  • Topical corticosteroids or calcineurin inhibitors

  • Dilators

  • Surgery for extensive synechiae/obliteration

  • Early gynecologic consultation

Gastrointestinal tract and liver

  • Surveillance for infection (e.g., viral, fungal)

  • Eliminate other potential etiologies

  • Dietary modification, enzyme supplementation for malabsorption, gastrointestinal reflux management, esophageal dilation, ursodeoxycholic acid

Lungs

  • Surveillance for infection (e.g., Pneumocystis carinii, viral, fungal, bacterial)

  • Eliminate other potential etiologies (e.g., infection, gastrointestinal reflux)

  • Inhaled corticosteroids and/or bronchodilators and/or leukotriene receptor antagonists

  • Supplementary oxygen

  • Pulmonary rehabilitation

  • Consideration of lung transplantation in appropriate candidates

Hematopoietic

  • Surveillance for infection (e.g., cytomegalovirus, parvovirus)

  • Eliminate other potential etiologies (e.g., drug toxicity, infection)

  • Hematopoietic growth factors, intravenous immune globulin for immune cytopenias

Neurologic

  • Calcineurin drug-level monitoring

  • Seizure prophylaxis including blood pressure control, electrolyte replacement, anticonvulsants

  • Occupational and physical therapies

  • Treatment of neuropathic syndromes with tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), or anticonvulsants

Musculoskeletal

  • Bone mineral metabolism is disturbed after allogeneic HCT, even at >6 years. The abnormalities include increased bone resorption, decreased bone formation, osteopenia and osteoporosis. After HCT, bone mineral density (BMD) of the femoral neck may be more affected than the vertebrae, unlike postmenopausal osteoporosis.

  • Management should include surveillance for decreased range of motion, measurement of bone density, calcium levels, and 25-OH vitamin D

  • Appropriate treatments may include physical therapy, calcium and vitamin D supplements, and bisphosphonates for osteopenia and osteoporosis.

Supportive care and monitoring

Infection prophylaxis, physical therapy, nutritional status, pain control, and monitoring of drug-drug interactions and drug-related adverse effects are vital components of GVHD management.

Patients often require close follow-up, which should include an assessment of signs and symptoms of disease progression, treatment response, and adverse effects of treatment.[147] Treatment plans may be adapted accordingly to improve treatment response, manage symptoms, and improve quality of life. 

Early recognition of high-risk features, such as thrombocytopenia, progressive onset chronic GVHD, extensive skin involvement with sclerodermatous features, and multiorgan involvement, and appropriate early intervention are also important considerations in the overall management.[1][8]​​​​

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