Chronic GvHD: management and future perspectives

aGvHD

cGvHD

Skin

Maculopapular rash

Depigmentation, poikiloderma, sclera-derma-like features

Liver

Cholestatic hyperbilirubinemia

Jaundice, elevated LFTs

Upper gastrointestinal tract

Nausea, anorexia

Anorexia, weight loss

Lower gastrointestinal tract

Diarrhea (bloody), severe abdominal pain

Mouth

Ulcerative and erythematous changes, lip crusting

Xerostomia, lichen planus-like features, SICCA syndrome-like features, trismus, mucoceles

Nails

n/a

Nail dystrophy, longitudinal ridging, onycholysis

Eyes

n/a

Dry eyes, sicca syndrome, conjunctivitis, panuveitis

Muscles/Joints

n/a

Myositis, fasciitis

Female genitalia

n/a

Vaginal sclerosis/stenosis, ulceration, lichen planus-like features

Male genitalia

n/a

Lichen planus-like features, phimosis, scarring/stenosis

Lungs

n/a

Pleural effusion, bronchiolitis obliterans, obstructive pulmonary disease

Kidneys

n/a

Nephrotic syndrome

Heart

n/a

Pericarditis

Score

Symptoms

0

No symptoms

1

Mild symptoms with disease signs but not limiting oral intake significantly

2

Moderate symptoms with disease signs and partial limitation of oral intake

3

Severe symptoms, disease signs and major limitations on oral intake.

Systemic therapy

Corticosteroids (CSs)

Considered first-line therapy and the backbone for cGvHD treatment, fast mechanism of action compared with other systemic immunosuppressive agents. For around 50% of those diagnosed and treated with corticosteroids, disease control is inadequate and so second-line systemic therapies are required.

Calcineurin inhibitors

These include cyclosporine and tacrolimus. They block the nuclear factor of activated T cells (NFAT), and weaken the expression of IL-2 which leads to the inhibition of donor T cell proliferation. However, calcineurin inhibitors often come with side effects such as hyperlipidemia, hirsutism, neurotoxicity and renal toxicity, with prolonged use possible leading to gingival hyperplasia.  

mTOR inhibitors

Mammalian target of rapamycin (mTOR) inhibitors have an inhibitory effect on T cell activation, by forming a complex that results in a G1 cycle cell arrest through the inhibition of DNA transcription, translation, and protein synthesis. Examples of mTOR inhibitors are sirolimus and everolimus, with side effects including renal failure, hyperlipidemia, cytopenia and aphthous-like oral ulcerations.

Antimetabolites

Mycophenolate mofetil (MMF)

This antimetabolite functions through the inhibition of purine synthesis in lymphocytes with a potent cytostatic effect on both T and B cells. This has a response of between 45% and 75%.¹⁰ Side effects associated with MMF include diarrhea, infections and thrombocytopenia.

Azathioprine (AZP)

AZP is an antimetabolite immunosuppressive agent that has a limited benefit. A double-blind, placebo-controlled study found, that in comparison with prednisone alone, AZD with prednisone resulted in an increase in non-relapse mortality (NRM) (40% vs 21%) and a decrease in overall survival (47% vs 61%).¹³ Pancreatitis and bone marrow suppression are two serious side effects of AZP.

Rituximab

This monoclonal IgG1 anti-CD20 antibody that targets B cells has been used to treat multiple immune-mediated conditions. A meta-analysis, which included 111 patients, found that the cumulative response rate to rituximab was 66%, with the best responses in patients with  musculoskeletal and cutaneous manifestations.¹⁴

Extracorporeal photopheresis

Approved by the FDA in the 1980s, the actions of this drug are complex, and include the apoptosis of leukocytes, increased production of anti-inflammatory cytokines and the inhibition of pro-inflammatory cytokines. Response rates ranged between 50% and 63%, with greater efficacy in patients with cutaneous disease.¹⁵ Despite this being considered relatively safe, it still carries an increased risk of infection.

Tyrosine kinase inhibitors (TKI)

Imatinib

This potential treatment for sclerodermatous cGvHD involves a mechanism using platelet-derived growth factor-driven fibrosis reduction. In a phase I/II study using 19 patients, imatinib 100mg/day, was associated with an overall response rate of 79% at six months. Of the 19, seven patients achieved complete remission.¹⁶ Side effects of imatinib include fluid retention and myelosuppression.

Ibrutinib

Approved by the FDA as a second-line treatment for cGvHD in 2017, this treatment involves Th2 and B cells, and was found to have a 67% response rate in multiple organs in a study that enrolled 42 patients with cGvHD resistant to CS (NCT 02195869). Known side effects of ibrutinib are infection and hemmorhage.

Low-dose IL-2

The cytokine interleukin IL-2 was administered to 35 patients. Of these patients, 61% demonstrated a clinical response in multiple organs and 20 achieved a reduction in CS.¹⁰

Ancillary therapy

Cutaneous cGvHD

Topical treatment is considered first-line because of better accessibility. Even when systemic therapy is used, the topical treatment is usually combined to maximize efficacy.

Oral cGvHD

Mild oral cGvHD can be managed using topical treatments alone, with some severe cases responding better to topical treatments than systemic therapies.

Ocular cGvHD

The application of artificial tears is usually the first step for ocular cGvHD, however topical CS and cyclosporine can also be used to reduce inflammation.

Genital cGvHD

Vulvovaginal mucosa can be treated with topical CS and estrogens. Systemic therapies include dilation therapy, systemic estrogen and even surgical intervention in severe cases.