All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional.

The GvHD Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Developments in the management of cGvHD

Dec 21, 2021
Share:

Chronic graft-versus-host disease (cGvHD) occurs in 3050% of patients receiving allogeneic hematopoietic stem cell transplantation with heterogeneous clinical manifestations.1 In their recent review, Holtzman and Pavletic summarize developments in the field of cGvHD that have occurred since the National Institutes of Health (NIH) consensus conference in 2014.

Figure 1 details a diagnostic, classification, and treatment algorithm laid out by Holtzman and Pavletic, which  demonstrates the complexity of cGvHD management.

Figure 1. A diagnostic, classification, and treatment algorithm for cGvHD*

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; NIH, National Institutes of Health.
*Adapted from Holtzman and Pavletic.1
Bronchiolitis obliterans syndrome is only diagnostic for lung cGvHD if there is a distinctive sign or symptom in another organ.

Figure 1

If you would like to view figure 1, please download the resource below.

Download here

Front-line therapy

There have only been a few studies attempting to optimize front-line GvHD treatment since 2014. An important study comparing prednisone/sirolimus vs prednisone/sirolimus/calcineurin inhibitor demonstrated that the two-drug induction regimen yielded similar clinical benefits as the three-drug regimen, but with a better toxicity profile. Another study assessing extracorporeal photopheresis (ECP) alongside standard of care, compared to standard of care, found no benefit in terms of response, quality of life, or toxicity.

Second-line therapy

With >50% of patients becoming steroid-dependent or -refractory, second-line therapies are a vital part of the cGvHD treatment pathway. Steroid-refractory disease is defined as: disease that has progressed despite treatment with prednisone (1 mg/kg/day) for 2 weeks, disease that is stable despite treatment with prednisone (0.5 mg/kg/day) for 48 weeks, or an inability to taper prednisone treatment below 0.5 mg/kg/day. Steroid-dependent disease definitions vary in clinical practice, though one suggested definition is: disease that flares when prednisone is tapered below 0.25 mg/kg/day on more than one taper attempt (≥8 weeks between).

Progression within 4 weeks or no response to front-line therapy within 812 weeks signals the need for second-line therapies. There are no standardized protocols for the selection of second-line treatments.

Studies of agents that may be used for refractory cGvHD, including full clinical study reports and smaller clinical studies, since 2014 are detailed in Table 1.

Table 1. Key published studies for steroid-refractory cGvHD*

Agent

Studies

N

Severe cGvHD, %

Outcomes, %

Important AEs

Comments

Ibrutinib

1 P

42

N/A

ORR, 67
CR rate, 21
FFS, N/A
OS, N/A

Pneumonia, fatigue, diarrhea, infections

Caution advised in cases of AF, anticoagulation and bleeding history, invasive fungal infections, taking strong CYP3A4

Ruxolitinib

6 R and 2 P

19–165

3386

ORR, 48–100
CR rate, 3.5
27
FFS, 54
85
OS, 67
97.4

Infection, CMV reactivation, cytopenia, hepatic impairment, heme toxicity, lung TB

Close monitoring for: infection, cytopenias, hyperlipidemia

ECP

2 P, plus 1 other

49–88

43–59

ORR, 43.5–80
CR rate, 6
45
FFS, N/A
OS, 64.5
90

Infection

Important quality of life implications

ECP + LD-IL-2

1 P

25

24

ORR, 62
CR rate, 0
FFS, N/A
OS, 80 at 1y

Dehydration, hypotension, syncope, anemia

IL-2 therapy associated with thrombotic microangiopathy, concurrent therapy with CNIs or sirolimus is discouraged

LD-IL-2

1 P

35

20

ORR, 61
CR rate, 0
FFS, N/A
OS, 83 at 3y

Flu-like symptoms, fatigue, DVT/PE, myalgia/arthralgia, hepatitis, psychiatric disturbances

Rituximab vs imatinib

1 P

75

100 sclerotic

ORR, 27 vs 26
CR rate, N/A
FFS, N/A
OS, N/A

Imatinib: infection Rituximab: infection, infusion reaction, neutropenia

Rituximab associated with infusion reactions and prolonged hypogammaglobulinemia requiring IV immunoglobulin supplementation
Caution for use of nilotinib in patients with history of arterial events, pancreatitis, or risk factors for pancreatitis, fluid retention, prolonged QTc, electrolyte abnormalities

Rituximab + nilotinib

1 P

29

76

ORR, 71
CR rate, 8
FFS, N/A
OS, 96.5 at 1y

Infection, encephalitis, osteomyelitis, dyspnea, avascular necrosis, anemia, leukopenia, prolonged QTc, nausea, pain, fatigue, pancreatitis, GBS-like neurologic syndrome

Nilotinib

1 P

21

100

ORR, 22.2–55.6
CR rate, N/A
FFS, 30 at 4y
OS, 75 at 4y

ALT increase, lipase/amylase increase, infection (meningitis), anemia

Imatinib

1 P

20

100 sclerotic

ORR, 36
CR rate, 0
FFS, N/A
OS, N/A

Edema, myalgia, muscle cramps, pleural effusions, hypophosphatemia, nausea, diarrhea, fatigue, tinnitus

Caution in patients with fluid retention, history of pleural effusions/HF.
Associated with dose-dependent GI toxicity, must be renally adjusted

Pomalidomide

2 P

13–34

85–94

ORR, 54–67
CR rate, 0
FFS, 49 at 2y
OS, N/A

Lymphopenia, infection, fatigue, neuropathy, myalgias, tremors, fatigue/anxiety, DVT/PE

Requires concurrent thromboprophylaxis (aspirin and/or other anticoagulation)

Ixazomib

1 P

50

84

ORR, 40
CR rate, 0
FFS, 57 at 1y
OS, 90 at 1y

Thrombocytopenia, diarrhea, fatigue, infection, respiratory failure

Associated with rash, GI toxicity, neuropathy, and rarely, thrombotic microangiopathy.
Requires close monitoring for cytopenias and liver injury

Belumosudil

1 P

132

67

ORR, 76
CR rate, 5
FFS, 56 at 1y
OS, 89 at 2y

Pneumonia, hypertension, hyperglycemia, increased liver function test

Efficacious in patients having previously received ibrutinib and/or ruxolitinib
Close monitoring of liver functions tests, blood pressure, and glucose

Tocilizumab

1 R

11

100

ORR, 70
CR rate, 0
FFS, 82 at 1
OS, 55

Infection

 

Ofatumumab

1 P

12

42

ORR, 80
CR rate, 36
FFS, N/A
OS, 82

Fatigue, infusion reactions, lung, and upper respiratory infection

No dose-limiting toxicities

Abatacept

1 P

17

59

ORR, 44
CR rate, 0
FFS, N/A
OS, N/A

Pulmonary infections

No dose-limiting toxicities

Sonidegib

1 P

17

59

ORR, 47
CR rate, 0
FFS, N/A
OS, N/A

Arthralgia, abdominal pain, myalgia, back pain, headache, hypercalcemia, anemia, cardiac arrest, CHF hypertension, diarrhea, SBO, SVC syndrome

Dose-limiting toxicities: increase in CPK
Accrual terminated early due to toxicity

AE, adverse event; AF, atrial fibrillation; ALT, alanine aminotransferase; CHF, congestive heart failure; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CPK, creatine phosphokinase; CR, complete response; DVT/PE, deep-vein thrombosis/pulmonary embolism; ECP, extracorporeal photopheresis; FFS, failure-free survival; GBS, Guillain–Barre syndrome; GI, gastrointestinal; HF, heart failure; IV, intravenous; LD-IL-2, low-dose interleukin-2; N/A, not available; ORR, overall response rate; OS, overall survival; P, prospective; R, retrospective; SBO, small bowel obstruction; SVC, superior vena cava; TB, tuberculosis; y, year(s).
*Adapted from Holtzman and Pavletic.1
Dependent on criteria used to determine ORR.

Organ-specific challenges

Sclerotic skin

Cutaneous sclerosis affects 1020% of patients and is one of the most challenging cGvHD manifestations. It can lead to a poor quality of life (QoL) due to skin stiffness leading to limited range of motion, movement restrictions, and effects on other organs. Although the pathophysiology behind sclerotic skin is yet to be elucidated, there has been interest in certain agents due to their potential antifibrotic effects. These include ruxolitinib, imatinib, low-dose IL-2, pomalidomide, belumosudil, ibrutinib, and rituximab.

Pulmonary

Affecting 512% of HSCT patients, bronchiolitis obliterans syndrome is another challenging cGvHD manifestation that is associated with decreased QoL, high morbidity, and high mortality. Although a 2016 study established FAM (fluticasone, azithromycin, and montelukast) as the standard front-line bronchiolitis obliterans syndrome treatment, the study findings have not been reproduced. ECP has shown promise in a small retrospective report, with a 100% response rate in six patients who had received prior FAM treatment. An alternative option seems to be lung transplantation, which has shown 100% survival at 19.5 months of follow up and 37% survival at 5 years.

Myofascial

This manifestation of cGvHD has a significant effect on patient QoL and mobility. Myofascial cGvHD is difficult to quantify, but a refined algorithm of the NIH response criteria has been proposed recently to improve response measurements. In retrospective analyses, the best responses were found to be following treatment with rituximab, imatinib, ECP, and bortezomib.

Topical therapies

In cases of mild cGvHD, topical organ-specific therapies are the main option and can enable patients who experience toxicity from systemic treatment to reduce those and benefit from topical treatments instead. Holtzman and Pavletic highlight the importance of a multidisciplinary approach to cGvHD management. Figure 2 details the management recommendations suggested for cGvHD that incorporate interdisciplinary, ancillary, and supportive care.

Skin

Topical steroids are the main treatment for skin cGvHD, provided that the disease is present in <50% of the skin and body surface area.

Oral

The priority treatment for oral cGvHD are high-potency topical corticosteroid rinses. Other symptoms may include a dry mouth, which can be treated with sialogogues and salivary stimulants. Dexamethasone has been shown to reduce the oral sensitivity score more than tacrolimus (58% vs 21%; p = 0.05) with similar safety profiles. Platelet gel has also been found to show promise as an option for patients with oral cGvHD (complete response, 70%; overall response, 27.343.2%).

Ocular

An estimated 3551% of patients with cGvHD experience ocular involvement, with significantly impacted QoL. Topical treatments currently include artificial tears, eye drops, ointments, immunosuppressive eye drops, warm compresses and lid hygiene, punctal plugs, and scleral lenses. There have been promising studies into topical steroids vs tacrolimus, platelet-derived eye drops, autologous serum eye drops, and scleral lenses. There have also been smaller studies of combined JAK/spleen tyrosine kinase (SYK) inhibitor ophthalmic eye solution, a mucin secretagogue eye drop (3% diquafosol ophthalmic solution), and a lymphocyte function-associated antigen-1 antagonist (lifitegrast).

Genital

Topical steroids or calcineurin inhibitors are the main treatment options for patients with vulvovaginal or penile cGvHD. Estrogen replacement may also be used if vulvovaginal cGvHD is associated with low estrogen levels.

Figure 2. Recommendations for interdisciplinary, system-based ancillary, and supportive care in cGvHD*

cGvHD, chronic graft-versus-host disease.
*Adapted from Holtzman and Pavletic.1

Figure 2

If you would like to view figure 2, please download the resource below.

Download here

Future directions

Despite the many recent advances in the treatment of cGvHD, there is much more work to be done. There are several active studies ongoing (Table 2), but further research is needed in areas such as new therapies, combinatorial treatments, organ-specific approaches, steroid-free or steroid-deprived regimens, and treatment algorithms for personalized treatments.

Table 2. Active clinical trials for cGvHD*

Agent

Target

Phase

Disease status

Treatment

Clinicaltrials.gov identifier

Study site country

Acalabrutinib

BTK/ITK inhibitor

II

SR-GVHD

Second-line

NCT04198922

USA

Anlotinib

anti-VEGF, -FGFR, -PDGFR

II

SR-GVHD

Second-line

NCT04232397

China

AMG 592

IL-2 cytokine mutein

I/II

SR-GVHD

Second-line

NCT03422627

USA, Belgium, France, Japan

Arsenic trioxide

N/A

II

cGVHD

First-line

NCT02966301

France

Axatilimab (SNDX-6352)

CSF-1R antibody

I/II

Refractory cGVHD

Second-line

NCT03604692

USA

Axatilimab (SNDX-6352)

CSF-1R antibody

II

Refractory cGVHD

Second-line

NCT04710576

USA

Baricitinib

JAK1/2

I/II

SR-GVHD

Second-line

NCT02759731

USA

Donor Tregs

Adoptive immunotherapy

I/II

SR-cGvHD

Second-line

NCT02385019

Portugal

Donor Tregs

Adoptive immunotherapy

I

cGVHD refractory to steroids and ruxolitinib

Second-line

 NCT03683498

Spain

Donor-derived purified Tregs (Treg DLI)

Adoptive immunotherapy

I

SR-cGVHD

Second-line

NCT02749084

Italy

ECP + LD-IL2

Cytokine

II

SR-cGVHD

Second-line

NCT03007238

USA

Everolimus and prednisone

mTOR inhibitor

IIa

cGvHD

First-line

NCT01862965

Germany

Glasdegib

Hedgehog inhibitor

I/II

Refractory cGVHD with sclerosis and/or fasciitis

Second-line

NCT04111497

USA

Glasdegib

Hedgehog inhibitor

I/II

Sclerotic refractory cGVHD

Second-line

NCT03415867

Spain

Ibrutinib

BTK/ITK inhibitor

III

SR-cGVHD

Second-line

NCT03474679

Japan

Ibrutinib + corticosteroids

BTK/ITK inhibitor

III

cGVHD

First-line

NCT02959944

USA, Australia, Austria, Canada, China, Croatia, France, Germany, Hungary, Italy, Japan, Republic of Korea, Singapore, Spain, Taiwan

Ixazomib

Proteasome inhibitor

II

cGvHD

Prophylaxis/
prevention

NCT03082677

USA

Ixazomib

Proteasome inhibitor

Ib/II

cGVHD

Prophylaxis/
prevention

NCT03225417

Spain

Itacitinib + corticosteroids

JAK1 inhibitor

II/III

cGVHD

First-line

NCT03584516

USA, Austria, Belgium, Canada, France, Germany, Greece, Israel, Italy, Poland, Spain, Switzerland, UK

KD025

ROCK2 inhibitor

II

cGVHD

Second-line

NCT02841995, NCT03640481

USA

Leflunomide

Pyrimidine synthesis inhibitor

I

SR-cGVHD

Second-line

NCT04212416

USA

MSCs

Adoptive immunotherapy

II

cGvHD

First-line

NCT04692376

China

Obinutuzumab

anti-CD20 monoclonal antibody

II

cGvHD

Prophylaxis/
prevention

NCT02867384

USA

Ofatumumab

anti-CD20 monoclonal antibody

I/II

cGVHD

First-line

NCT01680965

USA

Rituximab + ibrutinib

anti-CD20 monoclonal antibody; BTK/ITK inhibitor

II

cGvHD

First-line

NCT04235036

USA

Rituximab + ibrutinib

anti-CD20 monoclonal antibody; BTK/ITK inhibitor monoclonal antibody;

I/II

SR-cGVHD

Second-line

NCT03689894

USA

Ruxolitinib

JAK1/2

II

Sclerotic cGVHD

Second-line

NCT03616184

USA

Ruxolitinib

JAK1/2

III

SR-cGVHD

Second-line

NCT03112603

USA, Australia, Austria, Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Greece, Hungary, India, Israel, Italy, Japan, Jordan, Republic of Korea, Netherlands, Norway, Poland, Portugal, Romania, Russia, Saudi Arabia, Spain, Sweden, Switzerland, Turkey, UK

SCM-CGH/clonal MSCs

Adoptive immunotherapy

II

SR-cGvHD

Second-line

NCT04189432

Republic of Korea

Treg-enriched infusion + IL-2

Adoptive immunotherapy + cytokine

I

SR-cGvHD

Second-line

NCT01937468

USA

Organ specific and topical agents

Amniotic fluid eye drops (AFED)

N/A

I/II

Ocular cGVHD

Topical/organ specific

NCT03298815

USA

Alvelestat

Neutrophil elastase inhibitor

I/II

BOS/lung cGVHD

Organ specific

NCT02669251

USA

Itacitinib

JAK1 inhibitor

I

BOS/lung cGVHD

Organ specific

NCT04239989

USA

Nintedanib

NRTK and RTK inhibitor

II

BOS/lung cGVHD

Organ specific

NCT03805477

Austria, Germany, Switzerland

Pirfenidone

Antifibrotic

I

BOS/lung cGVHD

Organ specific

NCT03315741

USA

1% progesterone topical gel

Progesterone

II

Ocular cGVHD

Topical/organ specific

NCT03990051

USA

Ruxolitinib

JAK1/2

II

BOS/lung cGVHD

Organ specific

NCT03674047

USA

Ruxolitinib 1.5% topical cream

JAK1/2

II

Cutaneous cGVHD

Topical/organ specific

NCT03395340

USA

Umbilical mesenchymal stem cell-derived exosomes

Adoptive immunotherapy

I/II

Ocular cGVHD

Topical/organ specific

NCT04213248

China

BOS, bronchiolitis obliterans syndrome; BTK, Bruton’s tyrosine kinase; cGvHD, chronic graft-versus-host disease; CSF-1, colony-stimulating factor 1; ECP, extracorporeal photopheresis; FGFR, fibroblast growth factor receptor; IL-2, interleukin-2; ITK, interleukin-2-inducible kinase; n/a, not available; JAK, Janus kinase; LD IL-2, low-dose interleukin-2; mTOR, mechanistic target of rapamycin; MSC, mesenchymal stromal cell; NRTK, non-receptor tyrosine kinase; PDGFR, platelet-derived growth factor receptor; ROCK2, rho-associated coiled-coil-containing protein kinase-2; RTK, receptor tyrosine kinase; SR, steroid-refractory; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.
*Adapted from Holtzman and Pavletic.1
Date of access to clinicaltrials.gov: January 5, 2021.

  1. Holtzman NG and Pavletic SZ. The clinical landscape of chronic graft-versus-host disease management in 2021. Br J Haematol. 2021. Online ahead of print. DOI: 10.1111/bjh.17835

Share: