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Types Therapeutics Congresses Trials Expert Opinions DRUG UPDATES

GvHD Types

2021-12-21T16:26:56.000Z

Developments in the management of cGvHD

By Sam Larkin

Dec 21, 2021

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Chronic graft-versus-host disease (cGvHD) occurs in 30–50% 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.

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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 4–8 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 8–12 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	33–86	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 10–20% 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 5–12% 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, 27.3–43.2%).

Ocular

An estimated 35–51% 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.

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

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GvHD Types

Developments in the management of cGvHD

By Sam Larkin

Dec 21, 2021

Front-line therapy

Second-line therapy

Organ-specific challenges

Sclerotic skin

Pulmonary

Myofascial

Topical therapies

Skin

Oral

Ocular

Genital

Future directions

References (1)

More about...

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