Management of steroid-refractory chronic graft-versus-host disease

Chronic graft-versus-host disease (cGvHD) occurs in ≥30% of patients who survive ≥100 days following allogenic hematopoietic stem cell transplantation, and the complex and multifactorial pathogenesis of cGvHD—a disease with significant patient burden and effect on quality of life—can make diagnosis and treatment difficult. Mild cGvHD is generally managed with topical steroids, while moderate to severe disease requires systemic corticosteroids with or without a calcineurin inhibitor; however, more than half of patients become either steroid-resistant or steroid-dependent.¹

Steroid-refractory cGvHD (SR-cGvHD) is defined by a lack of response to steroids, and while there are a number of alternative treatment options available, there is no consensus on an approach to treatment of SR-cGvHD and therefore no standard second-line treatments currently exist. Daniel Wolff and colleagues reviewed the literature and provided a review of current treatment options as well as a series of theoretical case studies, which we summarize here.¹

Therapeutic options

Therapeutic interventions have been evaluated in clinical trials, though these results are difficult to interpret due to variations in patient populations and study design. Some of the currently available treatment options available for patients with SR-cGvHD are presented in Table 1. The Bruton’s tyrosine kinase inhibitor ibrutinib is the only therapy for SR-cGvHD that is approved by the U.S. Food and Drug Administration (FDA). 

Table 1. Therapy options for SR-cGvHD*

AST, aspartate aminotransferase; cGvHD, chronic graft-versus-host disease; CPK, creatine phosphokinase; FFS, failure-free survival; GGT, gamma-glutamyltransferase; SR-cGvHD, steroid-refractory cGvHD; URTI, upper respiratory tract infection. *Adapted from Wolff, et al.1 †II: Evidence from more than one well-planned non-randomized clinical trial, from cohort or case-controlled analytic studies (preferably at several sites; III–1: several reports from retrospective evaluations or small uncontrolled clinical trials; III–2: only one report from a small uncontrolled clinical trial or retrospective evaluations. ‡Values are given for cGVHD patients (steroid-refractory and steroid-dependent) unless otherwise stated. §On July 16, 2021, the U.S. Food and Drug Administration (FDA) approved belumosudil for the treatment of adults and pediatric patients 12 years of age and older with cGvHD after failure of at least two prior lines of therapy.2
Therapy	Recommendation	Evidence†	Overall survival‡	Toxicities	Study type
Ibrutinib	2nd line	III–1	71% at 2 years in cGvHD	Pneumonia, impaired platelet function	Phase 2a
Extracorporeal photopheresis	2nd line	II	53–78% at 1 year	Vascular access complications	Phase 2 randomized
Mycophenolate mofetil	2nd line	III–1	67–96% at 1 year	Viral reactivation, hypertension, pneumonia, posttransplantation lymphoproliferative disease	Retrospective cohorts
Rituximab	2nd line	II	72% at 1 year; 76% at 2 years	Infections, infusion-related symptoms, late neutropenia	Phase 2b randomized
Ruxolitinib	2nd line	II	97% at 6 months	Viral reactivation/infection, peripheral neuropathy, cytopenias, malignancy relapse	Phase 3 randomized
mTOR inhibitors	2nd line	III–1	—	Thrombotic microangiopathy, renal insufficiency, proteinuria	Phase 2a
Imatinib	2nd line	II	84% at 1.5 years	Fluid retention, myelosuppression, anemia	Phase 2b
Methotrexate	2nd line	III–1	96% at 1 year; 90% at 1.5 years	Hepatotoxicity, leukopenia, thrombocytopenia	Retrospective cohorts
Pentostatin	>2nd line	II	78% at 1 year; 70% at 2 years	Infections	Phase 2a
IL-2 therapy	>2nd line	III–1	Under investigation	Injection site induration, infections	Phase 2
Pomalidomide	>2nd line	III–1	In a phase 1/2 study, all responders were still alive after a median follow-up of 4.6 years	Lymphopenia, neutropenia, infections, muscle cramps, fatigue; early use after transplant may increase risk for inflammatory flares	Phase 2
Ixazomib	>2nd line	III–2	90% at 12 months	—	Phase 2
Low-dose total lymphoid irradiation	>2nd line	III–2	Median 13 months in responders vs 10 months in non-responders	Thrombocytopenia, neutropenia	Retrospective cohorts
Mesenchymal stem cells	>3rd line	III–2	78% at 2 years	None reported	Phase 2
Thalidomide	>3rd line	II	41% at 2 years in SR-cGvHD	Birth defects, constipation, rash, fatigue, somnolence, neuropathy	Phase 2
Alefacept	>3rd line	III–2	50% at 30 months	No dose-limiting toxicities	Phase 1
Abatacept	>3rd line	III–2	—	No dose-limiting toxicities were identified	Phase 1
Tocilizumab	>3rd line	III–2	82% with median follow-up of 22 months	Infections, granulocytopenia, thrombocytopenia	Retrospective cohorts
Cyclophosphamide	>3rd line	III–2	—	Short-term myelosuppression, neutropenia, fatigue, nausea	Retrospective cohorts
Baricitinib	>3rd line	III–2	FFS 74% at 1 year, 37% at 2 years	Viral reactivation, neutropenia, hypophosphatemia, hypertriglyceridemia, URTI	Phase 1/2 single arm
Belumosudil§	Available in clinical trials only	III–1	FFS 77% at 6 months	Pneumonia, hypertension, hyperglycemia, increased GGT	Phase 2 open label randomized
Axatilimab	Available in clinical trials only	III–2	—	Increased GGT, AST, and CPK, periorbital edema	Phase 1/2 dose escalation and expansion

Several factors should be considered when selecting treatment for patients with SR-cGvHD, including the patient’s disease history and comorbidities, as well as available published evidence and access to clinical trials; this is largely a patient-specific decision.

Case presentation: patient 1

The characteristics and initial treatment information for patient 1 are detailed in Figure 1.

cGvHD, chronic graft-versus-host disease; CMV, cytomegalovirus; d, day; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; HLA, human leukocyte antigen; PB, peripheral blood.

*Adapted from Wolff, et al.¹

Treatment options

The best option for most patients with SR-cGvHD is enrollment in a clinical trial, though this patient would likely be ineligible due to his active fungal infection. The use of ruxolitinib, ibrutinib, or mycophenolate mofetil (MMF) should also be avoided due to the potential of these agents to further exacerbate the patient’s active lung infections. Extracorporeal photopheresis (ECP) would be the best treatment option for this patient due to the severity of his airway obstruction and extrapulmonary involvement, as ECP has demonstrated efficacy and safety in patients with pulmonary, sclerodermatous, and mucosal GvHD.

The investigators suggest the following treatment plan:

• ECP twice weekly for the first month and then twice weekly every other week for 6 to 12 months
• prompt steroid tapering
• pulmonary function tests at least every 4 weeks during the first 3 months

Case presentation: patient 2

The characteristics and initial treatment information for patient 2 are detailed in Figure 2.

aGvHD, acute GvHD; ANA, antinuclear antibody; ASMA, anti-smooth muscle antibody; cGvHD, chronic GvHD; CMV, cytomegalovirus; CSP, cyclosporine; GvHD, graft-versus-host disease; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplant; Ig, immunoglobulin; MMF, mycophenolate mofetil; P-ROM, photographic range of motion scale.
*Adapted from Wolff, et al.¹

Treatment options

Ibrutinib and MMF are likely not the best options for this patient, as he is thrombocytopenic, and ECP takes time to induce a response. For this patient, the combination of ruxolitinib—which may target B cells in addition to T cells and macrophages—with rituximab and low-dose steroids was used. Both ruxolitinib and rituximab have been associated with infectious complications, however, and infection prophylaxis is required.

The investigators suggest the following treatment plan:

• ruxolitinib, rituximab, and low-dose steroids
• Pneumocystis jirovecii and varicella-zoster virus prophylaxis
• continuing antibiotic prophylaxis
• monitoring of blood counts and liver enzymes

Case presentation: patient 3

The characteristics and initial treatment information for patient 3 are detailed in Figure 3.

BSA, body surface area; cGvHD, chronic GvHD; CSP, cyclosporine; d, day; GvHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplant; PB, peripheral blood.
*Adapted from Wolff, et al.¹

Treatment options

While clinical trial enrollment would be the recommended course of action for this patient, a number of other treatment options are available, including ruxolitinib, ibrutinib, ECP or interleukin-2, rituximab, or MMF with steroids. Any of these treatment options should be given with best supportive care.

Conclusion

As illustrated by these three case studies, there are many options available for the treatment of SR-cGvHD, though only one that is currently approved by the FDA for this indication. The evidence from clinical trials is difficult to interpret, leaving the clinician to select treatment based on experience and on the individual patient’s presentation, including comorbidities. Clinical trial enrollment should be strongly considered in eligible patients.