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

Aug 25, 2021
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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*

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

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 

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.

Figure 1. Patient 1: characteristics and treatment information*

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.

Figure 2. Patient 2: characteristics and treatment information*

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.

Figure 3. Patient 3: characteristics and treatment information*

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.

  1. Wolff D, Fatobene G, Rocha V, et al. Steroid-refractory chronic graft-versus-host disease: treatment options and patient management. Bone Marrow Transplant. Online ahead of print. DOI: 10.1038/s41409-021-01389-5
  2. FDA approves belumosudil for chronic graft-versus-host disease [press release]. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belumosudil-chronic-graft-versus-host-disease. Published July 16, 2021. Accessed September 7, 2021.

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