Steroid-Refractory Chronic GVHD: Update on Treatment Options

By Clinical Content Hub

Graft-vs-host disease (GVHD) is a potentially severe clinical complication of allogeneic hematopoietic cell transplantation (aHCT). The acute form (aGVHD) and the chronic form (cGVHD) are recognized and defined by the National Institutes of Health consensus criteria based on time of onset and specific clinical features.1 Acute GVHD typically develops within the first 100 days after transplantation. It can affect the skin, gastrointestinal tract, or liver with symptoms including rash, nausea, vomiting, and jaundice.2 Between 30% and 70% of patients who survive at least 100 days after the transplant develop cGVHD. Several organs are impacted, including the mouth, skin, gastrointestinal tract, lungs, liver, muscles, joints, and genitalia.1,3 Organ involvement and comorbidities such as osteoporosis induced by corticosteroid treatment have a negative impact on quality of life and portend poor prognosis.1

Although the underlying pathophysiology of cGVHD is not precisely known, it is thought to be associated with dysregulation of B and T cells and innate responses such as the transition from inflammation to fibrosis involving fibrolasts and macrophages.1 The clinical manifestations can be mild, moderate, or severe and sometimes life-threatening. Chronic GVHD is the most common long-term complication of aHCT and the leading cause of non-relapse-related morbidity and mortality in patients surviving longer than 2 years after transplant.

The incidence of cGVHD has increased over the past 2 decades, due in part to increased use of aHCT in older patients.3 The risk of cGVHD is higher in patients who:4

  • Have previously experienced aGVHD;
  • Are older;
  • Had a mismatched or unrelated donor;
  • Were transplanted with stem cells from peripheral blood rather than from bone marrow or cord blood;
  • Are men who received cells from donors who are women; and
  • Received cells from donors who are women who had previously borne children.

A study by the Center for International Blood and Marrow Transplant Research (CIBMTR) investigated trends in the incidence of cGVHD over 3 time periods (1995-1999, 2000-2003, and 2004-2007) in 26,563 patients who underwent a first aHCT for acute myeloid leukemia (n=10,737), acute lymphoblastic leukemia (n=6756), chronic myeloid leukemia (n=6341), or myelodysplastic syndrome (n=2729) (Figure).5 Univariate and multivariate analyses demonstrated a significantly increased incidence of cGVHD in the recent time periods.

Limitations of Conventional Therapy

Patients with mild cGVHD may only require local therapies such as topical steroids, depending on the organ or site affected and the risk of relapse of the underlying disease.1 For patients with moderate or severe disease, the recommended first-line treatment for cGVHD is systemic high-dose steroids administered alone or combination with a calcineurin inhibitor1,6 plus a short course of methotrexate or mycophenolate mofetil with or without additional anti-thymocyte globulin in transplants from unrelated donors. Use of anti-thymocyte globulin has also been recommended as GVHD prophylaxis in cases of human leukocyte antigen-identical sibling transplantation.1,7 In general, less than 50% of patients respond adequately to first-line treatment. The majority will become steroid-resistant or steroid-dependent within 2 years, with resistance often associated with suboptimal responses, loss of response, or unsuccessful steroid tapering.1

Patients resistant to treatment require subsequent lines of therapy. However, owing to a lack of substantial data from prospective clinical trials, there is no consensus regarding optimal salvage treatment in the steroid-refractory setting. In addition, patient response is variable.6 Long-term use of steroids contributes to poor patient outcomes because it associated with significant toxicity and increased risk of infection.1 Consequently, heavily-treated cGVHD remains a significant cause of patient mortality, particularly in patients with steroid-refractory disease.6,8

Steroid-Refractory cGVHD Pathophysiology and Treatment Advances

Steroid-refractory cGVHD has been defined as disease progression in patients receiving treatment with prednisone at a dose of 1 mg/kg per day or higher for 1 to 2 weeks or stable cGVHD in patients receiving treatment with prednisone at a dose of 0.5 mg/kg per day or higher for 1 to 2 months. Some patients may remain steroid-dependent with repeated symptom flares during a corticosteroid taper to dosages below 0.25 mg/kg per day.9 Currently, there is no standard of care for steroid-refractory cGVHD and effective treatment options are limited. For these patient populations, treatment is individualized based on clinical experience, disease history, comorbidities, and individual tolerance to medication.

The pathophysiologic mechanism of steroid resistance in cGVHD is poorly understood but thought to involve an interplay of dysregulated pathways involving T cells, B cells, cytokines, and chemokines.10,11 Several kinase inhibitors have been investigated as potential treatments for cGVHD, including Janus kinases (JAK) 1 and 2, Bruton tyrosine kinase (BTK), and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitors. ROCK2 mediates Th17 differentiation in GVHD, and preclinical data suggest that inhibition of ROCK2 could reduce cGVHD severity by downregulation of cytokine production essential for disease progression. BTK is necessary for the survival, migration, and proliferation of B cells. In a mouse model of cGVHD, inhibition of BTK yielded clinical improvements.12 Similarly, preclinical evidence suggests that JAK 1/2 signaling is crucial in the steps leading to inflammation and tissue damage in aGVHD and cGVHD.13 Pharmacologic inhibition of JAK 1/2 prevents GVHD by blocking signaling of interferon-γ receptors and interleukin-6 receptors. Inhibition of JAK 1/2 in preclinical murine research has been shown to effectively treat cGVHD.13 Evidence supporting JAK 1/2 inhibition as a potential therapeutic option in heavily-pretreated cGVHD was demonstrated in a small single-site case series that resulted in a significant response with good tolerability.6

These clinical studies resulted in US Food and Drug Administration (FDA) approval of 3 therapies for the treatment of steroid-refractory cGVHD (Table).

The recent availability of new treatment options for cGVHD is anticipated to improve the management of this challenging disease. However, clinical data to inform optimal use of these agents in this setting remain limited.

Clinical Trials Involving FDA-Approved Therapies for cGVHD

Ruxolitinib

Efficacy and safety of the JAK 1/2 inhibitor ruxolitinib for the treatment of steroid-refractory aGVHD were demonstrated in REACH1 and REACH2 trials. The pivotal phase 3 REACH3 trial investigated the efficacy and safety of ruxolitinib and its results led to an FDA approval for patients with steroid-refractory cGVHD (ClinicalTrials.gov Identifiers: NCT02953678, NCT02913261, and NCT03112603, respectively).13,17

In the REACH3 trial, efficacy and safety of ruxolitinib were compared with the best supportive therapy in 329 patients with glucocorticoid-refractory or glucocorticoid-dependent cGVHD. At 24 weeks, patients treated with ruxolitinib demonstrated a significantly superior response compared with patients who received the investigator’s choice of therapy among 10 commonly used treatment options. Patients receiving ruxolitinib saw higher overall response rate (ORR; 49.7% vs 25.6%; P <.001), failure-free survival time (18.6 months vs 5.7 months; P <.001), and symptom response (24.2% vs 11.0%; P =.001) compared with best supportive therapy. The incidence of thrombocytopenia, anemia, and neutropenia was higher with ruxolitinib use than investigator’s choice of treatment. However, the incidence of infections of any type, including cytomegalovirus infection and reactivation, was similar.13

A retrospective study evaluated ruxolitinib as salvage therapy in 70 patients with steroid-refractory cGVHD. The ORR was 74.3%, the complete response (CR) rate was 48.6%, and the partial response (PR) rate was 25.7%. Patients who achieved a CR and PR with ruxolitinib had better survival outcomes (84.5%) compared with those who showed no response to therapy (16.7%; P <.001). Cytopenia — primarily anemia and thrombocytopenia — was the most common adverse effect (AE) associated with ruxolitinib.17

In the real-world setting, a single-site case series of 41 patients with steroid-refractory cGVHD who were heavily pretreated demonstrated a significant response to ruxolitinib. The drug was well-tolerated with an acceptable safety profile. Overall, CR was achieved in 15 (36.6%) patients and 14 (34.1%) had a PR. Significantly prolonged survival was observed in patients who had received cells from donors who are men (P =.006), skin-involved cGVHD (P =.001), and achieved CR before transplantation (P =.02). However, lung involvement and transplants where cells were received from a matched-related donor were significantly associated with a less favorable treatment response (P =.01 and P =.048, respectively). The most significant safety concerns were infections, primarily lung infections and reactivation of Epstein-Barr virus and cytomegalovirus. Cytopenia, necrosis, and malignancy relapse also occurred. The increased risk of infections highlights the need for infection prophylaxis, including the use of sulfamethoxazole/trimethoprim to prevent pneumocystis pneumonia and use of micafungin or posaconazole for prophylaxis against invasive fungal disease.6

What are common adverse effects of ruxolitinib in cGVHD?
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Adverse effects most commonly reported in cGVHD include anemia, thrombocytopenia, and infections.

Belumosudil

The FDA approval of the oral ROCK 1/2 inhibitor belumosudil was based on results from ROCKstar, a randomized, multicenter phase 2 study (ClinicalTrials.gov Identifier: NCT03640481) that evaluated belumosudil 200 mg once or twice daily in 132 patients with steroid-refractory cGVHD who received an aHCT.18 The primary endpoint was ORR. High response rates were observed with both dosages of belumosudil. The best ORRs were 74% for belumosudil 200 mg once daily and 77% for belumosudil 200 mg twice daily. Symptom reduction was reported in 59% and 62% of patients, respectively. High ORRs were maintained even in patients who had received prior therapy with ruxolitinib or ibrutinib (68% and 74%, respectively).18 The observed AEs were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. The most common grade 3 or 4 AEs were pneumonia (8%), hypertension (6%), and hyperglycemia (5%). There were low rates of grade 3 or higher cytopenia and cytomegalovirus infection.18

Ibrutinib

The BTK and interleukin-2-inducible kinase inhibitor ibrutinib is believed to affect pathways driving cGVHD. It was the first therapy to be approved by the FDA for the treatment of refractory cGVHD.19 Approval was based on a phase 1b/2, open-label, single-arm study (ClinicalTrials.gov Identifier: NCT02195869) that included 42 patients with active steroid-dependent or steroid-refractory cGVHD. The initial analysis of the data after a 14-month follow-up showed that the ORR was 67%. Approximately 21% of patients had a CR and 45% had a PR. The most common AEs were fatigue, diarrhea, muscle spasms, nausea, and bruising.20

The responses observed at 14 months follow-up were maintained at a median follow-up of 26 months. The best ORR was 69% (29/42) of patients with CR in 31% (13/42) of patients and PR in 38% (16/42) of patients.21 Patients with organ involvement showed a good response. Similarly, 61% (11/18) of patients with sclerosis at baseline had a sclerotic response (CR, 39%; PR, 22%). The safety signals reported are consistent with B-cell malignancies and AEs typically seen in patients with cGVHD treated with corticosteroid-containing therapies. The common all-grade AEs were fatigue, diarrhea, muscle spasms, nausea, and bruising.

Determining the optimal use of ibrutinib in the management of cGVHD has been a challenge due to limited investigation in this setting after FDA approval. However, insight have emerged from a real-world retrospective single-center study of 53 patients in which ibrutinib was used predominantly in patients with late, moderate-to-severe, multiorgan-involved steroid-refractory cGVHD.22 At 2 years, the overall survival rate was 76%. However, the failure-free survival rate with ibrutinib was 9%. Ibrutinib use was not associated with a reduction in corticosteroid dose. The observed safety profile was consistent with the drug class, including infections (lung, skin, enterocolitis), bleeding and bruising (hematoma, epistaxis, gastrointestinal bleeding), and muscle aches. Overall, real-world data show that the failure-free survival, clinical responses, and corticosteroid-sparing effect were reduced compared with results of the registration phase 1b/2 trial.22 Current real-world data on ibrutinib in the management of cGVHD suggest that it may be most suitable for narrow, targeted use such as advanced cGVHD — preferentially in patients with inflammatory features such as erythematous skin rash or oral involvement — in order to optimize treatment outcomes.

References

  1. Wolff D, Fatobene G, Rocha V, Kröger N, Flowers ME. Steroid-refractory chronic graft-versus-host disease: treatment options and patient management. Bone Marrow Transplant. 2021;56(9):2079-2087. doi:10.1038/s41409-021-01389-5
  2. Zeiser R, Blazar BR. Acute graft-versus-host disease – biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167-2179. doi:10.1056/NEJMra1609337
  3. Wolff D, Lawitschka A. Chronic graft-versus-host disease. In: Carreras E, Dufour C, Mohty M, Kröger N, eds. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. 7th ed. Springer; Cham. 2019.
  4. BMT Infonet.org. Chronic Graft-versus-Host Disease (cGVHD). Published 2022. Accessed March 9, 2022. https://www.bmtinfonet.org/transplant-article/chronic-graft-versus-host-disease-cgvhd
  5. Arai S, Arora M, Wang T, et al; for the Graft-vs-Host Disease Working Committee of the CIBMTR. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from CIBMTR. Biol Blood Marrow Transplant. 2015;21(2):266-274. doi:10.1016/j.bbmt.2014.10.021
  6. Wu H, Shi J, Luo Y, et al. Evaluation of ruxolitinib for steroid-refractory chronic graft-vs-host disease after allogeneic hematopoietic stem cell transplantation. JAMA Netw Open. 2021;4(1):e2034750. doi:10.1001/jamanetworkopen.2020.34750
  7. Flowers MED, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125(4):606-615. doi:10.1182/blood-2014-08-551994
  8. Luft T, Dietrich S, Falk C, et al. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood. 2011;118(6):1685-1692. doi:10.1182/blood-2011-02-334821
  9. Schoemans HM, Lee SJ, Ferrara JL, et al; on behalf of the EBMT (European Society for Blood and Marrow Transplantation) Transplant Complications Working Party and the EBMT-NIH (National Institutes of Health)-CIBMTR (Center for International Blood and Marrow Transplant Research) GvHD Task Force. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transplant. 2018;53:1401-1415. doi:10.1038/s41409-018-0204-7
  10. Min C-K. The pathophysiology of chronic graft-versus-host disease: the unveiling of an enigma. Korean J Hematol. 2011;46(2):80-87. doi:10.5045/kjh.2011.46.2.80
  11. Cooke KR, Luznik L, Sarantopoulos S, et al. The biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2017;23(2):211-234. doi:10.1016/j.bbmt.2016.09.023
  12. Braun LM, Zeiser R. Kinase inhibition as treatment for acute and chronic graft-versus-host disease. Front Immunol. 2021;12:760199. doi:10.3389/fimmu.2021.760199
  13. Zeiser R, Polverelli N, Ram R, et al; for the REACH3 Investigators. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122
  14. Jakafi. Prescribing Information. Incyte Corporation; 2021. Accessed March 10, 2022. https://www.jakafi.com/pdf/prescribing-information.pdf
  15. Rezurock. Prescribing Information. Kadmon Pharmaceutical, LLC; 2021. Accessed March 10, 2022. https://www.rezurock.com/full-prescribing-information.pdf  
  16. Imbruvica. Prescribing Information. Pharmacyclics, LLC, and Janssen Biotech, Inc; 2020. Accessed March 10, 2022. https://www.imbruvica.com/files/prescribing-information.pdf
  17. Wang D, Liu Y, Lai X, et al. Efficiency and toxicity of ruxolitinib as a salvage treatment for steroid-refractory chronic graft-versus-host disease. Front Immunol. 2021;12:673636. doi:10.3389/fimmu.2021.673636
  18. Cutler C, Lee SJ, Arai S, et al; on behalf of the ROCKstar Study Investigators. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021;138(22):2278-2289. doi:10.1182/blood.2021012021
  19. Jaglowski SM, Blazar BR. How ibrutinib, a B-cell malignancy drug, became an FDA-approved second-line therapy for steroid-resistant chronic GVHD. Blood Adv. 2018;2(15):2012-2019. doi:10.1182/bloodadvances.2018013060
  20. Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243-2250. doi:10.1182/blood-2017-07-793786
  21. Waller EK, Miklos D, Cutler C, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Biol Blood Marrow Transplant. 2019;25(10):P2002-P2007. doi:10.1016/j.bbmt.2019.06.023
  22. Chin K-K, Kim HT, Inyang E-A, et al. Ibrutinib in steroid-refractory chronic graft-versus-host disease, a single-center experience. Transplant Cell Ther. 2021;27(12):990.e1-990.e7. doi:10.1016/j.jtct.2021.08.017

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Oncology Nurse Advisor had no role in this content’s preparation.

                                                                                                            Reviewed April 2022

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