Navigating Steroid-Refractory GVHD Treatment: A Pharmacist’s Guide to Medication Management

Graft-vs-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT), manifesting as either acute GVHD (aGVHD) or chronic GVHD (cGVHD). aGVHD results from a donor T-cell–mediated attack on an immunocompromised host, whereas cGVHD mimics autoimmune diseases. Both forms lead to injury in host organs, with aGVHD primarily targeting the skin, the liver, and the gastrointestinal (GI) system; however, cGVHD can target most organ systems.^1,2 The development of GVHD is influenced by multiple risk factors, including the use of unrelated or human leukocyte antigen–mismatched donors and peripheral blood stem cell sources.^3,4

Image credit: MdBabul | stock.adobe.com

The best strategy to mitigate the complications of GVHD is prevention, using both pharmacologic and nonpharmacologic methods. Nonpharmacologic strategies center on selecting the most histocompatible donor match. Pharmacologic approaches involve various immunosuppressive agents, such as calcineurin inhibitors, sirolimus, methotrexate, mycophenolate, posttransplant cyclophosphamide, and anti–human T-lymphocyte immune globulin. Despite these preventive measures, GVHD still occurs in 25% to 80% of patients, as reported in the literature.⁵

This article provides a concise review of aGVHD and cGVHD treatment methods, with an in-depth discussion of emerging therapies and the role of pharmacists in treating patients with GVHD.

Standard of Care

GVHD remains a significant source of morbidity and mortality in patients with allogeneic HSCT. Treatment focuses on reducing B- and T-cell activation, suppressing inflammation, and preventing fibrosis.⁶ Corticosteroids are the cornerstone of first-line treatment for both aGVHD and cGVHD, with approximately 50% of patients responding to therapy.⁷ For those who do not respond, additional lines of therapy are required.

In recent years, ruxolitinib (Jakafi; Incyte Corporation) has received FDA approval and is an National Comprehensive Cancer Network Category 1 recommendation for steroid-refractory aGVHD and cGVHD.⁸ However, a standardized approach to managing GVHD beyond corticosteroids and ruxolitinib remains elusive.

Several third-line agents are options, depending on patient-specific and institutional considerations. cGVHD treatment has seen an expansion in FDA-approved therapies, including ibrutinib (Imbruvica; Janssen Biotech, Inc and Pharmacyclics LLC), belumosudil (Rezurock; Kadmon Pharmaceuticals, LLC), and axatilimab (Niktimvo; Incyte Corporation). Other options, such as abatacept (Orencia; Bristol Myers Squibb), alemtuzumab (Campath; Genzyme Corporation), alpha-1 antitrypsin, calcineurin inhibitors, mTOR inhibitors, mycophenolate mofetil, and monoclonal antibodies targeting interleukin-2, interleukin-6, α4β7 integrin, and tumor necrosis factor are available for both aGVHD and cGVHD.⁸

Emerging Therapies

Growing evidence highlights the potential of new and emerging therapies to address the unmet clinical needs in GVHD.

Axatilimab

Axatilimab, a colony-stimulating factor 1 receptor (CSF1R)–blocking antibody, has emerged as a promising treatment for cGVHD. The AGAVE-201 phase 2 trial (NCT04710576) evaluated 241 patients with refractory cGVHD randomly assigned to 3 axatilimab dosing regimens.⁹ The highest overall response rate (ORR; 74%) was observed with the lowest-dose group of 0.3 mg/kg every 2 weeks. Adverse effects (AEs) were primarily transient laboratory abnormalities, such as serum enzyme elevations and periorbital edema, linked to Kupf fer cell depletion induced by the CSF1R blockade. Axatilimab received FDA approval in August 2024 for use in adult and pediatric patients with cGVHD after the failure of at least 2 prior systemic therapies.¹⁰

Baricitinib

Baricitinib (Olumiant; Eli Lilly and Company), a Janus kinase (JAK) 1/2 inhibitor, has demonstrated efficacy in preventing and treating GVHD.¹¹ As seen in mouse models, baricitinib differs from ruxolitinib in expanding regulatory T cells by preserving JAK3-ST AT5 signaling, thereby preventing and treating GVHD. In a phase 1/2 study of 20 patients with refractory cGVHD, baricitinib (2 mg by mouth daily) achieved a 63% ORR at 6 months with a median time to OR of 1.4 months.¹² Responses were seen across most organs except the lungs. Common AEs included upper respiratory infections, neutropenia, hyperphosphatemia, and hypertriglyceridemia. Baricitinib’s broader mechanism of action and lower anemia and thrombocytopenia rates may position it as a complementary or alternative therapy to ruxolitinib.

Ixazomib

Ixazomib (Ninlaro; Takeda Pharmaceuticals America, Inc), an oral proteasome inhibitor, has shown promise in steroid-refractory cGVHD. In a phase 2 trial, ixazomib (4 mg on days 1, 8, and 15 of a 28-day cycle) reduced the 6-month treatment failure rate to 28%, significantly lower than the historical 44% benchmark (P = .01).¹³ The study authors reported 6-month and 12-month overall survival rates of 92% and 90%, respectively. Most patients in this study had skin, eye, joint/fascia, mouth, or lung involvement; however, there was no evidence of any significant difference in efficacy among the various organs. Although this study was performed before the FDA-approved agents such as ruxolitinib and ibrutinib, ixazomib demonstrated consistent efficacy across organ systems, offering a tolerable safety profile.

Teduglutide

Teduglutide (Gattex; Takeda Pharmaceuticals America, Inc), a glucagon-like peptide-2 (GLP-2) analog approved for short bowel syndrome, has shown potential for steroid-refractory acute GI GVHD.¹⁴ GLP-2 is an intestinal hormone secreted by L cells in the distal ileum and proximal colon that strengthens gut barrier function, promotes mucosal growth, and enhances blood circulation. A retrospective review of 3 pediatric patients with grade 3 to 4 GI GVHD treated with teduglutide (0.05 mg/kg subcutaneously daily) showed clinical improvement within 14 to 28 days. Although used alongside other systemic therapies, teduglutide represents a potential off-label, nonimmunosuppressive therapy for pediatric and adult GI GVHD, warranting further studies.

Pharmacists’ Role in GVHD Management

Pharmacists are integral to the multidisciplinary care of HSCT patients, contributing to medication management, patient education, and quality improvement.¹⁵ Pharmacists’ expertise guides therapeutic decisions, balancing efficacy, AEs, infectious disease risks, and patient-specific considerations in managing steroid-refractory GVHD.

Medication Management and Education

Following HSCT, patients often face complex medication regimens. Pharmacists play a vital role in educating patients and caregivers about proper medication use, thereby optimizing adherence and reducing anxiety. The transition of care between inpatient and outpatient is a critical chance for pharmacists to ensure the patients, caregivers, and members of the health care team have an accurate understanding of patients’ current medication regimens.

Therapeutic Drug Monitoring

Accurate monitoring of immunosuppressive agents, such as calcineurin and mTOR inhibitors, ensures optimal GVHD prevention and treatment. Ensuring adequate serum concentrations of these medications correlates to clinical outcomes. Additionally, antifungal prophylaxis often requires therapeutic drug monitoring to prevent opportunistic infections in immunosuppressed patients.

Quality Improvement and Research

Beyond direct patient care, pharmacists contribute to clinical research and quality improvement initiatives, ensuring compliance with Foundation for the Accreditation of Cellular Therapy accreditation standards.

Conclusion

As new therapies emerge for steroid-refractory GVHD, the role of pharmacists in optimizing patient outcomes through medication management, education, and evidence-based decision-making has become increasingly vital. Continued research into novel agents such as axatilimab, teduglutide, baricitinib, and ixazomib will expand treatment options, offering hope for improved quality of life and survival in this challenging patient population.

REFERENCES

1. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001

2. Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133(11):1191-1200. doi:10.1182/blood-2018-04-785899

3. Jagasia M, Arora M, Flowers MED, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119(1):296-307. doi:10.1182/blood-2011-06-364265

4. Flowers MED, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117(11):3214-3219. doi:10.1182/blood-2010-08-302109

5. 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

6. Vadakkel G, Eng S, Proli A, Ponce DM. Updates in chronic graft-versus-host disease: novel treatments and best practices in the current era. Bone Marrow Transplant. 2024;59(10):1360-1368. doi:10.1038/s41409-024-02370-8

7. Garnett C, Apperley JF, Pavlů J. Treatment and management of graft-versus-host disease: improving response and survival. Ther Adv Hematol. 2013;4(6):366-378. doi:10.1177/2040620713489842

8. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation (HCT), version 2.2024. Accessed December 15, 2024. https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf

9. Wolff D, Cutler C, Lee SJ, et al; AGAVE-201 Investigators. Axatilimab in recurrent or refractory chronic graft-versus-host disease. N Engl J Med. 2024;391(11):1002-1014. doi:10.1056/NEJMoa2401537

10. FDA approves axatilimab-csfr for chronic graft-versus-host disease. FDA. August 14, 2024. Accessed December 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axatilimab-csfr-chronic-graft-versus-host-disease

11. Choi J, Cooper ML, Staser K, et al. Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia. 2018;32(11):2483-2494. doi:10.1038/s41375-018-0123-z

12. Holtzman NG, Im A, Ostojic A, et al. Effi cacy and safety of baricitinib in refractory chronic graft-versus-host disease (cGVHD): preliminary analysis results of a phase 1/2 study. Blood. 2020;136(suppl 1):1. doi:10.1182/blood-2020-140392

13. Pidala J, Bhatt VR, Hamilton B, et al. Ixazomib for treatment of refractory chronic graft-versus-host disease: a chronic GVHD consortium phase II trial. Biol Blood Marrow Transplant. 2020;26(9):1612-1619. doi:10.1016/j.bbmt.2020.05.015

14. Ramos KN, Leino D, Luebbering N, et al. Use of teduglutide in the management of gastrointestinal graft-versus-host disease in children and young adults. Transplant Cell Ther. 2024;30(4):454.e1-454. e6. doi:10.1016/j.jtct.2024.01.080

15. Clemmons AB, Alexander M, DeGregory K, Kennedy L. The hematopoietic cell transplant pharmacist: roles, responsibilities, and recommendations from the ASBMT Pharmacy Special Interest Group. Biol Blood Marrow Transplant. 2018;24(5):914-922. doi:10.1016/j.bbmt.2017.12.803033