Oncology

Chronic Graft-versus-Host Disease

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Combination Treatment Strategies for Chronic Graft-versus-Host Disease

clinical topic updates by Miguel-Angel Perales, MD
Overview

Despite advances in the treatments available for chronic graft-versus-host disease (cGVHD), it remains a significant cause of morbidity and mortality. In an attempt to further improve patient outcomes, a treatment approach that is under investigation is to combine US Food and Drug Administration (FDA)–approved therapies.

“The rate of complete remission with ruxolitinib, belumosudil, axatilimab, and ibrutinib is not 100%. In fact, it is much lower than that, with most patients achieving partial remission. It is therefore logical to try combining these drugs, all of which are effective and do not have overlapping toxicities.”
— Miguel-Angel Perales, MD

Ruxolitinib, belumosudil, axatilimab, and ibrutinib are FDA approved for the treatment of patients with cGVHD who have failed prior systemic therapy. Ruxolitinib, belumosudil, and axatilimab were approved based on the results of a randomized phase 3 trial and 2 randomized phase 2 trials, respectively, while ibrutinib was approved based on the results of a single-arm, phase 1b/2 trial of 42 patients. So, I think that the clinical trial data are stronger for ruxolitinib, belumosudil, and axatilimab than for ibrutinib. Additionally, the ibrutinib trial required patients to have an inflammatory presentation of cGVHD, which is not necessarily the most common presentation. The patient characteristics of those participating in the ruxolitinib and belumosudil trials are probably a more typical presentation of cGVHD and are what we see in the clinic.

 

The rate of complete remission with ruxolitinib, belumosudil, axatilimab, and ibrutinib is not 100%. In fact, it is much lower than that, with most patients achieving partial remission. It is therefore logical to try combining these drugs, all of which are effective and do not have overlapping toxicities.

 

A retrospective study of 14 patients suggested that belumosudil can safely be added to ruxolitinib with improved efficacy. However, if you asked, say, 5 experts about this, you would probably get 6 different opinions. In my own discussions, I have heard some experts say that they stop ruxolitinib before starting belumosudil or they use ruxolitinib as a bridge to belumosudil if they think that ruxolitinib is not working. When ruxolitinib is working but its effect has plateaued, others say that they may add belumosudil on top of the ruxolitinib to see if the patient has a better response.

 

In general, if the patient is tolerating ruxolitinib and they have had a response, my approach has been to add belumosudil rather than to stop ruxolitinib. However, I will stop ruxolitinib if the patient is not tolerating it or if I think that it is not working. Another consideration is that it is challenging to give both drugs from an insurance point of view, and you sometimes have to go back-and-forth with insurance companies. Co-pays can also be an issue for patients.

 

An interesting study evaluated a switch-maintenance GVHD prophylaxis approach with ixazomib. It seems quite promising, so now we are thinking about trying it with other drugs and introducing active drugs before the patient has even developed cGVHD. We have already seen significant changes in the prevention and treatment of acute GVHD and cGVHD since I began performing transplants, with many more options now available to our patients, and I am no longer seeing cases of cGVHD involving patients who are almost wheelchair bound.

References

Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study. Blood. 2021;138(22):2278-2289. Published correction appears in Blood. 2022;139(11):1772.

 

Raju G, Walji M, Nemirovosky D, et al. Combined belumosudil-ruxolitinib therapy for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD) was associated with robust treatment response and was well-tolerated. Transplant Cell Ther. 2024;30(suppl 2):S281. doi:10.1016/j.jtct.2023.12.378

 

Rodriguez N, Lee J, Flynn L, et al. Oral proteasome inhibitor ixazomib for switch-maintenance prophylaxis of recurrent or late acute and chronic graft-versus-host disease after day 100 in allogeneic stem cell transplantation. Transplant Cell Ther. 2021;27(11):920.e1-920.e9. doi:10.1016/j.jtct.2021.05.008

 

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):2002-2007. doi:10.1016/j.bbmt.2019.06.023

 

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

 

Wolff D, Cutler C, Lee SJ, et al; AGAVE-201 Investigators. Safety and efficacy of axatilimab at 3 different doses in patients with chronic graft-versus-host disease (AGAVE-201). Blood. 2023;142(suppl_1):1. doi:10.1182/blood-2023-186963

 

Zeiser R, Polverelli N, Ram R, et al; REACH3 Investigators. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122

Miguel-Angel Perales, MD

    Chief, Adult Bone Marrow Transplant Service
    Memorial Sloan Kettering Cancer Center
    Professor of Medicine
    Weill Cornell Medical College
    New York, NY
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