Two heads are better than one: a synergistic strategy for conquering graft-versus-host disease

Lastovytska et al. have combined extracorporeal photopheresis (ECP) and ruxolitinib to treat acute graft-versus-host disease (aGvHD) and compared the response to a group of patients receiving ruxolitinib alone.¹ Glucocorticoids are the first-line therapy for aGvHD and chronic GvHD (cGvHD), with response rates of 40-60%, which indicates that potent second- and third-line therapies are essential.

The authors have combined two approaches with very different mechanisms of action. ECP induces immunomodulation in diseases mediated by pathologic auto-/ alloreactive T cells. Anti-inflammatory effects of ECP were recently shown to rely on the phagocytosis of apoptotic immune cells resulting in the production of adiponectin in the inflamed organ.² While not yet approved by the US Food and Drug Administration or the European Medicines Agency for this indication, ECP is broadly used in steroid-refractory a/cGvHD. Conversely, ruxolitinib interferes with Janus-associated kinases (JAK) 1 and 2 activation, which reduces signaling of multiple cytokine receptors.³ Ruxolitinib decreased the frequency of pathogenic T cells, e.g., CD4⁺IFN-γ⁺ and CD4⁺IL17A⁺ cells⁴ and MHC-II surface levels on dendritic cells⁵ in mice developing GvHD. In a murine model of cGvHD, ruxolitinib treatment reduced collagen deposition in the lungs and improved pulmonary function.⁶ A randomized, open-label, multicenter clinical trial of ruxolitinib compared to best available therapy (BAT) for corticosteroid-refractory or -dependent cGvHD (REACH-3; clinicaltrials.gov identifier 03112603) randomized 329 patients to receive either ruxolitinib 10 mg twice daily or one of 10 investigator-selected BAT.⁷ The overall response rates at week 24 after treatment start were higher in the ruxolitinib group compared to the BAT.⁷ The improved failure-free survival rate in the ruxolitinib group was also seen at a 3-year follow-up.⁸ Although response rates up to 59% can be achieved in patients with steroid-refractory aGvHD with ruxolitinib, around 18% of the patients have a secondary failure of ruxolinib and/or need an additional immunosuppressive drug for aGvHD management. Thus, Lastovytska et al.¹ investigated synergistic effects of a combined second-line treatment with ruxolitinib and ECP (RUX/ECP) for SR-aGvHD in a retrospective analysis. While short-term response rates were higher in the ruxolitinib monotherapy arm, significantly more patients had a sustained (complete) response one year after therapy initiation with RUX/ECP. A major observation made by the authors was that patients treated with RUX/ECP for aGvHD also had lower rates of cGvHD. This is consistent with aGvHD being a major risk factor for cGvHD. In accordance with the results of the authors, it was shown that RUX/ECP for patients with refractory cGvHD yielded response rates over 65% in a retrospective case study.⁹

A major clinical problem in patients with cGvHD is lung involvement because effective treatment and biomarkers for response to corticosteroids are lacking. A recent study showed that treatment with dexamethasone up-regulated the expression of total glucocorticoid receptor in patients with chronic obstructive pulmonary disease that responded to treatment, but not in non-responders.¹⁰ Preventing cGvHD of the lungs by the use of RUX/ECP for initial aGvHD, as described by Lastovytska et al., may be a strategy to reduce this severe complication. Furthermore, Lastovytska et al. also showed that patients treated with RUX/ECP had a superior composite endpoint cGvHD and relapse-free survival after 12 months, and significantly more patients in the RUX/ ECP arm had completely tapered any immunosuppressant. Both, cGvHD and the intake of immunosuppressive drugs negatively impact on quality of life. The combination of drug-blocking kinases that mediate cytokine and growth factor signaling with a tolerance-inducing approach that relies on apoptotic cells causing macrophage reprogramming and adiponectin production is novel and innovative (Figure 1).

A major concern of immunosuppression in GvHD patients is safety, in particular infections and relapse rate. Although not significant, more patients within the RUX/ECP arm deceased within one year after experiencing aGvHD, mainly for infectious complications in the study by Lastovytska et al. Safety of the combination treatment with ruxolitinib and ECP should be analyzed in detail in the prospective setting. Taken together, the results of the study by Lastovytska et al. combining ruxolitinib and ECP as second-line treatment for aGvHD after allo-HSCT are promising. However, several factors, such as imbalanced aGvHD grades among the two cohorts, the historical control group, longer ruxolitinib treatment duration in the RUX-ECP arm, higher death rates in the RUX-ECP treated patients, and other, unknown, variables might have biased the outcome. Randomized prospective studies should be performed to confirm these findings.

Figure 1.Proposed mechanism of action of ruxolitinib and extracorporeal photopheresis for acute steroid-refractory graft-versus-host disease. Ruxolitinib inhibits downstream signaling of multiple cytokine receptors and growth factors. Extracorporeal photopheresis (ECP) induces apoptotic cells that are taken up by local macrophages and induce tolerance. GvHD: graft-versus-host disease; UV: ultraviolet.

Footnotes

• Received April 1, 2025
• Accepted April 4, 2025

Correspondence

R. Zeiser robert.zeiser@uniklinik-freiburg.de

Disclosures

RZ received honoraria from Novartis, Incyte, Mallinckrodt, Medac, and Neovii. DS reports an unrestricted grant from OM-Pharma (paid to the institution), honoraria for participation in data safety monitoring or advisory boards or talks for CSL Behring, Berlin-Chemie Menarini, Roche, GlaxoSmithKline, AstraZeneca, Vifor, Merck, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, and Chiesi, and is the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) representative for Switzerland. SG has no conflicts of interest to disclose.

Contributions

All authors reviewed the literature, wrote the manuscript, and designed the figure.

Acknowledgments

RZ was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SFB-1479 – Project ID: 441891347.