Changes in Immunosuppressive Treatment of Chronic Graft-Versus-Host Disease: Results from a Survey within Allogeneic Hematopoietic Stem Cell Transplant Centers in Germany, Austria, and Switzerland
Authors: Denk Alexander , Fante Matthias , Heidenreich Silke , Greinix Hildegard T. , Wagner Drouet Eva-Maria , Egger-Heidrich Katharina , Marx Julia , Kodzhabasheva Darina , Krüger William , Bug Gesine , Wehr Claudia , Halter Joerg , Teichert von Lüttichau Irene , Mueller Lutz Peter Hermann , Penack Olaf , Hilgendorf Inken , Kobbe Guido , Klein Stefan , Lawitschka Anita , Frietsch Jochen , Wolff Daniel 
Published: December 2024

Chronic graft-versus-host disease (cGVHD) represents a major complication after allogeneic stem cell transplantation (alloHSCT). In 2009 and 2018 a survey among German, Austrian, and Swiss transplant centers was performed showing a homogeneous 1st-line treatment practice, while 2nd-line treatment as well as management of progressive onset type and bronchiolitis obliterans syndrome (BOS) displayed significant heterogeneity. Since the last survey, ruxolitinib (rux) has been approved and other agents are explored in treatment of cGVHD. Therefore, we conducted a new survey in 2024 to document the impact of recent approvals and new agents on treatment practice focusing on management of 2nd-line treatment, progressive onset type, BOS, and sclerotic manifestations.

Methods: A paper-and-pencil-based questionnaire on current clinical practice in cGVHD care was sent electronically to 60 German speaking centers performing alloHSCT. Nineteen centers responded, representing 41% of the patients receiving an alloHSCT in 2023 in Germany.

Results: In 1st-line treatment of classical standard risk cGVHD, single agent prednisolone represents standard of care (13/19 centers) which may be combined with calcineurin inhibitor (CNI) (4/19), while rux is used in selected cases only. In 2nd-line treatment rux is used by the majority of centers (17/19). In the presence of cytopenia, rux (10 - 20mg/d) is the preferred agent (10/19) while extracorporeal photopheresis (ECP) is applied in patients with cytopenia especially in steroid-dependent cGVHD in 7 of 19 centers. In case of active infections, ECP is preferred by 14 of 19 centers and both agents are regarded as steroid-sparing agents in 2nd-line treatment of steroid-dependent cGVHD. Rux would be applied in the presence of active infections by 5/19 centers only. Moreover, rux (15/19) and ECP (5/19) are also preferred treatment modalities in treatment of progressive onset cGVHD. For BOS, systemic and inhalative corticosteroids, montelukast and azithromycin (FAM), rux (14/19), ECP (16/19), CNI (9/19), and abatacept (9/19) are frequently applied agents, while belumosudil (7/19), imatinib (5/19) and ibrutinib (2/19) are used as salvage option in selected patients. In case of new sclerotic manifestations after failure of 2nd line treatment including steroids, CNI and rux, most centers would use ECP (13/19), whereas subsequent or alternative salvage treatment of sclerotic manifestations remains heterogenous comprising belumosudil (12/19), ibrutinib (5/19), imatinib (5/19), rituximab (4/19), cyclosporine (3/19), tacrolimus (3/19), everolimus (3/19), sirolimus (3/19), MTX (3/19) and MMF (3/19). Belumosudil is generally considered effective in treatment of cGVHD but remains to be used in selected patients only most likely due to the lack of EMA approval. The preferred taper sequence of immunosuppressive agents in case of response applied in 11/19 centers is primary taper of steroids, followed by taper of CNI and final termination of rux.

Conclusion: The survey documents the effect of evidence and approval on clinical care with single agent prednisolone representing the standard of care in 1st-line treatment while rux combined with steroids defines the new standard for 2nd line treatment of cGVHD. ECP is used in case of contraindication for rux and both agents are also used in progressive onset cGVHD. In contrast, treatment of BOS and sclerotic cGvHD remains heterogeneous after failure of 2nd-line treatment with new agents being integrated in the treatment landscape.