How might emerging therapies and combination approaches reshape sequencing strategies in cGvHD?

The GvHD Hub was pleased to speak with Robert Zeiser, University of Freiburg, Freiburg, DE. We asked, How might emerging therapies and combination approaches reshape sequencing strategies in chronic graft-versus-host disease (cGvHD)?  

In this interview, Zeiser discusses emerging treatment strategies under evaluation in cGvHD, including the latest clinical data for several combination approaches and novel agents. Whilst encouraging results have been observed to date, further research is needed to define their optimal placement within treatment sequencing pathways. 

Key points 

• cGvHD – and its treatment with prolonged immunosuppression – is associated with significant morbidity, including infections, cumulative organ toxicities, and secondary malignancies.​¹ 
• While targeted agents have improved outcomes in cGvHD, durable responses remain limited, and a substantial number of patients require subsequent immunosuppressive therapies.^2,3 ​ 
• Considering that inflammation and fibrosis often coexist in cGvHD, combining agents with complimentary mechanisms of action into treatment sequences may better address the complexity of cGvHD.^4–6​ 
• Extracorporeal photopheresis (ECP) + ruxolitinib (a Janus kinase [JAK] 1/2 inhibitor) is a well-characterized therapeutic combination. 
  • A retrospective, single-center study evaluated ECP + ruxolitinib in patients with steroid-refractory (SR) severe cGvHD (N = 23); 91% had received ≥2 prior lines of therapy (LoT).⁷ 
  • The best response at any time point was 74%, and the 2-year overall survival was 75%; the combination was well tolerated.⁷ 
  • These findings support the use of this combination in heavily pretreated patients with SR-cGvHD, with further evaluation planned in a prospective phase II trial. 
• Ruxolitinib is also under evaluation in combination with axatilimab (a colony-stimulating factor 1 receptor blocking antibody) in cGvHD.⁸ 
  • In an ongoing, randomized phase II trial (NCT06388564) in patients with moderate-to-severe cGvHD (N = 66), first-line axatilimab + ruxolitinib was well tolerated and had a similar safety profile to ruxolitinib alone, with no evidence of additive toxicity. 
• The combination of belumosudil (a Rho-associated kinase [ROCK] 2 inhibitor) + ruxolitinib has also been explored in cGvHD. 
  • In a retrospective, real-world study of patients with steroid-dependent (SD)- or SR-cGvHD receiving belumosudil + ruxolitinib (N = 14), the 6- and 12-month overall response rates (ORRs) were 64% and 57%, respectively, and the combination was well tolerated.⁹ 
  • A retrospective, single-center study evaluated ruxolitinib + belumosudil in patients with cGvHD (N = 20) who had received a median of three prior LoT. The ORR was 55% and the combination was well tolerated, with no discontinuations due to intolerance.¹⁰ 
• Axatilimab + ruxolitinib and/or belumosudil​ has been evaluated in cGvHD.⁶ 
  • In a retrospective, single-center study (N = 8), in which patients had received a median of five prior LoT, the ORR was 25% per 2014 National Institutes of Health Consensus Criteria and 75% per Clinically Significant Symptomatic Improvement (CSSI) as deemed by provider. Notably, four of the six CSSI responders were treated with ruxolitinib + belumosudil + axatilimab.  
• Mesenchymal stromal cells have demonstrated clinical activity as monotherapy in cGvHD;¹¹ however, there is limited evidence supporting their combination with other agents. 
• Several other novel approaches have shown encouraging results in cGvHD; however, larger-scale studies are needed to confirm benefit and determine their ideal placement within treatment pathways. 
  • Rovadicitinib, an oral JAK 1/2 and ROCK 1/2 inhibitor, was well tolerated and elicited a high response rate (86.4%) in a phase Ib/IIa trial (NCT04944043) of patients with moderate-to-severe SD- or SR-cGvHD who had received ≥2 prior LoT (N = 44).¹² 
  • Several case reports have shown a clinical benefit of chimeric antigen receptor (CAR) T cells, including a first-in-human trial of CD6-CAR regulatory T cells in patients with cGvHD (N = 6).¹³ 
• Further research is needed to define the optimal positioning of combination approaches and emerging therapies within treatment sequencing pathways in cGvHD. 

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