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Translational and clinical advances in aGvHD
Table 2. Therapeutic strategies for acute graft-versus-host disease.
Prophylaxis strategy
Non-specific
immunosuppression Cytokine targeting
Targeting lymphocyte trafficking
Targeting immunologic tolerance
Targeting dysbiosis
Intervention
Corticosteroids
JAK-2 inhibition: ruxolitinib JAK-1 inhibition: itacitinib Alpha-1 anti-trypsin (AAT)
Vedolizumab
Natalizumab
Extra-corporeal photochemotherapy
NOTCH inhibition
Fecal microbiota transplant
Level of evidence
Phase II/III RCT
Phase III RCT
Phase III RCT
Phase II, ongoing Phase III RCT
Proof-of-concept, retrospective review, ongoing Phase II randomized study
Phase II single-arm
Phase II single-arm Investigational
Pilot studies, case series
Comments
RCT comparing different steroid doses, no RCT
comparing steroids vs. placebo.
Ruxolitinib vs. investigator’s choice in SR-aGvHD: superior
ORR but no difference in 18-month NRM.
Itacitinib vs. itacitinib+steroids in upfront therapy: negative trial.
ORR of 65% in SR-aGvHD in Phase II, ongoing phase III RCT of AAT+steroids vs. steroids alone for high-risk aGvHD.
ORR of 64% in retrospective studies, CMV reactivation, C Diff. colitis seen
ORR of approx. 30%
ORR varies from 40-70% in small non-randomized studies.
No reported clinical studies at this time
Concern for fatal bloodstream infection hence still
investigational
aGvD: acute graft-versus-host disease; AAT: alpha-1-antitrypsin; aGvHD: acute graft-versus-host disease; ATG: anti-thymocyte globulin; C Diff.: Clostridium difficile colitis; CMV: cytomegalovirus; HSCT: hematopoietic stem cell transplantation; NRM: non-relapse mortality; ORR: overall response rate; RCT: randomized controlled trial; SR: steroid-refractory.
In the arena of prevention, PTCy-based GvHD prophy- laxis has been a significant advance and some selective methods of T-cell depletion and modulation of co-stimula- tory pathways appear promising. In the therapeutic arena, cytokine targeting with Rux is an exciting novel therapy for SR-aGvHD, while immunomodulatory strategies (e.g., ECP, AAT) offer therapeutic potential without immunosuppres- sive toxicity, and strategies targeting lymphocyte trafficking and inhibition of key canonical pathways (e.g., Notch) offer future potential. For the more long-term future, the impor- tance of the gut microbiome in aGvHD is becoming
increasingly apparent, and offers an opportunity for future therapeutic targeting (e.g., probiotics, metabolic modifica- tions).
A long-term rational approach to aGvHD care would involve precision prognostics pre- and peri-transplanta- tion (e.g., plasma biomarkers, microbiota dysbiosis, etc.) to select patients for innovative GvHD preventive strate- gies, as well as the early identification of high-risk patients at aGvHD onset, for novel treatment trials, ideal- ly avoiding additional immunologic dysfunction or impairing GvL.
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