Steroid-Refractory Chronic Graft-versus-Host Disease Treated with Ruxolitinib: A Narrative Review of Symptom Burden and Return to Daily Life
DOI:
https://doi.org/10.5281/zenodo.22227762Keywords:
Chronic Graft-versus-Host Disease, Ruxolitinib, JAK Inhibition, Steroid-Refractory Disease, Allogeneic, TransplantationAbstract
Chronic graft-versus-host disease is the price a proportion of transplant survivors pay for their cure. Roughly half of those
treated with glucocorticoids do not respond adequately, and until recently the second line was a list of options rather than a
standard.
Objectives: To review the published evidence on ruxolitinib for glucocorticoid-refractory or dependent chronic graft-versus-host
disease: what it achieves against the alternatives, how durable the effect is, what it costs in toxicity, and what the trial did not
measure.
Material and Methods: Narrative review of randomised trials, phase 2 studies, consensus criteria and outcome literature indexed
in PubMed and the major haematology and transplantation journals. No new patient data were generated; every estimate quoted
is one published by the original investigators.
Results: In a phase 3 randomised trial of 329 patients, overall response at week 24 was 49.7 per cent with ruxolitinib against
25.6 per cent with best available therapy (odds ratio 2.99, p < 0.001), and best overall response to week 24 was 76.4 against 60.4
per cent. Median failure-free survival was 18.6 against 5.7 months (hazard ratio 0.37, 95% CI 0.27 to 0.51), and symptom
response 24.2 against 11.0 per cent. At 36 months, 56.5 per cent against 18.2 per cent remained failure-free. Thrombocytopenia
and anaemia were more common with ruxolitinib.
Conclusion: Ruxolitinib is the first agent to beat a mixed comparator arm in a randomised trial in this disease, and the
failure-free survival difference is the most clinically meaningful of its findings. Half of treated patients still did not respond, the
comparator was heterogeneous by design, and the outcome measures capture organ scores rather than the daily function that
defines the illness for the patient.
Abbreviations: BAT – Best Available Therapy, cGVHD – Chronic Graft-versus-Host Disease, ECP – Extracorporeal
Photopheresis, FFS – Failure-Free Survival, JAK – Janus Kinase, mSGRC – Modified Lee Symptom Scale Response, ORR –
Overall Response Rate.
References
Zeiser R, Blazar BR. "Pathophysiology of chronic graft-versus-host disease and therapeutic targets". N Engl J Med 377(2017):2565-2579.
Lee SJ. "Classification systems for chronic graft-versus-host disease". Blood 129(2017):30-37.
Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, et al. "Long-term survival and late deaths after allogeneic hematopoietic cell transplantation". J Clin Oncol 29(2011):2230-2239.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. "National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report". Biol Blood Marrow Transplant 11(2005):945-956.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. "National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report". Biol Blood Marrow Transplant 21(2015):389-401.
Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. "Measuring therapeutic response in chronic graft-versus-host disease: 2014 response criteria working group report". Biol Blood Marrow Transplant 21(2015):984-999.
Flowers MED, Martin PJ. "How we treat chronic graft-versus-host disease". Blood 125(2015):606-615.
Wolff D, Fatobene G, Rocha V, Kroger N, Flowers ME. "Steroid-refractory chronic graft-versus-host disease: treatment options and patient management". Bone Marrow Transplant 56(2021):2079-2087.
Malagola M, Cancelli V, Skert C, Leali PF, Ferrari E, Tiburzi A, et al. "Extracorporeal photopheresis for treatment of acute and chronic graft versus host disease: an Italian multicentric retrospective analysis". Transplantation 100(2016):e147-e155.
Martin PJ, Storer BE, Carpenter PA, Chien JW, Flowers MED, Inamoto Y, et al. "Comparison of short-term response and long-term outcomes after initial systemic treatment of chronic graft-versus-host disease". Biol Blood Marrow Transplant 17(2011):124-132.
Penack O, Marchetti M, Ruutu T, Aljurf M, Bacigalupo A, Bonifazi F, et al. "Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation". Lancet Haematol 7(2020):e157-e167.
Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, et al. "Activity of therapeutic JAK1/2 blockade in graft-versus-host disease". Blood 123(2014):3832-3842.
Choi J, Cooper ML, Alahmari B, Ritchey J, Collins L, Holt M, et al. "Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect". PLoS One 9(2014):e109799.
Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, et al. "Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease". N Engl J Med 385(2021):228-238.
Zeiser R, Russo D, Ram R, Hashmi SK, Chakraverty R, Middeke JM, et al. "Ruxolitinib in patients with corticosteroid-refractory or corticosteroid-dependent chronic graft-versus-host disease: 3-year final analysis of the phase III REACH3 study". J Clin Oncol 43(2025):2566-2571.
Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, et al. "Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease". N Engl J Med 382(2020):1800-1810.
Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, et al. "Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial". Blood 135(2020):1739-1749.
Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et al. "Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey". Leukemia 29(2015):2062-2068.
Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. "Ibrutinib for chronic graft-versus-host disease after failure of prior therapy". Blood 130(2017):2243-2250.
Rager A, Frey N, Goldstein SC, Reshef R, Hexner EO, Loren A, et al. "Inflammatory cytokine inhibition with combination daclizumab and infliximab for steroid-refractory acute GVHD". Bone Marrow Transplant 46(2011):430-435.
Modi B, Hernandez-Henderson M, Yang D, Klein J, Dadwal S, Kopp E, et al. "Ruxolitinib as salvage therapy for chronic graft-versus-host disease". Biol Blood Marrow Transplant 25(2019):265-269.
Flowers MED, Apperley JF, van Besien K, Elmaagacli A, Grigg A, Reddy V, et al. "A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease". Blood 112(2008):2667-2674.
Miklos D, Zaid MA, Cooney JP, Albring JC, Flowers M, Skarbnik AP, et al. "Ibrutinib for first-line treatment of chronic graft-versus-host disease: results from the randomized phase III iNTEGRATE study". J Clin Oncol 41(2023):1876-1887.
Martin PJ, Storer BE, Rowley SD, Flowers MED, Lee SJ, Carpenter PA, et al. "Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease". Blood 113(2009):5074-5082.
Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S, et al. "Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium". Blood 117(2011):4651-4657.
Fiuza-Luces C, Simpson RJ, Ramirez M, Lucia A, Berger NA. "Physical function and quality of life in patients with chronic graft-versus-host disease: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients". Bone Marrow Transplant 51(2016):13-26.
Carpenter PA, Kitko CL, Elad S, Flowers MED, Gea-Banacloche JC, Halter JP, et al. "National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. The 2014 ancillary therapy and supportive care working group report". Biol Blood Marrow Transplant 21(2015):1167-1187.
Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, et al. "Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study". Blood 138(2021):2278-2289.
Lee SJ, Nguyen TD, Onstad L, Bar M, Krakow EF, Salit RB, et al. "Success of immunosuppressive treatments in patients with chronic graft-versus-host disease". Biol Blood Marrow Transplant 24(2018):555-562.
Inamoto Y, Flowers MED, Sandmaier BM, Aki SZ, Carpenter PA, Lee SJ, et al. "Failure-free survival after initial systemic treatment of chronic graft-versus-host disease". Blood 124(2014):1363-1371.
Palmer J, Chai X, Pidala J, Inamoto Y, Martin PJ, Storer B, et al. "Predictors of survival, nonrelapse mortality, and failure-free survival in patients treated for chronic graft-versus-host disease". Blood 127(2016):160-166.
Socie G, Ritz J. "Current issues in chronic graft-versus-host disease". Blood 124(2014):374-384.
Jamil MO, Mineishi S. "State-of-the-art acute and chronic GVHD treatment". Int J Hematol 101(2015):452-466.
Sarantopoulos S, Cardones AR, Sullivan KM. "How I treat refractory chronic graft-versus-host disease". Blood 133(2019):1191-1200.
Wolff D, Radojcic V, Lafyatis R, Cinar R, Rosenstein RK, Cowen EW, et al. "National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2020 highly morbid forms report". Transplant Cell Ther 27(2021):817-835.
