Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease
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Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. / Zeiser, Robert; von Bubnoff, Nikolas; Butler, Jason; Mohty, Mohamad; Niederwieser, Dietger; Or, Reuven; Szer, Jeff; Wagner, Eva M; Zuckerman, Tsila; Mahuzier, Bruyère; Xu, Judith; Wilke, Celine; Gandhi, Kunal K; Socié, Gérard; REACH2 Trial Group.
In: NEW ENGL J MED, Vol. 382, No. 19, 07.05.2020, p. 1800-1810.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease
AU - Zeiser, Robert
AU - von Bubnoff, Nikolas
AU - Butler, Jason
AU - Mohty, Mohamad
AU - Niederwieser, Dietger
AU - Or, Reuven
AU - Szer, Jeff
AU - Wagner, Eva M
AU - Zuckerman, Tsila
AU - Mahuzier, Bruyère
AU - Xu, Judith
AU - Wilke, Celine
AU - Gandhi, Kunal K
AU - Socié, Gérard
AU - REACH2 Trial Group
AU - Kroger, Nicolaus
N1 - Copyright © 2020 Massachusetts Medical Society.
PY - 2020/5/7
Y1 - 2020/5/7
N2 - BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]).CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.).
AB - BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]).CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.).
KW - Acute Disease
KW - Adolescent
KW - Adult
KW - Aged
KW - Child
KW - Female
KW - Glucocorticoids/therapeutic use
KW - Graft vs Host Disease/drug therapy
KW - Humans
KW - Janus Kinase Inhibitors/adverse effects
KW - Male
KW - Middle Aged
KW - Pyrazoles/adverse effects
KW - Stem Cell Transplantation/adverse effects
KW - Thrombocytopenia/chemically induced
KW - Transplantation, Homologous
KW - Young Adult
U2 - 10.1056/NEJMoa1917635
DO - 10.1056/NEJMoa1917635
M3 - SCORING: Journal article
C2 - 32320566
VL - 382
SP - 1800
EP - 1810
JO - NEW ENGL J MED
JF - NEW ENGL J MED
SN - 0028-4793
IS - 19
ER -