1.
Ruxolitinib resistance or intolerance in steroid-refractory acute graft-versus-host disease - a real-world outcomes analysis
Abedin, S., Rashid, N., Schroeder, M., Romee, R., Nauffal, M., Alhaj Moustafa, M., Kharfan-Dabaja, M. A., Palmer, J., Hogan, W., Hefazi, M., et al
British journal of haematology. 2021
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Abstract
Ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) results in resistance or intolerance in 1/5 of patients. Outcomes of such patients are undefined. We identified these patients in a multicentre review and reported outcomes. Ruxolitinib-resistant aGVHD was identified in 48/307 patients. Among patients receiving additional therapy, the overall response rate to next therapy was 36%. Median survival was 21 days. Ruxolitinib intolerance led to treatment discontinuation in 16/307 patients. Ten intolerant patients received additional therapy with 50% experiencing continued improvement of aGVHD. Median survival was 50 days in these patients. These data serve as a baseline for future SR-aGVHD studies.
2.
Efficacy, toxicity and infectious Complications in Ruxolitinib Treated Patients with Corticosteroid-refractory Graft-versus-host Disease after Hematopoietic Cell Transplantation
Abedin, S., McKenna, E., Chhabra, S., Pasquini, M., Shah, N. N., Jerkins, J., Baim, A., Runaas, L., Longo, W., Drobyski, W., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Corticosteroid-refractory GVHD (SR-GVHD) remains a significant source of morbidity after allogeneic hematopoietic cell transplantation (HCT). No standard therapy exists in this setting, however recent studies have demonstrated a very promising role for ruxolitinib, an oral Janus Kinase (JAK) 1/2 inhibitor. With increasing evidence of efficacy for SR-GVHD, limited data exists describing complications of ruxolitinib use, and specifically infectious complications during use in SR-GVHD. In this study, we report outcomes and infectious complications at our institution with ruxolitinib use. Overall, 43 patients were treated with ruxolitinib for SR-GVHD, 19 for acute SR-GVHD, and 24 for chronic SR-GVHD. With respect to acute SR-GVHD, fifteen patients had Grade 3 acute GVHD, and 4 patients had Grade 4 acute GVHD. At 28 days, a response rate of 84% was detected. With respect to chronic SR-GVHD, 16 patients had moderate refractory disease, and 8 had severe refractory disease. At around 28 days, a 63% response rate was detected. Overall, 42% (n=18) of patients treated with ruxolitinib had a documented infectious event. Infectious events were significantly more common among patients treated for acute SR-GVHD (p<0.005). Among patients treated for acute SR-GVHD, both viral (n=11) and bacterial (n=10) events were frequently encountered. CMV reactivation was detected in 4 patients without organ involvement in any patient. Bacteremia was the most common bacterial event (n=8), and two patients died after development of bacteremia. Only 5 of 24 patients treated with ruxolitinib for chronic SR-GVHD developed infectious complications after initiation of therapy. Nearly an even number of viral (n=3) and bacterial (n=4) were detected. This study supports the use of ruxolitinib in SR-GVHD, with impressive responses observed in both acute and chronic SR-GVHD. Infectious complications were particularly frequent among patients treated for acute SR-GVHD, nearly all of these patients were concurrently on high dose steroids while on ruxolitinib. This study suggests careful monitoring for viral reactivation is required for patients initiated on ruxolitinib, supports the role of continuing prophylactic antimicrobial measures in ruxolitinib treated GVHD patients, and raises the question of whether bacterial prophylaxis should be considered among patients initiated on ruxolitinib for acute SR-GVHD, particularly while on high dose steroids.
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Randomized Multicenter Trial of Sirolimus vs. Prednisone as Initial Therapy for Standard Risk Acute GVHD: BMT CTN 1501
Pidala, J., Hamadani, M., Dawson, P., Martens, M., Alousi, A. M., Jagasia, M., Efebera, Y. A., Chhabra, S., Pusic, I., Holtan, S. G., et al
Blood. 2019
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Editor's Choice
Abstract
Clinical- and biomarker-based tools may identify a lower risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted an NHLBI/NCI-funded Blood and Marrow Transplant Clinical Trials Network (CTN) multi-center, open label, randomized phase II trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs. prednisone as initial treatment for patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA 1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus n=58, prednisone n=64). Others were AA3 (n=4), or AA status missing (n=1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% CI 54.1%-75.5%) vs. 73% (90% CI 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone {less than or equal to} 0.25mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs. 31.7%, p < 0.001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, non-relapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2-3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based standard risk acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. Additionally, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life.
PICO Summary
Population
Patients with standard risk (SR) acute GVHD (n=127)
Intervention
Sirolimus initial treatment (n=58)
Comparison
Prednisone initial treatment (n=64)
Outcome
The day 28 CR/PR rates were similar for sirolimus 64.8% vs. 73% for prednisone. The day 28 rate of CR/PR with prednisone {less than or equal to} 0.25mg/kg/day was significantly higher for sirolimus than prednisone No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, non-relapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2-3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy.