scholarly journals Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease

2017 ◽  
Vol 1 (22) ◽  
pp. 1919-1922 ◽  
Author(s):  
Zachariah DeFilipp ◽  
Rosalynn M. Nazarian ◽  
Areej El-Jawahri ◽  
Shuli Li ◽  
Jami Brown ◽  
...  
Keyword(s):  
Adverse Events ◽  
Graft Versus Host Disease ◽  
Phase 1 ◽  
Hedgehog Pathway ◽  
Phase 1 Study ◽  
Graft Versus Host ◽  
Key Points ◽  
Clinical Responses ◽  
Hedgehog Pathway Inhibitor ◽  
Steroid Refractory

Key Points Physician-assessed clinical responses and immunohistochemical changes were seen in association with sonidegib therapy for cGVHD. Sonidegib therapy was limited by ongoing cGVHD symptoms and adverse events not attributed to treatment.

scholarly journals Phase 1 multicenter trial of brentuximab vedotin for steroid-refractory acute graft-versus-host disease

Blood ◽  
2017 ◽  
Vol 129 (24) ◽  
pp. 3256-3261 ◽  
Author(s):  
Yi-Bin Chen ◽  
Miguel-Angel Perales ◽  
Shuli Li ◽  
Maria Kempner ◽  
Carol Reynolds ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Phase 1 ◽  
Multicenter Trial ◽  
Brentuximab Vedotin ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points ◽  
Steroid Refractory ◽  
Acute Graft

Key Points BV has activity for SR-aGVHD. The MTD of BV was 0.8 mg/kg every 2 weeks for 4 doses.

scholarly journals Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease

Blood ◽  
2018 ◽  
Vol 131 (25) ◽  
pp. 2836-2845 ◽  
Author(s):  
Myrna R. Nahas ◽  
Robert J. Soiffer ◽  
Haesook T. Kim ◽  
Edwin P. Alyea ◽  
Jon Arnason ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Graft Versus Host Disease ◽  
Therapeutic Approach ◽  
Phase 1 ◽  
Phase 1 Clinical Trial ◽  
Graft Versus Host ◽  
Costimulatory Blockade ◽  
Key Points ◽  
Novel Therapeutic ◽  
Steroid Refractory

Key Points Costimulatory blockade using abatacept represents a novel therapeutic approach for the treatment of cGVHD. Abatacept resulted in a clinical response in 44% of patients with both decreased prednisone use and T-cell PD-1 expression in responders.

Mesenchymal stromal cell therapy for steroid-refractory acute and chronic graft versus host disease: a phase 1 study

2011 ◽  
Vol 95 (2) ◽  
pp. 182-188 ◽  
Author(s):  
Richard Herrmann ◽  
Marian Sturm ◽  
Kathryn Shaw ◽  
Duncan Purtill ◽  
Julian Cooney ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Graft Versus Host Disease ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

scholarly journals Ruxolutinib in Steroid Refractory Graft Versus Host Disease (SR-GVHD): Systemic Literature Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5682-5682
Author(s):  
Mostafa F. Mohammed Saleh ◽  
Shahrukh K. Hashmi
Keyword(s):  
Adverse Events ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Systemic Review ◽  
Close Monitoring ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

Background: Graft versus host disease (GVHD) is a main cause of morbidity and mortality in patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT). About 30-40% of patients have steroid‐refractory GVHD (SR‐GVHD) after the first‐line use of high doses of corticosteroids with a poor prognosis .Ruxolitinib is a promising treatment for SR-GVHD. However, data regarding optimum dosing, response rates and associated adverse events are scarce. Herein, we provide the first systemic review of literature for the use ruxolutinib in GVHD. Methods: A Medline (PubMed), google scholar, OVID and Cochrane Database of Systematic Reviews search using key words "Ruxolutinib and GVHD", "Ruxolutinib and SR-GVHD" was undertaken in June 2019. Only peer reviewed databases were searched and search was restricted to human studies of acute and chronic GVHD only. Results: 16 publications, as listed in Table 1. Only one was a prospective trial, all others were retrospective studies, case series (5), and case reports (2). Overall response, ranged 45% - 100%, complete response was noted in 5.2% -80% patients. Time to response was variable from 1-12 weeks. Cytopenias and infectious complications were frequently reported with dose reduction or interruptions needed in most studies. Maintained responses were reported in a small proportion after ruxolutinib discontinuation. Conclusion Ruxolutinib has promising efficacy in SR-GVHD , however cytopenias and infectious complications reported frequently mandate close monitoring. Results of ongoing prospective trials could provide answers for optimum dosing and response assessment, and management of related adverse events. Table Disclosures No relevant conflicts of interest to declare.

Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 1224-1226 ◽  
Author(s):  
Vincent T. Ho ◽  
David Zahrieh ◽  
Ephraim Hochberg ◽  
Eileen Micale ◽  
Jesse Levin ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Phase 1 ◽  
Interleukin 2 ◽  
Maximum Tolerated Dose ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Denileukin Diftitox ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 μg/kg intravenously on days 1 and 15; 18 received 9 μg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 μg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD. (Blood. 2004;104:1224-1226)

scholarly journals Treatment of chronic graft-versus-host disease with bortezomib

Blood ◽  
2014 ◽  
Vol 124 (10) ◽  
pp. 1677-1688 ◽  
Author(s):  
Chien-Chun Steven Pai ◽  
Mingyi Chen ◽  
Annie Mirsoian ◽  
Steven K. Grossenbacher ◽  
Joseph Tellez ◽  
...  
Keyword(s):  
B Cells ◽  
Graft Versus Host Disease ◽  
Germinal Center ◽  
Murine Models ◽  
Host Disease ◽  
Graft Versus Host ◽  
Therapeutic Benefits ◽  
Key Points ◽  
Steroid Refractory ◽  
Germinal Center B Cells

Key Points Bortezomib ameliorates sclerodermatous cGVHD responses by inhibiting germinal center B cells while maintaining GVT effects in murine models. Bortezomib provides therapeutic benefits for patients with active steroid-refractory cGVHD.

scholarly journals Comparative Effectiveness of Remestemcel-L-rknd versus Ruxolitinib in Pediatric Patients with Steroid-Refractory Acute Graft-Versus-Host Disease using Simulated Treatment Comparisons

2021 ◽  
Vol 8 (1) ◽  
pp. 10-17
Author(s):  
Gabriel Tremblay ◽  
Dimitrios Tomaras ◽  
Eric Strati ◽  
Anna Forsythe
Keyword(s):  
Adverse Events ◽  
Graft Versus Host Disease ◽  
Pediatric Patients ◽  
Inadequate Response ◽  
Host Disease ◽  
Graft Versus Host ◽  
Treatment Comparison ◽  
Grade Iii ◽  
Steroid Refractory ◽  
Acute Graft

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a lifesaving treatment for hematologic malignancies, but acute graft-versus-host-disease (aGVHD) is a potentially deadly adverse effect experienced by up to half of allo-HSCT recipients. Inadequate response to steroid therapy for aGVHD is associated with poor prognosis and high mortality, including among pediatric patients, who are the focus of this study. Ruxolitinib and remestemcel-L-rknd were evaluated for the treatment of steroid-refractory (SR) aGVHD in two separate single-arm trials. To effectively compare the safety and efficacy of these treatments without a head-to-head trial, a simulated treatment comparison (STC) was conducted. Methods: Regression techniques were used to adjust individual patient-level data from the remestemcel-L-rknd trial to mutually reported baseline characteristics from the ruxolitinib trial. Outcomes of interest included a 28-day overall response rate (ORR), a 28-day ORR in the grade III-IV aGVHD population, and adverse events (AEs). Results: In the full populations, the STC of risk ratios (RRs) found treatment with remestemcel-L-rknd to be associated with a numerical but not statistically significant improvement in the 28-day ORR versus ruxolitinib. In the grade III-IV aGVHD sub-group, the STC showed significantly improved 28-day ORR for remestemcel-L-rknd versus ruxolitinib (P=0.04). Remestemcel-L-rknd was also associated with improved safety outcomes (P<0.05) in 17 out of 30 AEs, including hematologic events, peripheral edema, muscular weakness, nausea, back pain, and fatigue. Conclusion: Remestemcel-L-rknd was associated with significant improvements in day 28 ORR compared with ruxolitinib in patients with severe (grade III-IV) SR aGVHD. Across all grades of SR aGVHD, remestemcel-L-rknd was associated with fewer all-grade treatment-emergent adverse events (TEAEs) (27/30) available for comparison, including the majority reaching statistical significance.

scholarly journals A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease

2020 ◽  
Vol 4 (8) ◽  
pp. 1656-1669 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Phase 1 ◽  
Janus Kinase ◽  
Open Label ◽  
Major Barrier ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation (HCT) is a primary cause of nonrelapse mortality and a major barrier to successful transplant outcomes. Itacitinib is a Janus kinase (JAK)1–selective inhibitor that has demonstrated efficacy in preclinical models of aGVHD. We report results from the first registered study of a JAK inhibitor in patients with aGVHD. This was an open-label phase 1 study enrolling patients aged ≥18 years with first HCT from any source who developed grade IIB to IVD aGVHD. Patients with steroid-naive or steroid-refractory aGVHD were randomized 1:1 to itacitinib 200 mg or 300 mg once daily plus corticosteroids. The primary endpoint was safety and tolerability; day 28 overall response rate (ORR) was the main secondary endpoint. Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting toxicity was reported (grade 3 thrombocytopenia attributed to GVHD progression in a patient receiving 300 mg itacitinib with preexisting thrombocytopenia). The most common nonhematologic treatment-emergent adverse event was diarrhea (48.3%, n = 14); anemia occurred in 11 patients (38%). ORR on day 28 for all patients in the 200-mg and 300-mg groups was 78.6% and 66.7%, respectively. Day 28 ORR was 75.0% for patients with treatment-naive aGVHD and 70.6% in those with steroid-refractory aGVHD. All patients receiving itacitinib decreased corticosteroid use over time. In summary, itacitinib was well tolerated and demonstrated encouraging efficacy in patients with steroid-naive or steroid-refractory aGVHD, warranting continued clinical investigations. This trial was registered at www.clinicaltrials.gov as #NCT02614612.

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