0
selected
-
1.
Randomized phase II trial of extracorporeal phototherapy and steroids vs. steroids alone for newly diagnosed acute GVHD
Mehta, R. S., Bassett, R., Rondon, G., Overman, B. J., Popat, U. R., Hosing, C. M., Rezvani, K., Qazilbash, M. H., Anderlini, P., Jones, R. B., et al
Bone marrow transplantation. 2021
-
-
-
Full text
-
Editor's Choice
Abstract
Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1?mg/kg at day 28 and <0.5?mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n?=?51) or steroids alone (n?=?30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
PICO Summary
Population
Patients with newly-diagnosed acute graft-versus-host disease (AGVHD, n=81)
Intervention
Prednisone with extracorporeal photopheresis (ECP, n=51)
Comparison
Prednisone alone (n=30)
Outcome
The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively).
-
2.
Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft-Versus-Host Disease
Mehta, R. S., Saliba, R. M., Jan, A., Shigle, T. L., Wang, E., Nieto, Y., Ciurea, S. O., Oran, B., Im, J., Olson, A., et al
Transplantation and cellular therapy. 2021;27(3):272.e1-272.e5
Abstract
Steroid-refractory (SR) lower gastrointestinal (LGI) acute graft-versus-host disease (aGVHD) has poor prognosis, and novel drugs are needed. We describe outcomes of patients with SR-LGI aGVHD treated with vedolizumab. The primary objective was to determine overall response rate (ORR) at days 14, 28, and 56. Secondary outcomes included overall survival (OS), non-relapse mortality and toxicities. Twenty patients, median age 46 years (range, 23-71), were included. All but 2 patients (90%) had grade 3 to 4 aGVHD (45% stage 4, 40% stage 3 LGI). Median time to vedolizumab was 21 days (range, 5-1031) and 13 days (range, 0-533) after diagnosis of LGI aGVHD and SR-LGI aGVHD, respectively. It was given as =3rd line (median 3; range 2-6) in 75% after failure of steroids, and additional treatments including ruxolitinib (n = 12) and others. Median follow-up was 17 months (range, 10-34). The days 14, 28 and 56 ORRs were 45% (9/20; complete response [CR] 25%), 35% (7/20; CR 20%), and 25% (5/20; CR 20%), respectively. Among ruxolitinib failures, it was 50% (6/12; CR 25%), 50% (6/12; CR 25%) and 25% (3/12; CR 16.7%), respectively. Fifteen patients died (14 GVHD, 1 leukemia relapse). The actuarial 6-month OS was 35% (95% confidence interval 16-55). No progressive multifocal leukoencephalopathy or infusion reaction occurred. Forty-four infection events (22 viral, 18 bacterial, and 4 fungal) were noted in 16 patients. Vedolizumab was well tolerated and demonstrated potential efficacy even after ruxolitinib failure for SR-LGI aGVHD. Yet the responses were suboptimal, and its use requires further investigation.
-
3.
A Phase 3 randomized study of Remestemcel-L versus placebo added to second line therapy in patients with steroid refractory acute graft versus host disease
Kebriaei, P., Hayes, J., Daly, A., Uberti, J., Marks, D. I., Soiffer, R., Waller, E. K., Burke, E., Skerrett, D., Shpall, E., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
-
-
-
Free full text
-
Editor's Choice
Abstract
BACKGROUND Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSC) may be effective against acute graft-versus-host disease (aGvHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid refractory aGvHD (NCT00366145). METHODS Two-hundred sixty patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009, and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at Day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGvHD symptoms for any period of at least 28 days after beginning treatment. FINDINGS Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% vs. 30%; p=0.42). In post-hoc analyses patients with liver involvement who received at least one infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% vs. 5%; p=0.047). Furthermore, pediatric patients had a higher OR with MSC compared with placebo (64% vs. 23%; p=0.05). Similar rates of adverse events were observed between treatment groups. INTERPRETATION Remestemcel-L was safe and well-tolerated. Results of this study did not demonstrate superior DCR compared to placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation.
PICO Summary
Population
Patients with steroid-refractory GvHD (n=260)
Intervention
Ex vivo cultured adult human mesenchymal stromal cells (remestemcel-L), alongside second-line therapy (n=173)
Comparison
Placebo, alongside second-line therapy (n=87)
Outcome
Remestemcel-L did not meet the primary endpoint of greater durable complete response (DCR) in the intent-to-treat population (35% vs. 30%). In post-hoc analyses patients with liver involvement who received at least one infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% vs. 5%). Furthermore, pediatric patients had a higher OR with MSC compared with placebo (64% vs. 23%). Similar rates of adverse events were observed between treatment groups.
-
4.
Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit
Ragon, B. K., Mehta, R. S., Gulbis, A. M., Saliba, R. M., Chen, J., Rondon, G., Popat, U. R., Nieto, Y., Oran, B., Olson, A. L., et al
Bone marrow transplantation. 2018;53(3):315-325
-
-
-
Free full text
-
Full text
Abstract
We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD-22% had stage 3-4 liver GVHD and 51% had stage 3-4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1-9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61-84%) and overall survival (OS) was 21% (95% CI 12-32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01-3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5-3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2-0.8, p = 0.01). On stratified analysis, patients <60 years with isolated LGI GVHD had the best outcomes with an ORR of 48% and OS of 42% at 18 months. Among older patients, OS was 14% in those with isolated LGI aGVHD and 0% in others. Pentostatin remains a viable treatment option for SR-aGVHD, especially in patients 60 years or younger with isolated LGI involvement.
Clinical Commentary
What is known?
NIHMS1717745
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
-
5.
Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis
Hashmi, S., Ahmed, M., Murad, M. H., Litzow, M. R., Adams, R. H., Ball, L. M., Prasad, V. K., Kebriaei, P., Ringden, O.
The Lancet Haematology. 2016;3(1):e45-52
Abstract
BACKGROUND Graft-versus-host disease (GVHD) is the major limitation of allogeneic haemopoietic stem-cell transplantation (HSCT), for which no approved treatments are available. Use of mesenchymal stromal cells (MSCs) has become standard practice in some European countries, but controversy exists for their benefit. The aim of this meta-analysis was to analyse available evidence for the benefit of MSC treatments in steroid-resistant acute GVHD. METHODS We did a systematic review and meta-analysis to assess response to and survival after MSC treatment in patients with steroid-refractory acute GVHD. We searched MEDLINE, Embase, Ovid, and Cochrane Central databases for published studies, and we used ClinicalTrials.gov and other websites to find unpublished studies and conference abstracts. We included prospective and retrospective studies in which MSCs were administered to patients with steroid-refractory acute GVHD. Data were extracted independently by two investigators based on strict selection criteria. A random-effects model was used to pool outcomes across studies because of anticipated heterogeneity. Our primary outcome was survival at 6 months from the first infusion of MSCs. FINDINGS We identified 628 citations with our search, of which 610 were excluded after review and a further five did not contain pertinent data. Thus, our meta-analysis included 13 non-randomised studies at moderate risk of bias, comprising a total of 336 patients. Six studies provided data for the primary outcome analysis (119 patients). Survival at 6 months after MSC treatment was 63% (95% CI 50-74; I(2)=41%). Survival did not differ with respect to age, MSC culture medium, or dose of MSCs delivered. INTERPRETATION Available evidence suggests that infusion of MSCs could be an acceptable treatment for patients with steroid-refractory acute GVHD. Randomised clinical trials are needed urgently to assess different treatment modalities for steroid-refractory acute GVHD. FUNDING None. Copyright © 2016 Elsevier Ltd. All rights reserved.