Ruxolitinib for treatment of steroid-refractory graft-versus-host disease in adults: a systematic review and meta-analysis
Expert review of hematology. 2020
Objectives: Authors assessed the impact of ruxolitinib (RUX) on steroid-refractory graft-versus-host disease (SR-GVHD) patients.Methods: Studies published before January 2019 were identified by electronic search of MEDLINE, EMBASE, Cochrane Library, Clinical Trials.Gov and Web of Science databases.Results: Sixteen cohort studies (414 adults) were included whose methodological quality ranged from poor to good. Pooled outcomes such as the response rates, steroid dose reduction, 1-year overall survival, overall infection, and grade 3 to 4 cytopenia were calculated separately for adults with steroid-refractory acute GVHD (aGVHD) and chronic GVHD (cGVHD). Further, the overall response rates were analyzed according to the affected organ. Adults with aGVHD as well as cGVHD showed high response with RUX, and steroid dose reduction was observed in both cases. Infection rates and cytopenia were important safety concerns for both aGVHD and cGVHD.Conclusion: Notwithstanding the need of randomized controlled trials to confirm the effect of RUX on SR-GVHD, response rates among adults with aGVHD and cGVHD seem to be high with use of RUX as a salvage treatment, particularly in cases with gastrointestinal and cutaneous involvement. However, high rates of myelosuppression and infection remain a cause for concern regardless of aGVHD or cGVHD.
Topical Corticosteroids a Viable Solution for Oral Graft Versus Host Disease? A Systematic Insight on Randomized Clinical Trials
Medicina (Kaunas, Lithuania). 2020;56(7)
Background and Objectives: This research attempts to provide a clear view of the literature on randomized clinical trials (RCTs) concerning the efficacy of topical dexamethasone, clobetasol and budesonide in oral graft versus host disease (GVHD). Materials and Methods: An electronic search of the PubMed, Web of Science and Scopus databases was carried out for eligible RCTs. Studies were included if they had adult patients with oral GVHD treatment with topical corticosteroids, and if the RCT study was published in English. The Cochrane Risk of Bias tool was used to assess the quality of these studies. Overall, three RCTs were included (an Open, Randomized, Multicenter Trial; a Randomized Double-Blind Clinical Trial; and an Open-Label Phase II Randomized Trial). Results: The trials involved 76 patients, of which 44 patients received topical dexamethasone, 14 patients received topical clobetasol and 18 patients received topical budesonide. Topical agents were most frequently used when oral tissues were the sole site of involvement. It appears that the best overall response is present for budesonide with no difference between the four arms, followed by clobetasol, and then by dexamethasone. The limitation of the current study is mainly represented by the fact that overall response was derived in two of the studies from other parameters. Moreover, both budesonide and clobetasol were used in only one study each, while two assessed dexamethasone. Conclusions: Based on the clinical trials, all three agents seem to be effective in treating oral GVHD and had a satisfactory safety profile. There is still a need for assessing high quality RCTs to assess the efficacy of these therapies on a larger cohort.
Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease-a meta-analysis
Stem cell research & therapy. 2020;11(1):64
BACKGROUND Graft-versus-host disease (GvHD) is the main life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty to 80% of GvHD patients do not respond to first-line treatment and a second-line treatment is not universally established. Based on their immunomodulatory properties, mesenchymal stromal cells (MSC) have been proposed for the prevention and the treatment of GvHD in patients undergoing HSCT. Unfortunately, previous studies reported conflicting results regarding the prophylactic and therapeutic effects of MSC for GvHD. Consequently, we carried out a meta-analysis to clarify whether MSC administration can improve the dismal outcome of these patients. METHODS We carried out a systematic review and selected studies (2004-2019) reporting data about the administration of allogeneic MSC for the prevention (n = 654 patients) or treatment of acute (n = 943 patients) or chronic (n = 76 patients) GvHD after HSCT. Our primary outcome was overall survival at the last follow-up. The secondary outcomes were the response and development of GvHD. Subgroup analyses included age, MSC dose, first infusion day after HSCT, number of organs and organ-specific involvement, acute GvHD grade (I-IV), and chronic GvHD grade (limited or extensive). RESULTS Patients infused with MSC for GvHD prophylaxis showed a 17% increased overall survival (95% CI, 1.02-1.33) and a reduced incidence of acute GvHD grade IV (RR = 0.22; 95% CI, 0.06-0.81) and chronic GvHD (RR = 0.64; 95% CI, 0.47-0.88) compared with controls. Overall survival of acute GvHD patients (0.50; 95% CI, 0.41-0.59) was positively correlated with MSC dose (P = 0.0214). The overall response was achieved in 67% (95% CI, 0.61-0.74) and was complete in 39% (95% CI, 0.31-0.48) of acute patients. Organ-specific response was higher for the skin. Twenty-two percent (95% CI, 0.16-0.29) of acute patients infused with MSC developed chronic GvHD. Sixty-four percent (95% CI, 0.47-0.80) of chronic patients infused with MSC survived; the overall response was 66% (95% CI, 0.55-0.76) and was complete in 23% (95% CI 0.12-0.34) of patients. CONCLUSIONS Our meta-analysis indicates that allogeneic MSC could be instrumental for the prophylaxis and treatment of GvHD. Future trials should investigate the effect of the administration of MSC as an adjuvant therapy for the treatment of patients with GvHD from the onset of the disease.
The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease
Stem cell research & therapy. 2019;10(1):182
BACKGROUND The use and effectiveness of hematopoietic stem cell transplantation (HSCT) are limited by lethal complications, i.e., acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively), in which immune cells from the donor attack healthy recipient tissues. GVHD presents both prophylactic and therapeutic challenges, and overall survival is poor. Mesenchymal stem cells (MSCs) show considerable promise in the treatment of GVHD because of their potential immunomodulatory activity. Multiple studies have been performed to explore the possible benefit of MSCs in GVHD, but the results of these studies are sometimes conflicting. Therefore, we performed a systematic review and meta-analysis to estimate the effect of MSC infusion on GVHD treatment and prevention. METHODS We systematically searched the MEDLINE (PubMed), Cochrane Library, EMBASE, ClinicalTrials.gov, and SinoMed CBM databases to identify studies published before February 2018 involving patients with hematologic malignancies undergoing HSCT and receiving MSC-based or conventional therapy. We included studies if they reported on the outcomes of interest. RESULTS Ultimately, 10 studies were selected from among 413 candidates. According to our meta-analyses, compared with conventional treatment, MSC therapy demonstrated substantial improvements in terms of complete response (CR) and overall survival for cGVHD. However, MSC therapy did not show substantial improvements in terms of engraftment, the incidence of aGVHD, relapse, death, death due to relapse, or death due to infection. Subgroup analyses showed that MSCs derived from the umbilical cord (U-MSCs) and MSC infusion after HSCT substantially improved engraftment and cGVHD incidence, whereas MSCs derived from bone marrow (B-MSCs) and MSC infusion before HSCT shows no improvement. In addition, B-MSCs and MSC infusion before HSCT tend to prolong engraftment time, as well as increase the rates of relapse and death. CONCLUSIONS MSC infusion can reduce cGVHD but not aGVHD incidence and showed a positive effect in patients who already had aGVHD. For GVHD prevention, the use of U-MSCs and MSC infusion after HSCT were optimal for reducing cGVHD incidence and promoting engraftment, and might help decrease the incidence rate of relapse and death. However, B-MSCs and MSC infusion before HSCT may be harmful to patients and thus require serious consideration. A lack of robust evidence, owing to the small number of studies and small sample sizes, indicates a need for further high-quality clinical trials including large numbers of patients to validate our findings.
Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition
The Cochrane database of systematic reviews. 2019;1:Cd009768
BACKGROUND Recipients of allogeneic haematopoietic stem cell transplants (HSCT) can develop acute or chronic, or both forms of graft-versus-host disease (a/cGvHD), whereby immune cells of the donor attack host tissues. Steroids are the primary treatment, but patients with severe, refractory disease have limited options and a poor prognosis. Mesenchymal stromal cells (MSCs) exhibit immunosuppressive properties and are being tested in clinical trials for their safety and efficacy in treating many immune-mediated disorders. GvHD is one of the first areas in which MSCs were clinically applied, and it is important that the accumulating evidence is systematically reviewed to assess whether their use is favoured. OBJECTIVES To determine the evidence for the safety and efficacy of MSCs for treating immune-mediated inflammation post-transplantation of haematopoietic stem cells. SEARCH METHODS We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2018, Issue 12), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (from 1990) and ongoing trial databases to 6 December 2018. No constraints were placed on language or publication status. SELECTION CRITERIA We included RCTs of participants with a haematological condition who have undergone an HSCT as treatment for their condition and were randomised to MSCs (intervention arm) or no MSCs (comparator arm), to prevent or treat GvHD. We also included RCTs which compared different doses of MSCs or MSCs of different sources (e.g. bone marrow versus cord). We included MSCs co-transplanted with haematopoietic stem cells as well as MSCs administered post-transplantation of haematopoietic stem cells. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane.We employed a random-effects model for all analyses due to expected clinical heterogeneity arising from differences in participant characteristics and interventions. MAIN RESULTS We identified 12 completed RCTs (879 participants), and 13 ongoing trials (1532 enrolled participants planned). Of 12 completed trials, 10 compared MSCs versus no MSCs and two compared different doses of MSCs. One trial was in people with thalassaemia major, the remaining trials were for haematological malignancies. Seven trials administered MSCs to prevent GvHD, whereas five trials gave MSCs to treat GvHD.In the comparison of MSCs with no MSCs, cells were administered at a dose of between 10(5) and 10(7) cells/kg in either a single dose (six trials) or in multiple doses (four trials) over a period of three days to four months. The dose-comparison trials compared 2 x 10(6) cells/kg with 8 x 10(6) cells/kg in two infusions, or 1 x 10(6) cells/kg with 3 x 10(6) cells/kg in a single infusion.The median duration of follow-up in seven trials which administered MSCs prophylactically ranged from 10 to 60 months. In three trials of MSCs as treatment for aGvHD, participants were followed up for 90 or 100 days. In two trials of MSCs as treatment for cGvHD, the mean duration of follow-up was 13.4 months (MSC group) and 23.6 months (control group) in one trial, and 56 weeks in the second trial. Five trials included adults only, six trials included adults and children, and one trial included children only. In eight trials which reported the gender distribution, the percentage of females ranged from 20% to 59% (median 35.8%).The overall quality of the included studies was low: randomisation methods were poorly reported and several of the included studies were subject to a high risk of performance bias and reporting bias. One trial which started in 2008 has not been published and the progress of this trial in unknown, leading to potential publication bias. The quality of evidence was therefore low or very low for all outcomes due to a high risk of bias as well as imprecision due to the low number of overall participants, and in some cases evidence based on a single study. We found that MSCs may make little or no difference in the risk of all-cause mortality in either prophylactic trials (HR 0.85, 95% CI 0.50 to 1.42; participants = 301; studies = 5; I(2) = 34% ; low-quality evidence) or therapeutic trials (HR 1.12, 95% CI 0.80 to 1.56; participants = 244; studies = 1; very low-quality evidence), and no difference in the risk of relapse of malignant disease (prophylactic trials: RR 1.08, 95% CI 0.73 to 1.59; participants = 323; studies = 6; I(2) = 0%; low-quality evidence) compared with no MSCs. MSCs were well-tolerated, no infusion-related toxicity or ectopic tissue formation was reported. No study reported health-related quality of life. In prophylactic trials, MSCs may reduce the risk of chronic GvHD (RR 0.66, 95% CI 0.49 to 0.89; participants = 283; studies = 6; I(2) = 0%; low-quality evidence). This means that only 310 (95% CI 230 to 418) in every 1000 patients in the MSC arm are expected to develop chronic GvHD compared to 469 in the control arm. However, MSCs may make little or no difference to the risk of aGvHD (RR 0.86, 95% CI 0.63 to 1.17; participants = 247; studies = 6; I(2) = 0%; low-quality evidence). In GvHD therapeutic trials, we are very uncertain whether MSCs improve complete response of either aGvHD (RR 1.16, 95% CI 0.79 to 1.70, participants = 260, studies = 1; very low-quality evidence) or cGvHD (RR 5.00, 95%CI 0.75 to 33.21, participants = 40, studies = 1; very low-quality evidence).In two trials which compared different doses of MSCs, we found no evidence of any differences in outcomes. AUTHORS' CONCLUSIONS MSCs are an area of intense research activity, and an increasing number of trials have been undertaken or are planned. Despite a number of reports of positive outcomes from the use of MSCs for treating acute GvHD, the evidence to date from RCTs has not supported the conclusion that they are an effective therapy. There is low-quality evidence that MSCs may reduce the risk of cGvHD. New trial evidence will be incorporated into future updates of this review, which may better establish a role for MSCs in the prevention or treatment of GvHD.
Adults and children with haematological malignancies (11 trials) or thalassaemia (1 trial) undergoing allogeneic stem cell transplantation, or suffering from GvHD.
Mesenchymal stromal cells
No MSCs (10 trials) or different dose of MSCs (2 trials)
MSCs were well-tolerated, no infusion-related toxicity or ectopic tissue formation was reported. In prophylactic trials, MSCs may reduce the risk of chronic GvHD. However, MSCs may make little or no difference to the risk of aGvHD. In GvHD therapeutic trials, it is very uncertain whether MSCs improve complete response of either aGvHD or cGvHD. In two trials which compared different doses of MSCs, no evidence was found of any differences in outcomes.
Evidence-based, Skin-directed Treatments for Cutaneous Chronic Graft-versus-host Disease
Chronic graft-versus host disease (cGVHD) occurs in 30% to 70% of patients undergoing allogeneic hematopoietic cell transplantation (HCT). Cutaneous cGVHD affects 75% of cGVHD patients, causing discomfort, limiting the range of movement, and increasing the risk of wound infections. Furthermore, systemic immunosuppression is often needed to treat cGVHD and long-term use can lead to adverse events. Optimal use of skin-directed therapies is integral to the management of cutaneous cGVHD and may decrease the amount of systemic immunosuppression required. This study reviewed English-language articles published from 1990 to 2017 that evaluated the effect of skin-directed treatments for cutaneous cGVHD. A total of 201 papers were identified, 164 articles were screened, 46 were read, and 18 publications were utilized in the review. Skin-directed treatments for cGVHD included topical steroids, topical calcineurin inhibitors, psoralen with ultraviolet A (PUVA) irradiation, ultraviolet A1 (UVA1) irradiation, and ultraviolet B (UVB) irradiation. We report the number of complete remissions, partial remissions, and systemic immunosuppression reduction in each study, as available. Twenty-two out of 30 (73.3%) patients experienced overall improvement with topical calcineurin inhibitors. At least 26 out of 76 patients (34.2%) receiving PUVA experienced complete remission, and 30 out of 76 patients (39.5%) experienced partial remission. In UVA1 studies, 44 out of 52 (84.6%) patients experienced overall improvement. In UVB studies, nine out of 14 patients (64.3%) experienced complete remission and four out of 14 patients (28.6%) experienced partial remission. As more HCTs are performed, more individuals will develop cGVHD. Awareness and optimal use of skin-directed therapies for cutaneous cGVHD may help improve patient outcomes and quality of life.
Steroid Refractory Chronic Graft-Versus-Host-Disease: Cost-Effectiveness Analysis
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Given the increasing incidence of cGVHD and its rapidly escalating costs due to many lines of drug treatments, we aimed to perform a meta-analysis to assess the comparative effectiveness of various treatment options. Using these results, we then conducted a cost effectiveness analysis (CEA) for the frequently utilized agents in SR-cGVHD. We searched for studies examining tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, extracorporeal photopheresis (ECP), pomalidomide and methotrexate. Studies with a median follow up period shorter than 6 months and enrolling fewer than 5 patients were excluded. Meta-analysis for overall and organ system specific GVHD response (overall (ORR), complete response (CR) and partial response (PR)) was conducted for each intervention. Cost per CR and cost per CR+PR were calculated as the quotient of the 6 month direct treatment cost by CR and CR+PR. Forty-one studies involving 1047 patients were included. CR rates were ranged from 7% to 30% with rituximab and methotrexate respectively and ORR were ranged from 30% to 85% with tacrolimus and ruxolitinib, respectively. Cost per CR ranged from US$1,187,657 with ruxolitinib to US$680 with methotrexate. Costs per ORR ranged from US$453 for methotrexate to US$242,236 for ibrutinib. The most cost effective strategy was methotrexate for all of the organs systems. Pomalidomide was found to be the least cost-effective treatment for eye, gastrointestinal, fascia/joint, skin and oral GVHD and imatinib was found to be the least for liver and ECP for lung GVHD. We observed huge cost effectiveness differences among available agents. Attention to economic issues when treating cGVHD is important to recommend how treatments should be sequenced, knowing that many patients will cycle through available agents.
Challenges in managing graft-versus-host disease in developing countries: a perspective
Bone marrow transplantation. 2018
Hematopoietic cell transplant (HCT) activity is increasing worldwide due to safer techniques, widening indications, and more availability of donors. New HCT centers have recently been established in many developing countries including Asian and African countries. Due to limited resources, logistic, political, and social issues in developing countries, the treatment of orphan diseases like graft-versus-host disease (GVHD) can be challenging. We intended to delineate the current issues that institutions and clinicians face in managing GVHD. We conducted a comprehensive systematic electronic review of peer-reviewed published articles on GVHD management in developing countries. We used PubMed, Cochrane, and Embase databases as our primary source of data. Studies that were included described the treatments for both acute and chronic GVHD. Consensus on the use of high-dose methyl-prednisone and prednisolone as the initial therapy was widely accepted and used in practice. Socio-economic factors were found to be the major factor involved in GVHD management in lower income patients. Delayed diagnosis and treatment, lack of availability of healthcare professionals, lack of knowledge among cancer patients, and poverty are major concerns in the developing world. For optimal management, HCT programs should develop systems in place for long-term follow-up of HCT survivors and have a low threshold to initiate treatments for GVHD early. Awareness and health policy programs must be initiated at the grass-root level for long-term management of these survivors in developing countries.
Efficacy and Safety of Topical Corticosteroids for Management of Oral Chronic Graft versus Host Disease
International Journal of Dentistry. 2017;2017:1908768
BACKGROUND Oral chronic graft versus host disease (cGVHD) is a major complication in transplantation community, a problem that can be addressed with topical intervention. Topical corticosteroids are the first line of treatment although the choice remains challenging as none of the available treatments is supported by strong clinical evidence. OBJECTIVE This systematic review aims to determine the clinical efficacy and safety of topical corticosteroids for the management of the mucosal alterations of oral cGVHD. DATA SOURCES Electronic search of different databases was conducted: PubMed, Cochrane library, Grey literature, WHO, and clinical trials.gov for clinical trial registration as well as hand search in the references of relevant articles up to November 2016. DATA EXTRACTION Extracted pieces of information were intervention, population, sample sizes, and outcomes. DATA SYNTHESIS Six studies were included: 2 randomized clinical trials (RCTs), 3 cohort studies, and 1 pre-post clinical trial. RESULTS There is a limited evidence concerning clinical efficacy of topical corticosteroids. Clobetasol, dexamethasone, and budesonide were the topical corticosteroid of choice. The highest level of evidence score was given to clobetasol followed by budesonide with a lower evidence level. CONCLUSION All three topical corticosteroid preparations are effective for management of oral chronic GVHD with minimal easily avoided side effects.
Remestemcel-L for the treatment of graft versus host disease
Expert Review of Clinical Immunology. 2017;13(1):43-56
INTRODUCTION Remestemcel-L, a third-party, off-the-shelf preparation of bone-marrow derived mesenchymal stromal cells (MSCs), has been developed for experimental use in acute graft-versus-host disease (aGvHD) and other immune-mediated conditions. Several preclinical and clinical studies have indeed suggested the potential of human mesenchymal stromal cells (MSCs) as an effective treatment for steroid-refractory aGvHD. However, an unambiguous demonstration of efficacy is still lacking. Areas covered: This review critically examines the biologic rationale supporting MSCs use in aGvHD and analyzes the results of published clinical trials in this setting, with a particular focus on the potential benefits and drawbacks of Remestemcel-L. For this purpose, a systematic literature search was performed in PubMed using the following keywords: 'mesenchymal stromal cells', 'mesenchymal progenitor cells', 'multipotent stromal cells', 'mesenchymal cells', 'MSC', 'Remestemcel-L', 'Prochymal', and 'graft-versus-host disease' or 'GvHD'. Expert commentary: Remestemcel-L represents a promising alternative to second-line immunosuppressive agents for the treatment of steroid-refractory aGvHD. Despite the safety and the favorable risk/benefit profile of this cell product, which has been demonstrated in several phase I-II studies, large and prospective randomized trials are required to confirm its efficacy in aGvHD and to define the optimal schedule of administration in terms of infusion timing, cell dose and pharmacological synergism.