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[The clinical observation of sirolimus combined with calcineurin inhibitors for steroid-resistant/steroid-dependent extensive cGVHD]
Zhu, W., Feng, Y. M., Chen, T., Yao, H., Quan, Y., Rao, J., Gao, L., Zhang, C., Liu, Y., Gao, L., et al
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2020;41(9):716-722
Abstract
Objective: To observe the efficacy and safety of sirolimus combined with calcineurin inhibitor (CNI) in the treatment of glucocorticoid resistant/dependent extensive chronic graft-versus-host disease (cGVHD) . Methods: A total of 27 patients with steroid-resistant/steroid-dependent extensive cGVHD from November 2015 to January 2019 were enrolled and given sirolimus capsules combined with cyclosporine or tacrolimus to observe the clinical efficacy and adverse events. Results: The median duration of medication was 14.2 months and the mean duration was 16.7 months. The median follow-up time was 20.1 months (12.9-46.1 months) . Following the 6-month follow-up, 3 cases achieved complete response (CR) and 12 cases partial response (PR) . The overall response rate (ORR) was 55.6% ; for progression-free survival (PFS) , PFS-6 reached 88.9% (24/27) , and for overall survival (OS) , OS-6 was 100% . At the 1-year follow-up, there were 5 cases of CR and 11 cases of PR, ORR was 59.3% , PFS-12 reached 62.9% (17/27) , and OS-12 was 100% . The subgroup analysis found that the program was more effective for cGVHD in male donors and the target organ analysis had an advantage in the treatment of oral cavity, skin, and liver rejection. Adverse events were observed: hyperlipidemia 11.1% , oral ulcer 7.4% , fungal infection 11.1% , liver injury 3.7% , renal insufficiency 0, and no new CMV and EB viremia. Conclusion: Sirolimus combined with calcineurin inhibitors is effective in treating steroid-resistant/steroid-dependent extensive cGVHD, especially because adverse reactions (renal toxicity, CMV, EBV infection) are low in number, which is suitable for long-term treatment of cGVHD.
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Adverse events in second- and third-line treatments for acute and chronic graft-versus-host disease: systematic review
Velickovic, V. M., McIlwaine, E., Zhang, R., Spelman, T.
Therapeutic advances in hematology. 2020;11:2040620720977039
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased risk of graft-versus-host disease (GvHD), a strong prognostic predictor of early mortality within the first 2?years following allo-HSCT. The objective of this study was to describe the harm outcomes reported among patients receiving second- and third-line treatment as part of the management for GvHD via a systematic literature review. METHODS A total of 34 studies met the systematic review inclusion criteria, reporting adverse events (AEs) across 12 different second- and third-line therapies. RESULTS A total of 14 studies reported AEs across nine different therapies used in the treatment of acute GvHD (aGvHD), 17 studies reported AEs of eight different treatments for chronic GvHD (cGvHD) and 3 reported a mixed population. Infections were the AE reported most widely, followed by haematologic events and laboratory abnormalities. Reported infections per patient were lower under extracorporeal photopheresis (ECP) for aGvHD (0.267 infections per patient over 6?months) relative to any of the therapies studied (ranging from 0.853 infections per patient per 6?months under etanercept up to 1.998 infections per patient on inolimomab). CONCLUSION The reported incidence of infectious AEs in aGvHD and grade 3-5 AEs in cGvHD was lower on ECP compared with pharmaceutical management.
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Ruxolitinib add-on in corticosteroid-refractory graft-vs-host disease after allogeneic stem cell transplantation: Results from a retrospective study on 38 Chinese patients
Dang, S. H., Liu, Q., Xie, R., Shen, N., Zhou, S., Shi, W., Liu, W., Zou, P., You, Y., Zhong, Z. D.
World journal of clinical cases. 2020;8(6):1065-1073
Abstract
BACKGROUND Graft-vs-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation. Some patients have steroid-refractory (SR) GVHD. AIM: To evaluate the effect and safety of ruxolitinib add-on in the treatment of patients with SR acute (a) and chronic (c) GVHD. METHODS We retrospectively analyzed 38 patients administered ruxolitinib add-on to standard immunosuppressive therapy for SR-aGVHD or SR-cGVHD following allogeneic hematopoietic stem cell transplantation. Ruxolitinib was administered 5-10 mg/d depending on disease severity, patient status, and the use of anti-fungal drugs. Overall response rate, time to best response, malignancy relapse rate, infection rate, and treatment-related adverse events were assessed. RESULTS The analysis included 10 patients with SR-aGVHD (grade III/IV, n = 9) and 28 patients with SR-cGVHD (moderate/severe, n = 24). For the SR-aGVHD and SR-cGVHD groups, respectively: Median number of previous GVHD therapies was 2 (range: 1-3) and 2 (1-4); median follow-up was 2.5 (1.5-4) and 5 (1.5-10) mo; median time to best response was 1 (0.5-2.5) and 3 (1-9.5) mo; and overall response rate was 100% (complete response: 80%) and 82.1% (complete response: 10.7%) with a response observed in all GVHD-affected organs. The malignancy relapse rates for the SR-aGVHD and SR-cGVHD groups were 10.0% and 10.7%, respectively. Reactivation rates for cytomegalovirus, Epstein-Barr virus, and varicella-zoster virus, respectively, were 30.0%, 10.0%, and 0% for the SR-aGVHD group and 0%, 14.3%, and 7.1% for the SR-cGVHD group. CONCLUSION Ruxolitinib add-on was effective and safe as salvage therapy for SR-GVHD.
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Topical Corticosteroids a Viable Solution for Oral Graft Versus Host Disease? A Systematic Insight on Randomized Clinical Trials
Sava, A., Piciu, A., Pasca, S., Mester, A., Tomuleasa, C.
Medicina (Kaunas, Lithuania). 2020;56(7)
Abstract
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.
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A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease
Schroeder, M. A., Khoury, H. J., Jagasia, M., Ali, H., Schiller, G. J., Staser, K., Choi, J., Gehrs, L., Arbushites, M. C., Yan, Y., et al
Blood advances. 2020;4(8):1656-1669
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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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GVHD-derived plasma as a priming strategy of mesenchymal stem cells
Silva-Carvalho, A. E., Rodrigues, L. P., Schiavinato, J. L., Alborghetti, M. R., Bettarello, G., Simoes, B. P., Neves, F. A. R., Panepucci, R. A., de Carvalho, J. L., Saldanha-Araujo, F.
Stem cell research & therapy. 2020;11(1):156
Abstract
BACKGROUND Mesenchymal stem cell (MSC) therapy is an important alternative for GVHD treatment, but a third of patients fail to respond to such therapy. Therefore, strategies to enhance the immunosuppressive potential of MSCs constitute an active area of investigation. Here, we proposed an innovative priming strategy based on the plasma obtained from GVHD patients and tested whether this approach could enhance the immunosuppressive capacity of MSCs. METHODS We obtained the plasma from healthy as well as acute (aGVHD) and chronic (cGVHD) GVHD donors. Plasma samples were characterized according to the TNF-alpha, IFN-gamma, IL-10, IL-1beta, IL-12p40, and IL-15 cytokine levels. The MSCs primed with such plasmas were investigated according to surface markers, morphology, proliferation, mRNA expression, and the capacity to control T cell proliferation and Treg generation. RESULTS Interestingly, 57% of aGVHD and 33% of cGVHD plasmas significantly enhanced the immunosuppressive potential of MSCs. The most suppressive MSCs presented altered morphology, and those primed with cGHVD displayed a pronounced overexpression of ICAM-1 on their surface. Furthermore, we observed that the ratio of IFN-gamma to IL-10 cytokine levels in the plasma used for MSC priming was significantly correlated with higher suppressive potential and Treg generation induction by primed MSCs, regardless of the clinical status of the donor. CONCLUSIONS This work constitutes an important proof of concept which demonstrates that it is possible to prime MSCs with biological material and also that the cytokine levels in the plasma may affect the MSC immunosuppressive potential, serving as the basis for the development of new therapeutic approaches for the treatment of immune diseases.
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Hydrogen in Patients With Corticosteroid-Refractory/Dependent Chronic Graft-Versus-Host-Disease: A Single-Arm, Multicenter, Open-Label, Phase 2 Trial
Qian, L., Liu, M., Shen, J., Cen, J., Zhao, D.
Frontiers in immunology. 2020;11:598359
Abstract
Chronic graft-versus-host-disease (cGVHD) is the leading cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation(HSCT). There is no standard therapy for patients refractory or dependent to corticosteroid treatment. We hypothesized that hydrogen may exert therapeutic effects on cGVHD patients with few side effects. A prospective open-label phase 2 study of hydrogen was conducted. Patients received hydrogen-rich water 4ml/kg orally three times a day. Responses were graded in the skin, mouth, Gastrointestinal(GI), liver, eyes, lungs and joints and fascia every 3 months. A total of 24 patients (median age 27) were enrolled. Of the 24 patients, 18 (75%; 95% CI, 55.1% to 88%) had an objective response. No significant toxicity was observed. The estimated 4-year overall survival rate was 74.7%(95% CI, 54.9%-94.5%). The survival time was significantly prolonged in the response group. The survival rate at 4 years in the response group is significantly higher than the nonresponse group (86.6% vs 0%; p= 0.000132). Hydrogen showed great efficacy on cGVHD patients and long-term administration of hydrogen was not associated with significant toxic effects. The trial was registered at www.ClinicalTrials.Gov, NCT02918188.
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Study 275: Updated Expanded Access Program for Remestemcel-L in Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD) in Children
Kurtzberg, J., Prockop, S., Chaudhury, S., Horn, B., Nemecek, E., Prasad, V., Satwani, P., Teira, P., Hayes, J., Burke, E.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Abstract
Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor with a high mortality rate and limited therapeutic options. We report here our updated investigational experience with mesenchymal stromal cell therapy (remestemcel-L) used in a multicenter expanded access protocol (NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies (IST). A total of 241 children with Grade B-D steroid refractory (SR) aGVHD were enrolled in 50 sites in eight countries and received eight biweekly intravenous infusions of human mesenchymal stromal cells (hMSCs) 2x10(6) per kg for four weeks, with an option for an additional four weekly infusions after day 28 for subjects who achieved either a partial or mixed response. Mean age of subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response rate (ORR, the sum of complete and partial response) at day 28. Across all subjects, the 28 day ORR, was observed in n=157 (65.1%) with 34 (14.1%) and 123 (51.3%) achieving complete and partial responses, respectively. Stratified by aGVHD grade at baseline, the rate of overall response at day 28 was 72.9% for aGVHD grade B, 67.1% for grade C, and 60.8% for grade D subjects. Survival through day 100, a secondary endpoint of the study was 66.9% (n=160/239). Importantly, survival through day 100 was significantly greater in subjects that achieved a day 28 OR (82.1%) compared with non-responders (38.6%), log rank p<0.001. Remestemcel-L safety was generally well tolerated with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L EAP confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.
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A Phase 3, Single-arm, Prospective Study of Remestemcel-L, Ex-vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Patients who Failed to Respond to Steroid Treatment for Acute GVHD
Kurtzberg, J., Abdel-Azim, H., Carpenter, P., Chaudhury, S., Horn, B., Mahadeo, K., Nemecek, E., Neudorf, S., Prasad, V., Prockop, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well-tolerated and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, Mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies (IST) for aGVHD treated with MSC product (remestemcel-L) dosed at 2x10(6) cells/kg twice weekly for four weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared to the pre-specified control OR value of 45% (70.4% versus 45%, P =0.0003). The statistically significant OR (70.4%) was sustained through day 100 including an increase in complete response (CR) from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days and survival was significantly greater in day 28 responders compared with non-responders through day 100 (86.8% vs. 47.1% for responders and non-responders, respectively, P=0.0001) and through day 180 (78.9% vs. 43.8%, p=0.003). Remestemcel-L was well-tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.

PICO Summary
Population
Children with primary steroid refractory aGVHD, naive to other immunosuppressant therapies (n=54)
Intervention
Mesenchymal stromal cell product (remestemcel-L) dosed at 2x10(6) cells/kg twice weekly for four weeks.
Comparison
None
Outcome
Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared to the pre-specified control OR value of 45% (70.4% versus 45%). The statistically significant OR (70.4%) was sustained through day 100 including an increase in complete response (CR) from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days and survival was significantly greater in day 28 responders compared with non-responders through day 100 (86.8% vs. 47.1% for responders and non-responders, respectively) and through day 180 (78.9% vs. 43.8%) Remestemcel-L was well-tolerated with no identified infusion-related toxicities or other safety concerns.
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10.
Facilitating resolution of life-threatening acute GVHD with human chorionic gonadotropin and epidermal growth factor
Holtan, S. G., Hoeschen, A. L., Cao, Q., Arora, M., Bachanova, V., Brunstein, C. G., Miller, J. S., Rashidi, A., Slungaard, A., Ustun, C., et al
Blood advances. 2020;4(7):1284-1295
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Abstract
Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin (uhCG) could help facilitate resolution of life-threatening aGVHD when added as supportive care via 2 potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF; to aid in epithelial repair). In a phase 1 study, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 receiving initial therapy for high-risk aGVHD [according to the Minnesota criteria] and 13 receiving second-line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. uhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the second-line cohort had a complete response at study day 28. Plasma EGF was elevated sixfold (from 4 to 24 pg/mL; P = .02) at 6 hours postdose in the high-risk cohort, in contrast to no peak in plasma EGF in the more severe second-line cohort. After 1 week of uhCG, patients reported a twofold increase in the regulatory T cell to conventional T-cell ratio, suggesting immune modulation despite high-dose steroids. Responding patients reported significantly lower plasma amphiregulin and higher plasma butyrate levels at study completion, suggesting improvement in mucosal damage over time. uhCG is a novel, safe, supportive therapy, proceeding to phase 2 testing at 2000 units/m2 in high-risk aGVHD. This study was registered at www.clinicaltrials.gov as #NCT02525029.