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ECP versus ruxolitinib in steroid-refractory chronic GVHD - a retrospective study by the EBMT transplant complications working party
Penack, O., Peczynski, C., Boreland, W., Lemaitre, J., Reinhardt, H. C., Afanasyeva, K., Avenoso, D., Holderried, T. A. W., Kornblit, B. T., Gavriilaki, E., et al
Bone marrow transplantation. 2024
Abstract
Ruxolitinib has become the new standard of care for steroid-refractory and steroid-dependent chronic GVHD (SR-cGVHD). Our aim was to collect comparative data between ruxolitinib and extracorporeal photophoresis (ECP). We asked EBMT centers if they were willing to provide detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. 31 centers responded positively and we included all patients between 1/2017-7/2019 treated with ECP or ruxolitinib for moderate or severe SR-cGVHD. We identified 84 and 57 patients with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-cGVHD (steroid dependent vs. refractory vs. intolerant to steroids). At day+180 after initiation of treatment for SR-cGVHD the odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.35 (95% CI = [0.64; 2.91], p = 0.43). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-cGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-cGVHD.
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ECP versus ruxolitinib in steroid-refractory acute GVHD - a retrospective study by the EBMT transplant complications working party
Penack, O., Peczynski, C., Boreland, W., Lemaitre, J., Afanasyeva, K., Kornblit, B., Jurado, M., Martinez, C., Natale, A., Pérez-Simón, J. A., et al
Frontiers in immunology. 2023;14:1283034
Abstract
INTRODUCTION Extracorporal Photophoresis (ECP) is in clinical use for steroid-refractory and steroid-dependent acute GVHD (SR-aGVHD). Based on recent Phase-III study results, ruxolitinib has become the new standard of care for SR-aGVHD. Our aim was to collect comparative data between ruxolitinib and ECP in SR-aGVHD in order to improve the evidence base for clinical decision making. METHODS We asked EBMT centers if they were willing to participate in this study by completing a data form (Med-C) with detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. RESULTS 31 centers responded positively (14%) and we included all patients receiving alloSCT between 1/2017-7/2019 and treated with ECP or ruxolitinib for SR-aGVHD grades II-IV from these centers. We identified 53 and 40 patients with grades II-IV SR-aGVHD who were treated with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-aGVHD (steroid dependent vs. refractory). At day+90 after initiation of treatment for SR-aGVHD we found no statistically significant differences in overall response. The odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.13 (95% CI = [0.41; 3.22], p = 0.81). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. DISCUSSION The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-aGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-aGVHD.
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Real-world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC-FFM in ruxolitinib-refractory acute graft-versus-host disease
Bonig, H., Verbeek, M., Herhaus, P., Braitssch, K., Beutel, G., Schmid, C., Müller, N., Bug, G., Döring, M., von Stackelberg, A., et al
Journal of translational medicine. 2023;21(1):837
Abstract
BACKGROUND Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. METHODS We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1-2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1-10) in adults and 7 (2-11) in children. RESULTS The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36-55%) in adults and 64% (45-80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38-56%), 35% (27-44%) and 30% (22-39%) for adults, and 59% (40-74%), 42% (24-58%) and 35% (19-53%) for children, respectively (whole cohort: median OS 5.8 months). CONCLUSION A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD.
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Nilotinib efficacy and safety as salvage treatment following imatinib intolerance and/or inefficacy in steroid refractory chronic graft-versus-host-disease (SR-cGVHD): a prospective, multicenter, phase II study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)
Srour, M., Alsuliman, T., Labreuche, J., Bulabois, C. E., Chevallier, P., Daguindau, E., Forcade, E., François, S., Guillerm, G., Coiteux, V., et al
Bone marrow transplantation. 2023
Abstract
Imatinib is used for patients with SR-cGVHD. However, in 50% of cases imatinib is discontinued due to intolerance or inefficacy. In order to investigate nilotinib's role as salvage therapy in those patients, we conducted a prospective, multicenter, phase II study. (NCT02891395). Patients with SR-cGVHD were included to receive imatinib. Patients who stopped imatinib due to intolerance or inefficacy switched to Nilotinib. The primary endpoint was defined as the week-12 response rate to Nilotinib. The response was considered successful if superior to the 30% endpoint. Sixty-two patients started the IM-phase. Fourteen patients (22%) discontinued imatinib before week 12 due to: cGVHD progression (10%) or TKI-class-specific intolerance (12%). At week 12, we observed complete remission in 13 patients (21%) and partial response in 8 patients (13%). Twenty-nine patients switched to Nilotinib. Nilotinib response at week-12 was observed in 6 patients (21%) while 23 patients (79%) discontinued Nilotinib due to intolerance/cGVHD progression. The primary endpoint was not reached. This prospective study confirmed the efficacy of imatinib in patients with steroid refractory cGVHD. It failed to demonstrate the efficacy of nilotinib as a salvage therapy in patients who were intolerant/unresponsive to imatinib.
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Topical treatment of oral chronic graft-versus-host- disease in hematopoietic stem cell transplant recipients: A systematic review
Haas, L., Cruz-Pamplona, M.
Journal of clinical and experimental dentistry. 2023;15(5):e420-e427
Abstract
BACKGROUND Oral graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation. This study systematically reviewed Randomized Controlled Trials (RCTs) with the objective to investigate the effectiveness and side effects of topical agents used for the treatment of oral GVHD. MATERIAL AND METHODS The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed to perform this study. An electronic search of four databases was conducted. RCTs published between January 2011 and March 2022 were included that were carried out on hematopoietic stem cell transplant recipients receiving topical treatment for oral GVHD. The Critical Appraisal Skills Program (CASP) standard checklist for RCTs was used for the bias risk evaluation. RESULTS Five RCTs were included for the qualitative synthesis of results. Two RCTs were linked to a certain risk of bias. Budesonide caused the highest overall treatment response. Malic acid, clobetasol, and dexamethasone increased resting salivary flow rates. Curcumin in orabase shows similar results to corticosteroid treatment. Adverse effects were observed in populations receiving budesonide, dexamethasone, clobetasol, and tacrolimus. Most frequent adverse effects were burning sensations, fungal infections, and gastrointestinal disorders, but none of them were severe. CONCLUSIONS Given the small number of RCTs performed and the heterogeneity of the different study designs, it is difficult to draw direct comparisons. Malic acid appears to be effective for the treatment of graft-versus-host disease-induced xerostomia. Budesonide had the highest overall response rates but was also associated with the highest number of adverse effects. Further research is needed to manifest those findings. Key words:Hematopoietic stem cell transplant, oral graft-versus-host disease, topical treatment.
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[Humanized anti-CD25 monoclonal antibody as a salvage therapy for steroid-refractory acute graft-versus-host disease after hematopoietic stem cell transplantation]
Wu, Y. X., Wu, D. P., Ma, X., Jiang, S. S., Hou, M. J., Jing, Y. T., Liu, B., Li, Q., Wang, X., Wu, Y. B., et al
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2023;44(9):755-761
Abstract
Objective: To investigate the efficacy of humanized anti-CD25 monoclonal antibody for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods: A total of 64 patients with SR-aGVHD between June 2019 and October 2020 in Suchow Hopes Hematology Hospital were enrolled in this study. Humanized anti-CD25 monoclonal antibodies 1 mg·kg(-1)·d(-1) were administered on days 1, 3, and 8, and then once per week according to the disease progression. Efficacy was assessed at days 7, 14, and 28 after humanized anti-CD 25 treatment. Results: Of the 64 patients with a median age of 31 (15-63) years, 38 (59.4%) were male and 26 (40.6%) were female. The overall response (OR) rate of the humanized CD25 monoclonal antibody in 64 patients with SR-aGVHD on days 7, 14, and 28 were 48.4% (31/64), 53.1% (34/64), and 79.7% (51/64), respectively. Liver involvement is an independent risk factor for poor efficacy of humanized CD25 monoclonal antibody for SR-aGVHD at day 28 (OR=9.588, 95% CI 0.004-0.291, P=0.002). The median follow-up time for all patients was 17.1 (0.2-50.8) months from the start of humanized CD25 monoclonal antibody therapy. The 1- and 2-year OS rates were 63.2% (95% CI 57.1% -69.3%) and 52.6% (95% CI 46.1% -59.1%), respectively. The 1- and 2-year DFS rates were 58.4% (95% CI 52.1% -64.7%) and 49.8% (95% CI 43.4% -56.2%), respectively. The 1- and 2-year NRM rates were 28.8% (95% CI 23.1% -34.5%) and 32.9% (95% CI 26.8% -39.0%), respectively. The results of the multifactorial analysis showed that liver involvement (OR=0.308, 95% CI 0.108-0.876, P=0.027) and GVHD grade Ⅲ/Ⅳ (OR=9.438, 95% CI 1.211-73.577, P=0.032) were independent risk factors for OS. Conclusion: Humanized CD25 monoclonal antibody has good efficacy and safety for SR-aGVHD. This study shows that SR-aGVHD with pretreatment grade Ⅲ/Ⅳ GVHD and GVHD involving the liver has poor efficacy and prognosis and requires early intervention.
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A novel approach to visualize clinical benefit of therapies for chronic graft versus host disease (cGvHD): the probability of being in response (PBR) applied to the REACH3 study
Hollaender, N., Glimm, E., Gauvin, J., Stefanelli, T., Zeiser, R.
Bone marrow transplantation. 2023
Abstract
Overall response rate (ORR) is commonly used as key endpoint to assess treatment efficacy of chronic graft versus host disease (cGvHD), either as ORR at week 24 or as best overall response rate (BOR) at any time point up to week 24 or beyond. Both endpoints as well as duration of response (DOR) were previously reported for the REACH3 study, a phase 3 open-label, randomized study comparing ruxolitinib (RUX) versus best available therapy (BAT). The comparison between RUX and BAT was performed on ORR and BOR using all randomized patients, while DOR was derived for the subgroup of responders only. Here we illustrate the application of the probability of being in response (PBR), a graphical method presenting simultaneously the time to first response and subsequent failure using all randomized patients. In REACH3, PBR showed an earlier time to first response, a higher probability of being in response and a longer duration of response for RUX compared to BAT. PBR is a clinically easily interpretable measurement and can serve as a novel efficacy endpoint to assess treatments for chronic graft versus host disease.
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8.
Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease
Al Malki, M. M., London, K., Baez, J., Akahoshi, Y., Hogan, W. J., Etra, A. M., Choe, H. K., Hexner, E. O., Langston, A., Abhyankar, S. H., et al
Blood advances. 2023
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Editor's Choice
Abstract
GVHD of the gastrointestinal (GI) tract is the main cause of non-relapse mortality following allogeneic HCT. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA 2/3 scores correlate with resistance to treatment and higher non-relapse mortality (NRM). We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA 2/3 GVHD. Seventy-five evaluable patients were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events (AEs) in more than 10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared to 150 well matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and corticosteroids alone controls (60% vs. 58%; P=0.67 and 48% vs. 48%; P=1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival (OS) at 12 months in patients treated with natalizumab plus corticosteroids compared to controls treated with corticosteroids alone (38% vs 39%, P=0.80 and 46% vs 54%, P=0.48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high risk GVHD.
PICO Summary
Population
Adults with new onset high risk GvHD from 12 centres in USA (n=75)
Intervention
Natalizumab combined with corticosteroids (n=75)
Comparison
Matched controls from the MAGIC database whose primary treatment was corticosteroids alone (n=150)
Outcome
There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and corticosteroids alone controls (60% vs. 58% and 48% vs. 48%, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival (OS) at 12 months in patients treated with natalizumab plus corticosteroids compared to controls treated with corticosteroids alone (38% vs 39% and 46% vs 54%, respectively).
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Advantage of First-Line Therapeutic Drug Monitoring-Driven Use of Infliximab for Treating Acute Intestinal and Liver GVHD in Children: A Prospective, Single-Center Study
Maximova, N., Nisticò, D., Riccio, G., Maestro, A., Barbi, E., Faganel Kotnik, B., Marcuzzi, A., Rimondi, E., Di Paolo, A.
Cancers. 2023;15(14)
Abstract
The high serum concentrations of TNF-α characterize acute graft-versus-host disease (aGVHD), for which infliximab treatment may be beneficial. In 28 pediatric patients, four doses of 10 mg/kg infliximab every seven days were administered after steroid failure (Standard Group, n = 14) or as a first-line therapy (Early Group, n = 14). Population pharmacokinetic analyses and evaluation of serum cytokines were performed. After two months of treatment, complete response in gastrointestinal and liver aGVHD was achieved in 43% and 100% of patients in the Standard and Early groups, respectively. During follow-up, four patients in the Standard Group (but none in the Early Group) experienced an aGVHD recurrence. Viral infections occurred more frequently in the Standard Group after the fifth dose. Infliximab clearance did not differ between groups or according to treatment outcome for each organ involved in aGVHD, whereas serum levels of cytokines significantly differed. Therefore, present findings show that use of first-line, TDM-driven infliximab to treat aGVHD in children may result in better clinical outcomes and tolerability, with a different pattern of cytokines generated according to the moment of beginning of treatment.
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Efficacy and Safety of Ibrutinib for Chronic Graft-Versus-Host Disease: A Systematic Review
Santosa, D., Rizky, D., Tandarto, K., Kartiyani, I., Yunarvika, V., Ardini, D. N. E., Setiawan, B., Pangarsa, E. A., Suharti, C.
Asian Pacific journal of cancer prevention : APJCP. 2023;24(12):4025-4033
Abstract
INTRODUCTION Allogeneic hematopoietic cell transplantation (allo-HCT) serves as a potentially curative intervention for various hematologic disorders. However, its utility can be limited by the emergence of chronic graft-versus-host disease (cGVHD). The clinical manifestations of cGVHD result from a complex immune response characterized by the involvement of both B and T cells. Ibrutinib, a pharmacological agent, acts as an inhibitor of Bruton's tyrosine kinase (BTK) pathway, which becomes activated through the B-cell receptor and regulates B-cell survival. By exerting inhibitory effects on both BTK and inhibitor of interleukin-2 inducible T-cell kinase (ITK), ibrutinib exhibits promise as a therapeutic approach for managing cGVHD. Ibrutinib may be considered as a viable treatment option for active cGVHD in cases where patients exhibit an inadequate response to corticosteroid-based therapies. This systematic review seeks to assess the efficacy and safety of ibrutinib in the context of cGVHD patient management. METHOD We incorporated search engines from PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov. The study was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and Assessing The Methodological Quality of Systematic Review (AMSTAR). We used Risk of Bias- 2 (RoB-2) tool for assess the risk of bias in randomized controlled studies (RCTs) and Newcastle Ottawa Scale (NOS) for observational and open-label studies. RESULTS A total of 7 studies were included in this study consisted of four open-label studies, two retrospective cohort studies, and one RCT study. These studies compared Ibrutinitib with standard therapies. Two studies investigated the pediatric population, and five studies investigated the adult population. Overall, these studies reported the overall response rate (ORR) of ibrutinib for cGVHD were 54%-78%. The results showed that in pediatric patients, the ORR were 54-78%. The results also showed that in adult patients, the ORR were 67%-76%. The most common adverse effects observed across the seven studies included pyrexia, diarrhea, abdominal pain, cough, nausea, stomatitis, vomiting, headache, bleeding and bruising, infection, muscle aches, fatigue, oral bleeding, elevated transaminases, lower gastrointestinal bleeding, persistent dizziness, sepsis, pneumonia, reduced platelet count, exhaustion, sleeplessness, peripheral edema, and fatigue. CONCLUSION The majority of studies have indicated that ibrutinib exhibits a high ORR and provides long-lasting responses, while also having manageable side effects.