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1.
Ruxolitinib in patients with graft versus host disease (GvHD): findings from a compassionate use program
Pattipaka, T., Sarp, S., Nakhaei, P., Güneş, S.
Bone marrow transplantation. 2024
Abstract
The ruxolitinib compassionate use (CU) program offered ruxolitinib to patients ≥2 years of age with confirmed steroid-resistant acute or chronic graft-versus-host disease (aGvHD and cGvHD, respectively). Data from 1180 patients (n = 775, 370 and 35 with cGvHD, aGvHD, and non-specified GvHD, respectively) were analyzed. Most patients had severe cGvHD (56%) or stage III/IV aGvHD (70%) disease and had previously received corticosteroids ( > 80%); ruxolitinib was requested primarily as a second-/third-line option. Patients <12 and ≥12 years old most often received the recommended ruxolitinib doses (5 mg twice daily [BID] and 10 mg BID, respectively); however, 23% and 30% of ≥12 year olds with cGvHD and aGvHD, respectively, received the lower dose of 5 mg BID. Notably, corticosteroid usage decreased with ruxolitinib treatment; at the initial ruxolitinib request, 81% and 91% of patients with cGvHD and aGvHD, respectively, were receiving corticosteroids whereas at resupply, 62% and 64%, respectively, were receiving corticosteroids. Eighty two percent of evaluable patients with cGvHD had a complete or partial response to treatment and 56% of evaluable patients with aGvHD had a best response of grade 0/I. These findings demonstrate the rapid and positive effects of ruxolitinib in patients with GvHD in a real-world setting.
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2.
Efficiency and Toxicity of Imatinib Mesylate combined with Atorvastatin Calcium in the Treatment of Steroid-Refractory Chronic Graft-Versus-Host Disease: A Single-center, Prospective, Single-arm, Open-label study
Chen, T., Li, J., Wei, X., Yao, H., Zhu, L., Liu, J., Liu, Y., Wang, P., Feng, Y., Gao, S., et al
Acta haematologica. 2024
Abstract
INTRODUCTION Steroid-refractory cGVHD (SR-cGVHD) presents new great challenges for treatment. We have reported imatinib monotherapy was effective to SR-cGVHD, but the CR rate was not satisfactory and the benefit was not showed specific to some target organs, previously. Imatinib and statin drugs have been recognized to regulate T-cell function, statins also have been demonstrated endothelia protection, but whether this combination therapy was able to improve the efficacy remains unknown. Therefore, we designed this prospective, single-arm, open-label trial to investigate the efficacy of imatinib-based combination therapy in the treatment of SR-cGVHD for the first time. METHODS 60 SR-cGVHD patients were entered into this trial to investigated the combination of imatinib mesylate and atorvastatin calcium for the treatment of SR-cGVHD. The primary endpoint included the overall response rate (ORR) after 6 months of combined treatment. The secondary endpoints included an evaluation of survival, changes in T-cell subsets and adverse events. RESULTS At baseline, 45% (27/60) of patients had moderate cGVHD, and 55.0% (33/60) of patients had severe cGVHD. At the 6-month follow-up, a clinical response was achieved in 70.0% of patients, and a complete response (CR) was achieved in 26.7%. A total of 11.7% (7/60) of patients stopped immunosuppressive therapy at this point. After 6 months of treatment, the ORR rates of the liver, skin, eyes and oral cavity were 80.6%, 78.1%, 61.5%, and 60.9%, respectively, with the liver also having the highest CR of 58.1%. The patients with moderate cGVHD had a better CR rate than those with severe cGVHD (55.6% vs. 3.0%, P<0.0001). The overall survival in patients who with ORR was improved (P = 0.0106). Lung involvement is an independent risk factor to affected ORR achievement (P = 0.021, HR = 0.335, 95%CI 0.133-0.847), and the dosage of steroids was reduced in ORR patients. In clinical response patients, the ratio of CD8+ T cells (P = 0.0117) and Th17 cells (P = 0.0171) decreased, while the number of Treg cells (P = 0.0147) increased after 3 months. The most common adverse events were edema, nausea, and neutropenia which were 13.3%, 11.7%, and 11.7%, respectively. CONCLUSION Combination treatment with imatinib mesylate and atorvastatin calcium was effective in treating SR-cGVHD and significantly decreased target organ injury, especially liver damage, indicating that T-cell regulatory function may play an important role in this process.
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3.
Chronic graft-versus-host disease-associated muscle cramps: severity and response to immunomodulatory therapies
Rastogi, S., Kim, E. J., Gelfand, J. M., Loren, A. W., Baumrin, E.
Transplantation and cellular therapy. 2024
Abstract
Muscle cramps in patients with chronic graft-versus-host disease (cGVHD) are common and associated with impaired quality of life and symptom burden. Muscle cramps are not currently captured in the 2014 NIH response criteria and thus characterization and response to immunomodulatory therapies is lacking. The objective of this study was to characterize muscle cramp frequency, duration, and pain level in patients with steroid-refractory cGVHD undergoing extracorporeal photopheresis (ECP). A single-center cohort of patients initiating ECP for the indication of steroid-refractory cGVHD with muscle cramps at treatment initiation were followed from April 2021-April 2023. Of 22 patients receiving ECP for cGVHD during the study period, 9 (41%) had muscle cramps at ECP initiation (6/9 [66%] males, median age 59 years [range 25-66]). Seven (78%) had multiple organs involved and 7 (78%) had severe disease by NIH Global Severity. Over median 28 weeks (range 10-48) of treatment, 8/9 (89%) had improvement in frequency of muscle cramps from median 5 episodes/week (range 3/day-2/week) to median <1 episode/week (range 1/month - 3/week). Pain and duration of muscle cramps were not meaningfully changed. NIH Global Severity remained unchanged in 6 (67%) and improved in 3 (33%) patients. Muscle cramps are a morbid feature of cGVHD that may be sensitive to change with standard immunomodulatory therapies. Muscle cramp frequency should be further validated as a response measure in cGVHD.
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4.
Ruxolitinib for the treatment of acute and chronic graft-versus-host disease in children: a systematic review and individual patient data meta-analysis
Baccelli, F., Gottardi, F., Muratore, E., Leardini, D., Grasso, A. G., Gori, D., Belotti, T., Prete, A., Masetti, R.
Bone marrow transplantation. 2024
Abstract
Steroid-refractory graft-versus-host disease (SR-GvHD) represents a major complication of pediatric allogenic hematopoietic stem cell transplantation. Ruxolitinib, a selective JAK 1-2 inhibitor, showed promising results in the treatment of SR-GvHD in adult trial, including patients >12 years old. This systematic review aims to evaluate ruxolitinib use for SR-GvHD in the pediatric population. Among the 12 studies included, ruxolitinib administration presented slight differences. Overall response rate (ORR) ranged from 45% to 100% in both acute and chronic GvHD. Complete response rates (CR) varied from 9% to 67% and from 0% to 28% in aGvHD and cGvHD, respectively. Individual-patient meta-analysis from 108 children under 12 years showed an ORR and CR for aGvHD of 74% and 56%, respectively, while in cGvHD ORR was 78% but with only 11% achieving CR. Treatment-related toxicities were observed in 20% of patients, including cytopenia, liver toxicity, and infections. Age, weight, graft source, previous lines of therapy, and dose did not significantly predict response, while a higher rate of toxicities was observed in aGvHD patients. In conclusion, ruxolitinib shows promising results in the treatment of SR-GvHD in children, including those under 12 years. Specific pediatric perspective trials are currently ongoing to definitely assess its efficacy and safety.
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5.
Second line extracorporeal photopheresis for cortico-resistant acute and chronic GVHD after allogeneic hematopoietic cell transplantation for hematological malignancies: Long-term results from a real-life study
Michallet, M., Sobh, M., Deloire, A., Revesz, D., Chelgoum, Y., El-Hamri, M., Barraco, F., Labussiere, H., Nicolini, F. E., Hequet, O.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2024;:103899
Abstract
BACKGROUND & OBJECTIVES The primary objective of this observational study was to perform an exhaustive description concerning patients receiving extracorporeal photopheresis (ECP) as second line treatment after steroid resistance for either acute or chronic GVHD following allo-HCT, secondary objectives were to evaluate the efficacy and long-term outcomes. STUDY DESIGN A total of 106 patients were included, 65 (61%) males and 41 (39%) females with a median age at transplantation of 52 years (range: 20-67). ECP was initiated after transplantation either for acute GVHD [N = 25 (24%), 12 grade III and 13 grade IV] affecting skin alone (N = 5), gut alone (N = 12), gut and liver (N = 8), or chronic GVHD [N = 81 (76%), 15 (14%) limited and 66 (62%) extensive]. RESULTS Among the 25 patients treated for acute GHVD, 67% were responders and among the 81 patients with chronic GVHD, 78% were responders. Patients with acute GVHD had a median OS of 6 months with a survival probability at 2 years of 35% [95%CI: 14-56]. Patients with chronic GVHD had a median OS of 72 months with a survival probability at 2 years of 68% [95%CI: 56-78]. There was a significant difference in terms of survival for patients responding to ECP compared to non-responders in both acute and chronic GVHD forms. Acute GVHD grade III-IV, negatively impacted on OS (HR=7.77, 95%CI: 1.7-34), p = 0.007 and on disease relapse HR= 5.88, 95%CI: 1.7-20, p = 0.005. CONCLUSION We demonstrated that ECP is an effective treatment for GVHD in a good proportion of patients with high overall response rate.
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6.
Fecal microbiota transplantation in capsules for the treatment of steroid refractory and steroid dependent acute graft vs. host disease: a pilot study
Youngster, I., Eshel, A., Geva, M., Danylesko, I., Henig, I., Zuckerman, T., Fried, S., Yerushalmi, R., Shem-Tov, N., Fein, J. A., et al
Bone marrow transplantation. 2024
Abstract
Acute graft-versus-host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem-cell transplantation with limited treatment options. The gut microbiome plays a critical role in aGvHD pathogenesis. Fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach to restore gut microbial diversity. In this prospective pilot study, 21 patients with steroid-resistant or steroid-dependent lower gastrointestinal aGvHD received FMT in capsule form. At 28 days after the first FMT, the overall response rate was 52.4%, with 23.8% complete and 28.6% partial responses. However, sustained responses were infrequent, with only one patient remaining aGvHD-free long-term. FMT was generally well-tolerated. Microbiome analysis revealed dysbiosis in pre-FMT patient stool samples, with distinct microbial characteristics compared to donors. Following FMT, there was an increase in beneficial Clostridiales and a decrease in pathogenic Enterobacteriales. These findings highlight the potential of FMT as a treatment option for steroid-resistant aGvHD. Trial registration number NCT #03214289.
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7.
Novel Management of Ocular Surface Inflammation in Patients With Ocular Graft-Versus-Host Disease in the Setting of Cataract Surgery
Roca, D., Jain, S., Mun, C., Akbar Sarwar, M., Shorter, E., Ortiz-Morales, G., Tarib, I., De La Cruz, J.
Eye & contact lens. 2024
Abstract
PURPOSE To report the outcomes of cataract surgery in patients with ocular graft-versus-host disease (oGVHD) using a novel preoperative immunomodulatory regimen in a collaborative subspecialty care setting. METHODS Retrospective case series of patients with oGVHD who underwent cataract surgery using a novel preoperative immunomodulatory regimen in a collaborative care setting. A preoperative regimen consisting of pooled human immune globulin 1%, autologous serum 50%, and methylprednisolone 1% eye drops was prescribed. Outcome measures included visual acuity (VA), ocular surface disease index (OSDI) score, lissamine green staining, and complications with a minimum of 2 years of follow-up. RESULTS Thirty-five eyes from 20 patients with oGVHD were studied. The mean age was 59 years (range 30-70 years). A healthy comparison group included 35 eyes from 24 patients with a mean age of 63 years (range 44-74 years). At the 2-year follow-up, the mean corneal staining score was 2.3/15, the mean OSDI score was 37.5, and the mean VA was 20/30 (logarithm of the minimal angle of resolution 0.17). The global complication rate was 2.8% at the last follow-up with no difference versus a healthy comparison group. CONCLUSIONS A collaborative care model improving ocular surface health before cataract surgery with dry eye and cataract subspecialists can optimize outcomes in patients with oGVHD.
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8.
Real-world experience with ruxolitinib therapy for steroid-refractory acute graft versus host disease
Murray, A., Linn, S. M., Yu, B., Novitzky-Basso, I., Mattsson, J., Kennah, M., Elemary, M., White, J., Lemieux, C., Jamani, K., et al
Bone marrow transplantation. 2024
Abstract
Acute graft versus host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplant (HCT) and is associated with significant morbidity and mortality. Steroid refractory aGVHD (SR-aGVHD) carries a particularly grim prognosis. Ruxolitinib has shown promise for treatment of SR-aGVHD in a phase 3 trial; however, safety and efficacy data outside of the clinical trial setting is lacking. We performed a multicenter retrospective study to examine the response to ruxolitinib and its efficacy in patients with SR-aGVHD. We included 59 patients treated with ruxolitinib for SR-aGVHD between 2015 and 2022. Of these 59 patients, 36 patients (61.0%) achieved a complete (CR) or partial response (PR) at 28 days, while 31 patients (52.5%) obtained a CR/PR at day 56. Patients that achieved a CR or PR at day 28 had a higher rate of overall survival (OS; 69.2%), compared with patients that did not (31.6%; p = 0.037). OS at 12 months was 41.5%, with a median OS duration of 5.3 months. Failure free survival (FFS) at 12 months was 29.1%, with a median FFS of 2.6 months. Overall, this real-world experience data support ruxolitinib as the standard of care for SR-aGVHD in a non-controlled trial population.
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9.
International society for cell & gene therapy stem cell engineering committee: Cellular therapies for the treatment of graft-versus-host-disease after hematopoietic stem cell transplant
Garcia-Rosa, M., Abraham, A., Bertaina, A., Bhoopalan, S. V., Bonfim, C., Cohen, S., DeZern, A., Louis, C., Oved, J., Pavel-Dinu, M., et al
Cytotherapy. 2023
Abstract
BACKGROUND AIMS Allogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment. METHODS We conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords "Graft-versus-Host Disease (GVHD)," "Cellular Therapies," "Regulatory T cells (Tregs)," "Mesenchymal Stromal (Stem) Cells (MSCs)," "Natural Killer (NK) Cells," "Myeloid-derived suppressor cells (MDSCs)," and "Regulatory B-Cells (B-regs)." All the published and available clinical studies were included. RESULTS Although most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario. CONCLUSIONS There are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future.
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10.
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.