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Salvage Therapy With Low-Dose Ruxolitinib Leads to a Significant Improvement in Bronchiolitis Obliterans Syndrome in Patients With cGVHD After Allogeneic Hematopoietic Stem Cell Transplantation
Zhao, Y., OuYang, G., Shi, J., Luo, Y., Tan, Y., Yu, J., Fu, H., Lai, X., Liu, L., Huang, H.
Frontiers in pharmacology. 2021;12:668825
Abstract
Bronchiolitis obliterans syndrome (BOS) is a life-threatening pulmonary manifestation of chronic graft versus host disease (cGVHD) post-allogeneic hematopoietic stem cell transplantation (HSCT), without clear standard of care. This study included 30 patients undergoing an allogeneic HSCT for a hematological malignancy and the outcomes with post-HSCT BOS treated with ruxolitinib as a salvage treatment were reviewed. After a median duration of ruxolitinib therapy of 9.25 (1.5-27) months, the best overall response (BOR) rate was 66.7%: three patients (10.0%) achieved complete remission, and 17 (56.7%) achieved partial remission. The median time from initiation of ruxolitinib to achieve the best responses was 3 months. Since initiating ruxolitinib, forced expiratory volume in 1 s of predicted (FEV1%pred) slightly increased after 3 and 6 months compared with measurements before ruxolitinib in responders. Only FEV1%pred mild decline before ruxolitinib with a ratio =15% was an independent predictor to achieve a response to ruxolitinib. Eleven patients (36.7%) had severe pulmonary infection of =3 grade. Following a median follow-up of 318 days after ruxolitinib, the 2-years incidence of nonrelapse mortality and 2-years overall survival rate after ruxolitinib among patients with BOS was 25.1 and 62.6%, respectively. Ruxolitinib is a promising treatment option to improve the prognosis of post-HSCT BOS.
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The disposable bandage soft contact lenses therapy and anterior segment optical coherence tomography for management of ocular graft-versus-host disease
Sun, Y. C., Inamoto, Y., Wang, R. K., Lee, S. J., Hung, K. F., Shen, T. T.
BMC ophthalmology. 2021;21(1):271
Abstract
PURPOSE To identify the ocular surface changes of ocular graft-versus-host disease (GVHD) using anterior segment optical coherence tomography (AS-OCT) and examine the efficacy of disposable bandage soft contact lens (BSCL) treatment in ocular GVHD patients. METHODS This study is a prospective, Phase II clinical trial. Nineteen patients diagnosed with chronic GVHD based on the NIH criteria and ocular symptoms of NIH eye score 2 or greater were enrolled. Disposable BSCL was applied to the GVHD-affected eyes with topical antibiotic coverage. Ocular exams, eye symptom surveys, and AS-OCT were performed with signed informed consent. Patients were followed for one to three months. RESULTS Thirty-eight eyes of 19 patients with ocular GVHD underwent BSCL treatment in this study. AS-OCT scans were done in 14 out of 19 patients. The mean best-corrected visual acuity at enrollment, 2-week, and 4-week visits was 0.180, 0.128, and 0.163 logMAR, respectively. Twenty-four out of 25 eyes (96 %) that initially presented with conjunctival inflammation, twenty-three out of 30 eyes (76.7 %) that initially presented with punctate epithelial erosion, and 8 out of 15 (53.3 %) eyes that initially presented with filamentous keratopathy showed improvement after wearing BSCL for 2 to 4 weeks. AS-OCT revealed corneal epithelial irregularity, abnormal meibomian gland orifice, and conjunctival hyperemia, in patients with ocular GVHD. CONCLUSIONS BSCL treatment provided significant subjective and objective improvements in ocular GVHD patients. Meanwhile, we found that AS-OCT can be a promising diagnostic tool to characterize the ocular surface changes associated with ocular GVHD.
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Efficacy and Safety of 1% Progesterone Gel to the Forehead for Ocular Chronic Graft-versus-Host Disease
Luo, Z. K., Domenech-Estarellas, E. A., Han, A., Lee, D., Khatri, R., Wahl, J. L., Cutler, C., Armand, P., Antin, J. H., Koreth, J., et al
Transplantation and cellular therapy. 2021
Abstract
There is no Food and Drug Administration-approved treatments for ocular chronic graft-versus-host disease (oGVHD) to date, and current therapeutic options are limited. Forehead application of 1% progesterone gel provides corneal antinociception in preclinical models, suggesting it may be useful in alleviating ocular irritations. This study was conducted to evaluate the efficacy and safety of 1% progesterone gel in treating moderate to severe symptomatic oGVHD. Thirty-three patients with oGVHD following allogeneic stem cell transplantation were enrolled in this single-center, sponsor-initiated, prospective exploratory randomized double-masked placebo-controlled phase II clinical trial. The inclusion criteria included a National Institutes of Health consensus score of =2, moderate to severe ocular discomfort level, and receipt of a stable immunosuppression regimen. Twenty-one of the 22 patients in the progesterone arm and all 11 patients in the placebo arm completed the course of twice-daily forehead drug application for 10 weeks. The changes from baseline of self-reported ocular symptom scores and physician-recorded cornea fluorescein staining scores were analyzed using mixed-model repeated-measures regression model in an intention-to-treat population. The 33 patients included 12 women and 21 men, with a median age of 66 years (range, 24 to 75 years). At 10 weeks, there was a significant reduction in ocular symptoms from baseline in the progesterone group compared with the placebo group in symptom frequency (-30.7 versus -2.2; P < .001) and severity (-19.8 versus +1.6; P = .005). At 10 weeks, there was also greater reduction of cornea fluorescein staining centrally (-1.2 versus +.1; P = .001) and inferiorly (-1.4 versus -0.2; P = .005). No difference was noted in superior cornea staining. There were no severe adverse events in the progesterone group. Forehead application of 1% progesterone gel significantly improved ocular signs and symptoms within 10 weeks. It appears to be a safe and effective new therapy for oGVHD, and a novel mechanism for neuroaxis drug delivery. A multicenter phase III clinical trial is planned for further validation.
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Resolved versus active chronic graft-versus-host disease: Impact on post-transplant quality of life
Kurosawa, S., Yamaguchi, T., Oshima, K., Yanagisawa, A., Fukuda, T., Kanamori, H., Mori, T., Takahashi, S., Kondo, T., Kohno, A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
The aim of this study was to determine if impaired quality of life (QOL) persisted among patients who experienced resolved chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Eligible participants were patients who were relapse-free for 3 years after allo-HCT who were aged ≥16 years at transplant and aged ≥20 years without relapse at survey. The SF-36, FACT-BMT, and VAS were administered to assess QOL. Physicians evaluated the current status of chronic GVHD at survey by NIH criteria, and pre-transplant characteristics and history of GVHD were extracted from the national transplant registry database. Patients without currently active GVHD but with a history of chronic GVHD were categorized as having "resolved GVHD." Of 1250 patients informed of the study, 1216 provided consent, and 1130 patients were included in the final analysis. A total of 745 patients (66%) had currently active chronic GVHD, 149 (13%) had resolved chronic GVHD, and 236 (21%) never had chronic GVHD after allo-HCT. Multivariable analyses showed that compared to patients with resolved or no chronic GVHD, those with active chronic GVHD reported significantly poorer QOL. QOL scores were similar between patients with resolved and no chronic GVHD. Larger differences were observed in SF-36 physical component and VAS scores between the two groups in patients aged ≥50 years, however these were not statistically significant. In conclusion, only currently active chronic GVHD has a significant impact on physical, mental, and social QOL in allo-HCT survivors, while past chronic GVHD does not impair QOL if it is resolved.
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Immunohistopathological characterization and the impact of topical immunomodulatory therapy in oral chronic graft-versus-host disease: A pilot study
Motta, A., Zhan, Q., Larson, A., Lerman, M., Woo, S. B., Soiffer, R. J., Murphy, G. F., Treister, N. S.
Oral diseases. 2018;24(4):580-590
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Abstract
OBJECTIVE To characterize the immunohistopathological features of oral chronic graft-versus-host disease (cGVHD), and the impact of topical immunomodulatory therapy on the infiltrating cells. MATERIAL AND METHODS Paired oral cGVHD biopsies obtained before (n = 12) and 1 month after treatment (n = 12) with topical dexamethasone (n = 8) or tacrolimus (n = 4) were characterized by immunohistochemistry using a panel of CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3. Controls included acute GVHD (aGVHD; n = 3), oral lichen planus (OLP; n = 5), and normal tissues (n = 5). RESULTS Oral cGVHD specimens prior to treatment were mainly characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating cells in oral cGVHD primarily consisted of CD3(+) , CD4(+) , CD8(+) , CD103(+) , CD163(+) , and FoxP3(+) cells, which were higher than in normal tissues. Topical dexamethasone or tacrolimus reduced neutrophilic exocytosis, basal cell squamatization, and lichenoid inflammation in oral cGVHD, and dexamethasone reduced the number of CD4(+) and CD103(+) cells. CONCLUSION The high expression of CD3, CD4, CD8, CD103, CD163, and FoxP3 confirms that oral cGVHD is largely T-cell-driven with macrophage participation. The impact of topical immunomodulatory therapy was variable, reducing histological inflammatory features, but with a weak clinicopathological correlation. Topical dexamethasone reduced the expression of CD4 and CD103, which may offer novel therapeutic targets.
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Efficacy and Safety of Topical Corticosteroids for Management of Oral Chronic Graft versus Host Disease
Elsaadany, B. A., Ahmed, E. M., Aghbary, S. M. H.
International Journal of Dentistry. 2017;2017:1908768
Abstract
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.
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A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation
Arai, S., Pidala, J., Pusic, I., Chai, X., Jaglowski, S., Khera, N., Palmer, J., Chen, G. L., Jagasia, M. H., Mayer, S. A., et al
Clinical Cancer Research. 2016;22(2):319-27
Abstract
PURPOSE Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. EXPERIMENTAL DESIGN We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly x 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy. RESULTS SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients. CONCLUSIONS These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab. Copyright ©2015 American Association for Cancer Research.
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A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease
Abud, T. B., Amparo, F., Saboo, U. S., Di Zazzo, A., Dohlman, T. H., Ciolino, J. B., Hamrah, P., Dana, R.
Ophthalmology. 2016;123(7):1449-57
Abstract
PURPOSE To evaluate the safety and efficacy of topical tacrolimus 0.05% versus topical methylprednisolone 0.5% in patients with ocular graft-versus-host disease (GVHD). DESIGN Phase 1/2 prospective, randomized, double-masked clinical trial. PARTICIPANTS Eighty eyes of 40 patients diagnosed with chronic ocular GVHD were enrolled. METHODS Forty patients with ocular GVHD were randomized; 24 patients were treated with topical tacrolimus 0.05% and 16 patients were treated with topical methylprednisolone 0.5% twice daily for 10 weeks, in addition to continuing their baseline treatment regimen. MAIN OUTCOME MEASURES Safety was evaluated based on occurrence of adverse events. Tolerability was assessed based on subject reports of discomfort after drop instillation. Intraocular pressure (IOP) was monitored. The main efficacy end points were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1). Symptoms were evaluated using the Ocular Surface Disease Index (OSDI). RESULTS After 10 weeks of treatment, no major adverse events occurred in either treatment group, and there was no significant difference in the composite tolerability scores between the 2 groups (P = 0.06). However, burning sensation was more pronounced with tacrolimus (P = 0.002). Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score at week 10 (55% vs. 23% reduction, respectively; P = 0.01) and achieved significant improvement in TBUT when compared with baseline (P < 0.001). Reduction in OSDI score achieved statistical significance with tacrolimus (27% reduction; P = 0.02), but was marginal with methylprednisolone (32% reduction; P = 0.06). Expression of ICAM-1 by ocular surface epithelium decreased significantly in both groups (tacrolimus, P = 0.003; methylprednisolone, P = 0.008), whereas HLA-DR expression decreased significantly only in the tacrolimus group (P = 0.03). Schirmer test scores did not change significantly in either group during the study; IOP increased significantly with methylprednisolone at week 10 (P = 0.04). CONCLUSIONS Topical tacrolimus 0.05% is safe, generally well tolerated, and effective for the treatment of ocular GVHD without the hypertensive effects of topical corticosteroids. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.