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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.
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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3.
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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4.
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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5.
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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6.
Exploration of efficacy and safety of combined therapy of basiliximab with ruxolitinib for grade 3-4 steroid-refractory acute graft-versus-host disease: a registered clinical trial (NCT05021276)
Zhou, F., Pan, T., Li, X., Du, F., Ma, X., Zhang, Y., Wu, D., Han, Y., Xue, S., Miao, M., et al
Bone marrow transplantation. 2023
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7.
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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8.
Bath psoralen plus ultraviolet-A photochemotherapy for chronic graft-versus-host disease: a retrospective cohort study
Kassem, R., Barzilai, A., Pras, E., Sizopoulou, C., Pavlotsky, F.
International journal of dermatology. 2023
Abstract
BACKGROUND Chronic graft-versus-host disease is a severe complication of allogeneic stem cell and bone marrow transplantation. First-line immunosuppressive agents, such as steroids, are used to prevent this disease; however, they have multiple side effects. Therefore, bath psoralen plus ultraviolet-A (PUVA) is an alternative second-line treatment. This study aimed to evaluate the clinical efficacy of bath PUVA for managing chronic graft-versus-host disease. METHODS This retrospective, case-control study included 14 patients with extensive cutaneous chronic graft-versus-host disease, resistant to systemic corticosteroid, treated with bath PUVA. Major and partial responses were defined as clinical improvements of >70% and 50-70%, respectively. We analyzed the graft-versus-host disease clinical presentation and timing after allogeneic stem cell and bone marrow transplantation, bath PUVA doses, background diseases, additional treatments, and adverse effects. RESULTS We observed eight major (three lichenoid and five sclerodermatoid) and six partial (three lichenoid and three sclerodermatoid) responses after a mean of 28 treatment sessions. After 6 to 25 months, four of the eight patients with sclerodermatoid lesions and all those with lichenoid lesions experienced relapse but responded to additional treatment cycles. CONCLUSIONS Bath PUVA is well-tolerated and effective for extensive cutaneous chronic graft-versus-host disease. It allows rapid tapering of adjuvant immunosuppressants; however, most patients require prolonged maintenance phototherapy.
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9.
Itacitinib Population Pharmacokinetics and Exposures/Response in Patients With Acute Graft-Versus-Host Disease
Chen, X., Xun, Z., Yuska, B., McGee, R., Yeleswaram, S.
Journal of clinical pharmacology. 2023
Abstract
This paper presents the population pharmacokinetic (PopPK) analysis and exposure/response analyses for the primary efficacy endpoint-acute graft-versus-host disease (aGVHD) Day 28 response-and select safety measures (incidence of thrombocytopenia, hypertriglyceridemia, and cytomegalovirus infection) from a phase 3 randomized, double-blind study comparing itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of aGVHD. The PopPK dataset contained sparse data from aGVHD patients and select enriched data from healthy volunteers. The structural model was a 2-compartment model with first-order elimination and dose-dependent nonlinear absorption with dual first-order absorption pathways with lag times. Strong cytochrome P450 3A (CYP3A) inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs aGVHD patients) were covariates on apparent clearance. Participant population was also a covariate on apparent intercompartmental clearance and lag time of the secondary absorption compartment. Apparent clearance decreased 42% with coadministration of strong CYP3A inhibitors. Simulations supported the following dose reductions with concomitant use of a strong CYP3A inhibitor: 300 mg once daily (QD) to 200 mg QD, 400 mg QD to 300 mg QD, and 600 mg QD to 400 mg QD. No dose adjustment is recommended for any other covariate based on the magnitude of impact when they were retained in the model. The exposure/response relationship was characterized between itacitinib exposure and probability of aGVHD Day 28 response using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were significant predictors of response. There was no relationship between itacitinib exposure and thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection. This article is protected by copyright. All rights reserved.
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10.
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.