Ruxolitinib is an effective steroid sparing agent in children with steroid refractory/dependent bronchiolitis obliterans syndrome after allogenic hematopoietic cell transplantation.
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ABSTRACT:
SUBMITTER: Schoettler M
PROVIDER: S-EPMC7988479 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Ruxolitinib is an effective steroid sparing agent in children with steroid refractory/dependent bronchiolitis obliterans syndrome after allogenic hematopoietic cell transplantation.
Schoettler Michelle M Duncan Christine C Lehmann Leslie L Furutani Elissa E Subramaniam Meera M Margossian Steven S
Bone marrow transplantation 20190125 7
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Project description:Bronchiolitis obliterans syndrome (BOS) is a pulmonary complication of allogeneic hematopoietic cell transplantation (aHCT). Recent National Institutes of Health consensus diagnostic criteria for BOS have not been assessed in a clinical setting. Modified National Institutes of Health diagnostic consensus criteria for BOS were applied to evaluate its prevalence, risk factors, and outcomes in the modern era of aHCT. Pulmonary function tests from 1145 patients were screened to identify patients with new-onset airflow obstruction. Clinical records were reviewed to exclude pulmonary infection and other causes. The overall prevalence of BOS among all transplanted patients was 5.5%, and 14% among patients with chronic graft-versus-host disease (cGVHD). The median time from transplant to meeting spirometric criteria for BOS was 439 days (range: 274-1690). Although many previously identified risk factors were not significantly associated, lower baseline FEV(1)/FVC ratio (P = .006), non-Caucasian race (P = .014), lower circulating IgG level (P = .010), and presence of cGVHD (P < 0.001) were associated with an increase in risk, with the latter associated with a 10-fold increase in risk. Multivariate analysis indicated that BOS conferred a 1.6-fold increase in risk for mortality after diagnosis. These results suggest that the National Institutes of Health diagnostic criteria can reliably identify BOS, and that it is more prevalent than previously suggested. Spirometric monitoring of high-risk patients with cGVHD may permit earlier detection and intervention for this often-fatal disease.
| S-EPMC3061253 | biostudies-literature
Project description:Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic SCT (HSCT) is recognized as a new-onset obstructive lung defect (OLD) in pulmonary function testing and is related to pulmonary chronic GVHD. Little is known about the different phenotypes of patients with BOS and their outcomes. We reviewed the data of all allogeneic HSCT recipients referred to our pulmonary department for a non-infectious bronchial disease between 1999 and 2010. We identified 103 patients (BOS (n=77), asthma (n=11) and chronic bronchitis (n=15)). In patients with BOS, we identified two functional phenotypes: a typical OLD, that is, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 (n=53), and an atypical OLD with a concomitant decrease in the FEV1 <80% and FVC <80% predicted with a normal total lung capacity (n=24). The typical OLD was characterized by more severe FEV1 and fewer centrilobular nodules on the computed tomography scan. The FEV1 was not significantly affected during the follow-up, regardless of the phenotype. In addition to acute and extensive chronic GVHD, only the occurrence of BOS soon after transplantation and the intentional treatment of BOS with steroids were associated with a poor survival. The determination of patient subgroups should be explored to improve the management of this condition.
| S-EPMC7091913 | biostudies-literature
Project description:The use of oral methotrexate for refractory eosinophilic asthma in a tertiary asthma referral centre, Glenfield Hospital, Leicester, was evaluated between January 2006 and December 2014. The patients ( n = 61) were carefully phenotyped at baseline with markers of airway inflammation. In addition, a structured oral methotrexate proforma was utilized to evaluate response to therapy and adverse events. Oral steroid withdrawal was attempted 3 months after commencing treatment. Several outcomes were evaluated at 12 months, including both efficacy and adverse effects; 15% ( n = 9/61) responded by achieving a decrease in daily oral corticosteroid dose (mean 8.43 (±8.76) mg), although we were unable to identify factors that predicted a treatment response. There were no other significant changes in any other clinical outcome measures. There was a high rate of adverse events (19/61 (31%)), primarily gastrointestinal/hepatitis. Our findings support the use of biological agents in preference to using oral methotrexate as a steroid sparing agent at the first instance. In the event of failure of these agents, oral methotrexate remains a therapeutic option, which can be considered in highly specialist severe asthma centres.
| S-EPMC5802657 | biostudies-literature
Project description:Bronchiolitis obliterans syndrome (BOS) is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation (HCT). Montelukast interrupts cysteinyl leukotriene (CysLT) activity and may diminish the activation and homing of cells to bronchioles and subsequent fibrosis. We performed a prospective phase II trial to test whether montelukast altered lung decline for patients with BOS after HCT. In this single-arm, open-label, multi-institutional study, the primary endpoints were stability or improvement (<15% decline) in forced expiratory volume in 1 second (FEV1) and a <1-point decline in the slope of FEV1 after 6 months of treatment. Secondary endpoints included symptom and functional responses and immune correlates investigating the role of leukotrienes in BOS progression. The study enrolled 25 patients with moderate to severe lung disease after 3 months of stable cGVHD therapy. Montelukast was well tolerated, and no patient required escalation of BOS-directed therapy. At the primary endpoint, all 23 evaluable patients met the criteria for treatment success using FEV1% predicted, and all but 1 patient had stable or improved FEV1 slope. In those with a >5% improvement in FEV1, clinically meaningful improvements were seen in the Lee scores of breathing, energy, and mood. Improvements in the Human Activity Profile and 6-minute-walk test were observed in those with a <5% decline in FEV1. Overall survival was 87% at 2 years. Immune correlates showed elevated leukotriene receptor levels on blood eosinophils and monocytes versus healthy controls, elevated urine leukotrienes in 45% of the cohort, and CysLT receptors in bronchoalveolar lavage subsets and a predominance of Th2 cells, all pretreatment. These data suggest that montelukast may safely halt the progression of BOS after HCT, and that leukotrienes may play a role in the biology of BOS.
| S-EPMC9081205 | biostudies-literature
Project description:In past years, a diagnosis of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant (HCT) conferred nearly universal mortality secondary to lack of consensus for diagnostic criteria, poorly understood disease pathogenesis, and very few studies of therapeutic or supportive care interventions. Recently, however, progress has been made in these areas: revised consensus diagnostic guidelines are now available, supportive care has improved, there is greater understanding of potential mechanisms of disease, and prospective trials are being conducted. This article describes these advances and provides suggestions to optimize therapy for patients with BOS after HCT.
| S-EPMC5270387 | biostudies-literature
Project description:AbstractBronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial, adult participants with BOS were treated with ruxolitinib 10 mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared with enrollment. The primary end point differed according to cohort (cohort A, improvement, defined as ≥10% increase in FEV1; cohort B, stabilization, defined as an absence of ≥10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting the criteria for BOS were enrolled and treated (cohort A, n = 36; cohort B, n = 13). The primary end point was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 National Institutes of Health Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response and 18.4% partial response), with most responses occurring in mild or moderate disease. Noninfectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03674047.
| S-EPMC11782820 | biostudies-literature
Project description:ImportanceRuxolitinib, a selective inhibitor of the Janus kinases 1/2 signaling pathway, has shown a significant response in steroid-refractory chronic graft-vs-host disease (SR-cGVHD), a major cause of morbidity and mortality in individuals who have undergone allogeneic hematopoietic stem cell transplantation (HSCT).ObjectivesTo investigate the clinical response to ruxolitinib in patients with SR-cGVHD after allogeneic HSCT and to evaluate its safety profile during the treatment course.Design, setting, and participantsThis single-center case series included 41 consecutive patients who were treated with ruxolitinib for SR-cGVHD after allogeneic HSCT between August 2017 and December 2019. Data were collected from each patient's medical record at the First Affiliated Hospital of Zhejiang University School of Medicine. Data analysis was conducted from March to May 2020.ExposureRuxolitinib.Main outcomes and measuresTreatment responses, factors associated with response, and adverse effects during ruxolitinib administration.FindingsOverall, 41 patients (median [range] age, 31 [17-56] years; 14 [34.1%] women) were treated with ruxolitinib and included in this study. A total of 15 patients (36.6%) had a complete remission, and 14 (34.1%) had a partial remission, with an overall response rate of 70.7% (29 patients; 95% CI, 56.2%-85.3%). Lung involvement (odds ratio, 0.112; 95% CI, 0.020-0.639; P = .01) and matched related donors (odds ratio, 0.149; 95% CI, 0.022-0.981; P = .048) were associated with less favorable treatment response. Major adverse events associated with ruxolitinib were cytopenias and infectious complications. The median (range) follow-up for this cohort was 14.9 (1.4-32.5) months. Prolonged survival was observed in patients with a male donor (P = .006), complete remission before transplantation (P = .02), baseline moderate cGVHD (P = .02), and skin cGVHD (P = .001).Conclusions and relevanceIn this small, single-site case series, ruxolitinib demonstrated a significant response in heavily pretreated patients with SR-cGVHD and a reasonably well-tolerated safety profile. The results add to the body of literature suggesting ruxolitinib as a promising treatment option in SR-cGVHD.
| S-EPMC7841467 | biostudies-literature
Project description:Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.
| S-EPMC7812291 | biostudies-literature
Project description:Bronchiolitis obliterans syndrome (BOS) is considered an airway-centered disease, with bronchiolitis obliterans (BO) as pathologic hallmark. However, the histologic spectrum of pure clinical BOS remains poorly characterized. We provide the first in-depth histopathologic description of well-characterized BOS patients and patients without chronic lung allograft dysfunction (CLAD), defined according to the recent consensus guidelines. Explant lung tissue from 52 clinically-defined BOS and 26 non-CLAD patients (collected 1993-2018) was analyzed for histologic parameters, including but not limited to airway lesions, vasculopathy and fibrosis. In BOS, BO lesions were evident in 38 (73%) patients and varied from concentric sub-epithelial fibrotic BO to inflammatory BO, while 10/14 patients without BO displayed 'vanishing airways', defined by a discordance between arteries and airways. Chronic vascular abnormalities were detected in 22 (42%) patients. Ashcroft fibrosis scores revealed a median of 43% (IQR: 23-69) of normal lung parenchyma per patient; 26% (IQR: 18-37) of minimal alveolar fibrous thickening; and 11% (IQR: 4-18) of moderate alveolar thickening without architectural damage. Patchy areas of definite fibrotic damage to the lung structure (i.e., Ashcroft score ≥5) were present in 28 (54%) patients. Fibrosis was classified as bronchocentric (n = 21/28, 75%), paraseptal (n = 17/28, 61%) and subpleural (n = 15/28, 54%). In non-CLAD patients, BO lesions were absent, chronic vascular abnormalities present in 1 (4%) patient and mean Ashcroft scores were significantly lower compared to BOS (p = 0.0038) with 78% (IQR: 64-88) normally preserved lung parenchyma. BOS explant lungs revealed evidence of various histopathologic findings, including vasculopathy and fibrotic changes, which may contribute to the pathophysiology of BOS.
| S-EPMC8745215 | biostudies-literature
Project description:BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK)1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited.Case presentationA 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34(+) cells/kg infused were 8.69 × 10(6) kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54.ConclusionsAt 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.
| S-EPMC4977623 | biostudies-literature