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Ruxolitinib in steroid refractory graft-vs.-host disease: a case report.

ABSTRACT: Allogeneic 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.A 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.At 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.

SUBMITTER: Maffini E

PROVIDER: S-EPMC4977623 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Ruxolitinib in steroid refractory graft-vs.-host disease: a case report.

Maffini Enrico E Giaccone Luisa L Festuccia Moreno M Brunello Lucia L Buondonno Ilaria I Ferrero Dario D Boccadoro Mario M Dellacasa Chiara C Busca Alessandro A Novero Domenico D Bruno Benedetto B

Journal of hematology & oncology 20160808 1

<h4>Background</h4>Allogeneic 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 ...[more]

PMID: 27502249

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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.

Project description:Ruxolitinib is an important treatment for steroid refractory graft-versus-host disease (SR-GVHD). Therefore, we reported the updated results of a systematic review and meta-analysis of ruxolitinib as treatment for SR-GVHD. In addition, we wanted to compare the efficacy and safety between children and adults with SR-GVHD. Overall response rate (ORR) after ruxolitinib treatment was chosen as the primary end point. Complete response rate (CRR), infection, myelosuppression, and overall survival (OS) were chosen as secondary end points. A total of 37 studies were included in this meta-analysis, and 1,580 patients were enrolled. ORR at any time after ruxolitinib treatment was 0.77 [95% confidence interval (CI): 0.68–0.84] and 0.78 (95% CI: 0.74–0.81), respectively, for SR-aGVHD and SR-cGVHD. CRR at any time after ruxolitinib treatment was 0.49 (95% CI: 0.40–0.57) and 0.15 (95% CI: 0.10–0.23), respectively, for SR-aGVHD and SR-cGVHD. The ORRs at any time after treatment was highest in mouth SR-cGVHD, followed by skin, gut, joints and fascia, liver, eyes, esophagus, and lung SR-cGVHD. The incidence rate of infections after ruxolitinib treatment was 0.61 (95% CI: 0.45–0.76) and 0.47 (95% CI: 0.31–0.63), respectively, for SR-aGVHD and SR-cGVHD. The incidence rates of overall (grades I–IV) and severe (grades III–IV) cytopenia were 53.2% (95% CI: 16.0%–90.4%) and 31.0% (95% CI: 0.0–100.0%), respectively, for SR-aGVHD, and were 28.8% (95% CI:13.0%–44.6%) and 10.4% (95% CI: 0.0–27.9%), respectively, for SR-cGVHD. The probability rate of OS at 6 months after treatment was 63.9% (95% CI: 52.5%–75.2%) for SR-aGVHD. The probability rates of OS at 6 months, 1 year, and 2 years after treatment were 95% (95% CI: 79.5%–100.0%), 78.7% (95% CI: 67.2%–90.1%), and 75.3% (95% CI: 68.0%–82.7%), respectively, for SR-cGVHD. The ORR, CRR, infection events, and myelosuppression were all comparable between children and adults with SR-GVHD. In summary, this study suggests that ruxolitinib is an effective and safe treatment for SR-GVHD, and both children and adults with SR-GVHD could benefit from ruxolitinib treatment.

Project description:Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P<0.001), while the percentages of NK (CD16+CD56+) cells and regulatory T cells (CD4+CD127 ± CD25+) decreased (P<0.001, P<0.001). Among the B cell subsets, the proportion of total B cells approximately tripled from 3.69% to 11.16% (P<0.001). Moreover, we observed a significant increase in IL-10 levels after ruxolitinib treatment (P=0.025) and a remarkable decrease in levels of suppression of tumorigenicity 2 (ST2) from 229.90 ng/ml to 72.65 ng/ml. The median follow-up after the initiation of ruxolitinib treatment was 401 (6-1076) days. The estimated one-year overall survival rate of the whole group was 66.0% (54.4-77.6%, 95% CI), and the one-year overall survival rate of patients with mild and moderate cGVHD was 69.6% (57.4-81.8%, 95% CI), which was better than that of patients with severe cGVHD (31.3%, 0.0-66.2%, 95% CI) (P=0.002). Patients who achieved a CR and PR achieved better survival outcomes (84.5%, 73.9-95.1%, 95% CI) than those who showed NR to ruxolitinib treatments (16.7%, 0-34.3%, 95% CI) (P<0.001). At the final follow-up, cGVHD relapse occurred in six patients after they reduced or continued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.

Dataset Information

Ruxolitinib in steroid refractory graft-vs.-host disease: a case report.

Publications

Ruxolitinib in steroid refractory graft-vs.-host disease: a case report.

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