Ruxolitinib Treatment for Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplant in a Patient with Primary Hemophagocytic Lymphohistiocytosis
Bronchiolitis obliterans syndrome (BOS) is a severe and often life-threatening complication that can arise following allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is considered a manifestation of chronic graft-versus-host disease (cGVHD) and is characterized by progressive airflow obstruction and decline in lung function. The pathogenesis of BOS remains poorly understood, and its clinical presentation can be insidious, with up to 20% of patients remaining asymptomatic. Despite advancements in transplantation medicine, the long-term prognosis for BOS remains poor, with a 5-year survival rate ranging from 13% to 56%. Current treatment strategies primarily focus on preventing disease progression and improving lung function, but the effectiveness of these approaches is often limited. This article discusses a case of BOS in a patient with primary hemophagocytic lymphohistiocytosis (HLH) who underwent allo-HSCT and highlights the potential role of ruxolitinib as a therapeutic option for steroid-refractory BOS.
Case Presentation
The patient, a 20-year-old male, was initially diagnosed with primary HLH, a rare and severe immune disorder characterized by excessive activation of immune cells. He was treated with a combination of methylprednisolone and etoposide (VP-16) for 24 weeks. However, one month after completing treatment, the HLH recurred. The patient was then referred to the Hematology Department of Beijing Friendship Hospital, where genetic testing revealed a PRF1 fusion gene mutation, confirming the diagnosis of primary HLH. He was subsequently treated with a regimen of liposomal doxorubicin, VP-16, and methylprednisolone (DEP), which resulted in complete remission.
In July 2014, the patient underwent allo-HSCT from a human leukocyte antigen (HLA)-5/10-matched bone marrow donor. The conditioning regimen prior to transplantation included total-body irradiation, cyclophosphamide, and VP-16 (TBI/CY/VP-16). To prevent GVHD, the patient received cyclosporine, methotrexate, and mycophenolate mofetil. Despite these prophylactic measures, the patient developed chronic GVHD (cGVHD) affecting the liver two years post-transplant. He was treated with methylprednisolone and tacrolimus (FK506), but his condition remained challenging.
Development of Bronchiolitis Obliterans Syndrome
Twenty-six months after the HSCT, the patient was re-admitted to the hospital due to progressive dyspnea. Prior to the transplant, his pulmonary function tests (PFTs) were normal, with a forced expiratory volume in 1 second (FEV1) of 115.2% of the predicted value and an FEV1/forced vital capacity (FVC) ratio of 87.5%. However, post-transplant PFTs revealed a significant decline in lung function, with an FEV1 of 31.7% and an FEV1/FVC ratio of 36.6%. A high-resolution computed tomography (CT) scan of the chest showed multiple columnar bronchiectasis and air-trapping in both lungs, consistent with a diagnosis of BOS. There was no evidence of lung or other organ infections.
Initial Treatment and Lack of Response
The patient was initially treated with methylprednisolone (8 mg twice daily) and FK506 (3 mg twice daily) for three months. Despite this treatment, his dyspnea symptoms did not improve, and there was no significant increase in FEV1. Subsequently, the patient received intermittent treatment with mesenchymal stem cells (MSCs) at a dose of 100 mL containing 5 × 10^7 cells per 100 mL. However, this intervention also failed to alleviate his symptoms, and his FEV1 continued to decline, reaching a nadir of 24.6%.
Introduction of Ruxolitinib
Given the lack of response to conventional therapies, ruxolitinib, a Janus kinase (JAK) inhibitor, was initiated at a dose of 10 mg twice daily, and MSC treatment was discontinued. After three months of ruxolitinib therapy, the patient achieved some degree of stability and improvement in BOS symptoms, with an FEV1 of 35.1%. During this period, the daily dose of methylprednisolone was gradually reduced to 2 mg twice daily. Ruxolitinib treatment was continued for a total of seven months, and the patient remained alive and attended a 3.5-year follow-up visit. However, chest CT imaging revealed that multiple bronchiectasis persisted despite the completion of ruxolitinib treatment.
Discussion
Allo-HSCT is a curative treatment for primary HLH, but it is associated with a high risk of late-onset complications, including BOS. The incidence of pulmonary complications in allo-HSCT recipients is approximately 20%, with BOS being one of the most common manifestations of cGVHD. The pathogenesis of BOS is not fully understood, but it is believed to involve immune-mediated damage to the small airways, leading to fibrosis and obstruction.
The current standard of care for BOS includes systemic corticosteroids, which are the first-line therapy for GVHD. However, long-term use of high-dose corticosteroids is associated with significant side effects, including an increased risk of infections, which can exacerbate BOS. In cases where corticosteroids are ineffective, alternative treatments such as MSCs and calcineurin inhibitors like FK506 are often employed. However, as demonstrated in this case, these interventions may not always provide significant clinical benefit.
Ruxolitinib has emerged as a promising second-line agent for steroid-refractory cGVHD. Its mechanism of action involves the suppression of pro-inflammatory signaling pathways and the promotion of tolerogenic regulatory T cells. Several studies have reported positive outcomes with ruxolitinib in patients with steroid-refractory cGVHD. For example, Ferreira et al. observed an overall response rate of 75% in 20 patients with steroid-refractory cGVHD treated with ruxolitinib. Similarly, Khoury et al. reported that 19 patients with steroid-refractory cGVHD showed varied degrees of response in several target organs, with 18 patients achieving a partial response and one patient achieving a complete response.
The use of ruxolitinib in the treatment of BOS, a pulmonary manifestation of cGVHD, has also been explored. Streiler et al. reported that six patients with BOS treated with ruxolitinib were able to tolerate a significant reduction in prednisone dosing, with one patient being taken off prednisone entirely. These patients also exhibited immediate and marked improvements in FEV1. Schoettler et al. described five pediatric patients with extensive cGVHD and steroid-refractory BOS who achieved partial or complete responses in all organ systems following ruxolitinib treatment.
In the present case, the patient achieved some degree of improvement in BOS symptoms and FEV1 after initiating ruxolitinib treatment, despite prior lack of response to steroids, FK506, and MSCs. This suggests that ruxolitinib may have a positive therapeutic effect on BOS that is refractory to conventional therapies. However, it is important to note that while ruxolitinib improved symptoms and stabilized lung function, it did not completely resolve the bronchiectasis observed on chest CT imaging.
Conclusion
This case highlights the challenges associated with the management of BOS following allo-HSCT and underscores the potential role of ruxolitinib as a therapeutic option for steroid-refractory BOS. While the patient experienced some degree of clinical improvement with ruxolitinib, the persistence of bronchiectasis suggests that further research is needed to optimize treatment strategies for this debilitating condition. Prospective studies are warranted to confirm the efficacy of ruxolitinib in the treatment of BOS and to explore its potential in combination with other therapies.
doi.org/10.1097/CM9.0000000000001324
Was this helpful?
0 / 0