To Respond or Not to Respond: That’s the Question in Bronchiolitis Obliterans Syndrome Treatment

Bronchiolitis obliterans syndrome (BOS), the obstructive phenotype of chronic lung allograft dysfunction (CLAD), remains the primary cause of long-term graft failure after lung transplantation.1 Although no therapies have been shown to fully reverse the spirometric loss of allograft function once BOS is established, certain interventions may temporarily slow the progressive decline of pulmonary function in some patients. Progression of BOS—typically reflected by a decrease in forced expiratory volume in the first second (FEV1) and occurring mainly within the first 6 mo after onset—is a known risk factor for mortality.2 Consequently, it is essential to better characterize the rate and trajectory of FEV1 decline in patients receiving the current standard-of-care (SOC) immunosuppressive therapy for BOS. This understanding is critical for identifying treatment-refractory BOS suitable for rescue or advanced therapies, such as extracorporeal photopheresis, and for informing the design of interventional clinical trials comparing investigational medicinal therapies with SOC treatment in BOS. The recent study by Hage et al3 analyzing the rate of FEV1 decline in a cohort of 258 patients with BOS treated with SOC therapy across 21 US transplant centers, represents an important advance in defining spirometric criteria for identifying refractory BOS. This work may also provide valuable guidance for evaluating treatment responses in future comparative studies.3 The authors examined FEV1-versus-time slopes before and after BOS diagnosis, categorizing changes in FEV1 decline according to response to SOC treatment (ie, partial response: any slowing of FEV1 decline; >50% response: >50% reduction in the rate of FEV1 decline), and identified several key findings. First, SOC interventions demonstrated only a modest ability to attenuate the rate of FEV1 decline in BOS. Most patients continued to experience post-treatment FEV1 loss, with only 19% achieving durable stabilization of FEV1 (defined as a decline <30 mL/mo). These findings highlight the substantial unmet need for more effective BOS therapies and provide strong justification for future randomized clinical trials (RCTs). Such trials could use spirometry-based stratification (eg, defining treatment-refractory BOS as an FEV1 decline >30 mL/mo) or use changes in FEV1 decline as a spirometric endpoint to assess treatment efficacy. Further guidance on clinical trial design in CLAD will be provided in the forthcoming International Society for Heart and Lung Transplantation consensus statement on lung transplant clinical trial endpoints, in which CLAD progression—defined by an FEV1 (±FVC) decline of >10%—is recognized as a valid endpoint for therapeutic studies.4 Next, considerable variability in response to SOC treatment was observed. Most patients exhibited, at best, a modest slowing in the rate of FEV1 decline, with only 25% of patients achieving a > 50% reduction in FEV1 decline (“strong responders”). Among patients with progressive disease, approximately half demonstrated some attenuation of decline with SOC therapy (“partial responders”), whereas the remainder showed no reduction in the rate of FEV1 decline—and, in fact, experienced a further acceleration in their monthly rate of FEV1 decline despite SOC intervention. This subgroup, characterized by an average decline of −150 mL/mo (or a 224% faster rate of loss), corresponds to the previously described “rapid decliners,” who are thought to be at particularly high risk for early graft failure and death following BOS onset.5,6 Currently, it remains impossible to prospectively identify these rapid decliners, which limits the ability to implement early or intensified therapeutic strategies. Furthermore, no single therapeutic agent—or combination thereof—was significantly associated with the observed treatment responses. This may, in part, reflect the fact that most patients in the study (81%) had advanced BOS (stage 2 or 3), disease severity known to be less responsive to therapy due to irreversible fibrotic small airway remodeling from constrictive bronchiolitis. The observed variability in SOC response and the absence of a clear treatment–response relationship underscores the current gaps in understanding BOS pathobiology, the pressing need for disease-specific biomarkers to guide clinical decision-making, the lack of RCTs to assess treatment efficacy, and the broader unmet need for personalized therapeutic approaches. Yet, in contrast with other serious disorders, novel biologicals remain vastly unexplored in CLAD, and over the past decade only a limited number of RCTs are conducted in BOS/CLAD, including studies comparing pirfenidone (NCT02262299 and NCT03473340), nintedanib (NCT03283007), inhaled cyclosporine-A (NCT03657342, NCT03656926, and NCT04039347), belumosudil (NCT06082037), and extracorporeal photopheresis (2022-002659-20) to SOC and/or placebo. However, these studies have either failed to produce positive results—as with pirfenidone7—or are still ongoing, with results yet to be published. Finally, substantial variability was observed in SOC regimens used to manage BOS across the 21 centers, encompassing 18 different immunosuppressive combinations involving seven agents, as well as modifications in 1 or more of 11 drugs used for active BOS management. Comparable heterogeneity in CLAD treatment practices was recently also reported in a European survey of 44 transplant centers, which demonstrated wide variation in preferred first-, second-, and third-line therapeutic strategies.8 Although BOS is a well-recognized and clearly defined clinical entity, there are currently no evidence-based treatment guidelines. Consequently, therapeutic approaches often differ markedly between clinicians and centers—shaped by individual experience and preference, institutional traditions, local drug availability, patient-specific preferences, and comorbidities. These differences can influence both the choice of SOC therapies and the selection of subsequent interventions or treatment-lines for BOS/CLAD. Such variability complicates cross-center comparisons of BOS cohorts and underscores the pressing need for international harmonization of management strategies, and the development of evidence-based guidelines for BOS treatment—akin to established frameworks in other obstructive airway diseases, such as the Global Initiative for Chronic Obstructive Lung Disease and Global Initiative for Asthma guidelines for chronic obstructive pulmonary disorder and asthma, respectively. In conclusion, BOS progression under current SOC therapy remains highly variable, with most patients continuing to experience functional decline. Employing the rate of FEV1 decline as a biomarker offers a practical approach to identifying refractory BOS and optimizing both clinical decision-making and patient selection for clinical trials—key steps toward the development of evidence-based guidelines for BOS management. Thus, the key question is therefore no longer whether or not a BOS patient will respond to SOC therapy, but whether the lung transplant community is ready, willing and able to conduct more comparative RCTs evaluating promising novel therapies against SOC/placebo treatment in BOS—and by extrapolation in CLAD.