Preemptive Intervention in Airflow Obstruction Status Prevents the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Stem Cell Transplantation: Multicenter, Prospective Phase II Study (Chiba AFO-01)

Abstract

Background: Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (allo-HCT) is recognized as pulmonary chronic graft-versus-host disease (GVHD), a progressive, irreversible, and sometimes fatal complication. Periodic pulmonary function testing (PFT) for early diagnosis and timely therapeutic intervention is essential. However, effective monitoring and adequate treatment strategy for BOS have not been established. The airflow obstruction (AFO) criteria (predicted FEV1 second decreased by 5% a year or more, and FEV1-second rate <80%) had proposed to detect of a precursor of BOS, and even at AFO status, it was confirmed that increasing the risk in mortality of 2.3-fold (95% CI, 1.6- 3.3; P < 0.001) (JW Chien et al. Am J Respir Crit Care Med. 2003). In our single-center retrospective analysis, 67.2% of AFO patients progressed to BOS, and similarly, the AFO was associated with poor survival (Nakao et al., in submission). Although immunosuppressive agents, especially steroids, are usually administered or augmented for new-onset BOS, sufficient response has not necessarily been obtained. The feasibility study with inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse had been reported, which was well tolerated; however, about one-third were a failure at 6 months, showed efficacy was extremely limited in advanced BOS. From these findings, we hypothesized that close monitoring and early intervention from the diagnosis of AFO using inhaled steroid long-acting β2-agonist budesonide/formoterol fumarate hydrate, clarithromycin, and montelukast (BCM) triplet therapy, could avert the progression to BOS. We conducted a multicenter, single-arm, open-label, prospective phase II study (Chiba AFO-01). This study was approved by the certified clinical research review board at Chiba University Hospital. (jRCTs031180338) Patients and Method: PFT was performed before and every 3 months after allo-HCT for 2 years, and from the time when the AFO criteria were met, BCM therapy was started and continued for 1 year. BOS and GVHD diagnoses were made according to the 2014 NIH Consensus Development Project on Criteria for Clinical Trials (BBMT 2015). The primary endpoint was the inhibition rate of BOS progression, and the secondary endpoints were AFO incidence rate, recurrence rate, survival rate, GVHD, intervention rate of systemic immunosuppressive therapy, and safety of BCM therapy. The statistical analysis plan considered it effective if the incidence of BOS with triple treatment was less than 65% with a two-sided P-value <0.10. Results: Between June 2016 and June 2018, 85 patients were enrolled, and 84 were included in the analysis. One was excluded from the analysis due to deviation. Fifteen of eighty-four (17.9%) met AFO criteria at the median of 178 days (63-728) after allo-HCT, and the 2-year cumulative incidence of AFO was 26.1%. Fourteen with AFO received the BCM treatment. Three patients developed BOS (0, 182, 420 days after onset of AFO). The BOS progression rate was 21.4% (95% CI: 4.7-50.8%), which was significantly below the threshold (65%) set by historical control, had demonstrated the inhibitory effect on BOS progression significantly ( P<0.001). No significant difference was observed in the relationship between AFO and primary disease, stem cell source, pretreatment, and chronic GVHD incidence compared to the non-AFO group. At the AFO diagnosis, 80% had not developed or concurrently diagnosed with chronic GVHD. During the study period, 80% had developed an active chronic GVHD in the AFO group and 54.2% in the non-AFO group. The BCM therapy was feasible, and 9 completed the treatment. Five were discontinued due to the development of IPS in 2, disease progression in 1, bacterial pneumonia in 1, and patient's preference in 1. No difference was observed between the two groups in 2-year OS (AFO 86.7% vs non-AFO 94.2%, Log-rank P=0.55) Conclusion: We revealed the target timeframe for PFT monitoring for early identifying patients at risk for subsequent BOS after allo-SCT. PFT monitoring and therapeutic intervention with BCM therapy for patients with AFO could improve outcomes. The therapeutic intervention from the BOS diagnosis is too late to improve prognosis, and early therapeutic intervention is essential when respiratory function decline is observed, regardless of the presence or absence of chronic GVHD.