IC-08. Dynamics of the airflow obstruction formation, response to treatment and overall survival in adult patients with bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

Summary

Introduction

Bronchiolitis obliterans (BO) is a rare and one of the most severe manifestations of chronic GVHD. In a previous large cohort study, we investigated the cumulative incidence, risk factors, and clinical characteristics of BO in the modern landscape of allogeneic HSCT with a frequent use of a haploidentical donor and post-transplant cyclophosphamide for GVHD prophylaxis (Kulagin E. et al., EBMT Meeting, 2020). The aim of this study was to assess the dynamics of the bronchial obstruction formation, response rate to treatment and overall survival (OS).

Patients and methods

A total of 42 patients (22 males and 20 females) were diagnosed with BO, according to the NIH criteria (2014), in a whole cohort of 1189 patients who received allo-HSCT between 2008 and 2019. Median age at the BO diagnosis was 35 (20-60) years. All the patients, except of one, had other manifestations of cGVHD which preceded the BO onset. The control group consisted of patients who did not develop BO and survived without signs of relapse or graft rejection at the landmark median time between HSCT and BO diagnosis. The dynamic profile of FEV1 data from initial pretransplant pulmonary function test to the last testing was studied. The presence of FEV1 changes with repeated testing after allo-HSCT was assessed by means of Friedman test. The majority of patients (79%) received a FAM (fluticasone, azithromycin and montelukast) or FAM-like treatment in combination with systemic corticosteroids (62%), and continued baseline immunosuppression (90%). Subsequent lines of therapy included tyrosine kinase inhibitors (38%), extracorporeal photopheresis (31%), a JAK kinase inhibitor (29%), low doses of IL-2 (17%) and rituximab (7%). Response to the treatment was assessed in 33 patients followed up for at least 12 months, according to the NIH criteria (2014), defined by complete response (normalization of FEV1), partial response (≥10% increase in FEV1), stable disease (<10% change in FEV1), or progression (≥10% decrease in FEV1). Overall survival (OS) was assessed using the Kaplan-Meier method from the date of BO diagnosis, or landmark in the control group to the date of death or the last follow-up.

Results

The FEV1 levels before allo-HSCT did not differ statistically significantly between the patients with BO and the control group: median 98.1% (range, 64-124) versus 99.0% (49-145) (p=0.3748). In a dynamic study, the control group did not show significant fluctuations in the FEV1 levels (p=0.98). The median FEV1 level varied within 92-101%. Few documented cases of a significant decrease in the FEV1 level of less than 75% were not considered a criterion for BO diagnosis due to the absence of other necessary criteria and had a transient nature. In contrast, the patients with BO showed a steadily progressing decrease in the FEV1 level (p<0.001). The fastest and most significant FEV1 decline occurred between the day +100 (median 91%), and 1 year (median 42%) after allo-HSCT. Further dynamics of the FEV1 level, along with the natural course of BO, reflects the response to the treatment used in patients with an established diagnosis. One year after the BO diagnosis, 24 (69%) patients had stabilization with the delta of FEV1 within the range from -10% to +10%; 8 patients (23%) demonstrated BO progression, and only 3 (8%) patients achieved partial response. At the last follow-up, there was a more significant polarization of response: progression (n=11, 32%), partial response (n=5, 14%), stabilization (n=19, 54%). As of August 1, 2020, 24 (57%) patients with BO were alive, 18 patients died due to cGVHD and infectious complications (n=14, 78%) or underlying disease relapse (n = 4, 22%). As a result, the 3-and 5-year OS was 54.8% (95% CI, 36.3-70.0), and 49.8% (95% CI, 30.8-66.2), respectively. The median OS was 60 months. In the control group, 69 patients (11%) died due to relapse/progression of the underlying disease (n=19, 28%) or other causes (n=50, 72%). The probability of OS at 3 and 5 years was 86.6% (95% CI, 82.9-89.9), and 82.5% (95% CI, 77.1-86.8). Differences in OS between the compared groups were statistically significant (p <0.0001).

Conclusion

This large study of BO after allo-HSCT has shown: (1) Early development of irreversible airflow obstruction (100 days to 1 year); (2) Stable disease (54%) as the most frequent best response to therapy, and rare achievement of a partial response (14%); (3) Significant decrease in OS compared to the control group.

Keywords

Bronchiolitis obliterans, allo-HSCT, chronic GVHD, FEV1.