Lung Complications after Allogeneic Hematopoietic Cell Transplant and Outcomes: Implications Beyond Bronchiolitis Obliterans Syndrome

Background Lung chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) comprises heterogeneous pulmonary phenotypes known as lung complications after transplantation (LCAT). While bronchiolitis obliterans syndrome (BOS) is well recognized and is associated with poor survival, restrictive phenotypes—including HCT–associated organizing pneumonia (HCT-OP) and truncal sclerosis (TS)– remain poorly defined. Prior studies often grouped restrictive phenotypes, potentially obscuring phenotype-specific risk profiles and introducing survival bias by not taking into account the variable timing of LCAT onset. Direct comparison between specific LCAT phenotypes and patients with cGVHD without lung involvement is limited, leaving uncertainty regarding the relative prognostic impact of individual LCAT phenotypes. Objective Using dynamic time-dependent Cox regression, we hypothesized that LCAT phenotypes represent clinically and prognostically distinct entities. Study Design We conducted a longitudinal retrospective cohort study of adults with cGVHD. LCAT phenotypes were adjudicated as BOS, HCT-OP, or TS based on clinical, physiologic, and radiographic criteria. Patients with cGVHD without lung involvement served as the control group. Baseline for all survival analyses was defined as the date of cGVHD diagnosis. Multivariable Cox proportional hazards models were fit with LCAT phenotype as a time-varying exposure to account for variable onset timing and mitigate immortal-time bias; adjusted survival curves were derived using dynamic standardization. Non-relapse mortality (NRM) was analyzed using cause-specific Cox models with relapse occurring after cGVHD onset as a competing event. Results Of 895 patients who met inclusion criteria, LCAT was identified in 183 patients: BOS (n=85), HCT-OP (n=42), TS (n=32), and mixed phenotypes (n=24). Median time from cGVHD diagnosis to LCAT onset differed significantly: 3.3 months for HCT-OP, 9.4 months for BOS and 20.5 months for TS ( p <0.001). Pulmonary function tests showed distinct patterns, with severe airflow obstruction in BOS, predominant diffusion impairment in HCT-OP; and restriction in TS. In multivariable time-dependent Cox models, BOS was independently associated with inferior OS (HR 2.14; 95% CI 1.51–3.02; p <0.001) and elevated NRM (HR 3.04; 95% CI 2.08–4.43; p <0.001) relative to controls. TS was independently associated with increased NRM (HR 2.33; 95% CI 1.12–4.86; p =0.024) but not OS (HR 1.53; 95% CI 0.78–3.05; p =0.217). HCT-OP was not significantly associated with increased OS or NRM risk relative to controls, a finding confirmed by sensitivity landmark analyses. In the LCAT burden model, mixed LCAT (≥2 phenotypes) conferred the greatest risk for both OS (HR 3.22; 95% CI 1.78–5.83; p <0.001) and NRM (HR 4.95; 95% CI 2.55–9.62; p <0.001) compared with controls, and also carried higher NRM than single LCAT (HR 2.04; 95% CI 1.03–4.02; p =0.041). Conclusion(s) LCAT phenotypes represent clinically distinct entities with divergent prognostic profiles. Accurate and granular phenotyping is essential to inform prognosis, guide surveillance strategies, and support therapeutic decision-making in patients with cGVHD.