Soto, Felipe

Abstract Background: Pulmonary function tests, forced expiratory volume in 1 s (FEV₁) and diffusing capacity for carbon monoxide (DLCO), are integral to pre-transplant evaluation of allogeneic hematopoietic cell transplantation (HCT) candidates because they estimate the risk of early post-HCT death and respiratory failure. Interpretation has historically relied on race-specific Global Lung Function Initiative equations from 2012 (GLI-2012). In 2021 the Initiative released race-neutral equations (GLI-Global). The influence of adopting GLI-Global on risk stratification, outcome prediction, and transplant eligibility is unknown. Methods: We retrospectively analyzed 8808 adults who underwent first allogeneic HCT at four United States centers between 1999 and 2021. FEV₁ values were converted to z-scores with both GLI-2012 and GLI-Global, whereas DLCO z-scores were calculated with GLI-2017 which is a race neutral equation. Pulmonary impairment was graded with the Lung Function Score (LFS); each component [FEV₁ and DLCO] receives 1 to 6 points based on percent predicted (> 80 % = 1, 70-79 % = 2, 60-69 % = 3, 50-59 % = 4, 40-49 % = 5, < 40 % = 6) and the sum of 2 to 12 maps to grades I (2), II (3-5), III (6-9), and IV (10-12). Primary endpoints were non-relapse mortality (NRM) at 120 days and 2 years, intensive care unit admission, and invasive mechanical ventilation. Prediction was assessed with Cox proportional hazards models and Harrell c-statistics. Results: Switching to GLI-Global reclassified 4.2 % of patients (368 of 8808) across LFS strata. Reclassification was racially asymmetric: 12.2 % of Black patients moved to higher-risk grades whereas 3.9 % of White patients moved to lower-risk grades. C-statistics for FEV₁ z-scores were nearly identical with GLI-Global versus GLI-2012: 2-year NRM 0.544 vs 0.542, 120-day NRM 0.566 vs 0.568, intensive care admission 0.545 vs 0.538, and mechanical ventilation 0.605 vs 0.605; confidence intervals overlapped for every comparison. Continuous z-score models consistently outperformed categorical cut-offs for each outcome: 2-year NRM 0.544 vs 0.518, 120-day NRM 0.566 vs 0.523, intensive care admission 0.545 vs 0.515, and mechanical ventilation 0.605 vs 0.529; confidence intervals did not overlap for every comparison. The composite LFS outperformed models that used FEV₁ or DLCO alone. Extrapolating cohort reclassification rates to 38,606 adults aged 40 to 84 who received allogeneic HCTs reported to the Center for International Blood and Marrow Transplant Research between 2009 and 2018 predicts that 1521 patients, including 509 Black adults, would shift LFS grades and could face altered transplant eligibility. Conclusions: Race-neutral GLI-Global equations modestly change pulmonary risk categorization, disproportionately raising scores for Black HCT candidates, yet maintain predictive accuracy for early mortality, respiratory failure, and intensive care use. Continuous dual-variable models and the composite LFS provide superior prediction. Although race-neutral interpretation aligns with current society guidelines, its tendency to classify Black individuals as higher risk highlights the need for refined continuous models that limit unnecessary reclassification and increased disparities in transplant eligibility.

Abstract Rationale: Hematopoietic cell transplantation (HCT) risk scores have seen minimal updates over the past 20 years, despite advancements in clinical practice. Pulmonary function test (PFT) thresholds, initially based on NHANES reference equations, now have alternative reference standards from the Global Lung Function Initiative (GLI) 2012 and GLI-Global, which may reclassify patients and affect outcomes. This study investigates the impact of GLI reclassification on outcomes in HCT, comparing traditional fixed thresholds with continuous (z-score) risk assessment models. Methods: A retrospective review of 3,120 adult patients who underwent autologous HCT at MD Anderson Cancer Center from 1999 to 2015 was conducted. Primary endpoints were ICU admission, mechanical ventilation (IMV), and survival within 120 days post-transplant. PFT measures (FEV1, FVC, DLCO) were calculated using GLI-2012 and GLI-Global reference equations, analyzed both continuously (z-scores) and categorically by ATS/ERS guidelines. Cox proportional hazards and logistic regression models were employed, with AUROC comparisons to evaluate predictive performance. Results: The cohort had a mean age of 49 years (SD 14), with 41% female and 77% White. Of the 3,120 patients included in the study, the cohort consisted of 77% White, 5.4% Black, 3.3% Asian, and 14% identifying as other ethnicities. At 120 days, mortality was 1% (n=41), ICU admission 5% (n=169), and IMV 2% (n=70). Continuous DLCO was associated with a lower risk of mortality (HR: 0.75; p=0.03), ICU admission (OR: 0.83; p=0.01), and IMV (OR: 0.80; p=0.02). GLI-Global's FEV1 z-scores were also significant for mortality (HR: 0.70; p=0.01), ICU admission (OR: 0.74; p<0.0001), and IMV (OR: 0.70; p=0.0003). Categorical analyses showed significant mortality reduction with normal DLCO (HR: 0.46; p=0.01) and ICU admission reduction with normal FEV1 GLI-2012 (OR: 0.63; p=0.02). Reclassification by race, as shown in Figure 1, indicated that race-specific equations overestimated PFT values in Black patients and underestimated them in Asian patients. Conclusion: Reclassification by GLI reference equations, particularly using continuous z-scores, significantly influences post-HCT outcomes, suggesting that continuous assessment may improve risk stratification. Including race does not improve the model's performance. These findings support integrating updated PFT references and continuous risk models into HCT prognostic tools for enhanced clinical decision-making.