Baseline patient characteristics and transplant-related factors predicting post-transplant spirometry decline and recovery in allogeneic hematopoietic stem cell transplant recipients.

BACKGROUND: Pulmonary graft-versus-host-disease (GVHD) is a common and serious complication of haematopoietic stem cell transplant (HSCT). Whilst many guidelines only diagnose pulmonary GVHD when spirometry goes below 80% predicted, we recently demonstrated that a drop of more than 10% from baseline spirometry was an important marker of mortality. While factors that increase the risk of lung GVHD are well-established, it remains unclear whether the same factors also predict ≥10% reductions in spirometry. OBJECTIVES: Our primary aim was to determine the factors predicting a ≥10% reduction in FEV1 and those associated with subsequent recovery. Our secondary aim was to compare overall survival probability between those who experience ≥10% reduction in FEV1, and those who do not. STUDY DESIGN: A 5-year retrospective audit of 364 patients who received an allogeneic HSCT at Westmead Hospital was conducted. Multivariate Cox proportional hazard modelling was used to assess the association between outcome variables (≥10%FEV1 decline, ≥10%FEV1 recovery, death, and relapse or death) and the fixed baseline potential risk factors, along with a categorical time-dependent variable. A time-dependent covariate examined change in mortality risk between periods: i) prior to a ≥10% reduction from baseline FEV1, ii) from first measured decline to maximum decline in FEV1, iii) from maximum decline to recovery of FEV1, and iv) time post FEV1 recovery. RESULTS: 173 patients (47.5%) had a decrease in spirometry of ≥10%. The 5-year cumulative mortality was 24.2%. Mortality risk was increased from the time of first measured ≥10% FEV1 decline (HR=4.6 [2.1-9.9, 95%CI], p<0.001), was greatest at the time of maximum decline, (FEV1 nadir, HR=6.1 [3.2-11.4, 95%CI], p<0.001), and remained elevated after recovery (HR=5.1 [2.6-9.9, 95%CI], p<0.001). Use of carmustine (HR=2.5 [1.7-3.8, 95%CI], p≤0.001) or busulfan (HR=1.9 [1.4-2.7, 95%CI], p≤0.001) in transplant conditioning increased the risk of ≥10% FEV1 decline. Patients receiving matched-unrelated donor stem cells had lower risk of FEV1 decline compared to those who received stem cells from a sibling donor (HR=0.7 [0.5-0.9, 95%CI], p≤0.010). Prescription of Alemtuzumab increased the likelihood of ≥10% FEV1 recovery after a decline (HR=2.7 [1.1-6.2, 95%CI], p≤0.024). CONCLUSION: In our patient cohort, FEV1 decline was the strongest predictor of increased mortality risk following HSCT. Patients receiving carmustine and/or busulfan are at a higher risk of decreased spirometry and thus may benefit from closer monitoring during follow-up. Observed differences in risk between matched-unrelated and sibling donor transplants are likely explained by less frequent use of ATG in recipients of matched sibling donor transplants during the period audited. A small number of patients receiving alemtuzumab were more likely to experience recovery of FEV1 decline. Further research is needed to improve understanding of risk factors for FEV1 decline and recovery in HSCT survivors. Improving pre-transplant risk stratification, avoidance of pulmonary toxins during conditioning, early detection of respiratory disease and identification of therapies to enhance respiratory recovery are likely to result in reduced mortality after HSCT.