Pulmonary Graft-Versus-Host Disease After Reduced Toxicity Conditioning with Fludarabin, Carmustine and Melphalan Prior to Hematopoietic Stem Cell Transplantation

Abstract 1266

Allogeneic hematopoietic stem cell transplantation (HSCT) of older or comorbid patients has become feasible due to new protocols for reduced toxicity/intensity conditioning. Particularly using fludarabine, BCNU and melphalan (FBM) as preparative regimen confers reduced toxicity with substantial anti-leukemic activity. Nevertheless, chronic Graft-versus-Host disease (cGvHD) of the lung remains a serious non infectious, late onset pulmonary complication, contributing to treatment related morbidity and mortality. Since the clinical entity of pulmonary cGvHD after reduced toxicity/intensity conditioning has not yet been well characterized, we performed a retrospective analysis of patients, who were transplanted after FBM conditioning at the University Hospital Freiburg between 1998 and 2007, were alive at least 100 days after HSCT and have pulmonary function tests available.

259 patients were enrolled in this study (median age at PBSCT of 61 years (range 24–76)) with a median follow up of 33 months (range 4–133). All patients received conditioning with fludarabin (4-5 × 30 mg/m²), BCNU (or carmustin, patients> 55 years: 2×150 mg/m², <55 years: 2×200 mg/m²) and melphalan (patients >55 years 1×110mg/m², <55 years: 1×140 mg/m², fo). Peripheral stem cell grafts were used in most of the cases together with cyclosporin based GvHD prophylaxis.

27 patients (10.4 %) developed a pulmonary cGvHD as defined by NIH criteria with a median time after HSCT of 13 months (range 4–102). In those patients, pulmonary function tests 6 months after HSCT revealed a significant reduction in mean % of predicted value in FEV1 (88 v. 79 %), MEF50 (63 v. 49 %) and the ratio of FEV1/FVC (80 v. 75 %), as early predictive parameters for developing pulmonary GvHD. However, no differences in pulmonary function tests were found predictive for developing pulmonary GvHD at the time of HSCT. The patients with pulmonary GvHD showed at the time of diagnosis in comparison to values before HSCT a reduction in % of predicted FEV1 (85 v. 57 %), of predicted VCmax (84 v. 71 %) and an increase of the ratio of RV/TLC (39 v. 49 %). In cumulative incidence curves, we found significant differences in decrease >10 % of the initial value of FEV1, in ratio of RV/TLC >45 %, in values of MEF50 <25% and MEF25 <25% of predicted value. In the multivariate analysis, following risk factors were associated with developing pulmonary cGvHD: age less than 55 years at HSCT, chronic GvHD, GvHD prophylaxis with in vivo anti T cell antibodies and lung disease (e.g. infections) after HSCT. Patients with pulmonary GvHD had a statistically significant longer disease free survival and overall survival and less relapse incidence.

In conclusion, we found several risk factors and changes in pulmonary function tests associated with developing pulmonary GvHD in HSCT after conditioning with a reduced toxicity protocol (FBM) in the largest cohort of patients investigated so far. These findings might help to identify a risk population after reduced intensity conditioning and therefore result in personalized measures for GvHD prophylaxis and therapy.