Azithromycin Exposure Following Hematopoietic Stem Cell Transplantation Is Associated With An Increased Risk Of Cancer Relapse In Acute Leukemia

Introduction Graft-versus-host disease (GVHD) of the lung, also known as bronchiolitis obliterans syndrome (BOS), is associated with high mortality, but treatment with the combination of fluticasone, azithromycin, and montelukast (FAM) stabilizes lung function in the majority of patients. Recently, a randomized controlled trial evaluating azithromycin given at the time of conditioning for GVHD prevention was closed prematurely due to an increased risk of cancer relapse in azithromycin recipients. We evaluated whether exposure to azithromycin after allogeneic hematopoietic cell transplantation (allo-HCT), primarily for treatment of BOS, was also associated with a higher rate of cancer progression. Methods We conducted a retrospective study of patients who underwent allo-HCT and experienced a significant decline in pulmonary function from pre-HCT values (decrease in forced expiratory volumes in 1 second of ≥10% OR mid-flow rates of ≥25%) between 2005 and 2015. Risk factors for cancer progression were examined using cause-specific univariate and multivariate Cox regression analysis with azithromycin exposure evaluated as a time-dependent covariate. Results Among 672 eligible allo-HCT recipients with pulmonary decline, 9% (n=63) received azithromycin, including 41 patients for BOS and 22 patients for chronic treatment for mycobacterial infection or bacterial prophylaxis. Table 1 shows characteristics of the entire study cohort. No patients with chronic lymphocytic or myeloid leukemia (n=13) or lymphoma (n=12) who were exposed to azithromycin experienced cancer progression during the study period. Therefore, we evaluated the impact of azithromycin exposure on the rate of cancer progression in the subset of patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS, n-327) or acute lymphoblastic leukemia (ALL, n=91). The median follow-up since allo-HCT in this subgroup was 73 months (range 5-148 months). 38 of these patients were exposed to azithromycin at a median time of 25 months (interquartile range 11-46 months) after allo-HCT. In multivariate analysis, azithromycin (HR 3.7, 95% CI 1.5-9.4, p=0.005) and unfavorable cytogenetics (HR 1.7, 95% CI 1.2-2.5, p=0.004) were associated with increased rates of cancer progression. Median time to cancer progression from time of allo-HCT was 8 months (range 1-98 months) for the entire cohort, while the median time to cancer progression was later in those exposed to azithromycin (median 21 months, range 4-25 months). The median time to cancer progression after exposure to azithromycin was 51 days (range 17-847 days). Conclusion Our findings show that recipients of allo-HCT for treatment of AML/MDS or ALL, exposure to azithromycin for BOS or infections is associated with an increased rate of cancer progression.