Azithromycin Use and Increased Cancer Risk among Patients with Bronchiolitis Obliterans after Hematopoietic Cell Transplantation

Abstract

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.

The pulmonary metatranscriptome prior to pediatric HCT identifies post-HCT lung injury

“…In the HCT population, long-term post-HCT azithromycin use has recently been associated with worse airflow decline-free survival and an increased risk for post-HCT hematologic malignancy relapse and secondary neoplasia, although it is unclear whether these findings were related to EDC activation or an off-target biological effect of azithromycin. [65][66][67] Ultimately, future studies are needed to determine whether the EDC can be selectively manipulated prior to HCT to amplify an adaptive response to chronic epithelial damage and prevent post-HCT lung injury.…”

Noninfectious lung complications of hematopoietic cell transplantation

“…63 One of these agents, azithromycin, came under scru tiny due to increased relapse rates in a ran dom ized trial of azithromycin prior to HCT, 64 which were not con firmed in a larger study of azithromycin in established BOS, though a higher rate of sec ond ary neo plasms was observed. 65 At this time, the ben e fits of azithromycin likely out weigh the risks for most BOS patients, though ste roids and other risks for sec ond ary neo plasms should also be min i mized and per son al ized risks eval u ated. In patients with ongo ing pul mo nary decline, extra cor po real photopheresis may improve sur vival, which builds upon prior ret ro spec tive data of a response rate of approx i ma tely 60%.…”

Bronchiolitis obliterans syndrome after lung or haematopoietic stem cell transplantation: current management and future directions

“…The data for azithromycin alone are less robust [ 95 ]. While one study suggested that azithromycin alone as a preventive strategy for BOS may be linked to relapse, more recent larger studies did not show increased risk of relapse with azithromycin post-GVHD, although increased risk of secondary cancers with higher use of concomitant steroids was observed [ 96 , 97 ]. A combination of inhaled long-acting bronchodilator plus inhaled corticosteroid has been shown to improve FEV 1 at 1 month (by 200 mL and 12%) in newly diagnosed patients with mild-to-moderate BOS, without the use of systemic corticosteroids [ 98 ].…”