Early termination of ALLOZITHRO trial due to increased risk of relapse in haematopoietic stem cell transplantation patients treated with azithromycin for prophylaxis of bronchiolitis obliterans syndrome

HSA would like to alert healthcare professionals to the findings from a clinical trial, ALLOZITHRO, which investigated the effectiveness of long-term azithromycin to prevent BOS in patients with haematological malignancy who underwent allogeneic HSCT.¹ The trial was prematurely terminated after an increased rate of relapses of haematological malignancies and mortality was seen in patients taking azithromycin compared with placebo. Locally, azithromycin is not approved for the prophylaxis of BOS in patients undergoing HSCT. It is also not approved for this indication in other countries such as the United States and in the European Union.

Bronchiolitis obliterans syndrome

BOS is a serious complication associated with chronic graft-versus-host disease that may occur after allogeneic HSCT. It is a type of obstructive lung disease, characterised by fibrosis of bronchioles that results in progressive and irreversible airway obstruction. BOS typically develops within two years of the HSCT and is associated with significant mortality and morbidity.

Findings from the ALLOZITHRO trial

The ALLOZITHRO trial was a randomised, double-blind, placebo-controlled, phase 3 trial conducted in 19 French academic transplant centres. Its aim was to investigate if early administration of azithromycin could improve airflow decline-free survival two years after allogeneic HSCT. The trial enrolled 480 patients who were at least 16 years old and had undergone allogeneic HSCT due to haematological malignancy. They were randomised to receive azithromycin 250mg (n=243) or placebo (n=237) three times a week for two years, starting from the day of the pre-transplant conditioning regimen.

In September 2016, at 13 months after completing enrolment, the Data and Safety Monitoring Board detected an unanticipated imbalance across blinded groups in the number of haematological relapses, which occurred in 77 patients (32.9%) on azithromycin treatment compared to 48 patients (20.8%) on placebo (Adjusted hazard ratio [HR] 1.6 [95% CI, 1.1-2.3]).  Patients in the azithromycin group also had a lower two-year survival rate (56.6%) compared to those receiving a placebo (70.1%) (Unadjusted HR 1.5 [95% CI, 1.1-2.0]). This led to the early termination of the trial in December 2016.

The trial investigators concluded that early administration of azithromycin for prophylaxis of BOS in HSCT patients resulted in worse airflow decline-free-survival than did placebo. However, these findings were limited by the early termination of the trial and further investigation into the harm related to the relapses was required.

Local situation and HSA’s advisory

Azithromycin, a macrolide antibiotic, is not approved for the prophylaxis of BOS in patients undergoing HSCT. Apart from Zithromax™ (Pfizer Pte Ltd) that has been registered locally since 1994, there are 14 other generic azithromycin-containing products registered in Singapore.

In September 2018, a Dear Healthcare Professional Letter was issued by Pfizer to inform healthcare professionals about the findings from the ALLOZITHRO trial.² The letter stated that evidence from the trial was considered strong enough to assume that long-term exposure to azithromycin following HSCT might be associated with an increased relapse risk of haematological malignancies and mortality, which outweighed its anticipated benefits for this off-label use. However, Pfizer’s analysis of all relevant available data did not suggest that this risk applied to the approved indications of azithromycin or other patient populations.

In view of the significant risk associated with off-label use of azithromycin in HSCT patients for prophylaxis of BOS, healthcare professionals should take into consideration the above information in the clinical management of their patients.

References

1. JAMA 2017; 318: 557-66

2. https://www.hsa.gov.sg/announcements/Dear-Healthcare-Professional-Letters