Long-term impact of bleomycin on lung function in Hodgkin lymphoma

Despite its significant toxicity, bleomycin remains an important component of classical Hodgkin lymphoma (HL) treatment. This analysis aimed to evaluate the impact of bleomycin on lung function up to five years after treatment in patients recruited to the international phase 3 RATHL trial. The results revealed a reduction in diffusion capacity with bleomycin plus chemotherapy compared to chemotherapy alone, which was only partially reversible and persisted at five years, supporting efforts to minimise or replace bleomycin use in the treatment of HL.

Bleomycin has been an integral part of classical Hodgkin lymphoma (HL) treatment for decades but carries significant toxicity. In particular, acute bleomycin-related lung toxicity occurs in a minority of patients but has mortality rates as high as 25%. Multiple risk factors are associated with this complication, including age (>40-60 years), number of cycles of treatment and G-CSF use. Unfortunately, the long-term effects of bleomycin in HL and its impact on lung function are not well known, and there is no established guidance for lung screening. This analysis aimed to evaluate the impact of bleomycin dose on lung function up to five years after treatment in patients recruited to the international phase 3 RATHL trial.

Methods

RATHL recruited patients with intermediate- or advanced-stage HL aged ≥18 years. These patients received two cycles of standard ABVD regimen (doxorubicin, bleomycin, vinblastine and dacarbazine) followed by PET assessment. Patients with complete metabolic response (CMR) received four further cycles of chemotherapy, with (ABVD arm; n=469) or without (AVD arm; n=464) bleomycin (12 or 4 doses of bleomycin in total, respectively). PET-positive patients switched to BEACOPP-based treatment (total 8-10 doses of bleomycin; n=172). Pulmonary function tests (PFTs) were performed at baseline, at the end of treatment (EOT), and annually for five years. Diffusion capacity (DLCO) was used as a principal measure. Linear regression was used to assess changes in DLCO from baseline. Cox regression was used to assess the time to return to within 10% of baseline values, censoring at relapse or death in all patients and those with a more than 10% reduction at EOT.

Results

The median age of the participants was 33 years, with 15.1% having a pre-existing respiratory disorder. Baseline DLCO values were low (<75%) in 327 (29.4%) patients. Grade ≥3 respiratory adverse events were uncommon in this study and occurred more frequently in the ABVD arm (3.6% vs. 1.5% in the AVD arm; p = 0.041). There was one respiratory death (pulmonary fibrosis) in the ABVD arm.

Following treatment completion, a change in DLCO was observed in most patients, with an 11.6% vs. 3.8% reduction in the ABVD and AVD arms, respectively (difference 7.1%, p<0.001). A considerable proportion of patients in the ABVD arm (59.8%) experienced a DLCO reduction of more than 10%, compared to 40.6% in the AVD arm. Multivariable analysis identified three factors associated with reduced diffusion capacity at EOT: treatment regimen (ABVD or AVD), increasing age, and female sex. Smoking and respiratory history were not correlated with changes in lung function. Intriguingly, a low baseline DLCO was not associated with reduced diffusion capacity at EOT. Among patients with a reduced baseline DLCO (<75%), the mean difference at the end of treatment was -0.66%, compared to -10.8% in those with ≥75% baseline DLCO. The primary determinant appeared to be the link between baseline DLCO and disease burden, with a lower baseline DLCO in patients with mediastinal mass (>10 cm) compared to those without (79% vs. 83%; p=0.016).

At two years after EOT, DLCO recovery to within 90% of baseline was observed in 69.6% vs. 81.4% of patients receiving ABVD or AVD, respectively. Factors associated with a slower DLCO recovery on the univariable analysis included treatment with the ABVD regimen compared with AVD (HR[95%CI]: 0.71[0.57-0.90]; p=0.004), a history of pulmonary disease (HR[95%CI]: 0.66[0.46-0.95]; p=0.023), and female sex (HR[95%CI]: 1.25[1.01-1.54]; p=0.041).

Throughout the follow-up period, DLCO values consistently favoured the AVD arm over ABVD, with a mean difference of 3.2% (p=0.029) at two years and 5.0% (p=0.010) at five years, adjusted for baseline DLCO values. Notably, there was no association with age (<40 and ≥40 years).

Conclusions

Baseline DLCO is influenced by disease burden and does not predict subsequent bleomycin-related changes in lung function. There was a reduction in diffusion capacity with ABVD compared to AVD, which was only partially reversible and persisted at five years. This may have clinical consequences in later years for patients cured of HL. These data strongly support efforts to minimise or replace bleomycin use in the treatment of HL.

Reference

Phillips EH , Kirkwood AA, Christina Hague, et al. Bleomycin Affects Lung Function for at Least 5 Years after Treatment for Hodgkin Lymphoma - Data from the International, Randomised Phase 3 Rathl Trial. Presented at ASH 2023; Abstract 612.