Bleomycin Linked to High Rate of Pulmonary Disorders among Patients with Hodgkin Lymphoma

A retrospective study of patients with Hodgkin lymphoma (HL) found high rates of sequelae including pulmonary events and cardiovascular disease (CVD) following frontline treatment with chemotherapy including bleomycin, according to a poster presentation at the 2018 Pan Pacific Lymphoma Conference in Maui, Hawaii.¹

The release of the findings, based on a review of electronic health records from the Department of Defense (DOD), comes after the March FDA approval of brentuximab vedotin (Adcetris) for use in combination with chemotherapy as a frontline treatment for adult patients with stage III or IV classical HL.² The approval represented a breakthrough alternative for bleomycin, which is associated with increased risk for pulmonary events including sometimes fatal lung toxicity.

The poster findings indicated that high proportions of HL patients experienced new sequelae after receiving chemotherapeutic agents: 29.6% of patients receiving bleomycin underwent new pulmonary events; for those receiving dacarbazine, 15.2% had a second malignancy; and 31.8% of those treated with doxorubicin had new CVD events. Thirty-two percent of pulmonary events (52/163) were acute.

The study looked at records for 642 eligible patients with HL who were treated in the US DOD healthcare system between January 1, 2005, and December 31, 2013. Patients with other primary malignancies, not including skin cancer, or those who received fewer than 2 chemotherapy agents as frontline treatment, were excluded from the study.

Patients were followed until death, disenrollment, or the end of the study (June 30, 2016), whichever came first. The mean age was 32 for patients with all-stage HL and 34 for those with stages 3/4 HL. Patients who had stage 3/4 HL numbered 224 (35%). The mean follow-up was 4.1 years.

The majority of patients received chemotherapy agents as a part of the ABVD regimen (adriamycin, bleomycin, vinblastine, and dacarbazine): 94.6% received bleomycin; 90.8%, dacarbazine; 97.9%, doxorubicin; 92%, vinblastine. The authors said 82% of patients with all-stage or stage 3/4 HL received ABVD or a variant of this regimen as frontline therapy.

During follow-up, 163 patients were identified with pulmonary events, 97 with secondary malignancies, and 205 with CVD events.

For those treated with bleomycin with or without radiation, 29.6% experienced a new pulmonary event at least 48 months after first exposure. Pulmonary events included bronchopneumonia, interstitial pneumonia, pulmonary fibrosis, acute lung edema, bronchiolitis, interstitial pulmonary disease, bronchiectasis, and acute respiratory distress syndrome. The most frequent type was acute respiratory distress syndrome/pulmonary edema (95% of patients with a pulmonary event).

The poster authors said most pulmonary events occurred within 24 months of treatment with bleomycin. Those with HL stage 3/4 had a 30.8% incidence of pulmonary events, which was similar to the all-stage cohort.

The secondary malignancy findings for dacarbazine and doxorubicin were also significant. The authors said 15.2% of patients treated with dacarbazine developed a second malignancy over more than 10 years, and among patients with stage 3/4 HL, 13.4% of patients developed a second malignancy. These malignancies included leukemia, myelodysplastic lesions, lung cancer, non-Hodgkin lymphoma, soft tissue sarcoma, head or neck cancer, and squamous cell skin cancer.

Among patients exposed to doxorubicin, 31.8% had a new CVD event over more than 10 years, and among patients with stage 3/4 HL, 37.5% had a new CVD event, which may have been arrhythmia, coronary artery disease, cardiomyopathy, congestive heart failure, myocardial infarction, pericarditis, and valvular disorders.

Investigators found that, among 14 demographic and clinical variables, age and the number of doses of bleomycin were the most significant predictors of a new pulmonary event among patients with HL. However, the relationship between the number of doses of bleomycin and pulmonary events was nonlinear, with peaks at 4 to 5 doses and ≥11 doses, but with a drop in between.

The authors said the nonlinear relationship between bleomycin dosage and pulmonary events may be attributable to interruptions in treatment because of respiratory complications, smoking status, and chemical exposure in the military, which alone may separate these patients from other patients with HL.

The FDA approval of the brentuximab vedotin combination was based on findings from the phase III ECHELON-1 trial, which demonstrated superior progression-free survival (PFS) with brentuximab vedotin plus AVD compared with standard ABVD. In the study, the brentuximab vedotin regimen reduced the risk of progression, death, or initiation of new therapy by 23% compared with ABVD. The 2-year modified PFS rate was 82.1% with brentuximab vedotin compared with 77.25% for standard chemotherapy (HR, 0.77; 95% CI, 0.60-0.98; P = .035).

The ECHELON-1 findings were hailed as a breakthrough that ended 4 decades of little progress in efforts to develop regimens that were less toxic and more effective.

References

1. Feliciano J, Fox KM, Alzola C, et al. Sequelae in patients with Hodgkin lymphoma after frontline chemotherapy in the US Department of Defense (DOD) healthcare system. Presented at: 2018 Pan Pacific Lymphoma Conference; July 16-20, 2018; Maui, Hawaii. Poster 43.
2. Connors J, Jurczak W, Straus D J, et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (HL): the phase 3 Echelon-1 study. Presented at: ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 6. bloodjournal.org/content/130/Suppl_1/6.