A 48-year-old woman with Hodgkin lymphoma (stage IIIB) is prescribed ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine). Before starting treatment, she is counseled about potential long-term complications. Six months into therapy, she develops progressive dyspnea and a dry cough. Chest X-ray shows bilateral interstitial infiltrates. Pulmonary function tests reveal a restrictive pattern with reduced DLCO. Which alkylating agent in her regimen is most likely responsible for this pulmonary toxicity?

Explanation

## Bleomycin-Induced Pulmonary Toxicity **Key Point:** Bleomycin is an antibiotic-type alkylating agent with a unique and serious dose-limiting toxicity: pulmonary fibrosis. This is NOT a common toxicity of other chemotherapy agents in the ABVD regimen. ### Mechanism of Bleomycin Pulmonary Toxicity 1. **Direct DNA damage**: Bleomycin binds to DNA and causes strand breaks via free radical generation 2. **Inflammatory cascade**: Triggers pulmonary inflammation and fibroblast proliferation 3. **Fibrosis development**: Progressive collagen deposition leads to pulmonary fibrosis 4. **Cumulative & dose-dependent**: Risk increases significantly above 400 units lifetime cumulative dose 5. **Irreversible**: Pulmonary fibrosis is often permanent and progressive ### Clinical Presentation of Bleomycin Pulmonary Toxicity The patient's presentation is classic: - **Timeline**: Usually develops during or shortly after therapy (weeks to months) - **Symptoms**: Progressive dyspnea, dry cough, chest discomfort - **Imaging**: Bilateral interstitial infiltrates (ground-glass or reticular pattern) - **PFTs**: Restrictive pattern with ↓ DLCO (hallmark finding) - **Histology**: Pulmonary fibrosis with inflammatory infiltration **High-Yield:** DLCO reduction is the earliest and most sensitive indicator of bleomycin-induced pulmonary toxicity. Baseline and serial DLCO monitoring is mandatory during bleomycin therapy. ### Risk Factors for Bleomycin Pulmonary Toxicity - Cumulative dose > 400 units - Age > 40 years - Prior or concurrent chest radiation - Concurrent oxygen therapy (increases risk) - Renal impairment (reduces clearance) - Prior chemotherapy **Warning:** Supplemental oxygen in bleomycin-treated patients can paradoxically worsen pulmonary toxicity—use with extreme caution. ### Comparison of ABVD Component Toxicities | Agent | Class | Dose-Limiting Toxicity | Mechanism | |-------|-------|------------------------|----------| | Doxorubicin | Anthracycline | Cardiomyopathy | Intercalation + free radicals | | Bleomycin | Antibiotic alkylator | Pulmonary fibrosis | DNA strand breaks + inflammation | | Vinblastine | Vinca alkaloid | Myelosuppression | Microtubule inhibition | | Dacarbazine | Alkylating agent | Myelosuppression | DNA methylation | **Clinical Pearl:** In ABVD regimens, bleomycin is often omitted in elderly patients or those with pre-existing pulmonary disease due to the high risk of irreversible pulmonary fibrosis. This is why baseline pulmonary function testing is essential before starting bleomycin.