Risk of Pulmonary Toxicity and Benefits of Bleomycin Containing Regimen in Early-Stage Hodgkin's Lymphoma - A Case Report and Insights from Literature Review

Background: Bleomycin is chemotherapeutic agent that has been used for cancer treatment for several years. However, potentially life-threatening lung toxicity is a major concern limiting its use. Case report: This is a case of a 64-year-old male presenting sub acutely with gradual onset of exertional shortness of breath and cough after completing 4 cycles of ABVD regimen for Stage 2b Hodgkin’s lymphoma. CT scan showed extensive bibasilar reticular opacities with honey combing suggestive of pulmonary fibrosis with Usual interstitial pneumonia pattern. Based on temporal relations to bleomycin chemotherapy, a diagnosis of bleomycin induced lung fibrosis was made. Bleomycin was subsequently discontinued with some improvement of symptoms. Conclusion: Pulmonary toxicity with irreversible lung fibrosis is a life threatening and menacing adverse effects in patients receiving Bleomycin therapy. The probability of developing lung toxicity from Bleomycin is increased in older patients receiving multiple cycles of chemotherapy, with risk potentially outweighing benefits in select patients with early-stage lymphoma and favorable prognosis. and malignant pleural effusion [1]. It is produced by Streptomyces verticillus and was first isolated by Umezawa, et al. in 1966 [2]. Its mechanism of action involves breakdown of DNA double helix by the production of free radicals, which is dependent on oxygen and iron [2]. Although dermatological adverse effects are the most observed, Bleomycin induced lung toxicity crop up in up to 10% patients which can be life menacing if not diagnosed early with mortality rate of up to 20% [1,3]. Bleomycin induced lung injury encompasses several clinical syndromes including hypersensitivity, bronchiolitis obliterans with organizing pneumonia, hypersensitivity pneumonitis which may progress to pulmonary fibrosis [3]. Several factors including older age and cumulative drug dose have been shown to increase the risk of developing pulmonary toxicity from Bleomycin [4]. The following is a case of pulmonary fibrosis following chemotherapy with Bleomycin for Stage 2B Hodgkin’s Lymphoma (HL). This case emphasizes the need for careful selection of chemotherapy regimen in older patients with Hodgkin’s lymphoma who are risk for bleomycin pulmonary toxicity and the necessity for diligent surveillance in patients with increased baseline risks for toxicity. Introduction Bleomycin is an anti-tumor antibiotic indicated in the treatment of lymphomas, germ cell tumors ISSN: 2378-3656 DOI: 10.23937/2378-3656/1410390 Adetiloye et al. Clin Med Rev Case Rep 2022, 9:390 • Page 2 of 6 • residual mass or metabolic uptake in the neck and mediastinum (Figure 1). Initial evaluation, revealed blood pressure of 127/82 mmHg, heart rate of 104 beats per minute, respiratory rate of 22 breaths per minute, SpO2 90% on room air and Temperature was 97.8 F. He had inspiratory rales bilaterally and use of accessory muscles of respiration on examination. Pertinent negatives on examination were absence of ascites, leg swelling, distended neck veins, neck mass, rales, wheezes or stridor. Complete blood count, Basic metabolic panel, procalcitonin, Pro BNP and troponin T values were unremarkable. Chest x-ray shows bilateral interstitial disease prominent at the lung bases. Computed tomography angiography of the neck and chest showed moderate subpleural thickening bilaterally with some ground glass opacity and extensive honeycombing at the lung bases suggestive of usual interstitial pattern (UIP) (Figure 2). No pulmonary embolus, mass, mediastinal, hilar or axillary adenopathy were present on CT scan. Echocardiogram was unremarkable with normal Right and left ventricular function. Sputum culture and markers of connective tissue diseases and vasculitidies were negative. A diagnosis of Bleomycin induced pneumonitis and lung fibrosis was made based on CT findings and temporal relationship with Bleomycin chemotherapy and negative infectious work up. Patient was admitted to the medical floor and started on Prednisolone at 1 mg/kg per day for 4 weeks and subsequent taper. He also received Trimethoprimsulfamethoxazole for Pneumocystis Jirovei prophylaxis while on steroids. Shortness of breath improved with steroid treatment. However, he desaturates to low 80s on SpO2 during 6 minutes’ walk test. He was discharged home one week later with supplemental oxygen during exercise. Based on negative PET and CT findings for active Hodgkin’s lymphoma, patient was chemotherapy was discontinued. In addition, patient did not receive Case Report A 64-year-old male from Bangladesh presented to the emergency department with gradual onset of exertional shortness of breath of 1 week which has progressively worsened to shortness of breath at rest. He had a history of dry cough of 1 month but denied fever, chills, pleuritic chest pain, hemoptysis, orthopnea, paroxysmal nocturnal dyspnea or leg swelling. He was diagnosed with HL Stage 2B nodular sclerosis subtype 5 months earlier after presenting to the hematology and oncology department with weight loss, low grade fever and neck mass. At that time, CT neck and chest revealed large necrotic mass on the right side of the neck with multiple enhancing lymph node in the neck, adjacent to the trachea and carina and paraesophageal region; ESR was elevated at 120 mm/hr and diagnosis was confirmed with biopsy of neck mass. At that time, he was started on ABVD regimen for treatment which consists of Adriamycin (Doxorubicin) 42.25 mg (25 mg/ m2), Bleomycin 17 units (10 units/m2), Vinblastine 10 mg (6 mg/m2) and Dacarbazine 634 mg (375 mg/m2) all on Day 1 and day 15 per cycle every 4 weeks to complete 6 cycles of treatment, with pegfilgrastim on Day 2 and Day 16 per cycle. Patient had completed 4 cycles of chemotherapy prior to onset of exertional dyspnea. He has no significant medical history prior to being diagnosed with Hodgkin’s lymphoma and denies history of cigarette smoking. He had a baseline pulmonary function test before commencement of chemotherapy which showed normal lung volumes, FEV1 and FVC were 82% and 80% of predicted values respectively and mild reduction in diffusing capacity for carbon monoxide. PET scan done at onset of exertional dyspnea and one-week prior to presentation to the emergency department showed hypermetabolic activity in the lung periphery without Figure 1: PET scan showing increases hypermetabolic activity in the periphery of the lungs. ISSN: 2378-3656 DOI: 10.23937/2378-3656/1410390 Adetiloye et al. Clin Med Rev Case Rep 2022, 9:390 • Page 3 of 6 • United States. Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of classical HL, accounting for 65% to 75% of cases [9]. Unfortunately, there is still conflicting data regarding how best to prevent complications extending from potentially fatal pneumonitis to irreversible and debilitating complication of pulmonary fibrosis in patients receiving Bleomycin containing chemotherapeutic regimen without compromising treatment efficacy. This is in part due to varying trial designs and treatment endpoints. Advances in chemotherapeutic agents and radiotherapy have improved patient outcomes; however, careful staging, risk stratification and consideration for potential treatment related adverse events are required in determining optimal standard of care. Prognostication and selection of treatment modalities is based on classification of Hodgkin’s lymphoma into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to Ann Arbor stage I or stage II disease. According to study groups (the European Organization for the Research and Treatment of Cancer (EORTC) and the German Hodgkin Study Group), earlystage Hodgkin lymphoma is stratified into a high risk (unfavorable) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), any mass of ≥ 10 cm in the largest dimension, extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms, age greater than 50 years of age, intraabdominal disease [8]. consolidative radiation therapy due to extensive lung fibrosis. Unfortunately, patient continued to experience limitation of exercise due to exertional dyspnea with modified medical research Council Scale grade 3 at 5 months follow up. Repeat Pulmonary function test at that time showed restrictive lung pattern with FEV1 and FVC 40% and 34% of predicted values respectively (Table 1).