Bleomycin Pulmonary Toxicity Research Articles

Assessment of fitness for bleomycin use and management of bleomycin pulmonary toxicity in patients with classical Hodgkin lymphoma: A British Society for Haematology Good Practice Paper.

This good practice paper (GPP) is intended to support clinicians in assessing patient fitness for bleomycin and in management of bleomycin pulmonary toxicity (BPT) where it occurs. Bleomycin, originally developed as an antibiotic in the 1960s, has been a cornerstone of therapy for classical Hodgkin lymphoma (CHL) since results of its use in combination with doxorubicin, vincristine and dacarbazine (ABVD) were first published by Bonadonna etal in 1975 1. The same author recognised high rates of respiratory morbidity in these patients 2, and bleomycin-;related pulmonary toxicity (BPT) is now a well-;recognised and feared complication with its use. ABVD and BEACOPP/ BEACOPDac (bleomycin, cyclophosphamide, etoposide, doxorubicin, vincristine and prednisolone, with procarbazine or dacarbazine) are standard first-;line treatments in CHL patients, but considerable variation remains in assessing patient fitness for bleomycin both clinically and with respiratory investigations. A recent survey of British haematologists regularly using bleomycin revealed that 87.5% have no local protocols for assessing patients in an evidence-;based fashion, with wide variations in practice captured in the same survey (personal data). A working group was established and a literature review undertaken with the goal of presenting practical recommendations for clinicians regarding bleomycin use based on available evidence and expert opinion.

Bleomycin and perioperative care: a case report.

Bleomycin is associated with pulmonary toxicity ranging from pneumonitis, pulmonary fibrosis, to fatal acute respiratory distress syndrome. Oxygen administration can potentiate or precipitate bleomycin pulmonary toxicity, and the most common setting of oxygen exposure is during anesthesia. We report here the successful management and perioperative care of a patient with documented bleomycin pulmonary toxicity who had to undergo an eight hour long retroperitoneal surgery. With proper preoperative assessment, chest physiotherapy, inhaled steroids and bronchodilators, antibiotics, operative restriction of oxygen and fluids and good postoperative care no further pulmonary insult was inflicted.

HL-172 FDG-PET/CT as a Tool for Early Detection of Bleomycin-Induced Pulmonary Toxicity

Bleomycin pulmonary toxicity (BPT) is a serious and potentially fatal complication of bleomycin, a key component of Hodgkin lymphoma (HL) treatment. Before ours, only one published study evaluated the predictability of FDG-PET/CT in the diagnosis of BPT. We aimed to determine whether FDG-PET/CT changes correlate with clinical BPT. Additionally, we assessed the correlation of clinical BPT with sociodemographic and disease characteristics. In this retrospective study, FDG-PET/CT scans of adult (age >18 years) HL patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) at a single urban academic center, University of Cincinnati Medical Center, from 2012 to 2016 were evaluated for pulmonary toxicity and then assessed for the development of clinical BPT. The images were evaluated by 2 separate radiologists, for whom the clinical information was anonymized. All P-values were two-sided; P<0.05 was considered statistically significant. Data were analyzed using SAS 9.4 software. We found 54 FDG-PET/CT scans from 11 patients who received bleomycin for HL. Five of the 11 (45%) patients had radiographic changes that were characteristically focal or diffuse opacities on PET/CT and developed clinical BPT. One patient had radiological changes but did not develop clinical BPT, whereas the other five had no signs of toxicity on imaging. Patients with clinical BPT had higher SUVmax than those without (mean [CI] 2.66 [1.8-3.7] vs. 0.86 [0.4-1.9], P<0.05, Mann-Whitney U test). In a separate analysis, we compared patients with clinical BPT (9/25, 36%) and without (16/25, 64%). Patients with clinical BPT had lower hemoglobin (mean 10.9 vs. 13.3 g/dL, P=0.037) and higher ESR (mean 63.3 vs. 30.2 mm/hr, P=0.0289). We found that gender, stage, histology, history of lung radiation, prior G-CSF, and steroids did not significantly confer a higher risk of BPT. Patients with bulky disease and prior lung disease had a higher risk of clinical BPT; however, the correlation was not statistically significant. We conclude that FDG-PET/CT imaging, which is routinely used to assess treatment response in HL, is useful for early detection and guiding interventions for BPT. Hemoglobin and ESR at diagnosis can be predictive of BPT; further studies are needed.

713P Assessment of bleomycin pulmonary toxicity in men with poor-prognosis non-seminomatous germ-cell tumors treated in the GETUG 13 phase III trial

In 2014, the GETUG 13 trial has established the role of early intensified treatment for men with poor prognosis germ-cell tumors (GCT) and unfavorable tumor marker decline (Fizazi K, Lancet Oncol 2014). Patients with unfavorable marker decline were randomized after 1 cycle of BEP to receive either 3 additional BEP or dose-dense chemotherapy with personalized cumulative doses of bleomycin (potentially exceeding the 300 mg recommended threshold) based on serial lung function assessments. We assessed pulmonary toxicity of this strategy.

Four Cycles of Etoposide plus Cisplatin for Patients with Good-Risk Advanced Germ Cell Tumors

BackgroundThe National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good‐risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience.Material and MethodsResponse and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good‐risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data.ResultsBetween 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five‐year progression‐free, disease‐specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow‐up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment‐related death. In the more recent 655‐patient cohort, full‐dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events.ConclusionEPx4 is highly effective and well tolerated in patients with good‐risk GCTs and remains a standard of care.Implications for PracticeFour cycles of etoposide and cisplatin (EPx4) is a standard‐of‐care regimen for all patients with good‐risk germ cell tumors with a favorable response rate and disease‐specific survival of 98%. Full‐dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e‐cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.

Hybrid and parallel extracorporeal membrane oxygenation circuits

Hybrid and parallel extracorporeal membrane oxygenation circuits

Amelioration of Bleomycin and Methotrexate-Induced Pulmonary Toxicity by Serratiopeptidase and Fisetin

Pulmonary toxicity by anticancer drugs often leads to discontinuation of therapy or switching the therapy to alternative drugs. In the present study, serratiopeptidase (SPTD) and fisetin (FST) were evaluated as chemoprotectant to counteract the pulmonary toxicity induced by BLM and MTX. Single dose of MTX (20 mg/kg) by intraperitoneal and BLM (5 mg/kg) by intra-tracheal route was administered on 7th day of study. SPTD (20 mg/kg), FST (25 mg/kg), and NAC (250 mg/kg) and combinations of SPTD + NAC, SPTD + FST, and FST + NAC were administered through oral gavage for 14 days. SPTD and FST showed significant (p < 0.05) effect in MTX-induced lung toxicity by increasing reduced glutathione (GSH) and decreasing malondialdehyde (MDA), hydroxyproline (HXP), and collagen. SPTD and NAC showed significant (p < 0.05) effect in BLM-induced pulmonary toxicity by increasing GSH and decreasing MDA, HXP, and collagen whereas FST was not much effective. In combination study, SPTD + NAC combination showed significant (p < 0.05) effect in BLM- and MTX- induced lung injury whereas other combinations did not prove to be highly effective. SPTD can be recommended along with BLM and MTX in chemotherapy protocol alone and in combination with NAC.

Bleomycin Use in the Treatment of Hodgkin Lymphoma (HL): Toxicity and Outcomes in the Modern Era

BACKGROUND: Historically, one in five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT), a life-threatening interstitial pneumonitis. The current treatment paradigm consists of prompt discontinuation of bleomycin, administration of corticosteroids, antibiotics, hospital admission, respiratory therapy, or intensive care. BPT represents a challenge for patients with HL as it not only impairs respiratory function, but also has negative impacts on clinical outcomes. A collection of a dozen studies suggest BPT has a mortality rate just short of 10% of patients who develop BPT. Given recent data on bleomycin omission with negative interim PET scan, we assessed changes in BPT rates and severity over the past 15 years. Overall, treatment protocol characterization and patient characteristics most responsive to BPT treatment are poorly understood. OBJECTIVES: In this study, we investigated the clinical impact and treatment strategies in patients with BPT. Our goals were to: 1) Identify HL patients in the last decades who developed BPT and identify risk factors for BPT, 2) evaluate the impact of BPT on long-term clinical outcomes, and 3) characterize patterns of treatment strategies among patients with HL who develop BPT. METHODS: A single-center, retrospective analysis was preformed using patient data from the Mayo Clinic Lymphoma Database (Rochester, MN) consisting of 1,299 patients diagnosed with HL. All patients were diagnosed between 2003-2018. Inclusion criteria included 1) newly diagnosed, biopsy proven HL, 2) upfront treatment with ABVD, 3) treatment was received at our institution. All patients were assessed for clinically relevant HL characteristics including stage of disease, presence of bulky disease, presence of B symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, BPT risk factors, and bleomycin treatment regimen. BPT was clinically defined as 1) Presence of pulmonary symptoms, 2) bilateral interstitial infiltrates on imaging, and 3) no evidence of infectious etiology. Patients treated in the "Early Era" (2000s) were compared to patients in the "Recent Era" (2010s). Comparison of continuous variables between BPT groups was assessed with Wilcox rank-sum test. OS and PFS were estimated via the Kaplan-Meier method. Approval of the protocol by the Mayo Clinic Institutional Review Board (IRB) was obtained and all patients were consented accordingly. RESULTS: One-hundred twenty six patients met the inclusion criteria for this study. Median follow-up for PFS and OS was 5.5 years (95%CI = 4.8-6.4) and 5.8 years (95%CI = 5.0-7.0), respectively. The 10-year OS and PFS among all patients were 85.1% (95%CI = 77.8-93.1) and 86.3% (95%CI = 80.1-93.0), respectively. Forty-seven patients (37% of all patients) met criteria for BPT. The estimated 10-year OS for BPT and non-BPT patients were 74.7% (95%CI = 61.8-90.5) and 91.7% (95%CI = 83.9-100.0), respectively. The estimated 10-year PFS for BPT and non-BPT patients were 84.7% (95%CI = 74.8-95.8) and 87.0% (95%CI = 79.1-95.8), respectively. In univariable analysis, BPT negatively impacted OS (HR=3.6, 95%CI: 1.2-10.6). However, bleomycin omission did not impact OS (HR=1.3, 95%CI=0.5-3.7). BPT-mortality was 17%. In multivariable analysis, BPT was not significantly associated with OS after adjusting for baseline characteristics (HR=3.0, 95%CI=0.9-9.9). Patients were older (median: 46 vs 33 years) and received less bleomycin (median: 107 vs 215 units) compared to non-BPT patients. BPT was most often managed with bleomycin omission with 59% of patients (74 of 126 patients) having omitted bleomycin at some point during treatment. Patients treated in the "Recent Era" (2010s) had lower BPT rates (28% vs 48%), mortality (10% vs 21%), bleomycin dose (143 vs 204 units), and bleomycin cycles (7 vs 12 cycles), yet higher prophylactic bleomycin omission (59% vs 8%) compared to "Early Era" (2000s). Patients treated in the Recent Era compared to Early Era had a reduction of BPT treatment with steroids, hospital admission, respiratory therapy, and ICU admission by 12%, 22%, 14%, 13%, respectively. CONCLUSION: Overall, our data suggests BPT continues to impact OS in HL patients treated with ABVD, however BPT treatment is decreasing as management changed in recent years. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding.

Advancing age and the risk of bleomycin pulmonary toxicity in a largely older cohort of patients with newly diagnosed Hodgkin Lymphoma

ObjectivesIn patients with Hodgkin Lymphoma (HL), the relationship between increasing age and bleomycin pulmonary toxicity (BPT) remains unclear. This study explores associations between age and BPT in a real-world cohort of largely older patients with HL. Material and methodsThis study retrospectively evaluated a nationwide patient cohort of United States Veterans diagnosed with HL in VA medical centers between October 1, 2002 and December 31, 2013 (follow up through April 15, 2016). The primary outcome was the development BPT, defined as: ambient air oxygen saturations <92% with pulmonary infiltrates on chest radiograph and no other etiologies OR clinician documentation of BPT. Multivariable logistic regression was used to evaluate variables associated with development of BPT. Cox proportional hazards analysis was performed to evaluate the risk of death up-to 5-years from diagnosis. ResultsOverall, 847 patients received chemotherapy and 739 of these patients received bleomycin. Sixty-six patients (9.3%) developed BPT. The incidence of BPT per age category: 0.03 (9/262), 0.07 (13/188), 0.13 (23/171), and 0.24 (21/88) for age categories: ≤ 49, 50–59, 60–69 and ≥ 70 years. Odds of BPT steadily increased with advancing age (compared to patients age ≤ 49 years) with odds ratios of 1.65 (95% CI 0.68–4.03), 3.24 (1.43–7.34), 6.01(2.52–7.34) for age categories 50–59, 60–69 and ≥ 70 years, respectively. The was no association between bleomycin and risk of death up-to 5-years [HR: 0.87; 95% CI (0.61–1.23)]. ConclusionThis study demonstrates a direct relationship between age >60 years and odds of developing clinically significant BPT.

Bleomycin use in the treatment of Hodgkin lymphoma (HL): toxicity and outcomes in the modern era

One-in-five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT). Given bleomycin-omission data with negative interim-PET, we assessed changes in BPT statistics. We retrospectively evaluated 126 ABVD-treated HL patients for overall survival (OS), progression-free survival (PFS), BPT factors, and management. Forty-seven patients developed BPT with 17% BPT-mortality. In univariable analysis, OS was negatively impacted by BPT (HR = 3.6, 95%CI = 1.2–10.6), but not bleomycin-omission (HR = 1.3, 95%CI = 0.5–3.7). In multivariable analysis, BPT was not associated with OS (HR = 3.0, 95%CI = 0.9–9.9). BPT patients were older (46 y vs 33 years) and received less bleomycin (107 vs 215 units) compared to non-BPT patients. BPT was managed primarily with bleomycin-omission. “Recent Era” patients had lower BPT rates (28% vs 48%), mortality (10% vs 21%), and bleomycin doses (7 vs 12 doses), yet higher bleomycin-omission in the absence of the BPT (59% vs 8%) compared to “Early Era”. Our data suggest BPT continually impacts OS in ABVD-treated HL patients, however management is changing.

The role of atopy in the pathogenesis of bleomycin pulmonary toxicity

Bleomycin pulmonary toxicity (BPT) is a potentially life-threatening consequence of bleomycin usage in patients. An overproduction of epithelium-derived cytokines, habitually linked to allergic inflammation, has been recently revealed in experimental models of BPT. We assessed retrospectively our cohort of patients with Hodgkin Lymphoma treated with bleomycin between 2014 and 2016 for their demographic, clinical features, including BPT development, atopy status and risk factors for BPT. Then they were invited for allergy testing and blood sample collection. The samples were stimulated with different stimuli (Bleomycin, IL-33, TSLP) for 24 h on cell culture. The culture supernatants were analysed for TGF-β, Galectin3, Arginin, Amphiregulin, Eotaxin, IFNγ, TNFα, IL1β, 4, 5, 6, 10, 13, 17, MIP-1α, and bleomycin hydrolase (BLH) levels. The cohort consisted of 51 patients showed that atopy was the only significant risk factor for BPT occurrence (OR: 7.2, p = 0.007). Fourteen subjects were included for blood analysis. The analysis of supernatants at the unstimulated condition revealed that BLH and Amphiregulin were significantly lower in patients who had BPT than controls. The BLH cut-off that best identified a history of BPT was 175.31 (Sensitivity: 62.5%, specificity: 100%). Following the stimulation, BLH reduced compared to the unstimulated condition and the difference between groups remained significant (p < 0.05). Our study is the first to report that low levels of bleomycin hydrolase in allergic individuals may be predisposing to a possible pathway of fibrosis.

Bleomycin in Hodgkin's Lymphoma - A Boon or a Bane? - A Retrospective Study of Bleomycin Pulmonary Toxicity in Hodgkin's Lymphoma.

Introduction:Hodgkin's lymphoma (HL) is one of the most curable malignancies with cure rates of above 85% across all stages. Bleomycin containing regimen is routinely employed in the treatment of HL. Pulmonary toxicity due to this drug is the most feared side effect in these regimens where the mortality rate is approximately 2%–3%. We have conducted this study to assess the genetic susceptibility among the Indian HL patients to bleomycin pulmonary toxicity (BPT).Materials and Methods:In a retrospective study conducted at a tertiary care hospital from South India between January 2013 and May 2019, we reviewed 100 HL patients who were treated with bleomycin-containing regimen (adriamycin, bleomycin, vinblastine, and dacarbazine or cyclophosphamide, vincristine, procarbazine, and prednisone/adriamycin, bleomycin, and vinblastine) for BPT.Results:A total of 100 patients with HL who had received bleomycin-containing regimen were analyzed, which included 23 females and 77 males. Twenty-nine patients had BPT and five deaths were attributed to the same. Radiology reports showed that 15 patients had acute BPT and eight patients had chronic changes. Four patients had rare findings of bleomycin-induced lung damage and computed tomography of the chest could not be done for two patients, whose chest X-ray showed features suggestive of BPT.Conclusion:The incidence of bleomycin induced pulmonary toxicity and mortality was significantly higher in our study compared to that of other Western studies. This could be probably due to the increased susceptibility of the Indian patients to bleomycin induced lung damage. In a highly curable cancer such as HL, it is unacceptable to have such a high life-threating toxicity. Hence, an alternative chemotherapy regimen without bleomycin is to be explored which would prevent toxicity and hence the compromise on survival.

Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with germ cell tumors

Bleomycin pulmonary toxicity (BPT) has been well described in patients with germ cell tumors treated with bleomycin etoposide and cisplatin chemotherapy (BEP). To assess the prognostic impact of BPT, we retrospectively identified 52 patients who underwent bleomycin etoposide and cisplatin chemotherapy from 2008 to 2017 in our institution, and evaluated the risk factors of BPT and its effect on prognosis. Patients who had received chemotherapy at another institution were excluded. BPT was defined as bleomycin discontinuation in response to pulmonary function test decline, pulmonary symptoms, or interstitial pneumonia on computed tomography without infection. We divided the patients into two groups according to this definition: BPT and non-BPT. Their median age was 34.2 years, and their median body mass index was 22.8kg/m2. Twenty patients had a smoking history, 37 were diagnosed with non-seminoma, and 20 had lung metastasis. The median cumulative bleomycin dose was 270mg/body. Fifteen patients were classified into the BPT group and 37 into the non-BPT group. Only body mass index < 22 was identified as a predictor of BPT in multivariable logistic models. Age or use of granulocyte-colony stimulating factor did not have a significant impact. Kaplan-Meier analysis revealed that the presence of BPT had no significant impact on either 5-year overall survival or progression-free survival. Lower body mass index can increase the risk of BPT in patients with germ cell tumors undergoing BEP. However, discontinuation of bleomycin with BPT does not adversely influence the survival outcomes.

Abstract 34: Bleomycin pulmonary toxicity in Hodgkin's lymphoma treated with ABVD regimen not followed by radiation

Abstract Introduction: One of the finest five accomplishments of medical oncology in the last fifty years is undeniably the evolution and advancement of curative systemic treatment of Hodgkin's disease. There are eight main chemotherapy regimens which are currently in use. Common regimens are BEACOPP (bleomycine, etoposide, adriyamycin, cyclophosphamide, vincristine, oncovin procarbazine, prednisone) and ABVD (ariyamycin, bleomycin, vinblastine, dacarbazine). In 1975 a report on the initial randomized control trial of ABVD pointed out its advantages and supported the combination along with the then-popular MOPP regimen. ABVD therapy alone unaccompanied by radiation therapy has a greater rate of overall survival. ABVD regimen, which was used as an alternative to first-line regimen, has now evolved as a highly preferred one and has become the mainstay. Bleomycin is a very effective antineoplastic drug and is a component of the ABVD regimen, which is a composite of water-soluble peptides. In 1992, there were studies conducted on mice which suggested the consistent and expeditious development of pulmonary fibrosis in them. Bleomycin pulmonary or lung toxicity can have a serious impact on treatment outcomes. Although there are no guidelines for screening pulmonary toxicity, various publications report pulmonary toxicity in patients receiving ABVD regimen. Bleomycin has been the pillar of many responsive cancers. Bleomycin is cytotoxic. In the presence of iron and oxygen it forms free radicals, and these free radicals binds to the DNA and produce single- or double-stranded DNA breaks. Although bleomycin-induced pulmonary toxicity has influence on the treatment outcome, there are currently no specific guidelines either for diagnosing or monitoring. Pulmonary fibrosis has been reported in various patients due to bleomycin administration in literature as early as the 1970s. A retrospective study from 1986 to 2003 including 141 cases of HL receiving bleomycin-containing treatment was reported in 2005 which observed that there is a marked reduction in five-year overall survival rate among the patients treated with the same. They add that the age of the patient increases the risk, especially above 40 years. Age, cumulative drug dose, renal function, stage of disease at presentation, radiation therapy, concomitant oxygen use, other chemotherapeutic agents, and G-CSF use may all influence the risk of developing BIP. Procedures: This is a retrospective study of patients who are treated with ABVD regimen without radiation therapy for newly diagnosed Hodgkin's lymphoma at a tertiary oncology care center in Mangalore, South India. Demographic details, histopathologic subtype, date of diagnosis, bone marrow involvement, B symptoms, biochemistry, and pulmonary toxicity will be analyzed and discussed. Results: 74 patients were diagnosed with Hodgkin's lymphoma from 2000 to now. Six to eight cycles of ABVD chemotherapy has been administered to all of the patients diagnosed as HL, not followed by radiation. Of these 74 patients, seven had bleomycin toxicity. The majority were males (5 of 7; 71%). Out of the two female patients one is in premenstrual stage, aged 38 years, and the other patient is in her post-menstrual stage, aged 68 years. None of the patients under the study were diagnosed with comorbidities or retroviral disease. There is wide distribution of ages. The majority of patients presented with lymph node enlargement as the chief complaint. Few patients had B symptoms. On clinical examination two patients had hepatosplenomegaly. Out of seven patients four had excision biopsy and three had an incision or Tru-cut biopsy. Twenty-nine percent were bulky and 71% were non-bulky. CD 15 and CD 30 were positive for majority of patients. The patients are reassessed on each follow-up visit using PETCT or CT scan since early treatment helps in better prognosis. Six to eight cycles of ABVD chemotherapy have been administered to all of the patients diagnosed as HL, not followed by radiation. Whenever a patient reports any respiratory system complaints such as cough or breathlessness, we start management for pulmonary toxicity. Oxygen saturation is monitored continuously. We stop administering bleomycin from the chemotherapy regimen. The patients are reassessed on each follow-up visit using PETCT or CT scan. Conclusion: Understanding of bleomycin toxicity continues to evolve. Bleomycin is an inevitable chemotherapeutic constituent which has the side effect of pulmonary toxicity. There are no specific guidelines to estimate the toxicity. The outcome of HL treatment with bleomycin-induced pulmonary toxicity will depend on how early treatment of pulmonary toxicity is started. The outcome is that all our patients are alive either without disease or ongoing treatment. Our center presents good outcome because of the immediate management of pulmonary toxicity. The literature shows that certain poor outcomes are due to lack of immediate reporting of respiratory complaints. Citation Format: Tara Rajendran, Krishna Prasad. Bleomycin pulmonary toxicity in Hodgkin's lymphoma treated with ABVD regimen not followed by radiation [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 34.

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation

The GHSG trial HD11 established 4 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by involved field radiation therapy (IFRT) as the standard of care for patients with early unfavorable Hodgkin lymphoma (HL). Despite these results, practitioners often still recommend 6 cycles of chemotherapy followed by radiation therapy (RT), especially for patients with high risk features. We compared the outcomes of patients treated with 4 vs. 6 cycles of ABVD followed by RT, including patients with bulky disease. We also examined the relapse rates of patients treated with involved site radiation therapy (ISRT) compared with IFRT. One hundred twenty-eight patients diagnosed with early stage, unfavorable HL by GHSG criteria and treated between 2000 and 2013 were identified. Medical records were reviewed for clinical, pathologic, and treatment information as well as toxicities. Clinical outcomes including overall survival (OS) and freedom from relapse (FFR) were estimated for the entire cohort as well as a subset of bulky patients using the Kaplan-Meier method. One hundred twenty-eight patients were included in the study with a median follow-up of 5.0 years. Seventy patients (55%) received 4 cycles of chemotherapy and 58 patients (45%) received 6 cycles. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4 cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6 cycle group. 68% of all patients received ISRT. Six year OS was 100% and 97% for patients receiving 4 and 6 cycles of chemotherapy, respectively (P = 0.35). Six year FFR was 100% and 98% for patients receiving 4 and 6 cycles of chemotherapy, respectively (P = 0.28). A greater proportion of patients received 6 cycles of chemotherapy if treated before 2010 (year of HD11 report) (P = 0.01) and if bulky disease was present (P < 0.01). A greater proportion of patients developed bleomycin pulmonary toxicity in the group receiving 6 cycles of chemotherapy (20% vs 31%, P = 0.16). Six year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P = 0.58). Patients with bulky disease had a median follow up of 4.7 years. Amongst these patients, there were no significant differences in 4 year FFR between the 4 (100%) and 6 (98%) cycle group (P = 0.48). Four year FFR was 100% and 98% for patients receiving IFRT and ISRT, respectively (P = 0.52). There were no deaths in the patient group with bulky disease. Patients diagnosed with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by radiation therapy. Six cycles of chemotherapy does not appear superior in terms of disease control and may provide little added value in this population, even for patients with high risk features such as bulky disease. Increased relapse rates are not seen with ISRT compared to IFRT after 4 cycles of ABVD.

Does Bleomycin Lung Toxicity Increase the Risk of Radiation Pneumonitis in Hodgkin Lymphoma?

Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in patients with Hodgkin lymphoma (HL). We undertook the present study to investigate the risk of radiation pneumonitis (RP) in the setting of BPT and to determine the need for delay or omission of radiation therapy (RT) in these patients. We identified 123 HL patients treated with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) followed by RT to the chest from January 2009 to December 2014. The medical records were reviewed for clinical, pathologic, and treatment information and toxicities. Our primary outcome was RP of any grade. Univariate and multivariate analyses were used to assess the association of BPT, baseline patient characteristics, and treatment variables with the incidence of RP. A total of 123 patients were included, of whom 99 (80%) received consolidation intensity modulated RT after ABVD treatment. We identified 31 patients (25.2%) with BPT after frontline ABVD. Seventeen patients (13.8%) developed RP a median of 8weeks (range 1-39) after RT completion. BPT did not correlate with the risk of developing RP (P=.36). We evaluated the RP outcomes with respect to the bleomycin to RT interval (≤6weeks vs >6weeks), and we found that this interval did not predict for RP risk (P=.60). Dosimetric parameters such as the volume covered by 5Gy and the mean lung dose were analyzed. A volume covered by 5Gy of >55% and mean lung dose >13.5Gy increased the risk of RP by 1.14-fold (P=.002) and 4.24-fold (P=.007), respectively. The results of our study suggest that BPT does not increase the risk of developing RP. Furthermore, RT initiation does not need to be delayed after chemotherapy, except to allow for the completion of steroid therapy or clinical recovery from BPT.

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation

The German Hodgkin Study GroupHD11 trial validated 4 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by involved field radiation therapy (IFRT) for early unfavorable Hodgkin lymphoma (HL) patients. However, practitioners often recommend 6 cycles followed by RT, especially for bulky disease. We compared patient outcomes after treatment with 4 or 6 cycles of ABVD followed by RT (IFRT and involved site RT [ISRT]). We identified 128 patients treated for early unfavorable HL (GHSG criteria) between 2000 and 2013. Clinical outcomes (overall survival [OS] and freedom from relapse [FFR]) were estimated using Kaplan-Meier analysis. Toxicities were evaluated. The median follow-up time was 5.0years. Patients received 4 (70 patients, 55%) or 6 (58 patients, 45%) cycles of chemotherapy. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4-cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6-cycle group. For patients receiving 4 and 6 cycles, the 6-year OS was 100% and 97% (P=.35), respectively, and the 6year FFR was 100% and 98% (P=.28), respectively. More patients received 6 cycles if they were treated before 2010 (HD11 report) (P=.01) and if they had bulky disease (P<.01). Sixty-eight percent of patients received ISRT. The 6-year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P=.58). More patients experienced bleomycin pulmonary toxicity in the 6-cycle group (20% vs 31%, P=.16). For patients with bulky disease, the 4-year FFR was similar with receipt of 4 (100%) or 6 (98%) cycles (P=.48) and IFRT (100%) or ISRT (98%) (P=.52). There were no deaths among patients with bulky disease. Patients with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by ISRT. Six cycles of chemotherapy does not appear superior for disease control, even for bulky disease.

Pulmonary Toxicity of Bleomycin - A Case Series from a Tertiary Care Center in Southern India.

Hodgkin's lymphoma is one of the curable cancers and the standard treatment regimen involves combination chemotherapy involving bleomycin. One of the fatal side effect of bleomycin is pulmonary toxicity. Here we present three cases of Hodgkin's lymphoma treated with ABVD chemotherapy who had pulmonary toxicity. All three developed bleomycin induced pulmonary toxicity in the form of pulmonary fibrosis during treatment of the disease. Mode of treatment, severity of the condition and the treatment outcome varied among the three. Two recovered following treatment and one patient died due to irreversible pulmonary damage. Causality assessment using Naranjo's scale gave a score of 7 for case one and three and a score of 6 for case two, both indicating the adverse drug reaction to be a probable bleomycin induced Lung fibrosis.

Bleomycin-induced flagellate hyperpigmentation: A case report with review of literature

Bleomycin is a commonly used chemotherapeutic agent for lymphomas, germ cell tumors, and malignant pleural effusions. Although the pulmonary toxicity of bleomycin is well reported; the cutaneous side effects are relatively uncommon, ranging from generalized hyperpigmentation, sclerodermoid changes, erythema multiforme, and gangrene to flagellate dermatosis. Here, we report a characteristic but relatively rare side effect of flagellate dermatitis, which developed secondary to bleomycin in a 28-year-old gentleman suffering from Hodgkin's lymphoma after two cycles of treatment with adriamycin, bleomycin, vinblastine, dacarbazine regimen.

Radiation Pneumonitis Risk after Bleomycin Toxicity in Hodgkin Lymphoma Patients

Introduction:Combined modality treatment with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) chemotherapy followed by consolidative radiation to start within 3-4 weeks is the current accepted approach in the treatment of patients with early stage Hodgkin lymphoma (HL). Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in HL patients. We undertook this study to investigate the risk of radiation pneumonitis (RP) in the setting of BPT and to determine the need for delay or omission of radiation in these patients.Methods:We reviewed the records of all HL patients treated with ABVD followed by radiation therapy (RT) to the chest between January 2009 and December 2014. We defined bleomycin toxicity as: the occurrence of clinical respiratory symptoms leading to discontinuation of bleomycin and/or bilateral opacities noted on computed tomography (CT) imaging and/or drop in diffusing capacity of the lung for carbon monoxide (DLCO) by 25%, in the absence of infection. We identified 129 patients, 100 of which received consolidation RT as part of combined modality and are the subject of this report, 29 patients were excluded because they developed relapse before getting RT. We compared patients with and without bleomycin toxicity for the following outcomes:•Frequency of RP using the Pearson chi-square test.•Interval between BPT and Radiation using Mann-Whitney U test (MWT)•Interval between end of chemotherapy and radiation using MWT.We used univariate Cox regression analysis to assess the risk of RP by looking at the time-interval in weeks from end of bleomycin to start of RT.Results:Median follow up was 23 months (6 - 69), Median age was 31 years (18-77), and 60% were females. Per our criteria, 28 patients developed BPT (25.5%). All patients received intensity modulated radiation therapy, radiation dose median was 30.60 Gy (20-42Gy). Mean lung dose (MLD) was a median of 9.4 Gy (2.6- 13.9 Gy). The median interval between chemotherapy and RT was 3 weeks (1- 8 weeks). Median interval from stopping bleomycin, either as a precaution or because of toxicity, to the start of RT was 5 weeks (1-20 weeks). Interval between documented bleomycin toxicity to start of radiation was a median of 8.5 weeks (2-20 weeks).We had 10 cases of RP (10%), 5 of which were ≥ Grade 2. There was no significant difference in RP risk in patients with or without BPT; 10.7% (3/28) versus 9.6% (7/72) respectively, P= 0.82.Patients with BPT versus those without BPT had no significant difference in baseline characteristics. The interval time from chemotherapy to radiation was a median of 3 weeks in both groups with or without BPT showing no difference; P= 0.83. However, Patients with BPT had a significantly longer interval from last bleomycin cycle to start of radiation compared to those without BPT (median 8.5 vs. 5 weeks, p =0.014).The intervals from chemotherapy to radiation treatment and from bleomycin to radiation treatment showed no significant correlation with RP on univariate Cox regression analysis (P= 0.41 and P= 0.12, respectively). This was maintained when adjusted for the number of bleomycin cycles.Treatment of BPTOf the 28 patients, 17 were managed by stopping bleomycin and observation only; 10 patients required a 2 week course of steroids. One patient went into severe respiratory compromise, was started on continuous oxygen and eventually recovered 48 hours later and went on to receive RT beginning 2 weeks after completing his steroid treatment. This patient did not have pulmonary complications after RT.All 28 BPT patients eventually completed their planned course of radiation. At last follow up, all 28 patients were alive and free of respiratory symptoms.Conclusion:In our cohort of Hodgkin lymphoma patients, those patients with bleomycin toxicity who received standard RT had no excess risk of subsequent RP. Moreover, patients were able to receive complete courses of RT to intended conventional radiation doses. Our findings suggest that RT does not need to be delayed following chemotherapy, except to allow for the completion of steroids or clinical recovery from BPT.Table 1BPT_clinicalBPT _imagingBPT_DLCO≥25%Clinical+(CTorDLCO≥25%)BPT per criteriaAll patients n=1002517101328RPNo n=90221591225Yes n=1032113 DisclosuresNo relevant conflicts of interest to declare.