Bleomycin-induced Lung Toxicity Research Articles

Investigate the potential lung-protective effects of Hidrosmin and/or Vitamin C in rats with Bleomycin-induced lung toxicity..

Investigate the potential lung-protective effects of Hidrosmin and/or Vitamin C in rats with Bleomycin-induced lung toxicity..

Protective efficacy of pirfenidone in rats with pulmonary fibrosis induced by bleomycin.

Bleomycin causes increased production of reactive oxygen species, leads to pulmonary toxicity, fibroblast activation, and fibrosis. This study aimed to evaluate the protective effect of pirfenidone on bleomycin-induced lung toxicity in rats. Twenty-eight adult rats were randomly divided into 3 groups; Bleomycin (B group, n=10), Bleomycin and Pirfenidone (B-PND group, n=13), and the control group (n=5). The bleomycin regimen was administered for 9 weeks. Pirfenidone was administered at 100 mg/kg daily. Total antioxidant level (TAS), total oxidant level (TOS), tumor necrosis factor (TNF-α), transforming growth factor (TGF-β1), matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor (PAI) levels were studied. Histopathologically, sections were stained with Hematoxylin-eosin and Masson-trichrome for grading-scoring according to the Ashcroft score. Stage 3 fibrosis was observed in 50% of the B group rats, stage 3 and higher fibrosis was never detected in the B-PND group and the difference was statistically significant (p=0.003). When evaluating tissue inflammation, the inflammation was higher in the B-PND group than in the other groups (p<0.001). Pleuritis was detected in all rats in group B, while was not observed in B-PND and control group (p<0.001). The TAS level was found to be significantly higher in group B than in group B-PND (p=0.034), while no difference was found between TOS, TNF-α, MMP-2, PAI, TGF-β1. Pirfenidone had a statistically significant protective effect in bleomycin-induced lung fibrosis and pleuritis in rats. Despite the presence of inflammation in the tissue, no significant changes were observed in inflammation markers in the peripheral blood. Novel serum biomarkers are needed to indicate the presence of inflammation and fibrosis in the lung.

A Review of Hodgkin Lymphoma in the Era of Checkpoint Inhibitors.

Hodgkin lymphoma (HL) is a hematopoietic malignancy of B-cells that has a bimodal distribution with respect to age and incidence. With the introduction of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) and radiation combined, the prognosis of HL has significantly improved, with five-year survival rates approaching 95%. While HL has become highly curable, the side effect profiles of ABVD are dire and warrant continuous review. Because HL is often diagnosed in populations in their 20s-30s, patients are forced to undergo fertility preservation procedures as well as deal with other long-term side effects of chemotherapy (including doxorubicin dose-dependent cardiotoxicity and bleomycin-induced lung toxicity). The opportunity cost of the treatment in the short term and vulnerability to treatment-induced malignancies decades later dramatically affect the quality of life of HL patients. New therapies have developed over the past several decades with respect to immunotherapies, particularly programmed death protein 1 inhibitors (e.g., nivolumab and pembrolizumab). Studies have shown checkpoint inhibitors to be effective in treating HL with an objective response rate of 69% for relapsed/refractory classical HL for nivolumab use. Checkpoint inhibitors will continue to help maintain the high five-year survival rate for HL and hopefully have a more favorable side effect profile in the short term, as well as later in the patient's life. This article seeks to summarize treatment options for HL while comparing outcomes and side effect profiles with the addition of checkpoint inhibitors.

Pharmacological Approach for Prevention of Bleomycin-Induced Lung Injury

Bleomycin is a chemotherapeutic medication commonly use in the treatment of Hodgkin's disease and germ cell tumors. Pulmonary fibrosis is major and dose limiting adverse effect of the drug. There is not currently any equal alternative approach or a medical agent for prevention of its pulmonary injury. We searched scientific databases in order to find investigational pharmacologic medicines in prevention of bleomycin-induced lung toxicity (BILI). Results revealed that some anti-inflammatory and antioxidant preparations such as statins, N-acetylcysteine (NAC), supplements (vitamin D3, L-arginine, selenium), and renin-angiotensin-aldosterone system (RASS) inhibitors might be effective in preclinical models of pulmonary toxicity mediated by bleomycin. However, we still need more in vivo studies and large human randomized clinical trials to confirm their benefits.

Bleomycin-Induced Lung Toxicity in Hodgkin's Lymphoma: Risk Factors in the Positron Emission Tomography Era.

IntroductionBleomycin is a major antimitotic agent in the first-line treatment for Hodgkin's lymphoma. The main limitation of its use is its pulmonary toxicity. The objectives of this study are to find out the risk factors for the occurrence of bleomycin-induced lung toxicity in patients with Hodgkin's lymphoma and, on the other hand, to determine if positron emission tomography scan is a reliable means of early detection of this toxicity.MethodsThis is a retrospective study conducted in the clinical Hematology Department of Mohammed V Military Instruction Hospital, Rabat, Morocco. All patients with Hodgkin's lymphoma and treated with a bleomycin-based chemotherapy were included. The impact of different clinical and biological factors on the risk of bleomycin-induced lung toxicity occurrence was assessed using univariate and multivariate logistic regression. The benefit of positron emission tomography, usually performed as part of the re-assessment of Hodgkin’s lymphoma after two and four cycles, has been evaluated in the detection of bleomycin-induced lung toxicity.ResultsAmong 124 patients included in the study, 18 (14.5%) patients experienced bleomycin-induced lung toxicity. On multivariate analysis, smoking (p = 0.038) and the use of the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) compared to the escalated BEACOPPe regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (p = 0.018) were statistically significant risk factors.After two and four courses of therapy, the positron emission tomography was able to predict the occurrence of bleomycin-induced lung toxicity before the appearance of clinical symptoms only in 36.4 % and 12.5% of patients, respectively.ConclusionStudies to identify risk factors for the development of bleomycin-induced lung toxicity are crucial to reduce toxicity in the treatment of Hodgkin's lymphoma. However, two- and four-cycle positron emission tomography scans cannot be considered as a reliable means of early detection of this toxicity.

Clinical Outcomes of Elderly Patients with Advanced-Stage Classic Hodgkin Lymphoma Who Received an ABVD Regimen: A Multi-Center Retrospective Study in Japan (HORIZON study)

Clinical Outcomes of Elderly Patients with Advanced-Stage Classic Hodgkin Lymphoma Who Received an ABVD Regimen: A Multi-Center Retrospective Study in Japan (HORIZON study)

The Possible Protective Effect of Melatonin and Coenzyme Q10 on Lung Injury Induced by Bleomycin in Adult Male Albino Rats

Background: bleomycin-induced lung toxicity and oxidative damage by decreasing the deactivating enzyme, genetic vulnerability, and released cytokines of inflammation. Melatonin has a free radical detoxifying effect, coenzyme Q10 has a strong antioxidant effect. Aim of the study: this study aimed to evaluate the possible protective role of melatonin and coenzyme Q10 in bleomycin-induced lung injury in Albino rats. Material and Methods: forty male Albino rats were categorized into five groups; group I (control group), group II (bleomycin group): rats were given a single dose of bleomycin intra-tracheal for inducing lung injury, group III (melatonin group): rats were given melatonin for three weeks after intratracheal installation of bleomycin, group IV (coenzymeQ10 group): rats were given coenzymeQ10 for three weeks after intratracheal installation of bleomycin and group V (combined melatonin and Co Q10 group): rats were given a combination of melatonin and coenzyme Q10for three weeks after induction of bleomycin lung toxicity. Lung tissues were prepared for biochemical, histological and immunohistochemical studies. Results: bleomycin produced a significant increase in the level of malondialdehyde and a significant reduction in glutathione peroxidase activity in lung tissues with loss of normal histological lung architecture, significant elevation in main area percent of collagen fibers deposition and caspase-3 immuno positive expression. In group III melatonin enhanced a significant improvement in the biochemical changes, moderate prevention of histopathological changes in lung tissue with a significant reduction in main area percent of collagen fibers deposition and caspase-3 immuno positive expression. While, in group IV co enzyme Q10 enhanced non significant improvement in the biochemical changes, mild prevention of histopathological changes and non-significant reduction in main area percent of collagen fibers deposition and caspase-3 immuno positive expression. Using a combination of both drugs in group V enhanced a significant improvement in the biochemical changes and almost preservation of normal histological architecture of the lung tissue. Conclusion: administration of both melatonin and coenzyme Q10 produced almost a complete recovery of bleomycin induced lung injury.

Bleomycin-Induced Fatal Lung Toxicity Misdiagnosed as Covid-19 Pneumonia: A Case Report

Bleomycin is a chemotherapeutic agent that is preferred for the treatment of testicular cancer, lymphoma and some squamous cell carcinomas Bleomycin-induced lung toxicity is a common, but rarely fatal side-effect, and the radiological image of which can be confused with other reasons which makes organizing pneumonia pattern We report here on the case of a 40-year-old male patient with testicular cancer with bleomycin-induced fatal lung toxicity that was misdiagnosed as Covid-19 pneumonia The patient suffered subsequent fatal spontaneous pneumomediastinum, pneumothorax, and pulmonary interstitial and subcutaneous emphysema, and died from respiratory failure

Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p=0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

PVAG Regimen (Prednisone, Vinblastine, Doxorubicin, Gemcitabine) Used in Real-Life Setting in First Line Therapy for Elderly Classical Hodgkin Lymphoma Patients: A Retrospective Study of Lysa Centers

Introduction: Older patients with an age above 60 years with classical Hodgkin lymphoma (cHL) represent a proportion of 20% to 30% of all cHL. Older cHL patients are characterized by unfavorable prognostic factors with an aggressive disease, a poor tolerance to chemotherapy especially with bleomycin-induced lung toxicity resulting to a significant reduced survival as compared to younger patients. PVAG regimen (prednisone, vinblastine, doxorubicin, gemcitabine) was developed by the German Hodgkin Study Group (GHSG) to improve results and reduce toxicities of ABVD regimen. In a prospective phase II study of 55 early unfavorable and advanced-stage elderly HL patients (median age, 68 years), 78% achieved complete response (CR) with a 3-year progression free survival (PFS) and overall survival (OS) rates of 58% and 66%, respectively (Böll et al, Blood 2011) with favorable toxicity profile. To the best of our knowledge, there is no report that described efficacy and toxicity of this protocol in real-life setting. Methods: Between June 2011 and February 2020, 49 elderly patients with cHL received first-line chemotherapy with PVAG (Prednisone 40 mg/m2, Vinblastine 6 mg/m2, Doxorubicin 50 mg/m2, Gemcitabine 1000 mg/m2, or adapted-dose of PVAG) in 6 LYSA centers. All medical records were reviewed for clinical and biological characteristics, modality of treatment, responses and outcome. Comorbidities were evaluated according to the cumulative illness rating scale for geriatrics (CIRS-G) and treatment-related toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Results: The median age of the 49 patients was 76 years (range, 61-87) with 44 patients ≥70 years old (69%) and 27 male (55%). Ann Arbor stages were as follows: II (n=16, 33%), III (n=12, 24%), IV (n=21, 43%). Altered performance status (PS 2-4) was presented in 35% of patients and B symptoms in 59%. IPS was ≥3 in 32 (65%) patients. CIRS-G Grade 3 or 4 in two or more categories was observed in 11 patients (22%) and 22 patients (43%) had a cumulative CIRS-G score over 6. Patients received a median of 6 cycles (range 1-8), 21 of them (43%) received adapted dose of PVAG. Seven patients (14%) received radiotherapy after respectively 3, 4, 6, or 8 cycles of PVAG. At the end of PVAG regimen, 26 patients were in CR (53%), 4 PR (8%), 19 patients progressed (39%). For the 46 patients who were evaluated by PET-CT after chemotherapy, the CR and PR rates were 52% and 13% with 35% of patients with stable or progressive diseases. For hematologic toxicity, 6 patients (12%) developed febrile neutropenia, 22 (45 %) had grade III-IV neutropenia; 8 (16 %) a grade 3-4 thrombopenia; 17 (35%) grade 3-4 anemia. Extra-hematologic toxicities were mild with three patients (6%) with grade 3-4 mucositis, 2 (4%) grade 3-4 nausea, 5 (10%) with grade 3-4 neuropathy, 3 (6%) acute heart toxicity. With a median follow up of 33,2 months (range, 14,3 -53,7), 26 (53%) patients progressed or relapsed. The median PFS was 21,6 months with a 3-year PFS rate of 48,6% (95%CI, 36,3-65,1). The median overall survival (OS) was 66,5 months with a 3-year OS rate of 73,7% (95%CI, 61,2-88,8). The cause of death was HL in 8 patients (16%), infection in 2 (4%); one toxic death occurred (sepsis after first cycle of PVAG). In univariate analysis, PFS (HR: 2,36, 95CI, 1,01-5,48, P=0.0,046) and OS (HR: 4,23, 95%CI, 1,15-15,6, P=0.03) were adversely affected by high number of medications (&amp;gt;3). OS was adversely affected by grade 3-4 CIRS-G in ≥2 categories (HR: 3,63, 95%CI, 1,23-10,71, P=0.019). Age, IPS, presence of B symptoms, lymphopenia, anemia, low albumin level, CIRS-G&amp;gt;6 did not affect outcome. Conclusions:Our real-life evaluation of PVAG regimen showed that patients were older than those included in the pivotal clinical trial and 58% of patients received adapted-dose of chemotherapy. We confirmed the favorable safety profile of this protocol. Using TEP-scan evaluation, the CR rate was 52%. Survival analyses supported initial results obtained in clinical trial. Combinations with immunotherapies with clinical activity in cHL should be evaluated to improve results of this regimen. Disclosures Brice: Takeda: Consultancy; Roche: Consultancy. Salles:Epizyme: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Janssen: Honoraria, Other: consultancy or advisory role; BMS/Celgene: Honoraria, Other: consultancy or advisory role; Takeda: Honoraria; Karyopharm: Honoraria; Genmab: Honoraria, Other; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role. Deau Fischer:Takeda: Consultancy; Roche: Consultancy.

Modified-BEP Chemotherapy in Patients With Germ-Cell Tumors Treated at a Comprehensive Cancer Center

Bleomycin, etoposide, and cisplatin (BEP) is the most common and successful chemotherapy regimen for germ-cell tumor (GCT) patients, accompanied by a bleomycin-induced dose-dependent lung toxicity in certain patients. In an attempt to reduce bleomycin-toxicity, we developed a modified-BEP (mBEP) regimen. Between August 2008 and February 2018, 182 unselected mainly testicular GCT patients (39 with adjuvant purpose and 143 with curative purpose) received a tri-weekly 5-day hospitalization schedule with bleomycin 15 U intravenous (IV) push on day 1 and 10 U IV continuous infusion over 12 hours on days 1 to 3, cisplatin 20 mg/m IV, and etoposide 100 mg/m IV on days 1 to 5. Pulmonary toxicity was assessed through chest computed tomography scan and clinical monitoring. Median number of mBEP cycles was 3 (range: 1 to 4). In the curative setting, according to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic system, 112, 21, and 9 patients had good-risk, intermediate-risk, and poor-risk class, respectively; 66 (46%) patients had complete response (CR), 67 (47%) had partial response (52 of whom became CR afterwards), 6 (4%) had stable disease (that in 3 became CR afterwards), 3 (2%) progressed, and 1 (1%) died of brain stroke. At a median follow-up of 2.67 years (interquartile range: 1.23-5.00 y), 1 and 5-year overall survival and progression-free survival were 99% and 95%, and 90% and 88%, respectively. In the entire patient population, there was grade 3/4 neutropenia in 92 patients (51%), febrile neutropenia in 11 patients (6%), grade 1/2 nausea in 74 patients (41%), and no death due to pulmonary toxicity. In GCT patients, our mBEP-schedule would suggest an effective treatment modality without suffering meaningful pulmonary toxicity.

Atypical radiological presentation of bleomycin-induced lung injury: Case report and review of literature

Bleomycin-induced lung injury manifesting after chemotherapy in patients with Hodgkin's disease is a known fatal entity. The histological picture encompasses from alveolar haemorrhage to diffuse alveolar damage, and the clinical picture is similar to that of interstitial pneumonitis. Radiologically, it is a spectrum of ground-glass opacities and infiltrates to finally consolidation and later fibrosis. This patient presented with atypical radiological sequelae of pneumomediastinum and extensive subcutaneous emphysema. The patient was managed in the intensive care unit with an intercostal drain, mechanical ventilation and vasopressor support. After a week, the intercostal drain was removed, and the patient was weaned off the ventilatory support. The patient was subsequently tracheostomised and shifted to the general ward. This case throws light on the rare radiological pattern of bleomycin-induced lung toxicity that can complicate the management of such patients.

An evaluation of brentuximab vedotin as a treatment option for stage III/IV Hodgkin lymphoma

ABSTRACTIntroduction: Outcomes of patients with classical Hodgkin lymphoma are excellent, and the intent of frontline therapy for even advanced-stage disease has been curative. This review summarizes the role of brentuximab vedotin in the upfront treatment of advanced stage classical Hodgkin lymphoma in the context of reducing therapy-related toxicity without compromising the high cure rate.Areas covered: Strategies to reduce bleomycin-induced lung toxicity include a response-adapted approach investigated in the RATHL study and a replacement of bleomycin with brentuximab vedotin in frontline chemotherapy regimens. In both studies, omission of bleomycin in the non-standard arms decreased the rate of pulmonary toxicity while maintaining high progression-free survival and overall survival rates.Expert opinion: The approval of A+AVD in North America offers a new bleomycin-free regimen for the treatment of advanced-stage HL, but it must be balanced against a risk-adapted approach. Recently presented subset analyses raise a question about which patients benefit most from this therapy.

The incidence of bleomycin induced lung toxicity is increased in Hodgkin lymphoma patients over 45 years exposed to granulocyte-colony stimulating growth factor

In Hodgkin lymphoma (HL) bleomycin can induce pulmonary toxicity (BPT). BPT consists of respiratory tract symptoms during bleomycin-exposure and radiologic pulmonary lesions without concomitant infection. Older age, bleomycin dose, smoking history and the use of granulocyte-colony stimulating factor (G-CSF) have been suggested as possible risk factors for BPT. It is still debated whether BPT affects overall (OS) and progression-free survival (PFS). We investigated the incidence of BPT along with possible risk factors in 412 HL patients treated in 1990-2014. BPT occurred in 34 patients (8%) and was significantly associated with disseminated disease and B-symptoms. It was more frequent in elderly patients (p = .05) but not significantly correlated with a history of smoking. BPT occurred more often in patients receiving G-CSF (p = .03), particularly the poly-ethylenglycol-bound molecule. All significant risk correlations were limited to the age group >45 years. In the present cohort, BPT did not influence OS or PFS regardless of age.

Pirfenidone for Treatment of Bleomycin-Induced Lung Toxicity

Pirfenidone for Treatment of Bleomycin-Induced Lung Toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials

AbstractDoxorubicin, bleomycin, vinblastine sulfate, and dacarbazine (ABVD) is associated with severe toxicity in older patients, particularly from bleomycin-induced lung toxicity (BLT). Therefore, using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients, especially in early-stage HL. We therefore analyzed feasibility, toxicity, and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients. We included patients ≥60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2×ABVD; n = 137) or AVD (2×AVD; n = 82), each followed by involved-field radiotherapy (IF-RT), with patients randomized to 4×ABVD+IF-RT (n = 68). Patients' median age was 65 years (range, 60-75) with comparable patient and disease characteristics. Grade III-IV adverse event rates were similar in patients receiving 2×AVD and 2×ABVD (40% and 39%, respectively), but considerably higher in patients receiving 4×ABVD (65%). Similarly, BLT was rare in patients receiving 2×ABVD/AVD, but occurred in 7/69 (10%) of patients randomized to 4×ABVD, with 3 lethal events. In conclusion, no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy. However, we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD. These trials are registered at www.clinicaltrials.gov and www.isrctn.com as #NCT00265018 (HD10) and #ISRCTN63474366 (HD13).

Doxorubicin, Vinblastine and Dacarbazine with or without Bleomycin for Older Patients with Early Stage Favorable Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 Trials

IntroductionBleomycin is commonly omitted from the ABVD regimen (doxorubicine, vinblastine, dacarbazine and bleomycin) in older Hodgkin Lymphoma (HL) patients due to excessive toxicity, particularly bleomycin-induced lung toxicity (BLT). Very recently, however, the GHSG HD13 trial indicated that the omission of bleomycin from the ABVD regimen has a negative impact on efficacy (Behringer et al., EHA 2014). Given the high rate of BLT in older patients, the role of bleomycin in the ABVD regimen for this particular group of patients is still unclear. We therefore analyzed feasibility, toxicity and efficacy of ABVD or AVD in 287 older early stage favorable HL patients.MethodsAs described in detail previously elsewhere, HD10 and HD13 were prospective, randomized international multicenter trials including early stage favorable HL patients defined as stages I and II without any of the GHSG risk factors (Engert et al. NEJM 2010). For the present study, we focused on older HL patients (≥60 years), who were randomized to receive either 2 cycles ABVD (2 x ABVD) or AVD, in both cases followed by either 20 or 30 Gy involved-field radiotherapy (IF-RT). To estimate cumulative BLT, we also analyzed older HL patients who received 4 x ABVD followed by IF-RT in the HD10 trial.Results287 patients with a median age of 65 years (range 60-75) were included with an equal distribution of gender, IPS scores, histology and age between the treatment groups.Treatment consisted of 2 x ABVD in 137 patients (HD10 and HD13), 2 x AVD in 82 patients (HD13), and 4 x ABVD in 68 patients (HD10). Pulmonary function test (PFT) prior to therapy was available for 117 patients (HD13 only) showing impaired PF in 14 (26%) and 9 (15%) of the patients randomized to receive ABVD or AVD, respectively.Although patient numbers were too small to draw statistically sound conclusions, in our analysis, patients treated with AVD tended to receive higher relative dose intensity than patients treated with 2 x ABVD. Early termination of chemotherapy was only observed in 1 patient of each treatment arm.Overall, frequency of grade III-IV adverse events was similar for both patient groups. Respiratory adverse events were rare even in patients receiving 2 cycles of bleomycin (1 and 0 cases with 2 x ABVD and AVD, respectively). However, BLT occurred in 6 patients (9%) receiving 4 cycles ABVD and was lethal in half of the affected patients. PFTs or (chest x-ray) within two years after therapy were available for 80 HD13 patients and showed pathological results for 2 patients each out of 34 and 46 patients treated with 2 x ABVD or AVD, respectively.Regarding the efficacy, patient numbers were far too small for testing on (non-)inferiority of the AVD regimen as done in the HD13 trial. However, differences in PFS and OS were about the same magnitude as observed in the HD13 trial (Behringer et al., submitted), indicating that the effect of bleomycin on efficacy observed in this trial does also hold true for the subgroup of older patients.ConclusionIn this study of 219 older early stage favorable HL patients treated with 2 cycles of either ABVD or AVD, no significant effect of bleomycin on the incidence and severity of adverse events was detectable. In contrast, the additional 67 older patients receiving 4 x ABVD had more grade III/IV toxicity and a strikingly higher rate of BLT, indicating a cumulative toxicity of bleomycin in older HL patients. DisclosuresOff Label Use: Everolimus in relapsed or refractory Hodgkin Lymphoma. von Tresckow:Novartis: Honoraria, Research Funding; Takeda: Honoraria, Travel grants, Travel grants Other. Borchmann:Takeda: Honoraria, Research Funding, Travel grants Other.

Older patients and risk of developing and dying from bleomycin-induced lung toxicity.

8584 Background: Bleomycin-induced pneumonitis (BIP) has been well described in classical Hodgkin lymphoma (cHL) patients treated with bleomycin-containing chemotherapy regimens. The incidence of acute and subacute pulmonary toxicity varies widely and multiple factors contribute to mortality in patients with BIP. We therefore reviewed the outcome of cHL patients treated at a single institution to further define the incidence of BIP and to identify major contributors to BIP-associated morbidity and mortality. Methods: One hundred sixty-one pediatric and adult patients who were treated with bleomycin-containing chemotherapy for newly diagnosed cHL between January 2000 and December 2012 were eligible for this retrospective review. BIP was defined by fever, pulmonary symptoms, pulmonary infiltrates, or a decline in DLCO, with no evidence of an infectious etiology. Results: BIP was observed in 43.5 % (n=70) of patients. Age >/=45 years was associated with both an increased incidence (p= <0.0001) and increased severity (p=0.0005) of lung toxicity. ABVD regimen as initial therapy (p= <0.001), obesity (p=0.0331) and the presence of at least one cardiac or respiratory comorbidity (p=0.0088) was also associated with the development of BIP. Higher BMI was associated with earlier onset of lung toxicity. No significant increase in pulmonary toxicity was noted with co-administration of G-CSF (p=0.7249). Bleomycin related mortality rate was 4.97 % (n=8) when all patients were considered and 11.43 % (8/70) in patients who developed pulmonary symptoms. Seventy five percent (6/8) of those who died were older than 60 years. Conclusions: The risk of BIP is significant in cHL with the use of bleomycin-containing regimens. Age >/= 45 years appears to increase the risk of BIP and is associated with increased mortality. These findings highlight the need for testing novel treatment combinations in cHL patients that omit bleomycin.

Protective Effect Of Thymoquinone And Aminoguanidine Against Bleomycin Induced Lung Damage: Possible Role Of Nitric Oxide Synthase

Bleomycin-induced lung injury is due to oxidative damage produced by free radicals generations. The present study was undertaken to investigate whether aminoguanidine, an inhibitor of Nitric Oxide (NO) synthase, and thymoquinone, a potent superoxide radical scavenger, can protect against bleomycin-induced lung damage in rats. Administration of bleomycin, 15 mg/kg, i.p. every other day for 4 weeks, induced lung toxicity as indicated by a significant increase in the level of lipid peroxide , significant depletion of the reduced glutathione in lung tissue and significant increase in the activity of antioxidant enzymes glutathione peroxidase and glutathione S-transferases. Oral administration of aminoguanidine (50 mg/100mL) or thymoquinone (5 mg/100mL) for one day before and during the period of bleomycin treatment leads to normalize the alterations in the biochemical parameters induced by bleomycin toxicity. In conclusion, this study demonstrated that both thymoquinone and aminoguanidine significantly attenuate the development of pulmonary toxicity. The thymoquinone is a potent superoxide radical scavenger, scavenging power being as effective as superoxide dismutase against superoxide. The superoxide scavenging and anti-lipid peroxidation may play a part in the protective effect of thymoquinone against bleomycin-induced lung toxicity. However the effect of aminoguanidine was predominantly mediated by inhibition of inducible nitric oxide synthase (iNOS) activity, thereby reducing peroxynitrite formation. We propose that the development of a more specific and potent inhibitors of iNOS might be beneficial in the prevention and treatment of lung toxicity.

Synthetic liposomes are protective from bleomycin-induced lung toxicity

Idiopathic pulmonary fibrosis is a devastating disease characterized by a progressive, irreversible, and ultimately lethal form of lung fibrosis. Except for lung transplantation, no effective treatment options currently exist. The bleomycin animal model is one of the best studied models of lung injury and fibrosis. A previous study using mouse tumor models observed that liposome-encapsulated bleomycin exhibited reduced lung toxicity. Therefore, we hypothesized that airway delivery of synthetic phosphatidylcholine-containing liposomes alone would protect mice from bleomycin-induced lung toxicity. C57BL/6 mice were administered uncharged multilamellar liposomes (100 μl) or PBS vehicle on day 0 by airway delivery. Bleomycin (3.33 U/kg) or saline vehicle was then given intratracheally on day 1 followed by four additional separate doses of liposomes on days 4, 8, 12, and 16. Fluorescent images of liposomes labeled with 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate confirmed effective and widespread delivery of liposomes to the lower respiratory tract as well as uptake primarily by alveolar macrophages and to a lesser extent by type II alveolar epithelial cells. Results at day 22, 3 wk after bleomycin treatment, showed that airway delivery of liposomes before and after intratracheal administration of bleomycin significantly reduced bleomycin-induced lung toxicity as evidenced by less body weight loss, chronic lung inflammation, and fibrosis as well as improved lung compliance compared with controls. These data indicate that airway-delivered synthetic liposomes represent a novel treatment strategy to reduce the lung toxicity associated with bleomycin in a mouse model.