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Does Granulocyte Colony Stimulating Factor Increase the Risk of Bleomycin Induced Lung Injury?


Bleomycin, a mixture of bacteria-derived peptides with antitumor activity, is frequently utilized alongside other anticancer agents to treat classic Hodgkin lymphoma (CHL) and germ cell tumor (GCT).1-3 An important concern with bleomycin is its dose-limiting potential for pulmonary toxicity. The reported incidence of bleomycin pulmonary toxicity (BPT) is highly variable, with some estimates ranging from 2% to 46% and associated mortality rates  as high as 25%.4,5 BPT typically manifests as a dry cough with fine rales, exertional dyspnea, and infiltrates on chest x-ray, possibly leading to life threatening pulmonary fibrosis.2,3,6 Most people who recover from BPT experience significant improvement, but fibrosis may be irreversible.2 The pathophysiology of BPT remains uncertain; potential pathways involve activated bleomycin-induced DNA cleavage, free radical formation, and deoxynucleotide oxidizing reactions, leading to alveolar epithelial injury. These insults may be aggravated by relatively low expression of bleomycin hydrolase, the enzyme principally responsible for bleomycin metabolism, in lung tissues. Dysfunctional repair responses may contribute to the development of pulmonary fibrosis.7 Currently, no specific treatment exists for BPT, and the management is primarily supportive. Steroids have shown mixed degrees of effectiveness and may be most useful during the initial inflammatory stages of the condition.2,8

Risk factors for BPT include high cumulative doses of bleomycin (eg, exceeding 400 units), older age (eg, ≥70 years), pre-existing pulmonary conditions, high concentrations of inspired oxygen, concurrent radiation fields involving the lung, and the use of combination chemotherapy regimens, especially those containing cyclophosphamide.3,6 The concomitant use of granulocyte colony stimulating factor (GCSF) has also been proposed as a potential risk factor for BPT based on early reports of a possible association and subsequent clinical studies, but its association with this condition remains controversial.9

GCSFs (eg, filgrastim and pegfilgrastim) are used as primary prophylaxis against febrile neutropenia in some patients receiving cancer treatment. Additionally, they may be used as treatment and, subsequently, secondary prophylaxis for patients experiencing febrile neutropenia during a chemotherapy cycle.10 There are several proposed mechanistic explanations for the potential increased risk of BPT due to GCSF. Among the most prominent is that GCSF-induced increases in the number and activity of neutrophils may exacerbate bleomycin-induced interstitial lung damage (eg, due to neutrophil release of reactive oxygen species). Neutrophil-independent GCSF effects, such as induction of inflammatory cytokines involved in BPT pathogenesis, have also been proposed to worsen BPT.11-13

While their concurrent use is cautioned against in some cases, there is not clear consensus regarding risk of GCSF use in patients receiving bleomycin-containing regimens in US guidelines for use of growth factor support or management of CHL or GCT. This review summarizes key literature evaluating the risk of BPT with concomitant GCSF use in patients with CHL or GCT.

Literature Review

Mahdi Seyedzadeh Sani and colleagues (2022) performed a systematic review and meta-analysis of controlled studies reporting incidence of BPT in patients receiving bleomycin-containing treatment with versus without concomitant GCSF.14 The authors identified 22 studies in the systematic review (16 retrospective cohort studies, 4 case-control studies, and 2 clinical trials). These studies were published between 1993 and 2019 and included patients with Hodgkin lymphoma (approximately 1470 patients, 308 of whom were specified as CHL), GCT (approximately 1693 patients), or non-Hodgkin or unspecified malignant lymphoma (approximately 389 patients). Diagnostic criteria for BPT varied by study; approximately half of the included studies used criteria combining pulmonary function tests (PFTs) and clinical diagnosis, while the remainder used PFTs alone, clinical diagnostic criteria alone, or did not report diagnostic criteria.

The primary pooled analysis included extracted effect sizes (adjusted or unadjusted odds ratios [ORs] reported in the individual studies or calculated by the authors from crude reported rates) representing data for 1956 patients from 14 studies published between 1994 and 2019.14 Concomitant use of GCSF was found to be associated with BPT incidence (OR 1.82; 95% confidence interval [CI] 1.37 to 2.40, p<0.0001). Most of the data for the pooled analysis were from 3 retrospective studies conducted in patients with GCT or Hodgkin lymphoma; sensitivity analysis indicated similar pooled findings when omitting any one of the studies from the model. Stratified analyses indicated risk of BPT was associated with GCSF use in patients receiving lower cumulative doses of bleomycin (higher odds in patients receiving <200 units) but not with higher cumulative doses, and in retrospective but not prospective analyses. Risk was increased with GCSF use regardless of whether studies used PFTs for BPT diagnosis and when analysis was restricted to patients with GCT or to patients with Hodgkin lymphoma. The authors did not identify an association between year of study publication and risk of BPT.

Some studies describing risk of BPT in patients receiving bleomycin with or without GCSF were not included in or were published after the systematic review/meta-analysis. Characteristics and results of these studies are described in the Table.

Table. Additional studies on the effect of GCSF on risk of BPT5,15-18
Study design and duration
Jona et al 202115
Prospective observational study (2013 to 2019)
84 patients receiving front-line treatment for CHL
Median age 35 years
85% treated with ABVD (n=71)

15% treated with non-bleomycin-containing chemotherapy (BV-AVD [n=12] OR EVD [n=1])

19% received mediastinal IFRT
61% received concomitant GCSF
Clinically-apparent BPT reported in 3.6%

No association between GCSF use and BPT or PFT measures
Taparra et al 202016
Retrospective cohort (2003 to 2018)
126 patients treated with front-line ABVD for HL
Median age 37 years
68% received concomitant GCSF
BPT reported in 37% (47% of patients treated pre-2010; 28% of patients treated in 2010 or later)

BPT associated with (unadjusted logistic regression):
- GCSF (OR 2.26, 95% CI 1.01 to 5.41)
- Age ≥40 years (OR 4.61, 95% CI 2.16 to 10.23)
- Treatment in 2010 or later (OR 0.44, 95% CI 0.21 to 0.91)
Thomas et al 202017
Retrospective cohort (2002 to 2013)
847 patients treated with doxorubicin-containing regimens for CHL
Median age 54 years
Individual regimens not reported; 87% received ≥1 dose of bleomycin
43% received concomitant GCSF
BPT reported in 9.3%

Multivariate logistic regression for BPT risk:
- Adjusted OR* for age 60 to 69 years (vs ≤50 years): 3.24 (95% CI 1.43 to 7.34)
- Adjusted OR* for age ≥70 years (vs ≤50 years): 6.01 (95% CI 2.52 to 7.34)
- Adjusted OR** for GCSF use: 1.26 (95% CI 0.74 to 2.16)
Evens et al 20125
Retrospective cohort (1999 to 2009)
95 patients aged ≥60 (median 67) years with newly-diagnosed HL
72% treated with bleomycin-containing chemotherapy (ABVD [n=67] or BEACOPP [n=1])
25% received non-bleomycin-containing treatment; 3% did not receive active treatment
78% received concomitant GCSF
Unadjusted incidence of BPT in patients receiving vs not receiving GCSF: 38% vs 0% (p=0.0001)
BPT case fatality: 25%
Ngeow et al 201118
Retrospective cohort (1990 to 2007)
184 patients treated with front-line ABVD for HL

Median age 30.5 years
Rate of GCSF use not reported
BPT reported in 15%

BPT associated with (unadjusted comparison of incidence rates):
- Serum albumin <4 g/dL (20% incidence, vs 8% in patients with higher levels; p=0.04)
- GCSF (incidence not reported; p=0.02)
*Adjusted for race, tobacco use, Charlson comorbidity index, and GCSF use
**Adjusted for race, age, tobacco use, and Charlson comorbidity index
Abbreviations: ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine; BEACOPP=bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; BPT=bleomycin pulmonary toxicity; BV-AVD=brentuximab vedotin, doxorubicin, vinblastine, dacarbazine; CHL=classic Hodgkin lymphoma; CI=confidence interval; EVD=epirubicin, vinblastine, and dacarbazine; GCSF=granulocyte colony stimulating factor; HL=Hodgkin lymphoma; IFRT=involved-field radiation therapy; OR=odds ratio; PFT=pulmonary function test


High cure rates achieved with modern front-line regimens for CHL and most GCTs necessitate careful consideration of the balance of efficacy with toxicity. A major component of maintaining this balance is to minimize overall treatment exposure. As a result of research efforts centered around this principle, most patients with newly-diagnosed CHL or GCT receive treatment with bleomycin-containing chemotherapy via a risk-adapted approach incorporating disease stage, adverse prognostic indicators, and, in some CHL cases, interim restaging before treatment completion.

The potentially devastating consequences of BPT have driven development of regimens for CHL from which bleomycin is omitted after a limited number of treatment cycles, as well as increased scrutiny of other potential risk factors for BPT. The possible association between GCSF use and BPT risk originally identified in the 1990s led to numerous studies of this relationship; due in part to these investigations, many clinicians tend to avoid GCSF in patients receiving bleomycin-based therapy. Nearly all patients with CHL receiving front-line treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), including those who experience severe uncomplicated neutropenia, are able to complete their chemotherapy without GCSF support; nevertheless, some patients receiving ABVD, as well as a proportion of patients receiving bleomycin, etoposide, and cisplatin (BEP) for GCT or other bleomycin-based treatment, will require GCSF as primary or secondary prophylaxis or as treatment for febrile neutropenia.19-22 Prospective interventional trials designed to address this situation are unlikely to be forthcoming due to a lack of clinical equipoise for whether to use GCSF in such circumstances.

The 2022 meta-analysis by Mahdi Seyedzadeh Sani and colleagues suggests that concomitant use of GCSF in patients receiving bleomycin-based chemotherapy increases risk of BPT.14 However, this analysis carries important limitations that may temper this conclusion, including those inherent to the retrospective nature of most of the included studies and the heterogeneity of the malignancies and chemotherapy regimens studied (some of which were not reported). Moreover, as the meta-analysis authors note, age has a well-recognized direct association with BPT. Older age is also strongly associated with risk of febrile neutropenia.23-28 Age cutoffs of 60 to 65 years are widely accepted as risk factors warranting consideration of GCSF; thus, in addition to association with risk of BPT, age is associated with GCSF use.29-31 Most of the BPT risk effect size estimates extracted for the meta-analysis were not adjusted for potential confounding factors; among the 5 included studies with adjusted estimates, models were adjusted using age as a 2-category variable with relatively low age group cutoffs (ranging from >37 to ≥45 years).14,32-36 The likely collinearity of older age and GCSF use is an important confounding factor that was not accounted for in these studies or those with unadjusted effect estimates, and may therefore have influenced the findings of the meta-analysis.14 This possibility is corroborated by the findings in the large 2020 analysis by Thomas and colleagues; after adjustment for age as a 4-category variable (using age groups of <50 years, 50 to 59 years, 60 to 69 years, and ≥70 years), the authors found that GCSF use was not independently associated with BPT risk, whereas ages ≥60 years were independently associated with risk of BPT after adjustment for GCSF use.17


Well-designed prospective trials addressing GCSF as a possible risk factor for BPT are lacking and unlikely to be performed. While a recent meta-analysis suggests that GCSF use is associated with risk of BPT, this finding may have been driven by the collinearity of older age, which is a well-established risk factor for BPT, with use of GCSF. A large retrospective analysis in patients with CHL indicated that, after adjustment for the effect of older age, GCSF may not be independently associated with BPT risk. Additional studies with well-designed statistical analyses adjusting for covariates for both BPT risk and use of GCSF may provide further guidance in this setting. Clinicians caring for patients receiving bleomycin who have an indication for GCSF should consider these findings in the context of the presence or absence of better-established risk factors for BPT relative to the anticipated benefit of GCSF use.


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Prepared by:
Elna Shibu
PharmD Candidate Class of 2024
Michael Buege, PharmD, BCOP
Clinical Assistant Professor, Drug Information Specialist

University of Illinois Chicago College of Pharmacy

September 2023

The information presented is current as August 22, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.