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.
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.
Table1 Heading link
|Table. Additional studies on the effect of GCSF on risk of BPT5,15-18|
|Study design and duration||Sample||Interventions||Results
|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.
- Cordes LM, Shord SS. Cancer treatment and chemotherapy. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th McGraw Hill; 2020: chap 144. Accessed July 10, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577§ionid=236522223
- Wellstein A, Giaccone G, Atkins MB, Sausville EA. Cytotoxic drugs. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 13th McGraw Hill; 2017: chap 66. Accessed July 10, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=172486857
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- Azambuja E, Fleck JF, Batista RG, Menna Barreto SS. Bleomycin lung toxicity: who are the patients with increased risk? Pulm Pharmacol Ther. 2005;18(5):363-366.
- Evens AM, Helenowski I, Ramsdale E, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood. 2012;119(3):692-695.
- Raissy HH, Harkins M. Drug-induced pulmonary diseases. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th McGraw Hill; 2020: chap e47. Accessed July 10, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577§ionid=223396970
- Li S, Shi J, Tang H. Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics. Cell Biol Toxicol. 2022;38(5):699-723.
- Leikauf GD. Toxic responses of the respiratory system. In: Klaassen CD, eds. Casarett & Doull’s Toxicology: The Basic Science of Poisons. 9th McGraw Hill; 2019: chap 15. Accessed July 21, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2462§ionid=202674297
- Iki S, Yoshinaga K, Ohbayashi Y, Urabe A. Cytotoxic drug-induced pneumonia and possible augmentation by G-CSF–clinical attention. Ann Hematol. 1993;66(4):217-218.
- Bennett CL, Djulbegovic B, Norris LB, Armitage JO. Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med. 2013;368(12):1131-1139.
- Dirix LY, Schrijvers D, Druwè P, Van den Brande J, Verhoeven D, Van Oosterom AT. Pulmonary toxicity and bleomycin. Lancet. 1994;344(8914):56.
- Sleijfer S. Bleomycin-induced pneumonitis. Chest. 2001;120(2):617-624.
- Yokose N, Ogata K, Tamura H, An E, Nakamura K, Kamikubo K, Kudoh S, Dan K, Nomura T. Pulmonary toxicity after granulocyte colony-stimulating factor-combined chemotherapy for non-Hodgkin’s lymphoma. Br J Cancer. 1998;77(12):2286-2290.
- Mahdi Seyedzadeh Sani S, Sahranavard M, Jannati Yazdanabad M, et al. The effect of concomitant use of Colony-Stimulating factors on bleomycin pulmonary toxicity – A systematic review and meta-analysis. Int Immunopharmacol. 2022;112:109227.
- Jona A, Miltenyi Z, Pinczes L, et al. Pulmonary toxicity of Hodgkin lymphoma treatment: a prospective single-center study. J Hematol. 2021;10(6):266-273.
- Taparra K, Liu H, Polley MY, Ristow K, Habermann TM, Ansell SM. Bleomycin use in the treatment of Hodgkin lymphoma (HL): toxicity and outcomes in the modern era. Leuk Lymphoma. 2020;61(2):298-308.
- Thomas TS, Luo S, Reagan PM, Keller JW, Sanfilippo KM, Carson KR. Advancing age and the risk of bleomycin pulmonary toxicity in a largely older cohort of patients with newly diagnosed Hodgkin Lymphoma. J Geriatr Oncol. 2020;11(1):69-74.
- Ngeow J, Tan IB, Kanesvaran R, et al. Prognostic impact of bleomycin-induced pneumonitis on the outcome of Hodgkin’s lymphoma. Ann Hematol. 2011;90(1):67-72.
- Boleti E, Mead GM. ABVD for Hodgkin’s lymphoma: full-dose chemotherapy without dose reductions or growth factors. Ann Oncol. 2007;18(2):376-380.
- Evens AM, Cilley J, Ortiz T, et al. G-CSF is not necessary to maintain over 99% dose-intensity with ABVD in the treatment of Hodgkin lymphoma: low toxicity and excellent outcomes in a 10-year analysis. Br J Haematol. 2007;137(6):545-552.
- Nangalia J, Smith H, Wimperis JZ. Isolated neutropenia during ABVD chemotherapy for Hodgkin lymphoma does not require growth factor support. Leuk Lymphoma. 2008;49(8):1530-1536.
- Minuk LA, Monkman K, Chin-Yee IH, et al. Treatment of Hodgkin lymphoma with adriamycin, bleomycin, vinblastine and dacarbazine without routine granulocyte-colony stimulating factor support does not increase the risk of febrile neutropenia: a prospective cohort study. Leuk Lymphoma. 2012;53(1):57-63.
- Aslani A, Smith RC, Allen BJ, Pavlakis N, Levi JA. The predictive value of body protein for chemotherapy-induced toxicity. Cancer. 2000;88(4):796-803.
- Chrischilles E, Delgado DJ, Stolshek BS, Lawless G, Fridman M, Carter WB. Impact of age and colony-stimulating factor use on hospital length of stay for febrile neutropenia in CHOP-treated non-Hodgkin’s lymphoma. Cancer Control. 2002;9(3):203-211.
- Lyman GH, Dale DC, Friedberg J, Crawford J, Fisher RI. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol. 2004;22(21):4302-4311.
- Lyman GH, Delgado DJ. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer. 2003;98(11):2402-2409.
- Lyman GH, Morrison VA, Dale DC, et al. Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy. Leuk Lymphoma. 2003;44(12):2069-2076.
- Morrison VA, Picozzi V, Scott S, et al. The impact of age on delivered dose intensity and hospitalizations for febrile neutropenia in patients with intermediate-grade non-Hodgkin’s lymphoma receiving initial CHOP chemotherapy: a risk factor analysis. Clin Lymphoma. 2001;2(1):47-56.
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- Zahid KF, Muzaffar N,Usman M, Uddin N. 7182 Risk factors for bleomycin induced pulmonary toxicity in germ cell tumor patients. Poster presented at: ESMO Multidisciplinary Congress; 2009; Berlin, Germany.
- Sun HL, Atenafu EG, Tsang R, et al. Bleomycin pulmonary toxicity does not adversely affect the outcome of patients with Hodgkin lymphoma. Leuk Lymphoma. 2017;58(11):2607-2614.
- Kwan EM, Beck S, Amir E, et al. Impact of granulocyte-colony stimulating factor on bleomycin-induced pneumonitis in chemotherapy-treated germ cell tumors. Clin Genitourin Cancer. 2017;S1558-7673(17)30267-7.
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PharmD Candidate Class of 2024
Michael Buege, PharmD, BCOP
Clinical Assistant Professor, Drug Information Specialist
University of Illinois Chicago College of Pharmacy
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.