Is bleomycin safe to use with granulocyte-colony stimulating factors (G-CSF)?

Please provide data on the use of bleomycin and supportive growth factors. Why is there a limitation?

Comment by InpharmD Researcher

Despite conflicting data in humans, primarily retrospective evidence suggests concomitant bleomycin and granulocyte-colony stimulating factors (G-CSF) increases the risk of bleomycin-induced pulmonary toxicity. While a cumulative bleomycin dose >400 U is an independent risk factor for pulmonary toxicity, a recent meta-analysis found that bleomycin doses less than 200 U and concomitant G-CSF use also significantly increases the risk of pulmonary toxicity. The risk of pulmonary toxicity should be balanced with the potential for increased hospitalization duration and reduced life expectancy due to febrile neutropenia when not using G-CSF.

Background

Per the National Comprehensive Care Network (NCCN), the risk of bleomycin-induced pulmonary toxicity may be increased in patients treated with granulocyte-colony stimulating factors (G-CSFs). While retrospective studies have shown an increased incidence of pulmonary toxicity when G-CSF is administered with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), the risk is less clear with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Due to the risk of pulmonary complications, the routine use of G-CSF is not recommended in conjunction with the most common chemotherapy regimens for classical Hodgkin lymphoma (ABVD and Stanford V); however, G-CSF support is recommended for patients with Hodgkin lymphoma treated with the escalated BEACOPP regimen. [1]

The main reason for considering G-CSF as a risk factor for bleomycin-induced pulmonary toxicity (BPT) is based on animal studies, as human data is controversial. Additional risk factors for BPT include a cumulative bleomycin dose >400 U, renal impairment, cigarette smoking, inflammatory markers, a high fraction of inspired oxygen (FiO2), other concurrent chemotherapy (e,g., cisplatin, gemcitabine), and thoracic irradiation. Due to conflicting evidence, a 2022 systematic review and meta-analysis assessed the risk of pulmonary toxicity when G-CSF is given to bleomycin-treated patients compared to bleomycin alone. Twenty-two studies were included for analysis: 16 cohort studies, 4 case-control studies, and 2 clinical trials. Cancer types included Hodgkin’s lymphoma, germ cell tumor, or non-Hodgkin’s lymphoma for which ABVD and BEP (bleomycin, etoposide, and cisplatin) were most commonly used. [2]

Of 14 studies (N= 1,956) with quantitative data, concomitant G-CSF use was a significant risk factor for BPT with low heterogeneity (odds ratio [OR] 1.82; 95% CI 1.37 to 2.40; p<0.0001; I^2= 10.7%). A subgroup analysis found that concomitant G-CSF use was also a risk factor for BPT when cumulative bleomycin doses were less than 200 U (OR 2.01; 95% CI 1.40 to 2.88; p= 0.0002; I^2= 9.5%); no significant association was noted with bleomycin doses >200 U (OR 3.57; 95% CI 0.23 to 56.41; p= 0.3656; I^2= 80%), but there was unacceptable heterogeneity. Similar results were seen when using 150 U as a bleomycin cutoff dose instead of 200 U. Additional subgroup analyses found the risk of BPT with G-CSF to be significant in patients with Hodgkin’s lymphoma and germ cell tumor, but not with non-Hodgkin’s lymphoma. This meta-analysis found that co-administration of colony-stimulating factors and bleomycin increases the risk of bleomycin pulmonary toxicity. This should be considered by healthcare professionals, as increased hospitalization time and reduced life expectancy due to febrile neutropenia when not using G-CSF should be balanced with the risk of pulmonary toxicity. [2]

Relevant Prescribing Information

The most serious side effects are pulmonary adverse reactions, occurring in approximately 10% of treated patients. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis. Pulmonary toxicity is both dose- and age-related, being more common in patients over 70 years of age and in those receiving over 400 units total dose. This toxicity, however, is unpredictable and has been seen in young patients receiving low doses. Some published reports have suggested that the risk of pulmonary toxicity may be increased when bleomycin is used in combination with G-CSF (filgrastim) or other cytokines. However, randomized clinical studies completed to date have not demonstrated an increased risk of pulmonary complications in patients treated with bleomycin and G-CSF. [3]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Please provide data on the use of bleomycin and supportive growth factors. Why is there a limitation?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

Risk of pulmonary toxicity of bleomycin and filgrastim
Design	Nested case-control study N= 153
Objective	To estimate the relative risk of pulmonary toxicity in patients exposed to a bleomycin-based chemotherapy including filgrastim compared to a similar chemotherapy without filgrastim
Study Groups	Bleomycin (n= 88) ABVD (n= 69) BEP (n= 19) Control (n= 65)
Inclusion Criteria	Age 18 years or older, received BEP (bleomycin, etoposide, and cisplatin) for germ cell tumors or ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for Hodgkin’s lymphoma (HL)
Exclusion Criteria	Developed pulmonary toxicity more than 6 months after the end of chemotherapy, receiving radiotherapy with partial or complete irradiation of the lung before or during treatment
Methods	Cases of patient data were matched with a control group, although a systematic review of the database was not possible. The controls consisted of patients with no pulmonary toxicity. Study groups were stratified based on the regimen they received for baseline analysis. The baseline characteristics of the control group were not presented.
Duration	October 2022 to June 2016
Outcome Measures	Primary: relative risk of pulmonary toxicity (defined by the odds ratio [OR])
Baseline Characteristics		ABVD (n= 69)	BEP (n= 19)
	Age, years	40	38
	Female	37.7%	15.8%
	Patients that developed pulmonary toxicity	9 (13%)	4 (21%)
	Use of filgrastim	51 (73.9%)	9 (47.4%)
	Dose of bleomycin, units	191.9	244.7
Results	Endpoint	Pulmonary toxicity cases (n= 13)	Control (n= 65)	Odds ratio (95% confidence interval [CI])
	Exposure to bleomycin without filgrastim	3 (23.1%)	20 (30.8%)	1.448 (0.372 to 5.638)
	Exposure to combination of bleomycin and filgrastim	10 (76.9%)	45 (69.2%)	--
Study Author Conclusions	The results add further evidence that the concomitant use of filgrastim might not increase the risk of pulmonary toxicity of bleomycin. A clinical trial would be needed to confirm this result.
InpharmD Researcher Critique	The presented data should be treated as exploratory due to the non-systematic inclusion of patients, suggesting a significant source of inclusion bias.

References:
[1] Laprise-Lachance M, Lemieux P, Grégoire JP. Risk of pulmonary toxicity of bleomycin and filgrastim. J Oncol Pharm Pract. 2019;25(7):1638-1644. doi:10.1177/1078155218804293

The incidence of bleomycin-induced lung toxicity is increased in Hodgkin lymphoma patients over 45 years exposed to granulocyte-colony stimulating growth factor
Design	Retrospective analysis N= 412
Objective	To investigate the incidence of bleomycin-induced pulmonary toxicity (BPT) and its impact on overall survival (OS) and progression-free survival (PFS) in a cohort of Hodgkin lymphoma (HL) patients treated at study institution between 1990 and 2014
Study Groups	BPT (n= 34) No-BPT (n= 378)
Inclusion Criteria	Patients diagnosed with HL and treated with bleomycin at this respective institution during the investigated period
Exclusion Criteria	Not specified
Methods	Relevant information on a number of parameters considered as possible BPT risk factors is collected from the medical records. Patients who received granulocyte-colony stimulating factor (G-CSF) support related to at least one cycle of chemotherapy were considered exposed to G-CSF. BPT was defined as the occurrence in the same patient of the following three features: (i) pulmonary symptoms occurring during the course of chemotherapy or in close proximity of the last chemotherapy course, (ii) presence of infiltrates on chest X-ray or CT-scan, and (iii) absence of infection.
Duration	Between 1990 and 2014
Outcome Measures	Incidence of BPT, OS, PFS according to BPT and no-BPT
Baseline Characteristics		BPT (n= 34)	No-BPT (n= 378)	p-value
	Age, years	49.7 (16.8 to 73.4)	38.2 (12.1 to 91.5)	0.05
	Female	18 (53%)	159 (42%)	n.s.
	International Prognostic Score (IPS) > 2 (n= 412)	15 (44%)	118 (31%)	n.s.
	B-symptom (n= 410)	23 (68%)	175 (47%)	0.02
	Ann Arbor Stage (n= 406) 1 + 2 3 + 4	13 (38%) 21 (62%)	239 (64%) 133 (36%)	0.003
	Bulky disease	10 (30%)	117 (32%)	n.s.
	Smoking history	16 (59%)	137 (46%)	0.19
	Allergy	5 (15%)	57 (16%)	n.s.
	G-CSF (n= 409)	26 (76%)	213 (57%)	0.03
	Types of G-CSF (n= 239) Filgrastim/Lenograstim Pegfilgrastim	17 (65%) 9 (35%)	180 (85%) 33 (15%)	0.02
	Thoracic radiation (n= 409)	9 (26%)	132 (35%)	0.31
	Bleomycin dose, IE/m², median (n= 405) Early clinical stage (CS) (n= 251) Advanced CS (n= 154)	90,000 80,000 90,000	80,000 60,000 120,000	0.006 - -
	n.s.: not significant
Results	Endpoint	BPT (n= 34)	No-BPT (n= 373)	Hazard Ratio (HR); 95% confidence interval (CI)	p-Value
	5-year OS	80%	85%	1.6 (0.8 to 3.2)	0.15
	5-year PFS	70%	73%	1.2 (0.7 to 2.2)	0.51
	Among eligible patients, BPT occurred in 34 (8%) patients.
Study Author Conclusions	In the present cohort, BPT did not influence OS or PFS, regardless of age.
InpharmD Researcher Critique	A significant number of BPT events were observed among the patients exposed to G-CSF, particularly the pegylated forms; however, the occurrence of BPT did neither impact OS nor PFS. The study did not further characterize the patient demographic of G-CSF recipients who developed BPT. This study is subject to the limitations inherent to retrospective analysis and is limited to a single-center experience.

References:
[1] Andersen MD, Kamper P, d'Amore A, Clausen M, Bentzen H, d'Amore F. The incidence of bleomycin induced lung toxicity is increased in Hodgkin lymphoma patients over 45 years exposed to granulocyte-colony stimulating growth factor †. Leuk Lymphoma. 2019;60(4):927-933. doi:10.1080/10428194.2018.1515939

Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with germ cell tumors
Design	Single-center, retrospective study N= 52
Objective	To determine the risk factors for bleomycin pulmonary toxicity (BPT) and evaluated the discontinuation of bleomycin in response to BPT on overall survival (OS) and progression-free survival (PFS)
Study Groups	BPT (n= 15) Non-BPT (n= 37)
Inclusion Criteria	Patients with germ cell tumors (GCT; non-seminoma or seminoma arising in the testis and extragonadal regions (retroperitoneum, mediastinum, or unknown primary), treated with the bleomycin etoposide and cisplatin chemotherapy (BEP) regimen as first-line chemotherapy
Exclusion Criteria	Received chemotherapy at other institutions
Methods	The BEP regimen consisted of intravenous (IV) injection of bleomycin 30 mg/body weekly on days 2, 9, and 16, etoposide 100 mg/m² on days 1–5, and cisplatin 20 mg/m² on days 1–5, typically scheduled for three or four cycles depending on patients' International Germ Cell Consensus Classification (IGCCC). Presence of asymptomatic decline in pulmonary function tests, such as diffusing capacity of the lung for carbon monoxide (DLCO) compared with a baseline pulmonary function test or the presence of pulmonary symptoms accompanied by interstitial infiltrates on chest X-ray or computed tomography scan without evidence of infection indicated BPT. Upon confirmation of BPT, bleomycin was discontinued, and the regimen was switched to EP. BPT was graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Logistic regression analysis (univariate and multivariate) was utilized to identify risk factors for BPT.
Duration	Between January 2008 and December 2017
Outcome Measures	Risk factors for BPT, OS, PFS
Baseline Characteristics		BPT (n= 15)	Non-BPT (n= 37)
	Age, years	30	40
	Body mass index, kg/m^2*	23	21
	Smoking history	27%	43%
	Underlying lung disease	13%	5%
	Histology Seminoma Non-seminoma	13% 87%	35% 65%
	Primary set Testis Extragonadal	100% 0%	81% 19%
	IGCCC Good Intermediate Poor	13% 53% 33%	46% 35% 19%
	Lung metastasis	53%	32%
	*p= 0.015
Results	Endpoint	BPT (n= 15)	Non-BPT (n= 37)	p-value
	Course of bleomycin discontinuation First course Second course Third course Fourth course	2 (13%) 3 (20%) 4 (27%) 6 (40%)	2 (5%) - 2 (5%) 5 (14%)	0.645
	Cumulative dose (range)	180 (30 to 270)	270 (30 to 360)	0.006
	Cumulative dose 0–90 mg 91–180 mg 181–270 mg >271 mg	4 (27%) 4 (27%) 7 (47%) 0	3 (8%) 3 (8%) 22 (59%) 9 (24%)	0.016
	Continuous granulocyte-colony stimulating factor (G-CSF) use	14 (93%)	33 (89%)	1.000
		Odds ratio (95% confidence interval)		p-value
	BMI<22 kg/m²	Multivariate: 6.90 (1.69 to 28.2)		0.007
	Continuous G-CSF use	Univariate: 1.70 (0.17 to 16.6)		0.649
	While the univariate analysis found cumulative bleomycin dose < 270 mg/body to be associated with the risk of developing BPT (p= 0.030), the risk was not significant with multivariate analysis. Development of BPT had no impact on 5-year OS (87 vs. 89%, p= 0.911) and 5-year PFS (80 vs. 76%, p= 0.675)
Study Author Conclusions	In conclusion, lower BMI was the risk factor for developing BPT in patients with GCT. Age, renal dysfunction, and G-CSF use did not increase the risk. OS and PFS did not appear to be compromised after the discontinuation of bleomycin. Our data support the need for the clinician to carefully monitor patients who have low BMI, and support the decision to discontinue bleomycin when BPT is suspected in patients with GCT.
InpharmD Researcher Critique	The study was limited by its small sample size and retrospective design. Additionally, results may not be generalized to patients with different types of cancers at baseline or receiving other chemotherapies. As most patients used prophylactic G-CSF, complete influence of G-CSF on the incidence of BPT cannot be ruled out.

References:
[1] Maruyama Y, Sadahira T, Mitsui Y, et al. Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with germ cell tumors. Med Oncol. 2018;35(6):80. Published 2018 Apr 26. doi:10.1007/s12032-018-1140-5

The Use of Filgrastim in Patients with Hodgkin Lymphoma Receiving ABVD
Design	Retrospective, single-center, observational, cohort study N= 54
Objective	To evaluate whether there was evidence for an increase in bleomycin-induced pulmonary toxicity in patients who received granulocyte-stimulating factors (G-CSF)
Study Groups	Bleomycin alone (n= 21) Bleomycin + filgrastim (n= 33)
Inclusion Criteria	Diagnosed with Hodgkin's lymphoma; received at least 1 dose of bleomycin during the specified time frame
Exclusion Criteria	Not diagnosed with Hodgkin's lymphoma; received chemotherapy elsewhere
Methods	This was a retrospective chart review of Hodgkin's lymphoma patients from a large medical center in New York. Patients who received at least one dose of bleomycin were separated into patients who did and did not also receive filgrastim during the treatment period. Patients were also stratified into subgroups based on pre-identified risk factors for pulmonary toxicity (i.e., age > 40, preexisting pulmonary disease, renal dysfunction (Cr >1.5, EGFR <80), smoking history, cumulative bleomycin dose > 300 units, the need for supplemental oxygen, mediastinal radiation pre- or post-treatment with bleomycin). Patients were reviewed for pulmonary toxicity within 1 year of the first bleomycin dose. Pulmonary toxicity was defined as documentation of respiratory symptoms and one of the following: chest radiograph infiltrate with negative infectious workup, computed tomography (CT) scan pulmonary infiltrate with negative infectious workup, decline in diffusing capacity of the lung for carbon monoxide (DLCO), or bleomycin discontinuation due to respiratory symptoms without other findings.
Duration	January 2003 to July 2015
Outcome Measures	Incidence of pulmonary toxicity
Baseline Characteristics		Bleomycin alone (n= 21)	Bleomycin + filgrastim (n= 33)	p-value
	Age, years (range) >40 years	32 (19-67) 9 (43%)	28 (9-78) 13 (39%)	0.6129 0.8007
	Male	12 (57%)	16 (48%)	0.5348
	Impaired renal function	18/19 (95%)	33 (100%)	0.3654
	Pulmonary disease	2 (10%)	7 (21%)	0.4559
	Smoking history	7 (47%)	9 (27%)	0.2063
	No patients had a cumulative bleomycin dose > 300 units, supplemental oxygen, or pre-chemotherapy radiation; these risk factors were not included as part of the multivariate analysis.
Results		Bleomycin alone (n= 21)	Bleomycin + filgrastim (n= 33)	p-Value
	Pulmonary toxicity	3 (14%)	7 (22%)	0.5042
	Median days from first bleomycin dose to filgrastim administration (range)	N/A	14 (0-153)	N/A
	Follow-up duration after bleomycin start, months (range)	29.5 (3.3-122.4)	24.8 (2.5-59.2)	0.1039
	All 10 cases of pulmonary toxicity occurred within the first 9 months after the start of treatment.
Adverse Events	N/A
Study Author Conclusions	This study does not find evidence that the combination of bleomycin and G-CSF increases the risk for bleomycin-induced pulmonary toxicity. We recommend G-CSF use in Hodgkin's lymphoma patients receiving bleomycin when needed to maintain dose intensity.
InpharmD Researcher Critique	This was a small study of patients with Hodgkin's lymphoma who were receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy at a single center in New York. As such, these results may not be extrapolated to other chemotherapy regimens or malignancies; however, the results found here are consistent with other retrospective reviews on bleomycin and G-CSF usage. While the cumulative bleomycin dosages were reported, individual dose changes or interruptions were omitted. As this was a retrospective study, additional limitations include the possibility of confounding variables and reliance on accurate reporting.

References:
[1] Binder AF, Rai S, Steinberg A. The Use of Filgrastim in Patients with Hodgkin Lymphoma Receiving ABVD. Int J Hematol Oncol Stem Cell Res. 2017;11(4):286-292.