Abstract

 Objectives: 

Bleomycin is a chemotherapeutic agent also used as a sclerosant for the management of vascular malformations. Although effective and with a low complication profile, the safety and monitoring necessary for this indication is still controversial. This study examines routine periprocedural laboratory results on a cohort of patients undergoing bleomycin sclerotherapy.

 Methods: 

Retrospective chart review of prospectively collected data was performed on patients who underwent bleomycin sclerotherapy for vascular malformations from 2011 to 2018. Complete blood count and liver function were assessed before and after sclerotherapy.

 Results: 

Forty-six patients were identified who underwent a total of 71 sclerotherapy sessions with bleomycin. A median dose of 5 U/m² of bleomycin was used per procedure (8 U total). No difference between preprocedure and postprocedure values was detected for white blood cell count (7.7–7.9; P = .63) or absolute neutrophil count (4009–4414; P = .20). A nominal difference was found in hemoglobin (12.7–13.0; P = .001), hematocrit (37.0–38.6; P = .001), and platelet counts (278–302; P = .001). No patient had absolute neutrophil count levels below 500 cells/μL. On liver function tests, no change was detected for direct bilirubin (0.19–0.17; P = .4). A small decrease in total bilirubin (0.49–0.41; P = .004), aspartate aminotransferase (32.1–26.9; P < .001), and alanine aminotransferase (31.2–24.3; P < .001) was shown.

 Conclusion: 

This study suggests that laboratory assessment of immune and liver function, as commonly performed in chemotherapy protocols, is not required following intralesional bleomycin sclerotherapy. Clinically relevant abnormalities are unlikely to be detected as demonstrated in this cohort of patients with vascular malformations.

 Introduction

Vascular malformations are congenital lesions of abnormal blood vessel and lymphatic channel development. Many treatment options exist, but a frequently-used modality is sclerotherapy.¹ This involves intralesional injection of a cytotoxic agent, called a sclerosant, to induce localized endothelial cell injury or inflammation, leading to vessel occlusion and a reduction in the malformation’s size.^1–3 Risks of sclerotherapy may be transient fever, nausea, vomiting, and swelling, or more significant skin ulceration, necrosis, and scarring.⁴ Multiple sclerosing agents are available, including doxycycline, alcohol, sodium tetradecyl sulfate, and bleomycin, each with its own side effect profile.

Of available agents, bleomycin has gained traction as a sclerosant due to a low rate of swelling, pain, and nerve injury.^2,5 It is a cytotoxic antibiotic and antineoplastic agent that causes breaks in DNA strands and has been commonly used in the treatment of Hodgkin lymphoma, germ cell tumors, and other malignancies.^5–7 When used in cancer treatment, much higher doses of bleomycin are used and adverse events are experienced at a higher rate compared with when used in sclerotherapy.^2,5,8 Hematologic and hepatic toxicity are among the most common concerns; however, this is frequently attributed to the other chemotherapy agents used in these regimens as bleomycin has a comparatively minimal effect on the bone marrow and liver.^6,9,10 This is thought to be due to the high concentration of bleomycin hydrolase, an endogenous enzyme that deactivates bleomycin, in these tissues.^9–11 There is a low concentration of bleomycin hydrolase in lung parenchyma, which can cause bleomycin-induced pulmonary toxicity.^12,13 This can present as interstitial pneumonitis or in severe cases as pulmonary fibrosis.^14,15 It has been associated with risk factors of smoking, kidney failure, and age.^16,17

Since most experience with bleomycin comes from the oncologic realm, there are habitual patterns for frequent laboratory checks to monitor for toxicities. No established consensus on the proper protocol and follow-up for patients has emerged. Patients with vascular malformations are a different demographic than those with malignancies. When used for sclerotherapy, the total administered intralesional dose of bleomycin is small and is thought to have reduced systemic absorption.^5,18 It is also being administered alone, so concurrent toxicities due to other chemotherapeutic drug exposures are reduced.^3,19 Given these differences, investigation into safe practice and appropriate monitoring is needed. This study was conducted to analyze routine laboratory testing with complete blood counts (CBC) and liver function tests (LFT) in patients undergoing bleomycin sclerotherapy to determine its utility.

 Methods

Institutional Review Board approval was obtained (IRB#202187). A retrospective chart review was performed for patients treated between the years 2011 and 2018. All reported units are in United States Pharmacopoeia units, where 1.5 United States Pharmacopoeia units is equivalent to 1500 IU, and is equivalent to 1 mg by weight.^18,20,21 Laboratory values (CBCs and LFTs) had been prospectively collected on patients with vascular malformations at baseline and after sclerotherapy with bleomycin per institutional protocol. Patients included were required to have preprocedure laboratories within 3 days before and repeated again within 10–28 days following treatment with intralesional injection of bleomycin. Any hemolyzed samples were excluded from analysis. Patients’ cumulative lifetime dose is monitored with an institutional maximum dose of 400 U. Pulmonary function testing is monitored at baseline and regular intervals. Treatments were performed both by interventional radiology and surgeons on the vascular anomaly team. Pre- and postprocedure values were compared using paired sample t tests.

 Results

Forty-six patients were identified who underwent a total of 71 sclerotherapy sessions. Patient median age was 12.8 years (range less than 1–65 years). Vascular malformations treated included venous malformation (21, 45.7%), lymphatic malformation (14, 30.4%), arteriovenous malformation (7, 15.2%), mixed capillary venous malformation (1, 2.2%), mixed venous lymphatic (1, 2.2%), capillary malformation (1, 2.2%), and angiokeratoma (1, 2.2%). A median of 3 procedures (range 1–10) were performed per patient with a median dose of 5 units per body surface area (U/m²) of bleomycin per procedure (median dose of 8 U, range 0.33–15 U). The median cumulative dose per patient was 17.6 U/m² (range 2.1–102.5 U/m²).

 Complete blood counts

All patients included in this study had paired CBCs before and after bleomycin sclerotherapy (Table 1). There was minimal difference in white blood cell count and absolute neutrophil count. No postprocedure absolute neutrophil count level was below 500 cells/μL. There was a minimal increase in hemoglobin (12.7–13.0; P = .001) and hematocrit (37.0–38.6; P = .001). No postprocedure hemoglobin was below 10 g/dL. Platelet counts demonstrated a small increase (278–302; P = .001). One patient with a lymphatic malformation had a postprocedure platelet count of 71, not associated with bleeding or other clinical symptoms. This resolved on repeat testing without intervention. No other patients had a postprocedure platelet count below 170.

Table 1. - CBC Pre- and Postprocedural Values

Abbreviations: ANC, absolute neutrophil count; CBC, complete blood count; WBC, white blood cell count.

 Liver function testing

Twenty-two patients had paired LFTs which spanned 56 total procedures (Table 2). No change was detected for direct bilirubin. A small decrease was detected after treatment for total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Eight patients had slightly elevated AST (between 40 and 51) before treatment. This mild elevation was not thought to be severe enough to serve as a contraindication to bleomycin therapy. After treatment, 6 patients continued to have a mild elevation (between 40 and 44) in AST. Similarly, 6 patients had a mildly elevated ALT (between 44 and 78) before treatment and after treatment 2 patients remained within that range. Two patients had slight elevations in both baseline AST and ALT. One patient had both values normalize on post-treatment check; the other had a slight persistent elevation in ALT (from 71 to 78).

Table 2. - LFT Pre- and Postprocedure Values

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test.

 Discussion

Bleomycin is a commonly utilized sclerosing agent for the treatment of vascular malformations due to its equivalent efficacy and low risk of secondary complications.^2,3,5,8 Intralesional injection of bleomycin leads to endothelial cell damage with minimal thrombosis, leading to fibrosis and vessel narrowing with reduced inflammation and swelling to adjacent soft tissues compared with other sclerosants.^5,22 While consensus exists on bleomycin’s utility as a sclerosant, there is a lack of guidelines or protocol to ensure appropriate use, monitoring, and follow-up to ensure maximal effect with minimal toxicity. Currently, many providers use methods similar to those used in protocols for oncologic therapy for surveillance and follow-up, although the amount of exposure and the route of administration are different with bleomycin sclerotherapy.

Despite the low correlation between bleomycin and bone marrow toxicity, many practitioners still obtain postprocedure CBCs following sclerotherapy as is typical of follow-up in oncologic patients. In our analysis, no hematologic parameter showed a consistent decrease following bleomycin; however, we found that some parameters actually showed a small but statistically significant increase following its use. While there could be some influence from the local inflammatory response induced in the sclerosing process and the release of acute-phase reactants, these differences are very slight. They could easily be attributed to variation in laboratory testing or minor changes in hydration and are not thought to be clinically impactful. This study further supports bleomycin’s activity as a nonmyelosuppressive agent and suggests that follow-up laboratory testing with a CBC is of limited utility.

LFTs and bilirubin levels are also commonly collected following sclerotherapy. The results in this study showed no increase in these parameters following treatment, suggesting that these follow-up laboratories are unnecessary in patients without other risk factors. Similarly, a recent study in animal models comparing the use of bleomycin injections to sodium tetradecyl sulfate injections, a commonly used sclerosant, showed no statistically significant differences in the mean values of these tests or in CBC values between treatment groups.²³

While bleomycin in this patient population has overall been safe with no demonstrable myelosuppression or hepatotoxicity, these may be rare complications and difficult to detect without large-scale trials. Data analysis was also somewhat limited by available results and retrospective design. Since this institution has a large geographic referral pattern, often postprocedure testing is done closer to home for patients and results may not be relayed back for review, although marked abnormalities would likely be reported.

 Conclusion

The use of bleomycin as a sclerotherapy agent for the treatment of vascular malformations is appealing due to its efficacy and favorable side effect profile, although no universally-accepted dosing or monitoring recommendations exist. In this study, no clinically significant laboratory abnormalities indicating myelosuppression or hepatic toxicity were detected. While early, these data are reassuring that bleomycin is safe and suggests that routine postprocedure laboratory evaluation has limited utility in this patient population.