Bleomycin Pulmonary Toxicity Has a Negative Impact on the Outcome of Patients With Hodgkin's Lymphoma
Bleomycin pulmonary toxicity (BPT) has been well described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. The influence of this pulmonary complication, along with the omission of bleomycin from further chemotherapy, on overall survival (OS) and progression-free survival (PFS) in HL remains unclear. We reviewed our experience with BPT in HL to better delineate outcome and appropriate treatment in these patients.
One hundred forty-one patients who were treated with bleomycin-containing chemotherapy for newly diagnosed HL between January 1986 and February 2003 were eligible for this retrospective review. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence of an infectious etiology.
BPT was observed in 18% of patients. Increasing age, doxorubicin, bleomycin, vinblastine, and dacarbazine as initial therapy, and granulocyte colony-stimulating factor use were associated with the development of BPT. Patients with BPT had a median 5-year OS rate of 63% v 90% (P = .001) in unaffected patients. The mortality rate from BPT was 4.2% in all patients and 24% in patients who developed the pulmonary syndrome. BPT incidence and mortality were highest in patients older than 40 years. The omission of bleomycin had no impact on obtaining a complete remission, PFS, or OS.
Hodgkin’s lymphoma (HL) remains one of the true success stories in malignant hematology. Mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) combination chemotherapy, which was first used in 1964, created a new standard for treating advanced HL, with complete response rates approaching 84% and long-term disease-free survival rates of approximately 66%.1 Despite this progress, a substantial percentage of patients remained with relapsed or refractory disease. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was proposed in the early 1970s as a non–cross-resistant alternative to MOPP for such patients.2 Subsequent trials have shown ABVD to be at least equal in efficacy as front-line therapy compared with MOPP or MOPP/ABV(D) combinations but with an improved long-term toxicity profile.3-5 This superior risk-to-benefit ratio made ABVD a standard chemotherapy regimen for HL. The incorporation of bleomycin into this four-drug regimen was based on single-agent activity observed in previous lymphoma trials, its unique mechanism of action, and its toxicity profile.2,6,7 Newer treatment regimens, which attempt to increase efficacy and reduce toxicity in HL, have continued to incorporate bleomycin.8,9
Bleomycin-containing chemotherapy is not without toxicity. Bleomycin pulmonary toxicity (BPT) has been well described in HL patients treated with bleomycin-containing regimens such as ABVD or MOPP/ABV(D) hybrids.4 The risk of BPT ranges from 0% to 46%,10 with mortality as high as 27%.11 Although debated, previously suggested risk factors for the development of BPT include age, bleomycin regimen, bleomycin dose, renal insufficiency, radiation, underlying lung disease, smoking history, and granulocyte colony-stimulating factor (G-CSF) support.10 Therefore, bleomycin may adversely affect outcome in this otherwise good-prognosis population.
Although there is no accepted standard treatment for BPT, corticosteroid treatment, withholding bleomycin from subsequent chemotherapy, and proceeding with a nonbleomycin-containing regimen in suitable patients is the most common approach. Dose-intensity is compromised as the course of bleomycin is abbreviated, and treatment is often delayed for the remaining cytotoxic agents. The impact this has on outcome in HL remains unclear. We undertook a review of our experience to answer this question.
The Mayo Clinic Lymphoma Database (Rochester, MN) was searched for all patients with a diagnosis of HL between 1986 and 2003. Of the 942 patients initially identified, our final study group comprised all patients treated with a bleomycin-containing chemotherapy regimen who received treatment at our facility (n = 141). HL diagnoses were confirmed by hematopathology review of all specimens at our institution. Patients with all histologic subtypes of HL were eligible for this study.
Inclusion criteria included newly diagnosed, biopsy-proven HL, treatment with any bleomycin-containing chemotherapy regimen, and therapy administered under the care of a hematologist at our institution. Patients who did not receive a bleomycin-containing regimen as part of their front-line therapy were excluded. Additionally, patients who were seen only in consultation and who did not receive their therapy at our institution were omitted from the study.
A group of patients who developed BPT was identified (n = 25). BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates on chest x-ray or computed tomography scan, and the absence of infection. Patients were required to meet all three criteria to be included in the BPT group. Infection was excluded by a combination of blood cultures, sputum culture, bronchoscopy, transbronchial biopsy with tissue culture, and lack of response to antimicrobials in the majority of patients. However, no standard algorithm was in place, and diagnostic testing was determined by the treating clinician. A second group was defined to include patients who had bleomycin omitted from therapy at any time, including asymptomatic patients who did not meet BPT criteria (n = 31). This group included 20 of the 25 patients who met criteria for BPT and 11 patients who did not meet these criteria but had bleomycin omitted from their regimen for any reason. Five BPT patients received a full course of bleomycin-containing chemotherapy, developing symptoms after their final cycle of chemotherapy. There was no standard protocol in place for the treatment of BPT during the study period. In the majority of patients, corticosteroids were administered, bleomycin was withheld, and a nonbleomycin-containing regimen was used to complete HL therapy.
Data for previously described BPT risk factors, including age, bleomycin regimen, bleomycin dose, renal function, thoracic radiation, underlying lung disease, G-CSF support, and smoking history, were collected. Patients who received G-CSF support with one or more of their bleomycin-containing chemotherapy cycles were considered as being treated with G-CSF. Thoracic radiation included all patients receiving either traditional mantle radiation or involved-field radiation therapy with exposure of any pulmonary tissue. The other BPT risk factors were defined as follows: age ≥ 40 years, creatinine more than 1.5 mg/dL, the presence of any clinically diagnosed underlying lung disease (primarily asthma and chronic obstructive pulmonary disease), or smoking history.
Prognostic factors for HL outcome were also collected. Patients were staged by the Ann Arbor classification. The prognostic factor index described by Hasenclever and Diehl12 was scored for all patients. The presence of bulky disease was assigned based on the clinician’s impression or radiologist’s measurement. A lactate dehydrogenase level of more than 220 U/L was considered elevated according to the institutional lab reference range. Weight loss greater than 10%, fevers, and night sweats were considered as B symptoms. Patients were classified by Eastern Cooperative Oncology Group performance status.
Response to front-line therapy was defined as complete remission (CR), partial remission, progressive disease, or not assessable. Patient considered not assessable were not used to determine response rates. Overall survival (OS) and progression-free survival (PFS) were calculated from the time of diagnosis to the date of death or date last seen and to the date of relapse or date last seen, respectively.
OS and PFS were estimated using the Kaplan-Meier method. Differences between survival curves were tested for statistical significance using the two-tailed log-rank test. Factors that significantly predicted survival rate in the univariate model were then studied in a multivariate analysis using Cox’s proportional hazards model. The χ2 and Fisher’s exact tests were used to compare differences in nominal variables between the BPT and non-BPT groups. An unpaired t test was used to compare continuous variables between BPT groups.
Approval of the protocol by the Mayo Clinic institutional review board was obtained in accordance with US federal regulations and the Declaration of Helsinki. Consent to use the clinical record was obtained from all patients.
Review of the HL database revealed 942 patients with HL evaluated at the Mayo Clinic during the specified study period. One hundred forty-one patients met the inclusion criteria of being treated at our institution with a bleomycin-containing regimen as initial therapy. Excluded patients included 557 patients seen in consultation only, with therapy received at an outside institution, and 244 patients who did not receive a bleomycin-containing regimen as front-line therapy. The clinical characteristics of our patient population are listed in Table 1. There were no significant differences between the BPT and non-BPT patients except for age (P = .0009). Regarding treatment, a higher proportion of patients in the BPT group received front-line ABVD and G-CSF support. The median 5-year OS and PFS rates for all patients were 87% (OS time: range, 4 to 220 months) and 79% (PFS time: range, 4 to 220 months), respectively. Twenty deaths were observed with the following etiologies: 45% (nine of 20 patients) had treatment-related complications, 30% (six of 20 patients) died of HL, and 25% (five of 20 patients) died of causes unrelated to disease or therapy.
BPT was observed in 18% of patients (25 of 141 patients). Patients with BPT had a median 5-year OS rate of 63% (OS time: range, 4 to 137 months) compared with 90% (OS time: range, 7 to 220 months) in unaffected patients (P = .001; Fig 1). Seven deaths were seen in the BPT group (six from BPT and one from HL). The mortality from BPT was 4.2% (six of 141 patients) in all patients and 24% (six of 25 patients) in patients who developed the pulmonary syndrome. BPT-specific therapy, such as the use of corticosteroids, was similar between patients who died of the pulmonary complication and patients who survived. All six BPT deaths were observed in patients more than 40 years old. These six patients all died within 9 months of their HL diagnosis from BPT. CR rates were equal at 91% and 93% in BPT and non-BPT patients, respectively (P = .299). BPT had no impact on 5-year PFS in BPT and non-BPT patients (71% v 80%, respectively; P = .531).
Several patient and therapy-related factors seemed important in BPT risk. Advancing age correlated with the development of BPT. The median age for BPT and non-BPT patients was 49 and 29 years, respectively (P = .0009). The observed rate of BPT was 33% (15 of 46 patients) v 11% (10 of 95 patients) in patients ≥ 40 years old and patients less than 40 years old, respectively (P = .001). Both the front-line chemotherapy regimen and G-CSF support increased the risk of BPT in univariate analysis (Table 1). Twenty-seven percent of ABVD-treated patients (22 of 81 patients) developed BPT compared with 4% of patients (two of 47 patients) treated with MOPP/ABV(D) (P = .006). A higher rate of BPT was observed in patients receiving G-CSF (26%; 19 of 74 patients) compared with patients who did not received G-CSF (9%; six of 67 patients; P = .014). In total, G-CSF was administered to 52% of patients (74 of 141 patients). There was no difference between BPT and non-BPT patients for other associated risk factors including radiation, bleomycin dose, renal insufficiency, smoking history, and underlying lung disease. The small number of BPT events made a multivariate analysis of age, G-CSF, and ABVD as BPT risk factors unreliable.
Despite an apparent increased risk of BPT in univariate analysis, front-line ABVD and G-CSF had no impact on other clinical outcomes. CR rates were equal between the G-CSF and non–G-CSF groups at 92% and 94%, respectively. Five-year OS and PFS rates were equal between the G-CSF and non–G-CSF groups at 82% v 89% (P = .473) and 74% v 84% (P = .152), respectively. CR rates were equal between the front-line ABVD patients and patients treated with other front-line regimens (92% v 93%, respectively). There was no difference in OS or PFS rates in ABVD-treated patients compared with patients receiving an alternative regimen, with rates of 82% v 93% (P = .262) and 76% v 82% (P = .378), respectively.
Advancing age predicted for a decreased OS. The median 5-year OS rates were 70% (OS time: range, 4 to 192 months) and 93% (OS time: range, 8 to 220 months) for patients ≥ 40 years old compared with patients less than 40 years old, respectively (P = .0003). Twenty-eight percent of patients (13 of 46 patients) ≥ 40 years old died in our study compared with 7% of patients (seven of 95 patients) less than 40 years old. Treatment-related complications accounted for this major difference between older and younger patients. Fifteen percent of patients (seven of 46 patients) ≥ 40 years old died from treatment compared with 2% of patients (two of 95 patients) less than 40 years old (P = .006). In patients ≥ 40 years old, six of seven treatment-related deaths were caused by BPT. There were no BPT deaths in patients less than 40 years old.
Both age and the presence of BPT were found to decrease 5-year OS in univariate analysis. Comparison by multivariate analysis using the Cox proportional hazards model showed both age ≥ 40 years (P = .006) and BPT (P = .039) to remain statistically significant risk factors. Age ≥ 40 years compared with less than 40 years had no impact on PFS rate (73% v 82%, respectively; P = .389).
Twenty-two percent of patients (31 of 141 patients), either symptomatic or asymptomatic, had bleomycin omitted at any time from their regimen. Response rates and survival were equal for these patients (Table 2 and Fig 2). Autologous transplantation was required as salvage therapy equally between patients given abbreviated bleomycin and patients treated with a full course, with rates at 10% (three of 31 patients) and 19% (21 of 110 patients), respectively (P = .218). The mean bleomycin dose was 84 mg/m2 (range, 20 to 180 mg/m2). Bleomycin dose had no impact on OS or PFS (data not shown). In these patients, subsequent nonbleomycin therapy included AVD and MOPP/AV, with no difference in 5-year OS and PFS (Table 3). In patients who received no further chemotherapy because of illness or patient/physician choice, survival was markedly compromised.
Bleomycin-containing chemotherapy regimens have become the mainstay of treatment in HL. ABVD has emerged as a standard of care, and newer regimens currently under study, such as doxorubicin, vincristine, vinblastine, bleomycin, mechlorethamine, cyclophosphamide, etoposide, and prednisone (Stanford V) and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), continue to incorporate bleomycin into their treatment schemes. Excellent response rates in excess of 90% and overall survival rates at 5 years exceeding 70% have been reported with these regimens, making the impact of treatment toxicities a major issue.3-5 BPT is one such toxicity seen in bleomycin-containing chemotherapy regimens.
Bleomycin, an antitumor antibiotic, was isolated from Streptomyces verticillus in 196513 and was reported to have activity in lymphoma, including HL, in 1972.6 In the phase I setting of previously treated HL patients, a response rate of 43% was observed. However, the mean duration of response was relatively short at approximately 3 months.7 On the basis of phase I activity in HL, a unique mechanism of action, and minimal bone marrow toxicity, bleomycin was incorporated into ABVD with other agents showing single-agent activity. This provided a new non–cross-resistant alternative to MOPP in treating HL. Subsequent trials showed ABVD to be superior to MOPP and at least equal in efficacy to MOPP/ABV(D) combinations.3-5 Bleomycin-containing regimens, such as ABVD, Stanford V, and BEACOPP, currently dominate the chemotherapy landscape for HL. Defining the role of bleomycin and its impact on outcomes in patients with HL is important as the treatment of HL is refined.
This retrospective study demonstrates for the first time a detrimental impact on 5-year OS rates in HL patients who develop BPT, with a decrease in the median survival from 90% to 63%. The major impact on outcome was related to acute pulmonary death, with six of seven deaths in the BPT group resulting from the pulmonary toxicity. All six patients died within 9 months of their HL diagnosis. In patients who survived the pulmonary toxicity, BPT had no effect on HL outcome.
The incidence of this complication is substantial. Eighteen percent of patients (25 of 141 patients) treated with a bleomycin-containing regimen developed BPT. This is consistent with other reports that have also reported substantial rates of pulmonary toxicity associated with bleomycin-containing chemotherapy regimens in HL.3,4 Duggan et al4 reported pulmonary toxicity in 28% of patients (224 of 814 patients) treated with either ABVD or MOPP/ABV. Although BPT was not strictly defined, bleomycin was discontinued in all these patients.
Age seems to play a significant role in the development of BPT and in the OS of HL patients. In our study, a 20-year difference was seen in the median age of patients developing this pulmonary complication compared with unaffected patients (49 v 29 years, respectively). Additionally, the rate of BPT was increased by a factor of 3 in patients ≥ 40 years old compared with younger patients (33% v 11%, respectively). Duggan et al4 reported a similar age effect. In this Cancer and Leukemia Group B (CALGB) study, a higher rate of pulmonary toxicity was reported in patients ≥ 40 years old compared with younger patients (38% v 22%, respectively). Initial phase I trials also suggested an increased risk for older patients.7 Age in association with BPT had a dramatic impact on mortality. In our study, all patients who died of BPT were older than 40 years. Although 10 patients who were younger than 40 years old developed BPT, none died from this pulmonary complication. This is opposed to a 40% death rate from BPT (six of 15 patients) in patients ≥ 40 years.
Omitting bleomycin from HL therapy interestingly had no effect on HL outcome in our series. In 31 patients who had bleomycin omitted from their chemotherapy, response rates remained equal to the rates for patients administered full-dose bleomycin. OS and PFS also remained equal between the two groups. In patients requiring the omission of bleomycin, continuing with AVD or MOPP/AV resulted in excellent outcomes, with OS rates of 91% at 5 years in both groups. Finally, the total dose of bleomycin had no impact on PFS or OS in our study. Canellos et al14 have recently reported similar findings. In a brief review of two CALGB trials, CALGB 8251 and CALGB 8952, the authors report the omission of bleomycin in 40 of 363 patients enrolled onto these trials. The response rate in these 40 patients was equal to the rate in patients receiving full bleomycin (90% v 91%, respectively). Also, 2-, 5-, and 10-year relapse rates were equal when comparing the two groups.
We did observe a higher rate of BPT in patients treated with ABVD as front-line therapy compared with MOPP/ABV(D) combinations. The reason for this observed difference is not clear. One could hypothesize that a larger exposure to bleomycin in patients treated with ABVD alone might incite more pulmonary toxicity. Alternatively, drugs incorporated in MOPP, such as prednisone, might be protective in patients treated with the combination. Other risk factors previously described, such as G-CSF therapy and age, were balanced between the two treatment groups.
A synergistic effect between bleomycin and G-CSF in promoting pulmonary toxicity has been previously suggested.15 Bleomycin binds to DNA and produces free radicals, which then cause DNA strand breaks and cell death. Bleomycin is inactivated by bleomycin-hydrolase, which has markedly decreased activity in skin and lung tissue.16 Although the exact mechanism is unknown, it seems that bleomycin-induced cell injury in the lung stimulates an inflammatory response with recruitment of inflammatory cells and an increase in cytokine production. G-CSF has been shown to augment these effects in animal models.17
In univariate analysis, we found a statistically significant increase in risk for BPT in patients treated with G-CSF. The association between G-CSF and increased BPT risk has been debated previously.15,18-21 Data has been presented to refute the role of G-CSF in augmenting BPT in both advanced germ cell tumors and non-HL.18-20 However, the relationship between G-CSF and bleomycin in promoting pulmonary toxicity in HL patients is less clear in the literature. This report is the largest to date attempting to address this question.
In conclusion, BPT results in a significant decrease in OS at 5 years in patients being treated for HL. In patients who do not die from acute pulmonary toxicity, both OS and PFS seem equal, despite the omission of bleomycin. AVD and MOPP/AV seem to be appropriate and equally efficacious nonbleomycin-containing regimens for HD patients who develop BPT. In patients older than 40 years, the risk of bleomycin therapy seems heightened, with a higher rate of BPT and pulmonary death. Our data suggest that G-CSF may contribute to BPT risk.
The authors indicated no potential conflicts of interest.
|Characteristic||All Patients (N = 141)||BPT (n = 25)||No BPT (n = 116)||P|
|No. of Patients||%||No. of Patients||%||No. of Patients||%|
|Ann Arbor stage||.78|
|BPT risk factors|
|≥ 120 mg/m2||13||9||1||4||12||10|
Abbreviations: BPT, bleomycin pulmonary toxicity; NLPHL, nodular lymphocyte-predominant Hodgkin's lymphoma; ECOG, Eastern Cooperative Oncology Group; PS, performance status; HL, Hodgkin's lymphoma; ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine; MOPP-ABV(D), mechlorethamine/vincristine/procarbazine/prednisone–doxorubicin/bleomycin/vinblastine ± dacarbazine; COPP-ABV(D), cyclophosphamide/vincristine/procarbazine/prednisone–doxorubicin/bleomycin/vinblastine ± dacarbazine; BEACOPP, bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone; Stanford V, doxorubicin/vincristine/vinblastine/bleomycin/mechlorethamine/cyclophosphamide/etoposide/prednisone; G-CSF, granulocyte colony-stimulating factor; LDH, lactate dehydrogenase.
*LDH > 220 U/L.
†Creatinine > 1.5 mg/dL.
|Response||Omit Bleo (n = 31)||Full Bleo (n = 110)||P|
|No. of Patients||%||No. of Patients||%|
Abbreviations: Bleo, bleomycin; CR, complete response; PR, partial response; NR, no response.
|Nonbleomycin Regimen||Patients||5-Year OS (%)*||P||5-Year PFS (%)*||P|
Abbreviations: OS, overall survival; PFS, progression-free survival; AVD, adriamycin/vinblastine/dacarbazine; MOPP-AV(D), mechlorethamine/vincristine/procarbazine/prednisone-adriamycin/vinblastine ± dacarbazine.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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