Incidence and Predictors of Bleomycin Pulmonary Toxicity in Hodgkin Lymphoma (HL) Patients Treated with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD),

Bleomycin pulmonary toxicity (BPT) is a well described complication of bleomycin-containing chemotherapy regimens, with a reported incidence of 0–46%. Prior data in Hodgkin Lymphoma (HL) have been heterogeneous with some series reporting inferior survival in patients (pts) with BPT. We reviewed the outcome of ABVD treated pts at our institution with the goals of determining the incidence and risk factors for BPT, as well as the effect of BPT on overall and progression-free survival (OS and PFS).

We retrospectively reviewed 253 newly diagnosed pts with HL treated with ABVD at Princess Margaret Hospital from 1999–2009. Pts typically received 3 cycles of ABVD + IFRT for localized disease and 6–8 cycles for advanced stage or bulky disease. BPT was defined by the presence of symptoms (fever, cough, dyspnea), bilateral interstitial infiltrates on CT, and no evidence of infection. Predictors of BPT were identified in bivariate followed by multivariable logistic regression analysis. Kaplan-Meier estimates as well as Cox proportional hazards model were used to compare OS and PFS between groups.

Median age at HL diagnosis was 34 years (range 17–77); 129 (51%) were male, 49% had advanced stage disease, while localized presentations were favourable: 25% and unfavourable: 26% by NCIC criteria. 77 (30%) patients had a smoking history, 121 (48%) received thoracic radiation for HL and 27(11%) had underlying lung disease. BPT was observed in 29 (11%) patients, with a median onset time of 4 months from initiation of ABVD. Bleomycin was discontinued in 20/29 patients (69%) and 19/29 (66%) patients were treated for BPT with corticosteroids (median duration: 11 weeks (range 3–23)).

On bivariate analysis, risk factors associated with increased risk of BPT include age ≥45 years (55% BPT vs 28% non-BPT, p=0.003), G-CSF use (90% vs.71%, p=0.043), and ECOG PS ≥2 (24% vs.10%, p=0.02). On multivariable analysis, age ≥45 years (HR=3.1, p=0.005) and G-CSF use (HR=3.5, p=0.045) remained as independent predictors of BPT development. There was no sufficient evidence of a statistically significant difference in pulmonary risk factors in patients with or without BPT. There was a trend towards lower baseline serum albumin in BPT group, although this did not reach statistical significance (p=0.052).

At a median follow-up of 5 years, OS and PFS for all 253 pts were 88% and 82%. 30 pts died due to disease progression (15), treatment-related complications (5; 3 secondary malignancies), and other causes (4). Only 3 deaths occurred among the 29 pts with BPT (2 unrelated, 1 from concomitant BPT and sepsis with multiorgan failure). On multivariable analysis, age≥60 (HR 3.7 for OS, p=0.003; HR 2.5 for PFS, p=0.019) and ECOG PS≥2 (HR 3.1 for OS, p=0.009; HR 3.0 for PFS, p=0.003) were identified as predictors of inferior survival in advanced stage HL. Increased age was associated with inferior OS (HR 1.05, p=0.031) and PFS (HR 1.06, p=0.004) in limited stage HL. Development of BPT had no significant impact on CR (97% BPT vs. 89% in non-BPT, p=0.77), 5-year OS (93% vs. 87%, p=0.80) or PFS (83% vs. 82%, p=0.98) in multivariate analysis. Bleomycin discontinuation (66 pts, 27%; 20 due to BPT, 5 skin toxicity, 36 non-BPT respiratory symptoms, 5 other) had no impact on CR rate (88% vs. 91%, p=0.19), 5-year PFS (81% vs. 83%, p=0.98), or 5-year OS (85% vs. 89%, p=0.89).

The incidence of BPT in this series is low at 11%. Our study confirms advanced age and G-CSF usage as risk factors for BPT and identified poor PS as an independent predictor of BPT. In contrast to some prior studies, we demonstrate similar OS and PFS for pts who developed BPT or had bleomycin discontinued. This may be attributed to earlier recognition and management for suspected BPT in the past decade.

Kukreti:Celgene: Honoraria; Ortho Biotech: Honoraria; Roche: Honoraria. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.