Omission of Bleomycin in Limited Stage Classic Hodgkin Lymphoma Patients with a Negative PET Scan Following 2 Cycles of ABVD Is Associated with Comparable Outcomes and Reduced Pulmonary Toxicity
Authors: Yang Jiayu , Villa Diego , Gerrie Alina S. , Tonseth Petter , Wilson Don C. , Benard Francois , Slack Graham W. , Venner Christopher P. , Lo Andrea C. , Scott David W. , Sehn Laurie H. , Savage Kerry J. 
Published: December 2024

Introduction: Treatment strategies in limited stage classic Hodgkin lymphoma (cHL) have evolved to minimize toxicity. The RATHL study in advanced stage cHL established that bleomycin can be omitted from subsequent cycles if the PET scan after ABVD x 2 (PET2) is negative (PET2 neg). This has not been formally evaluated in limited stage cHL. At BC Cancer, a similar approach was endorsed in January 2016 in limited stage cHL to minimize bleomycin pulmonary toxicity.

Methods: All patients (pts) aged 17-70 years (y) with radioencompassable, limited stage cHL (stage IA, IB, IIA, non-bulky [&lt;10 cm], +/- extranodal extension) diagnosed December 2011-June 2022, an era where staging PET scans were available, and planned for curative intent treatment with ABVD were identified. PET scans performed 2011-2014 were evaluated based on the International Harmonization Project and were retrospectively re-reviewed by the Deauville (D) criteria (D1-2, DX = negative, D3-5 = positive). All pts received ABVD x 2 and those with a positive PET2 (PET2 pos) were switched to radiotherapy (RT). If PET2 neg, pts were recommended to receive a further ABVD x 2 ('ABVD era') or AVD x 2 after the policy change ('AVD era'), for a total of 4 cycles. An era-to-era outcome comparison and a secondary analysis comparing outcomes in the as-treated PET2 neg groups (ABVD4 vs. ABVD2/AVD2) were performed. Bleomycin pulmonary toxicity was determined by the treating physician based on clinical and radiographic features, resulting in permanent bleomycin discontinuation +/- steroid treatment.

Results: 188 pts were identified, 69 in the ABVD era, 119 the AVD era. Median age 34 y (range 17-68), 22 (12%) were age ≥60, 98 (52%) females, 34 (18%) stage I. The median size of the largest mass was 4 cm (range 1-9 cm). The majority of pts (179, 95%) had a staging PET. Overall, 17 (9%) pts received RT at a similar frequency between eras (p=0.30).

159/188 pts (85%) were managed per policy recommendation with all deviations in the later era. Two pts did not have PET2, 1 was planned for combined modality therapy and 1 non-compliant. For the remaining 27 pts, 19 continued ABVD with PET2 neg and 5 continued chemotherapy following PET2 D3 by physician discretion. The remaining 3 pts had individual treatment modifications. Median follow-up for alive pts was 73 months (range 15-149), 122 months (range 15-149) in the ABVD era, 59 months (range 26-101) in the AVD era. For all pts, the 5-year (5 y) PFS was 93.8%, and 5 y OS was 99.3% with only 1 death due to cHL.

There was no difference in age ≥60 y (p=0.93), sex (p=0.57), stage (p=0.40), or mass size ≥5 cm (p=0.94) distribution across the two eras. In the era-to-era (ABVD era vs. AVD era) comparison (n=188), outcomes were similar: 5 y PFS 92.3% vs. 94.9% (p=0.504), 5 y OS 98.4% vs. 100% (p=0.220). In total, 15 pts (8%) were determined to have bleomycin toxicity: 11 (16%) in the ABVD era, 9 (82%) during cycle 3 or 4, while only 4 (3%) had pulmonary toxicity in the AVD era, all during cycle 2 of ABVD (p=0.001). The median age was 55.5 y for all pts with pulmonary toxicity during cycle 2 (3.2%).

163/186 pts (88%) had a PET2 neg scan. All but 2 completed treatment with chemotherapy alone, with 158 (97%) completing 4 cycles. Two PET2 neg pts switched to RT due to poor chemotherapy tolerance. The remaining 23 (12%) were PET2 pos; 14 (61%) switched to RT as planned, and the remainder completed treatment with 2 further cycles of chemotherapy by physician choice. PET2 response status was unaltered with D score re-review. By PET2 status, 5 y PFS was 95% for PET2 neg, with no difference by D score (p=0.33) and 82% for PET2 pos pts (p=0.15).

In an as-treated analysis of PET2 neg pts who completed treatment with either ABVD x 2 (n=65) or AVD x 2 (n=96) in both eras, there was no difference in baseline clinical features. There further was no difference in PFS (5 y 91.2% vs. 95.9%, p=0.39) or OS (5 y 98.4% vs. 100%, p=0.998) in the ABVD and AVD groups, respectively. In total, 6 pts (9%) in the PET2 neg ABVD group relapsed, 4 at the original disease site and 2 pts (3%) died, 1 from cHL. Four pts (4%) in the PET2 neg AVD group relapsed, all at the original site, and 1 pt died due to cardiac cause.

Conclusion: Omission of bleomycin for cycles 3 and 4 in limited stage cHL following a PET2 neg scan (D1-2, DX), preserves excellent outcomes and may reduce the incidence of pulmonary toxicity. Rare pulmonary toxicity can occur during cycle 2 of ABVD and with older adults at risk, omission of bleomycin for all cycles should be strongly considered.