IMPACT OF BLEOMYCIN AND DACARBAZINE WITHIN THE ABVD REGIMEN IN THE TREATMENT OF EARLY-STAGE FAVORABLE HODGKIN LYMPHOMA: FINAL RESULTS OF THE GHSG HD13 TRIAL

ABSSUB-3466

Background: Combined modality treatment consisting of two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by involved-field radiotherapy (IFRT) is regarded as standard of care for early-stage favorable Hodgkin Lymphoma (HL).

Aims: To analyze the impact of bleomycin and dacarbazine within the ABVD regimen.

Methods: The GHSG HD13 study compared two cycles of ABVD with a dacarbazine-deleted variant (ABV), a bleomycin-deleted variant (AVD), and a variant in which both, dacarbazine and bleomycin were deleted (AV). In each treatment arm, chemotherapy was followed by IFRT of 30 Gy. Primary objective was to demonstrate non-inferiority of the three experimental variants compared to ABVD regarding the primary endpoint freedom from treatment failure (FFTF) by excluding a difference of 6% after 5 years, corresponding to a non-inferiority margin of 1.72 for the Hazard Ratio, via a 95% confidence interval (CI). Recruitment started in 01/2003. In our continuously performed safety analyses, higher event rates were observed with AV and ABV. Thus, these two arms were closed early in 09/2005 and 02/2006, respectively. Randomization between ABVD and AVD continued until 09/2009 with a total of 1710 patients. Two hundred eight patients were excluded from the final analysis due to revision of HL diagnosis, loss to follow-up before start of treatment, revision of staging, or violation of other inclusion criteria. Of 1502 qualified patients analyzed for therapy adherence, toxicity, and efficacy, 566 were randomized into the standard arm and 198, 571, and 167 patients were randomized to receive experimental chemotherapy with ABV, AVD, or AV, respectively.

Results: Patient characteristics were well balanced between the four treatment arms: median age was 39 years, 67% had stage II disease, and there were more male patients included (60%). The most frequent histologic subtypes were mixed cellularity and nodular sclerosis (40% and 37%, respectively).  The rate of acute toxicities ranged between 26.3% with AVD and 32.7% with ABVD; leukopenia (14.4%), hair loss (10.9%), and nausea/vomiting (5.8%) were most frequently observed. Interestingly, pulmonary toxicity was observed in four patients only, including one patient receiving AV. Only moderate reduction in acute toxicities was observed when omitting Bleomycin (leukopenia) and Dacarbazine (nausea/vomiting). FFTF at five years was 93.1%, 81.4%, 89.2%, and 77.1% after treatment with ABVD, ABV, AVD, and AV, respectively. Inferiority of the early closed treatment arms without dacarbazine was confirmed in this final analysis with five-year-differences in FFTF of 11.5% (95% - CI 4.7% to 18.3%) with ABV and 15.2% (95% - CI 7.4% to 23.0%) with AV compared to ABVD, respectively. In addition, non-inferiority of AVD compared to ABVD could not be confirmed, with a five-year-difference in FFTF of 3.9% (95% - CI 0.1% to 7.7%). The respective Hazard Ratio was 1.5 with a 95% - CI ranging from 1.0 to 2.3, including the pre-specified non-inferiority margin. Overall survival was excellent and did not differ between treatment arms, with five-year-estimates of 97.6%, 94.1%, 97.6%, and 98.1% after treatment with ABVD, ABV, AVD, and AV, respectively.

Summary/Conclusion: Dacarbazine cannot be deleted from the ABVD regimen without a significant loss of efficacy. With respect to the predefined non-inferiority margin of 6% after 5 years, also Bleomycin cannot be safely omitted. Importantly, the reduction in tumor control in the experimental arms did not translate into inferior overall survival.

Keywords: Clinical trial, Hodgkin's lymphoma

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