Reduced-Intensity Chemotherapy in Patients With Advanced-Stage Hodgkin Lymphoma: Updated Results of the Open-Label, International, Randomised Phase 3 HD15 Trial by the German Hodgkin Study Group

Abstract

The international, randomized phase 3 HD15 trial established 6xeBEACOPP as standard therapy for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) within the German Hodgkin Study Group (GHSG). We performed a follow-up analysis to assess long-term efficacy and safety of this approach. Between 2003 and 2008, 2182 patients aged 18 to 60 years were recruited and randomized in a 1:1:1 ratio between 8 or 6 cycles of eBEACOPP or 8 cycles of the dose-dense BEACOPP-14 regimen, each followed by 30 Gy radiotherapy in case of positron emission tomography (PET)-positive residual lesions ≥2.5 cm. The study aimed at demonstrating non-inferiority regarding efficacy of the 2 experimental arms on a significance level of 2.5% each. The intention-to-treat analysis comprised 2126 patients with a median follow-up of 102 months. Ten-year progression-free survival was 81% (97.5% CI 77-85) with 8xeBEACOPP, 84% (80-87) with 6xeBEACOPP, and 84% (80-87) with 8xBEACOPP-14; the non-inferiority margin of 1.51 for the hazard ratio (HR) could be excluded for both comparisons (6xeBEACOPP, HR = 0.7, 97.5% CI 0.5-1.0; 8xBEACOPP-14, HR = 0.9, 97.5% CI 0.7-1.2). Overall survival at 10 years was 88% (85-91), 90% (88-93), and 92% (89-94), respectively. A total of 142 second malignancies corresponding to 10-year cumulative incidences of 10%, 7%, and 7% and standardized incidence ratios of 4.3, 2.5, and 2.8 were reported for 8xeBEACOPP, 6xeBEACOPP, and 8xBEACOPP-14, respectively. This updated analysis of the HD15 trial thus confirms the efficacy and reports on the long-term safety of a shortened first-line chemotherapy consisting of 6xeBEACOPP followed by PET-guided radiotherapy in advanced-stage HL.

Keywords: Advanced stages; Hodgkin lymphoma; long-term outcome.

Figure 1

Trial profile. ITT is defined as the set of all patients except for those with disconfirmed diagnosis of Hodgkin lymphoma, withdrawal of consent or revision of staging and participation in another study before start of treatment. PP contains all ITT patients without severe protocol deviation, having complete therapy documentation or progressive disease or death during therapy. BEACOPP-14 = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in dose-dense variant, eBEACOPP = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated dose, ITT = intention-to-treat, PP = per-protocol. (a) Analysis set definition based on data from final analysis.

Figure 2

Kaplan-Meier estimates for the intention-to-treat set. (A) Progression-free survival. (B) Overall survival. BEACOPP-14 = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in dose-dense variant, eBEACOPP = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated dose, HR = hazard ratio, PFS = progression-free survival. (a) Hazard ratios adjusted for stratification factors age, sex, Ann Arbor stage, international prognostic score and hemoglobin level.

Figure 3

Kaplan-Meier estimates for the per-protocol set. (A) Progression-free survival. (B) Overall survival. BEACOPP-14 = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in dose-dense variant, eBEACOPP = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated dose, HR = hazard ratio, PFS = progression-free survival. (a) Hazard ratios adjusted for stratification factors age, sex, Ann Arbor stage, international prognostic score and hemoglobin level.

Figure 4

Progression-free survival by outcome after chemotherapy. Analysis includes patients with complete remission after chemotherapy and those with a partial remission, residual lesions of at least 2.5 cm in the largest diameter and centrally reviewed PET available. Radiotherapy was recommended in case of a positive PET scan. HR = hazard ratio, PFS = progression-free survival.

Figure 5

Second PFS for patients with progression or relapse. PFS = progression-free survival.

Figure 6

Cumulative incidence of second malignancies accounting for death as a competing risk. (A) Cumulative incidence of any second malignancy by treatment arm. (B) Cumulative incidence of secondary leukemia and myelodysplastic syndrome by treatment arm. (C) Cumulative incidence of any second malignancy by radiotherapy group (radiotherapy was recommended in case of partial remission including residual lesions of at least 2.5 cm in the largest diameter and a positive PET after chemotherapy). BEACOPP-14 = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in dose-dense variant, CIF = cumulative incidence function, eBEACOPP = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated dose, MDS = myelodysplastic syndrome, sHR = subdistribution hazard ratio.