Phase III H9-U trial in newly diagnosed early-stage classical Hodgkin Lymphoma with risk factors – 4 cycles of ABVD-IFRT or BEACOPPbaseline-IFRT found to be non-inferior to 6 cycles of ABVD-IFRT

On 7^th June 2017, Christophe Fermé from The Institute Gustave Roussy, France, and colleagues published in the European Journal of Cancer results of their phase III, randomized, open-label, multicenter, non-inferiority trial (NCT00005584) assessing ABVD or BEACOPP_baseline with Involved-Field Radiotherapy (IFRT) in newly diagnosed patients with stage I–II supradiaphragmatic classical Hodgkin Lymphoma (cHL) with risk factors.

The following were the defined risk factors in this study: age ≥50, stage II with 4–5 involved nodal areas, Mediastinum/Thoracic (M/T) ratio ≥0.35, no B-symptoms and Erythrocyte Sedimentation Rate (ESR) ≥50, or B-symptoms and ESR ≥30.

Between October 1998 and September 2002, 808 patients (median age, 30.7 years; range, 15–69) were randomly assigned to the control arm (6-ABVD-IFRT; n=276), or one of the two experimental arms: 4-ABVD-IFRT (n=277) or 4-BEACOPP_baseline-IFRT (n=255). Of patients who achieved a PR after chemotherapy, 71% received 36Gy with a 4Gy boost according to protocol.

Key Highlights:

Patients and treatment delivery

• Protocol violations reported in 7% (n=60) pts, equally distributed between arms
• ≥90% of target dose was achieved in 85% of pts receiving ABVD (4 or 6 cycles) and 67% of pts receiving BEACOPP_baseline
• ≥95% of doxorubicin target dose was achieved in 47% and 57% of pts receiving 4 and 6 cycles of ABVD, and in 67% of pts receiving BEACOPP_baseline

Responses to treatment and outcomes

• CR/CRu rate: overall = 68%; 6-ABVD-IFRT arm = 75%; 4-ABVD-IFRT = 71%; 4-BEACOPP_baseline-IFRT = 59%
• After chemotherapy, PR was achieved by 221 pts; of these, 134 achieved CR/CRu after RT (6-ABVD-IFRT arm, n=35; 4-ABVD-IFRT arm, n=43; 4-BEACOPP_baseline-IFRT arm, n=56)
• At end of treatment, 83 pts remained in PR and 3 had PD; no statistically significant difference in response rate was observed between the three treatment groups
• Estimated 5-year EFS: 4-ABVD-IFRT (85.9%) and 4-BEACOPP_baseline-IFRT (88.8%) were not inferior to 6-ABVD-IFRT (89.9%): difference of 4.0% (90% CI, -0.7 to -8.8%) and 1.1% (90% CI, -3.5 to -5.6%), respectively
• Estimated 5-year EFS in the 490 pts who achieved a CR/CRu after chemotherapy = 93% (95% CI, 90–95%); in the 221 pts who achieved PR after chemotherapy = 84% (95% CI, 79–88%)
• Estimated 5-year OS: 6-ABVD-IFRT = 94%; 4-ABVD-IFRT = 93%; 4-BEACOPP_baseline-IFRT = 93%
• Progression/relapse was reported in 70 pts:
  • PD during treatment/within 3 months following end of RT = 28 pts (2.5%)
  • Early relapse within 4–12 months following end of RT = 15 pts
  • Late relapse = 27 pts (25 took place 13–60 months following end of RT)
• At the end of treatment, of the 622 pts who achieved CR/CRu, 30 pts subsequently relapsed (4.8%)
• Estimated 5-year RFS: 6-ABVD-IFRT = 97%; 4-ABVD-IFRT = 92%; 4-BEACOPP_baseline-IFRT = 96%
• Among the 91 pts who achieved a PR at the end of treatment, 24 subsequently failed: 14 progressed within 3 months, 6 developed early relapses, and 4 developed late relapses

Toxicity

• During chemotherapy, grade 3–4 hematological toxicity was experienced by 74% of pts
• SAEs were experienced by 13% of pts, resulting in 8 chemotherapy-related deaths
• Grade 3–4 neutropenia and use of growth factors was less common after BEACOPP_baseline
• Administration of antibiotics, RBC transfusions, hospitalization, and SAEs occurred almost two times more frequently with BEACOPP_baseline versus the pooled ABVD arms (P ≤ 0.001 each single test)
• Overall, 3% of pts experienced a grade 3–4 infection
• During or after RT, 2 and 15 pts developed hematological and non-hematological toxicity, respectively
• Late cardiovascular toxicity was observed in 1% of pts giving a 5-year cumulative estimate of 0.8%
• Late pulmonary complication was experienced by 2% of pts giving an overall 5-year cumulative estimate of 1.7%
• A second malignancy developed in 25 pts 8–118 months after randomization giving a 5-year cumulative incidence estimate of 1.5%

The authors concluded that the H9-U trial of patients with early-stage supradiaphragmatic cHL and risk factors, the H9-U trial demonstrated the non-inferiority of both experimental arms (4-ABVD-IFRT or 4-BEACOPP_baseline-IFRT) compared to the reference arm (6-ABVD-IFRT). Similar EFS and OS was achieved with 4-ABVD-IFRT and 6-ABVD-IFRT (including IFRT 30Gy in both). The authors went on to state that since the time of the H9 trial design, the standard treatment strategy of early stage cHL with risk factors has changed: 4-ABVD-IFRT 30Gy has been replaced by a combination of 2-BEACOPPescalated and 2-ABVD followed by IFRT 30Gy. RT volumes have also been reduced from IFRT to involved node or involved site RT and a risk-adapted treatment strategy has been associated with response adapted treatment using early PET.

Overall, 4 cycles of ABVD and IFRT 30Gy has been a reference strategy to develop new therapies. “It remains an effective option for patients with early-stage HL and risk factors responding to chemotherapy.”

Abstract:

PURPOSE: For early-stage Hodgkin lymphoma (HL), optimal chemotherapy regimen and the number of cycles to be delivered remain to settle down. The H9-U trial compared three modalities of chemotherapy followed by involved-field radiotherapy (IFRT) in patients with stage I-II HL and risk factors (NCT00005584).

PATIENTS AND METHODS: Patients aged 15-70 years with untreated supradiaphragmatic HL with at least one risk factor (age ≥ 50, involvement of 4-5 nodal areas, mediastinum/thoracic ratio ≥ 0.35, erythrocyte sedimentation rate (ESR) ≥ 50 without B-symptoms or ESR ≥ 30 and B-symptoms) were eligible for the randomised, open label, multicentre, non-inferiority H9-U trial. The limit of non-inferiority was set at 10% for the difference between 5-year event-free survival (EFS) estimates. From October 1998 to September 2002, 808 patients were randomised to receive either the control arm 6-ABVD-IFRT (n = 276), or one of the two experimental arms: 4-ABVD-IFRT (n = 277) or 4-BEACOPPbaseline-IFRT (n = 255).

RESULTS: Results in the 4-ABVD-IFRT (5-year EFS, 85.9%) and the 4-BEACOPPbaseline-IFRT (5-year EFS, 88.8%) were not inferior to 6-ABVD-IFRT (5-year EFS, 89.9%): difference of 4.0% (90%CI, -0.7%-8.8%) and of 1.1% (90%CI,-3.5%-5.6%) respectively. The 5-year overall survival estimates were 94%, 93%, and 93%, respectively. Patients treated with combined modality treatment chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vincristine (Oncovin), cyclophosphamide, procarbazine, etoposide and prednisone (BEACOPP)baseline more often developed serious adverse events requiring supportive measures and hospitalisation compared with patients receiving the chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD).

CONCLUSIONS: The trial demonstrates that 4-ABVD followed by IFRT yields high disease control in patients with early-stage HL and risk factors responding to chemotherapy. Although non-inferior in terms of efficacy, four cycles of BEACOPPbaseline were more toxic than four or six cycles of ABVD.