PET-adapted chemotherapy for advanced stage HL: Results from a phase III trial

On 15 January 2019, the results of the randomized, multicenter, phase III trial, AHL2011 (NCT01358747) were published in The Lancet Oncology by Rene-Olivier Casasnovas from the Dijon Bourgogne University Hospital, Dijon, FR, and colleagues.

The aim of this non-inferiority phase III trial was to investigate whether PET-adapted treatment for newly-diagnosed advanced Hodgkin lymphoma (HL) patients results in better disease management and treatment. The authors specifically assessed if PET monitoring would allow switching from increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP_escalated) to oxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in early responders, so as to minimise BEACOPP-associated toxicity without loss of disease control. The primary endpoint was investigator-assessed progression-free survival (PFS). The non-inferiority margin of this study was 10%, to show non-inferiority of PET-adapted treatment as compared to standard care with 80% power and 2.5% alpha. Secondary endpoints included overall survival (OS), event-free survival (EFS), and disease-free survival.

Study design

• N = 823 newly-diagnosed HL patient from 90 centers across Belgium and France.
• Patients were randomly assigned to either standard treatment (n = 413) or PET-driven treatment (n = 410)
• Eligible patients were aged 16−60, had an Eastern Cooperative Oncology Group (ECOG) performance status < 3, Ann Arbor disease stage III, IV or IIB, and who had not received previous treatment for HL
• Dosing:
  • BEACOPP_escalated (repeated every 21 days):
    • Bleomycin: 10 mg/m² intravenously on Day 8
    • Vincristine: 1.4 mg/m² intravenously on Day 8
    • Etoposide: 200 mg/m² intravenously on Day 1−3
    • Doxorubicin: 35 mg/m² intravenously on Day 1
    • Cyclophosphamide: 1250 mg/m² intravenously on Day 1
    • Procarbazine: 100 mg/m² orally on Day 1−7
    • Prednisone: 40 mg/m² orally on Day 1−14
  • ABVD (repeated every 28 days):
    • Doxorubicin: 25 mg/m² intravenously on Day 1−15
    • Bleomycin: 10 mg/m² intravenously on Day 1−15
    • Vinblastine: 6 mg/m² intravenously on Day 1−15
    • Dacarbazine: 375 mg/m² intravenously on Day 1−15
  • Induction treatment (all patients): two cycles of BEACOPP_escalated and then PET was performed
  • Standard treatment group: four cycles of BEACOPP_escalated irrespective of PET2 results
  • PET-driven group:
    • Patients with positive PET2 scans: two further BEACOPP_escalated cycles
    • Patients with negative PET2 scans: switched to ABVD for the remaining two treatment cycles
  • Consolidation treatment (all patients at end of four cycles; PET4):
    • Patients with positive PET4 scans:
    • Patients with negative PET4 scans: two further BEACOPP_escalated cycles (if in the standard treatment group) or two further BEACOPP_escalated or ABVD cycles (if in the PET-driven group)
  • Granulocyte-colony-stimulating factor (GCSF) administration was mandatory during BEACOPP_escalated treatment (Day 9 of each cycle) and optional for ABVD treatment
• Data cut-off: 31 October 2017
• Baseline characteristics were well balanced between the two groups
• Median age (range): 30 (24−41) years
• Sex: 63% male
• Ninety-seven percent of patients had evaluable PET2 scans (n = 799/823)

Key findings

• PET2 scans were negative in 87% of patients
• In the intention-to-treat (ITT) population:
  • Patients assigned to ABVD in the PET-driven group: 84%
  • Patients assigned to four additional BEACOPP_escalated cycles in the PET-driven group: 12%
  • Patients not receiving allocated treatment due to clinician decision: 4%
• Median follow-up (range): 50.4 (42.9−3) months
• Events that led to progression, relapse or death:
  • Standard treatment group: 10% of patients
  • PET-driven group: 12% of patients
• Estimated 5-year PFS rates:
  • Standard treatment group: 86.2% (95% CI, 81.6−8)
  • PET-driven group: 85.7% (95% CI, 81.4−1)
  • Comparison: HR = 1.084; 95% CI, 0.737−596; P_{non-inferiority} = 0.65
• Median PFS:
  • Standard treatment group: not reached
  • PET-driven group: not reached
• Five-year OS rates:
  • Standard treatment group: 95.6% (95% CI, 91.2−8)
  • PET-driven group: 95.9% (95% CI, 92.5−8)
  • Comparison: HR = 1.284; 95% CI, 0.53−88; P = 0.69
• Five-year EFS rates:
  • Standard treatment group: 76.8% (95% CI, 71.7−81.0)
  • PET-driven group: 78.6% (95% CI, 73.9−6)
  • Comparison: HR = 0.925; 95% CI, 0.686−248; P = 0.31
• Five-year disease-free survival rates:
  • Standard treatment group: 89.9% (95% CI, 85.1−93.2)
  • PET-driven group: 90.0% (95% CI, 86.0−9)
  • Comparison: HR = 1.099; 95% CI, 0.667−711; P = 0.66

Safety

• Patients discontinuing treatment because of disease progression:
  • Standard treatment group: n = 10
  • PET-driven group: n = 12
• Patients discontinuing treatment because of toxicity:
  • Standard treatment group: n = 24
  • PET-driven group: n = 4
• Deaths from toxicity (all groups: 1%):
  • Standard treatment group: n = 6
  • PET-driven group: n = 2
• Treatment-related serious adverse events (AEs) occurred in:
  • Standard treatment group: n = 192 (47%)
  • PET-driven group: n = 114 (28%)
  • Were mainly (standard vs PET-driven group):
    • Infections: 20% vs 12%
    • Febrile neutropenia: 5% vs 6%
    • Deaths from serious treatment-related AEs: 1% vs  < 1%

Conclusions

• Interim PET-monitoring of chemotherapy response led to similar outcomes in advanced-stage HL patients
• Reducing chemotherapy intensity in patients who achieved early metabolic response was safe and without losing disease control
• The primary endpoint of the study was met; with a 5-year PFS of 86.2% in the standard treatment group and 85.7% in the PET-driven group
• A limitation of this study is its non-inferiority design with the predesigned wide margin (10%) between the two treatment arms