HL

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 (BEACOPPescalated) 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:
    • BEACOPPescalated (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 BEACOPPescalated and then PET was performed
    • Standard treatment group: four cycles of BEACOPPescalated irrespective of PET2 results
    • PET-driven group:
      • Patients with positive PET2 scans: two further BEACOPPescalated 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 BEACOPPescalated cycles (if in the standard treatment group) or two further BEACOPPescalated or ABVD cycles (if in the PET-driven group)
    • Granulocyte-colony-stimulating factor (GCSF) administration was mandatory during BEACOPPescalated 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 BEACOPPescalated 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; Pnon-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
References
  1. Casasnovas O. et al. PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study. Lancet Oncology. 2019 Jan. DOI: 10.1016/S1470-2045(18)30784-8
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