AHL2011: PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma

Casasnovas et al.
Lancet Oncology 2019

Introduction

 

  • Standard treatment for advanced Hodgkin lymphoma is 6-8 cycles of escalated BEACOPP
  • Improves progression-free survival compared to ABVD, but has increased toxicity
  • PET after 2 cycles (PET2) is highly prognostic
  • Hypothesis: PET2 could guide treatment de-escalation in early responders

Methods

 

  • Phase 3 randomized non-inferiority trial
  • 823 patients with newly diagnosed advanced Hodgkin lymphoma
  • Randomized 1:1 to:
    • Standard arm: 6 cycles of escalated BEACOPP
    • PET-driven arm: Treatment adapted based on PET2 results
  • Primary endpoint: Progression-free survival

Eligibility criteria

 

  • Age 16-60 years
  • Newly diagnosed classical Hodgkin lymphoma
  • Ann Arbor stage III-IV or stage II with B symptoms or mediastinal bulk
  • ECOG performance status 0-2
  • No prior treatment for Hodgkin lymphoma
  • Adequate organ function

Patient characteristics

 

  • Median age: 30 years
  • Ann Arbor stage III-IV: 89%
  • B symptoms: 68%
  • IPS ≥3: 58%
  • Bulky disease (≥10 cm): 34%

Methods

 

  • Phase 3 randomized non-inferiority trial
  • 823 patients with newly diagnosed advanced Hodgkin lymphoma
  • Randomized 1:1 to:
    • Standard arm: 6 cycles of escalated BEACOPP
    • PET-driven arm: Treatment adapted based on PET2 results
  • Primary endpoint: Progression-free survival

escBEACOPP

BEACOPP (regular): Bleomycin, Etoposide, Adriamycin (doxorubicin), Cyclophosphamide, Oncovin (vincristine), Procarbazine, and Prednisone.

Escalated BEACOPP is an intensified version

  1. Higher doses of etoposide, doxorubicin, and cyclophosphamide.

  2. Granulocyte colony-stimulating factor (G-CSF) support is mandatory to manage the increased myelosuppression

  • Etoposide dose is increased from 100 mg/m² to 200 mg/m² on days 1-3

  • Doxorubicin is increased from 25 mg/m² to 35 mg/m² on day 1

  • Cyclophosphamide is increased from 650 mg/m² to 1250 mg/m² on day 1

ABVD

ABVD: Adriamycin (doxorubicin), Bleomycin, Vinblastine, and Dacarbazine.

typically:

  • Doxorubicin: 25 mg/m² IV on days 1 and 15
  • Bleomycin: 10 units/m² IV on days 1 and 15
  • Vinblastine: 6 mg/m² IV on days 1 and 15
  • Dacarbazine: 375 mg/m² IV on days 1 and 15

Each cycle of ABVD is typically 28 days long.

AHL2011 Trial Schema

Standard Arm

2 cycles BEACOPPesc
Day 1 - Day 42 (21 days per cycle)
↓
PET2 (no impact on treatment)
~Day 42
↓
2 cycles BEACOPPesc
Day 43 - Day 84 (21 days per cycle)
↓
PET4 (no impact on treatment)
~Day 84
↓
2 cycles BEACOPPesc
Day 85 - Day 126 (21 days per cycle)

PET-driven Arm

2 cycles BEACOPPesc
Day 1 - Day 42 (21 days per cycle)
↓
PET2
~Day 42
↓
PET2 Negative
↓
4 cycles ABVD
Day 43 - Day 154 (28 days per cycle)
PET2 Positive
↓
4 cycles BEACOPPesc
Day 43 - Day 126 (21 days per cycle)
↓
PET4 (for response assessment)
ABVD arm: ~Day 154
BEACOPPesc arm: ~Day 126

GITIL/FIL HD 0607 Trial Schema

2 cycles ABVD
Baseline - ~2 months
↓
PET2
~2 months
↓
PET2 Negative
↓
4 cycles ABVD
~2 - 6 months
↓
PET6
~6 months
↓
Randomization (if LNM ≥ 5cm and PET6 negative)
RT to LNM
No Further Treatment
PET2 Positive
↓
Randomization
4 cycles BEACOPPesc + 4 cycles BEACOPPbase
4 cycles BEACOPPesc + 4 cycles BEACOPPbase + Rituximab

Trial schema

Radiation details

 

  • No planned radiotherapy in either arm
  • Radiotherapy was allowed at investigator discretion for:
    • Residual PET 4 - positive disease after completion of chemotherapy
    • bulky sites
  • 32 patients received consolidation radiotherapy:
    • 18 patients (4%) in the standard treatment group
    • 14 patients (3%) in the PET-driven treatment group

Primary outcome

 

  • 5-year progression-free survival:
    • Standard arm: 86.2% (95% CI 81.6-89.8)
    • PET-driven arm: 85.7% (95% CI 81.4-89.1)
    • HR 1.084 (95% CI 0.737-1.596), p=0.65
  • Met pre-specified non-inferiority margin of 10%

Secondary outcomes

 

  • 5-year overall survival:
    • Standard arm: 95.2%
    • PET-driven arm: 96.4% (HR 0.936, p=0.43)
  • Complete response rate: Similar between arms
  • Toxicity:
    • Grade 3-4 adverse events lower in PET-driven arm
    • Fewer secondary malignancies in PET-driven arm
    • More pregnancies reported in PET-driven arm

Results by arm

Results by PET response

Results by PET response

Results by PET response

Conclusions

 

  • PET-adapted treatment strategy was non-inferior to standard escalated BEACOPP
  • 84% of patients were able to de-escalate to ABVD after 2 cycles of escalated BEACOPP
  • PET-adapted approach reduced toxicity without compromising efficacy
  • Combining PET2 and PET4 results provided strong prognostic information
  • PET-adapted strategy could be considered for routine management of advanced Hodgkin lymphoma

Strengths and limitations

 

  • Strengths:
    • Large, randomized phase 3 trial
    • Long-term follow-up (median 50.4 months)
    • Centralized PET review
  • Limitations:
    • Wide non-inferiority margin (10%)
    • No details on radiotherapy use
    • Limited data on long-term toxicity