RATHL

Background

Phase III, open-label RCT (RATHL — Response-Adapted Therapy in Advanced Hodgkin Lymphoma). 1,214 patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (stage IIB, III, or IV). All patients received 2 cycles of ABVD followed by PET scan (iPET2). The 937 iPET2-negative patients (84%) were randomized to continue ABVD or de-escalate to AVD (omit bleomycin). The 182 iPET2-positive patients received escalated BEACOPP off-protocol.

Interventions and follow up

Arm A: Continue ABVD (cycles 3–6) — 4 additional cycles with bleomycin (n=470)
Arm B: De-escalate to AVD (cycles 3–6) — bleomycin omitted in iPET2-negative patients (n=467)
Primary endpoint: PFS; noninferiority of AVD vs. ABVD (margin 5 percentage points)
Median follow up: 41 months (primary); 5-year data reported

Results

3-yr PFS (ABVD vs. AVD, iPET2-negative): 85.7% vs. 84.4% — difference −1.3 pp (90% CI −5.1 to 2.6); noninferiority met
3-yr OS: 97.2% (ABVD) vs. 97.6% (AVD) — no difference
5-yr PFS (AVD arm): 80.6% (95% CI 76.2–84.2)
iPET2-positive patients (n=182, BEACOPP escalation): 3-yr PFS 67.5%

Adverse events

Pulmonary (ABVD vs. AVD): any-grade pulmonary toxicity 22% vs. 9%, P<.001; grade ≥3 pulmonary toxicity 3.4% vs. 0.9%
Treatment-related mortality: 4 patients from pulmonary toxicity (ABVD) vs. 0 (AVD)
Other: neurotoxicity and hematologic toxicity comparable between arms

Conclusions

Bleomycin omission in iPET2-negative advanced-stage cHL (de-escalation to AVD) met noninferiority criteria for PFS with significantly lower pulmonary toxicity and no treatment-related respiratory deaths. RATHL established PET-adapted AVD as the standard de-escalation strategy for iPET-negative advanced-stage cHL.

Key Limitations

The 5% noninferiority margin was chosen based on clinical judgment rather than statistical power calculations for OS. Long-term follow-up (5-yr PFS 80.6% in AVD arm) is modest compared to BV+AVD (ECHELON-1 5-yr PFS 82.2%) and N+AVD (S1826 2-yr PFS 92%), suggesting RATHL-era ABVD/AVD may be suboptimal. iPET2-positive patients receiving BEACOPP had inferior outcomes (3-yr PFS 67.5%), raising questions about whether upfront more intensive therapy (BV+AVD or N+AVD) would have avoided this group entirely. BEACOPP escalation for positive PET was a nonrandomized decision.

Clinical Context

RATHL established that bleomycin can be safely omitted in iPET-negative advanced-stage cHL, reducing pulmonary toxicity without compromising efficacy — incorporated into ESMO guidelines. However, RATHL-era outcomes (AVD 5-yr PFS ~80%) have been substantially improved by ECHELON-1 (BV+AVD, 5-yr PFS 82.2%) and especially S1826 (N+AVD, 2-yr PFS 92%). In current practice, N+AVD or BV+AVD are the preferred frontline regimens in the US, making RATHL-style PET-adapted AVD de-escalation less commonly applied as a primary strategy.

References