Background
Phase 3, open-label, international RCT. 372 patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) who had received ≥1 prior systemic therapy. Mogamulizumab is a defucosylated anti-CCR4 monoclonal antibody (enhanced ADCC); CCR4 is expressed on malignant T-cells in MF and SS. Vorinostat is an oral pan-HDAC inhibitor FDA-approved for refractory CTCL. Stratified by disease type (MF vs SS) and ECOG PS. SS patients (30% of cohort) represent a particularly aggressive subgroup with historically poor outcomes.
Interventions and follow up
Arm A: Mogamulizumab 1 mg/kg IV weekly × 4 doses (cycle 1), then every 2 weeks (28-day cycles)
Arm B: Vorinostat 400 mg orally once daily
Primary endpoint: Progression-free survival (independent review)
Median follow up: 17 months
Arm B: Vorinostat 400 mg orally once daily
Primary endpoint: Progression-free survival (independent review)
Median follow up: 17 months
Results
mPFS (overall): 7.7 vs 3.1 months, HR 0.53, 95% CI 0.41–0.69, P<.0001
mPFS (MF subgroup): 6.7 vs 3.8 months, HR 0.62
mPFS (SS subgroup): 15.1 vs 3.5 months, HR 0.31
ORR: 28% vs 5%, P<.0001
ORR (SS subgroup): 37% vs 2%
mOS: HR 0.84, 95% CI 0.62–1.13, P=.28 — not significant
mPFS (MF subgroup): 6.7 vs 3.8 months, HR 0.62
mPFS (SS subgroup): 15.1 vs 3.5 months, HR 0.31
ORR: 28% vs 5%, P<.0001
ORR (SS subgroup): 37% vs 2%
mOS: HR 0.84, 95% CI 0.62–1.13, P=.28 — not significant
Adverse events
General/skin: Grade ≥3 AEs 41% (mogamulizumab) vs 47% (vorinostat); infusion-related reactions 33% (mostly grade 1–2); drug-related rash 23% vs 16%
Hematologic/other: Grade ≥3 thrombocytopenia 4% vs 18%; grade ≥3 fatigue 2% vs 5%
Immune-mediated/SCT caution: Autoimmune hepatitis, pneumonitis. Mogamulizumab depletes CCR4+ regulatory T-cells (Tregs), causing severe or fatal graft-versus-host disease after subsequent allogeneic SCT — a ≥50-day washout before allogeneic transplant is mandatory
Hematologic/other: Grade ≥3 thrombocytopenia 4% vs 18%; grade ≥3 fatigue 2% vs 5%
Immune-mediated/SCT caution: Autoimmune hepatitis, pneumonitis. Mogamulizumab depletes CCR4+ regulatory T-cells (Tregs), causing severe or fatal graft-versus-host disease after subsequent allogeneic SCT — a ≥50-day washout before allogeneic transplant is mandatory
Conclusions
Mogamulizumab significantly improved PFS and ORR versus vorinostat in R/R MF and Sézary syndrome, with particularly pronounced benefit in SS (mPFS 15.1 vs 3.5 months, ORR 37% vs 2%). OS was not significantly improved, likely due to high crossover. These results led to FDA approval of mogamulizumab and established it as a preferred option — especially for Sézary syndrome — over HDAC inhibitors in R/R CTCL.
Key Limitations
OS was not improved (HR 0.84, P=.28), likely due to high crossover from vorinostat to mogamulizumab after progression; this limits interpretation of the primary survival endpoint. Clinical benefit is substantially more pronounced in SS than MF — MF patients with lower CCR4 expression may have limited incremental benefit over alternatives (BV, HDAC inhibitors). The Treg depletion mechanism creates a critical and potentially fatal SCT interaction. Open-label design. PFS assessed by composite CTCL response criteria limits cross-trial comparisons.
Clinical Context
Mogamulizumab (Poteligeo) received FDA approval (2018) for adult patients with R/R MF or SS who have received ≥1 prior systemic therapy, based on MAVORIC. It is a preferred choice for Sézary syndrome given high CCR4 expression and superior response rates (ORR 37%). The mandatory ≥50-day SCT washout must be factored into treatment planning for transplant-eligible patients — mogamulizumab should generally be deferred in this setting. ESMO lists mogamulizumab as a preferred option for R/R MF and SS.