TRANSFORM-1 trial

Background

Double-blind, placebo-controlled phase 3 trial. N=252 JAK-inhibitor-naive adults with intermediate-2 or high-risk myelofibrosis and ECOG PS ≤2 (>80% intermediate-2; ~50% high-molecular-risk). Navitoclax is an oral BCL-X_L/BCL-2 inhibitor. Tested adding navitoclax to first-line ruxolitinib.

Results

Interventions and follow up: Arm A: Navitoclax (200 mg/day, or 100 mg escalated to 200 mg/day) + ruxolitinib per label (n=125)
Arm B: Placebo + ruxolitinib per label (n=127)
Primary endpoint: ≥35% spleen volume reduction at week 24 (SVR35W24)
mFollow up: 20.3 months
Results: SVR35W24: 63.2% vs 31.5%, P<.0001
TSS change at wk 24: −10.2 vs −11.6, P=.2852 (not significant)
SVR35 anytime: 76.8% vs 44.1% (nominal P<.0001)
≥20% VAF reduction (exploratory): 58.5% vs 45.5%

Adverse events

Hematologic G3/4: thrombocytopenia 54.0% vs 19.2%; neutropenia 40.3% vs 8.8%
Gastrointestinal: diarrhea (any grade) 41.9% vs 16.8%
Note: cytopenias generally manageable/reversible with dose adjustment

Conclusions

Adding navitoclax to ruxolitinib doubled the rate of ≥35% spleen volume reduction versus ruxolitinib alone but did NOT improve symptom burden (TSS). The regimen produced markedly more cytopenias.

Key Limitations

The key patient-reported secondary endpoint (TSS at week 24) was not met, so the clinical value of the higher spleen response is uncertain. Overall survival and long-term outcomes are not yet mature (NR). High rates of grade 3/4 thrombocytopenia and neutropenia require dose management.

Clinical Context

Ruxolitinib monotherapy remains first-line standard of care for higher-risk myelofibrosis. Navitoclax is NOT FDA-approved for myelofibrosis; TRANSFORM-1 met its spleen primary endpoint but missed the symptom endpoint, and its regulatory path remains uncertain. Positioning within NCCN/ESMO MPN guidance is unchanged pending survival data.

References