STOP-2

Background

Phase III open-label RCT. 79 children with SCD who had been on chronic transfusion for ≥30 months and achieved TCD normalization (<170 cm/s on two measurements). Designed to determine whether chronic transfusion could be safely discontinued in patients with normalized TCD velocities. Patients were enrolled at 13 STOP sites and stratified by baseline TCD and transfusion duration. Trial stopped early after 14 primary events in the discontinuation arm vs 0 in the continuation arm.

Interventions and follow up

Arm A: Continue chronic transfusion (target HbS <30%)
Arm B: Discontinue transfusion (observation)
Primary endpoint: First stroke or TCD reversion to ≥200 cm/s on two measurement
mFollow up: 18 months (median; stopped early)

Results

Primary events: 14 events in discontinuation group (2 strokes + 12 TCD reverted to ≥200 cm/s) vs 0 events in continuation group, P=.002
Median time to TCD reversion: 4.3 months in discontinuation arm

Adverse events

Main adverse events: Continuation arm: ongoing iron overload and alloimmunization risk from continued transfusions. Discontinuation arm: 2 clinical strokes, 12 TCD reverts. Median time to reversion was rapid (4.3 months), indicating quick loss of protection on stopping transfusions.

Conclusions

Discontinuing chronic transfusions in SCD patients with previously normalized TCD resulted in rapid TCD reversion and stroke events, establishing that transfusions must not be abruptly discontinued without a validated transition strategy (e.g., hydroxyurea).

Key Limitations

Key Limitations: Small sample size (n=79); stopped early, limiting long-term inference. No hydroxyurea transition arm evaluated. Patients selected only if TCD had previously normalized (excludes those who never normalize). No comparison of iron burden between arms. The rapid reversion (4.3 months median) may limit generalizability to patients with less severe underlying vasculopathy.

Clinical Context

STOP=.2 definitively established that abrupt transfusion discontinuation in SCD is unsafe. Current ASH/NCCN/BSH guidelines advise against transfusion discontinuation without a hydroxyurea transition strategy. TWiTCH (2016) later showed that gradual transition to hydroxyurea (while tapering transfusions) is non-inferior to continuing transfusions for maintaining normal TCD, providing the exit strategy that STOP=.2 demonstrated was needed.

References

References: Adams RJ et al, NEJM 2005 (STOP=.2 primary)