Femur registration, attempt to register without the follow-up segmented ROI.
Attempted the following scenario:
baseline Target+ROI (WALS1)  is registered with the Source WALS2 only (no ROI).

Mutual Info measure was used.  On the screenshot below you can see the WALS2 registered and then overlayed with the WALS1-ROI.  Visually appears to be a good match.
This makes it very likely that follow-up ROI would not be required for registration.

One downside - it took about 20 min, vs.  5 min on ROI->ROI scenario.

WALS2 (transformed after registration) overlayed by the WLAS1-ROI (static as the Target)