I've updated from X3 32-bit to X3 64-bit.
Since I've just done so, whenever I put an audio region fx (melodyne, V-Vocal) onto a clip, the audio engine drops out and I can't start playback.  I remove the region FX and I still can't play the project back until I restart Sonar.
 
Any ideas?
I have the same settings as I did in 32-bit.

But you are not saying anything about your computer specs which would be a big help in this case. As it sounds like your straining your system. 
Example, my computer is a little sad, 2 cores @ 2.5 Mz and only 4 Gigs of RAM. I can use V Vocal on a 1 bar segment fine, but if the section is 4 bars it will bomb.  

Ah sorry :(
Windows 7 (x64).
16GB ram.
AMD Phenom II x6 1100T Processory 3.30Ghz
 
I have a Lynx Aurora 16 interface with a Lynx AES16 card.
 
Hard drive is at 28% throughput capacity at the time of the clip in particular.  46% filled.
 
My soundcard buffer is set to 1024.
 
Project is 48k.
32 or so tracks.
 
Without region FX, things are smooth and my system isn't pressed at all.
I've mixed muuuuch bigger projects in 32-bit with Melodyne not skipping a beat.
I tried to up the read-buffers from 512 to 1024 as Celemony suggests, but nothing changed.  I didn't have any buffer issues before.

Wow, you shouldn't be having issues with that kind of system?? Lynx are the best etc. 
 
One thing is to run the DPCLAT test. 
 
http://www.thesycon.de/deu/latency_check.shtml

No idea what that is at the moment but I'll read up on it and report back once I'm able to run it!

It tests your computer system for it's ability to stream audio without interruption from background processing. Laptops are real bad for this. It's all about having a computer that is optimized for audio. 
There is other stuff too like core parking etc. Green Hard drives that fall asleep on you.. using a clean 7200 RPM Hard drive, but this is all par for the course. 

I've tried the region FX on other projects.  One in particular was very very similar.  I was able to use Melodyne on it without issue.

So it's just this ONE project (thus far).
I'm going to start removing plugs I guess.

Anyone know of what could cause this on a certain project?

Okie... no word of a lie.
I start debugging by saving a new session file (new name).  Eventually I remove all FX from my vocal track.Melodyne works.
 
So I go back to my actual session, drag all the fx to another track's bin....and BAM melodyne works.
Drag them back, and melodyne continues to work.
 
No idea what happened, why it's different, or the reasoning behind the continuous issues I had for an hour earlier today.  Bummer.... but good... ?