I did originally have my camapign run under the assumption that the ToT had occured, though I used or ignored novelized canon as appropriate, and in fact, changed when certain events occured in the timeline to better offer options for the PCs to get involved in "interesting events."
However, as time went on, most of the directions that the Realms went in after the ToT were not to my liking, let alone the constant edition revisiting of places where there was already a perfectly functional sub-setting with good adventure hooks. I never followed canon slavishly anyway, but most products after the ToT that didn't explore a new area in detail had limited use to me.
In the end, I used the ToT as the lynchpin in the main villains' plans, and in fact if the PCs undid their plots correctly (which they did), they would undo a lot of the recent history of the Realms, both good and bad. Which they did.
My next campaigns will be starting back with the Grey Box.
The really important changes in my opinion would be:
Less "Wars among the Gods" which lead to RSEs, and instead more struggles between followers of the gods.
(Especially less god conflicts which made no sense AT ALL.)
More flavors of gods of evil, rather than trying to stuff them all into one super-package. Opens up more opportunity for alliances of convenience between PCs and evil faiths to stymie other evil faiths.
Many organizations and groups retaining their original flavor:
Red Wizards as infighting power mongers rather than magic merchants; Zhentil Keep being an actual power group rather than a laughing stock of evil in a ruin; the various merchant and power seeking groups actually involved in intrigues that the PCs can get involved in; More stable countries/cities that PCs can get attached to as a home base and fight to protect rather than just another pustulent boil of corruption that will get sacked, or bombed with meteors, or have it's entire flavor writeup changed at a whim because someone needed an excuse to steal an idea from a different TSR campaign product that never got published.
I think the biggest benefit is because their wouldn't be a chain reaction of RSEs, it becomes easier to run campaigns of any level and focus - from diplomatic intrigue, to guild wars, to honest to goodness wars, to basic frontier exploration and dungeon delves into ancient ruins without needing to feel some strange and unreasoning obligation to get the PCs involved in the Cataclysm of the Week.
In addition, a lot of really entertaining and interesting NPCs from the Grey Box and 1E supplements got almost summarily written off by the ToT almost before you got to use them, if you are going by canon. Not having the ToT means you have a lot more interesting people around to play off against or join with your PCs.
