A321 was an stretched version of an A320 designed for short sectors with high volume (read Europe only ), if you have this type of market it would be very good.
But if you use it on routes longer than 3 hrs. the altitude capability on a heavy load is poor (310 to 340 the most) so this will have an impact on fuel flow.
757 has the flexibility to be operated on short sectors with a fuel penalty certainly, but will be able to operate in a lot more demanding environtment, longer routes,high altitude etc.... It is a shame that it came at a wrong time a 757 airframe with newer engines would have done a great airplane....
My vote goes to 757 (of course I am a pilot, not an accountant)