This question had been nagging me for a few years when I recently stumbled upon this thread.
I just found it to be a remarkable coincidence that two similarly named companies from the same City would make almost identical card sets but that one would be a full year earlier than the other. Not that it wasn't possible, but it just seemed strange, and I wondered whether the two companies were maybe affiliated and released similar cards under different brands.
Anyway, I tried to find some information on the companies themselves and, maybe this is a doozy?
From page
681 from the History of Lancaster County, PA
In case the image doesn't come through, two points:
1. National Caramel Company wasn't incorporated until May 1921
2. The founders of National Caramel were both Executives at American Caramel until they left and started the competitor in 1921.
Now, does this mean that E220 wasn't a 1921 release? No, but boy it sure does tighten up that window.
It may also give insight into the similarities behind the cards. Not unreasonable to think that these American Caramel executives were well aware of the E121 cards, knew what it took to design and produce and simply took that concept with them over to National Caramel for their own E220. That would start to explain the visual/design similarities between the two sets.
Less charitably: I don't think it is a stretch to say that National Caramel stole the American Caramel idea -- and very possibly photos, designs, printers etc. -- and copied it for themselves.
This assumption would make it especially odd that a player like Stan Coveleski would have a card with identical photos in E121-120 and E220 but NOT E121-80. Same with Herb Pennock. I find it far more likely that those E121-120 cards were issued in the same year as E220, on the basis that the American Caramel Executives that were involved with the one left the company and moved to the other. It certainly didn't happen the other way around.
Anyway, food for thought (or something to chew on

) in an old thread.