Louis Gossett Jr. played 6 performances as Billy Flynn in Chicago before departing due to asthma.
Jeremy Piven abruptly left Speed the Plow due to... sushi
My favorite coincidence is Craig Bierko in Matilda and Jeffrey Tambor in La Cage. Both left abruptly, and were first replaced by their understudy, Chris Hoch, before being permanently replaced by Christopher Sieber.
Additionally, I saw Joan Jett in Rocky Horror, she was at best underwhelming and miscast. If I recall correctly Daphne said in an interview somewhere that she had to teach Joan backstage etiquette, including tipping her dresser. I do however love the lowered keys for Columbia on the cast recording with Kristen Lee Kelly.
"Grease," the fourth revival of the season, is the worst show in the history of theater and represents an unparalleled assault on Western civilization and its values. - Michael Reidel