Nicieza will depart DC Comics' New 52 title after issue #6 due to a scheduling conflict.
"His schedule just couldn't keep up with a monthly series right now," said series editor Brian Cunningham on the publisher's official blog The Source.
"It's a bummer because Fabian and I had discussed some really cool ideas for the series, but I understood his reasons, and we parted on a positive note with hopes that someday we can reteam on something else down the road."
DC teased some of the ideas DeFalco has for his run, including a Teen Titans crossover, a leadership struggle and a traitor in the team's midst.
DeFalco is best known for his work on Marvel Comics' Spider-Man.
Legion Lost sees a group of Legion of Super-Heroes members trapped in the present day with a deadly virus from the future threatening the planet.
Legion Lost #4 will be released on December 14.