The big four are Kamuzu Barracks, Adams FC, Support Battalion and Airborne Rangers.
Adams, who have finished as league runners-up, lost 2-0 to Kungoni Stars whereas Support Battalion lost 3-1 to Airborne Rangers in the first round.
Airborne, who are fighting for the third slot with Support Battalion were beaten by Madisi Medicals 4-1 in the second round.
League champions Kamuzu Barracks (KB) were the last to be shown the exit.
KB, who will join the Super League this season lost 4-2 to Division One Alinafe Medicals in penalties in the PIS regional quarter-finals.
CRFL chairperson Dean Josiah Banda said the development is a clear sign of stiff competition in the region.
“As far as Central Region standard of football is concerned, there is no gap between teams from the Premier Division and Division One. Of course, the game is now in the youth,” said Banda.
He cautioned the senior teams not to underrate junior teams to avoid being humiliated.
KB coach Kenwood Nkhoma blamed their defeat on uncertainty of fixtures which made them fail to prepare well.
Meanwhile, Alinafe Medicals will play Kasungu Police in the semi-finals whereas Green Rangers will meet Blue Eagles Youth.