The loss still rings in Leo's ears, like a stiff jab to the side of the head, because his father and trainer, Jose Santa Cruz Sr., missed out on critical weeks of training and preparing Leo. Jose, sitting ringside, is battling the ultimate body blow -- cancer.
"When I first found out he had cancer I cried; I imagined myself suffering," Leo Santa Cruz told CNN. "They say when you have cancer it's very hard to defeat it."
Jose managed to climb up ringside to watch his son fight Northern Ireland's dangerous Frampton, but Leo believes he suffered without the constant pushing he usually got from his dad.
Jose got knocked down by what the family called stage III multiple myeloma and renal failure. After his April 2016 diagnosis, the family said, a spinal disc collapsed, requiring reconstructive spine surgery in May 2016. Radiation followed and two types of chemotherapy.
Jose is now in remission, but still getting one form of the chemotherapy.
"The toughest part right now physically is the chemotherapy, because it comes with a lot of side effects," Jose explained to CNN through an interpreter. "I'm suffering from having a swollen stomach and my feet feel like they are on fire. But (I) have not been afraid of the cancer."
Fearless defines the Santa Cruz family, originally from Michoacán, Mexico, and now living in and around neighborhoods east of Los Angeles. Jose and his wife, Elodia, have four sons and a daughter.
The youngest, Leo, 28 years old, remembers being so poor that they took a bus to boxing training because they couldn't afford to put gas in the car.
Leo slugged his way to millions of dollars in the boxing ring and his dad now drives a Corvette.
When Leo fights Frampton at the MGM Grand hotel in Las Vegas on January 28, they will introduce him as "El Terremoto" -- "the earthquake" in Spanish. Frampton is called "The Jackal."
The fighters, both around 125 pounds, deliver and receive blows in an era when many boxers plod around the ring refusing to mix it up at the risk of getting hit hard.
"I am really training hard for the rematch, for all the fans that I let down in the first fight," said Leo at his La Puente training facility.
"I want to tell (fans) thank you, I am going to try to give them the best fight and the best show, as long as I can. As long as my body is able."
Leo is the superstar among the boxers training inside the gym, but you wouldn't know it. There's no bling, no pre-fight boasting -- just tireless effort with jump ropes, speed bags, heavy bags and sparring. Jose simulates punches and chirps commands to Leo as he spars with his brother, Antonio.
The father stops only when a nurse walks up to him ringside and delivers a sharp reminder of his cancer fight at the end of a needle. The nurse then begins a weekly test and drains blood from Jose's arm.
"He's strong, he's doing well, he's definitely pushing through," said his nurse, Jennae Fischer. "He's driven and he is doing what he has to do to get better."
Jose, who is never seen in public without his cowboy hat, makes an uncharacteristic slip from the family's usual penchant for humility.
"For this fight, I want to make a promise to his (Leo's) audience," says Jose, sitting in the same chair where his blood was just drawn.
"(Leo) is not only going to beat him, he is going to beat him down."