The family revealed the news on their Facebook page to more than 16,000 supporters of the youngster's campaign.
Margot was diagnosed last year, aged almost 14 months, with both Acute Lymphoblastic Leukaemia (ALL) and Acute Myeloid Leukaemia (AML).
The 'Swab4Margot' campaign to find the perfect stem cell match inspired more than 50,000 to be tested and eventually a match was discovered.
But last month, father Yaser and mother Vicki, originally from Essington, revealed their daughter had suffered a relapse.
But the family's hope it was slight set-back were dashed last week when the family revealed that disease had progressed from a one per cent presence to somewhere between 60 and 80 per cent.
Yaser posted on the 'Team Margot' Facebook page: "Unfortunately, we received some bad news on Friday evening.
"To recap, three weeks ago there was around one per cent of the disease present in the marrow, up from 0.75 per cent a couple of weeks earlier and still only just within the limits of detection - the early stages of relapse.
"Whilst the peripheral blood counts are still OK, the two completed bone marrow tests now show 84 per cent blasts (leukaemia cells) using the microscope and 63 per cent in the FLOW test ie the disease has progressed from one per cent three weeks ago to somewhere between 60-80 per cent."
He continued: "We have another meeting with the doctor tomorrow to discuss the options in person. We quickly need to make a decision on what action to take next.
"It's all so confusing and hard to comprehend because Margot looks and is behaving perfectly normally.
"Yesterday we went to Peppa Pig World. Margot is a huge fan.
"As we drove home, Rufus described it as "the best day ever".
In February a donor was found for the little girl and she underwent treatment at Great Ormond Street Hospital in London.
Margot's diagnosis had sparked a worldwide hunt to find her perfect stem cell match, to which 50,000 people signed up and had been backed by celebrities including Gary Barlow, Stephen Fry and Catherine Tate.