All parents believe their babies are exceptional. But when doctors at a respected medical center told Dustin and Crystal Ellwood their daughter was the “rarest of the rare,” their hearts did not soar with happiness. Four-year-old Stella had an extremely uncommon form of cancer called acute megakaryoblastic leukemia, or AMKL.
The day before Stella was scheduled to start treatment, the Ellwoods asked the oncologist a simple question: “How many children with this subtype have you taken care of?”
The physician responded, “Well, honestly, none.”
Upon learning that St. Jude Children’s Research Hospital had extensive experience treating children with this type of leukemia, the family obtained a referral. Within 24 hours, they were on a plane to Memphis, Tennessee.
“If we’ve got the rarest of the rare and nobody knows much about it, we want to go to a place that’s thinking outside the box and doing research,” Dustin explains. “As St. Jude helps Stella, the research they do will help others, as well. We felt 100 times more comfortable coming here.”
Tackling the toughest cases
Since 1962, St. Jude clinicians and researchers have made dramatic progress in increasing the survival rates for childhood leukemias. But despite their best efforts, some children still die of their disease. Teams of scientists at St. Jude are working nonstop to find cures for those children, many of whom have rare subtypes that do not respond to chemotherapy.
“In 2012, we identified a fusion gene that had a poor prognosis,” Gruber recalls, referring to a gene that is created when pieces of broken genes fuse together. “But we were still left with a lot of cases for which we didn’t know the underlying genetic cause of the cancer.”
To increase the amount of available data, Gruber led the world’s largest study of the genetic changes that cause AMKL.
In the past, clinicians assumed that bone marrow transplants were required to cure AMKL. But a transplant also has risks, as the immune system is wiped out and replaced with donor cells.
Gruber and her team found several genetic alterations that can help determine which children will likely be cured with chemotherapy alone and which ones must have blood stem cell transplants. A lab test can show whether a child has one of three particular fusion genes. If the test is negative, then that child can likely be cured by chemotherapy alone. If the test is positive, the child requires a transplant.
“All institutions can now take this prognostic data and act on it,” Gruber says.
Motivation, inspiration, collaboration
When Gruber arrived at St. Jude in 2009, she had already conducted research on a high-risk subtype of acute lymphoblastic leukemia (ALL) called Philadelphia chromosome-positive ALL. At St. Jude, she turned her sights to infant ALL, identifying drugs and designing therapies for babies with a subtype called MLL-R. Eventually, her research expanded to AMKL.
“I’ve always been interested in high-risk subtypes,” says Gruber, who notes that more than 25 AML subtypes have been identified thus far.
“When you take care of high-risk patients in the clinic and they do not do well, it motivates you to work harder,” she explains. “If I lose a patient, I take it as a personal failure. I know intellectually you’re not supposed to do that, but it makes me want to work even harder.”
This year, Gruber will head a new AML clinical trial. Patients from 10 institutions will have their genes sequenced so clinicians can identify which mutations are present. Gruber says she hopes the study will shed even more light on AML and its subtypes.
In addition, the hospital is developing a St. Jude-funded clinical research consortium to create international clinical trials for children with high-risk leukemias and other rare diseases.
“Each institution might see only a couple of cases a year, so nobody makes progress toward cures,” says James R. Downing, MD, St. Jude president and chief executive officer. “But with this coordinated approach, we can make that progress.”
New insights into rare leukemias
Only a small number of children have the form of AML Stella has. Another subtype, known as core-binding factor acute myeloid leukemia (CBF-AML), accounts for about 20 percent of childhood AML cases. Recently an international team headed by St. Jude scientists created a detailed map of the genetic variations that drive CBF-AML.
Researchers had already identified two genes affected by chromosomal rearrangements in CBF-AML. Until recently, scientists did not know what other mutations worked with those rearrangements to cause disease.
Jeffery Klco, MD, PhD, of St. Jude Pathology, teamed up with Downing; St. Jude Computational Biology Chair Jinghui Zhang, PhD; and other scientists to identify the genetic changes that contribute to this cancer.
The findings were an outgrowth of the St. Jude – Washington University Pediatric Cancer Genome Project, an unprecedented initiative to uncover the genetic origins of childhood cancer.
“This study highlights how the Pediatric Cancer Genome Project continues to generate new insights into genetic alterations and cooperating mutations that give rise to diseases like AML,” Downing says.
Scientists are already at work to determine the precise roles of the genetic changes discovered as part of that study.
Homing in on ALL
As teams of researchers toil to solve the mysteries of AML, scientists in nearby labs and clinics study rare ALL subtypes. ALL is the most common childhood cancer, so even though its overall survival rate is 94%, it remains one of the top causes of childhood cancer deaths. The 6% of children who are not cured often have high-risk subtypes or have disease that is initially identified as standard-risk and yet fails to respond to treatment.
“Every person is important, so obviously we want to cure every child with ALL,” says St. Jude pathologist Charles Mullighan, MD, MBBS, who has spent most of his career identifying new subtypes of the disease. His work has led to many new approaches to diagnosis and therapy, with several of his discoveries incorporated into precision medicine trials.
Last fall, the American Society of Hematology honored Mullighan for his success in providing insights into the genetic basis of ALL, particularly high- risk forms of the disease.
And yet, for all his expertise even Mullighan cannot yet identify exactly how many high-risk subtypes are in existence.
“There’s still an appreciable chunk of leukemia cases—both in children and adults—that don’t fall into one of the subgroups historically defined by conventional methods,” says Mullighan, who predicts the main subtypes of ALL will soon be mapped.
“There will always be more to learn,” he says. “You’ll always find another gene or another type of mutation or another fusion partner, but the overall grouping will be largely resolved in the next year or two as some very large studies come to completion.”
The best place
Mullighan and his colleagues have experienced great success in uncovering new information about high-risk subtypes.
Last October, Mullighan led an international team that discovered the genetic origins of one subtype of B-precursor ALL. The researchers described a unique mechanism showing how one genetic change or rearrangement—in this case, a gene called DUX4—can trigger another change in regulation of a second gene, ERG, which then results in leukemia. That paper is the culmination of research Mullighan began when he was a postdoctoral fellow in 2004.
“The study highlights the importance of detailed genetic study to fully understand how the disease develops,” he says. “While we advanced our understanding over several years, it wasn’t until the advent of genome sequencing that we could crack the case.”
A month after that paper published, he and his colleagues revealed new details about a new, high-risk ALL subtype called MEF2D-rearranged ALL. The team also found a promising targeted therapy for patients with that disease.
Also in November of 2016, Mullighan’s lab announced that the prevalence of Ph-like ALL remains high among adults of all ages with ALL. The researchers found that the outcome for these patients may be improved by using medications that are already available.
Mullighan says he’s in the best place to make those kinds of discoveries.
“St. Jude offers the perfect convergence of opportunity and resources and expertise,” he explains. “There’s the hospital’s mission and its strategic direction; the infrastructure and resources; the historic biorepository of tumor samples; our leading role in frontline leukemia trials; our collaborations with investigators around the world; and our culture of very careful annotation, follow-up and uniform treatment of children with leukemia.
“Those things are often done elsewhere,” he adds, “but it’s rare that everything is under the same roof like it is here.”
Reasons for the research
All of those discoveries are occurring on the same campus where Stella Ellwood is pursuing equally important activities.
While she’s fighting for her life, she’s making jewelry and painting pictures. Reading books and playing practical jokes on her mommy. Swinging on the playground and playing dress-up. Making plans to be a pediatrician when she grows up.
If all goes according to schedule, Stella will undergo a bone marrow transplant in the summer of 2017. Then this bright and intelligent little girl will return home to Maryland with her loving family—who have always known, after all, that Stella truly is the rarest of the rare.
From Promise, Spring 2017