When 16-month-old Graham Robertson began taking two naps per day and eating a bit less, Holly and Colby Robertson took note, but their son otherwise seemed fine. Then one day during a grocery outing, Graham pinched his finger and tried to scream, but passed out instead.
“That was our big sign something was wrong,” Holly says.
The couple rushed Graham to the Children’s Hospital at Saint Francis in Tulsa, Oklahoma, a clinic affiliated with St. Jude Children’s Research Hospital.
“They said Graham had a rare leukemia,” Holly recalls, “and flew us to Memphis two days later.”
Conferring about cures
Jeffrey Rubnitz, MD, PhD (at left), and Thomas Alexander, MD, joined Hiroto Inaba, MD, PhD, and Charles Mullighan, MD, MBBS, in discovering the genetic basis of mixed-phenotype acute leukemia.
Kaleidoscope of features
Graham had mixed-phenotype acute leukemia (MPAL), a subtype that accounts for only 2% to 3% of all acute leukemia cases.
The best treatment for MPAL has puzzled the medical community because the disease has aspects of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Just as a chameleon morphs from blue to green, the features of MPAL can change with time or treatment, enough to switch the diagnosis from one acute leukemia to the other.
Long-term survival for children with MPAL is 50% to 75%, compared with about 94% for ALL and 65% to 75% for AML.
“Selecting the right treatment is important,” says St. Jude oncologist Hiroto Inaba, MD, PhD. “If we treat ALL with AML therapy or vice versa, patients do not do as well as we would hope.”
ALL treatment involves less intensive chemotherapy for two to two-and-a-half years. By contrast, AML treatment requires more intensive chemotherapy over about six months. About a third of children with AML require bone marrow transplants.
Chuckles, giggles and grins
Three-year-old Graham Robertson shares a laugh with his clinical fellow, Dave Cervi, DO, PhD.
Finding the best treatment
When the Robertsons arrived at St. Jude in August 2016, Inaba and other investigators were already collaborating on an international study examining whether patients with MPAL experienced better survival rates with ALL or AML therapy. The data, published in the journal Blood, indicated outcomes were superior with treatment traditionally used for ALL.
Jeffrey Rubnitz, MD, PhD, chief of the St. Jude Leukemia/Lymphoma Division, started Graham on ALL therapy.
“We were scared, but Dr. Rubnitz gave us confidence,” Colby says. “He told us to take things one step at a time with the less-invasive approach and see how Graham responds.”
True colors
In another international study, St. Jude researchers including Inaba; Rubnitz; pathologist Charles Mullighan, MD, MBBS; former clinical fellow Thomas Alexander, MD, and others helped uncover the genetic underpinnings of MPAL.
“We discovered progenitor cells that can turn into either myeloid or lymphoid cells,” Mullighan says. These newly identified “immature” blood stem cells explain why MPAL cancer cells can have both myeloid and lymphoid features.
In a 2018 paper, published in the journal Nature, the investigators also reported genetic mutations defining the two most common subtypes of MPAL called B/myeloid and T/myeloid. Until this study, the genetic basis of these subtypes had been unknown.
The scientists found that some children with MPAL may benefit from targeted therapies already in existence.
“We see only two or three cases of MPAL each year at St. Jude,” Inaba says. “Through these internal and international collaborations, we have been able to conduct much larger studies and discover important insights to help us optimize treatment plans for these children.”
As a result of this study, St. Jude will continue its collaborations with the Children’s Oncology Group, which is formally examining MPAL outcomes using ALL therapy and its relationship to genomic features. Researchers have also proposed updating World Health Organization’s classifications of acute leukemia to include three new MPAL subtypes, including the two identified in this study.
Graham had B/myeloid MPAL with an MLL gene rearrangement. A couple of months after he began ALL therapy, his minimal residual disease was negative, confirming Graham was on the best treatment path.
The researchers identified genetic mutations defining the two most common subtypes of MPAL. Until this study, the genetic basis of these subtypes had been unknown.
Bright future
Graham receives weekly treatments in Oklahoma, at the St. Jude Affiliate Clinic at The Children’s Hospital at Saint Francis. He returns to Memphis for milestone checkups. Soon, his 120 weeks of ALL therapy should be complete. With the cancer in remission, Graham’s prognosis is promising.
Like many 3-year-olds, Graham has a big imagination. When he’s at St. Jude, he likes to wave to the statue of hospital founder Danny Thomas. At home, he “cooks” for his parents with toy vegetables and sings “Johnny B. Goode” while playing his toy guitar.
Thanks to St. Jude international research, more children like Graham with rare, high-risk leukemias are getting back to their lives and looking forward to more promising futures.
As Chuck Berry might have sung, “Go, Graham, go, go!”
What is mixed-phenotype acute leukemia?
Mixed-phenotype acute leukemia (MPAL) incorporates features of two forms of leukemia: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The term “mixed phenotype” means “both types.”
- MPAL is rare: Only 2-3% of all acute leukemia cases are MPAL.
- It can change from MPAL to AML or ALL, or vice versa.
- It grows very quickly.
- It can be hard to treat.
- The survival rate is 50–75%, compared with about 94% for acute lymphoblastic leukemia.
- St. Jude scientists recently discovered the mutations that cause MPAL’s two most common subtypes.
- The mutations occur early in blood cell development.
- Researchers from St. Jude also found why MPAL has both myeloid and lymphoid features.
- Based on these findings, clinicians will be able to design more effective treatments for children with MPAL.
More articles from this issue
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Sharing Smiles
Delta Dental and the Smile180 Foundation have donated $2 million to support St. Jude treatment, research and awareness.
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Science Alliance: Fighting PKAN Together
Married St. Jude researchers broaden their collaboration to develop a novel medication for pantothenate kinase-associated neurodegeneration (PKAN), a life-threatening neurological disorder.
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St. Jude and WHO Unite to Save Lives
The greatest predictor of survival for a child with cancer is where that child happens to live. St. Jude and World Health Organization join forces to change that sobering fact.
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Flu Fighters: How the Immune System Protects Infants from Influenza
St. Jude investigators discover how guardian T cells help combat influenza in infants and young children.
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Dance of the T Cells
A new therapy at St. Jude called CAR T-cell therapy holds hope for many children who have cancer that returns or is hard to treat.
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Dawn of a New Era for Aggressive Brain Tumors
Relapsed brain tumors have been difficult to treat, but a new approach at St. Jude offers a ray of hope.
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Cryo-EM: It’s a Small, Small World
Scientists in the new St. Jude Cryo-EM and Tomography Center zoom in on staggeringly small structures to better understand biological systems.
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Touchdown, St. Jude
Football stars from Lausanne Collegiate School turn fundraising champs for the hospital by winning the 2018 Touchdowns Against Cancer national championship.
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Run for a Reason
More than 26,000 runners and walkers recently laced up their shoes for the 2018 St. Jude Memphis Marathon Weekend, the largest single-day fundraising event for St. Jude.
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Research Highlights - Winter 2019
Learn about whole genome sequencing; the Hippo pathway; scavenger immune cells; tumor suppressor gene SPOP; free acute leukemia models; and more.