St. Jude patient Graham.

High spirits, high hopes: Thanks to St. Jude research, Graham Robertson and other children with rare, high-risk leukemias have more reasons to smile.

 

A Cancer Chameleon: Mixed-phenotype Acute Leukemia

Is a chameleon blue or green or both? Is a rare leukemia AML or ALL? Mixed-phenotype acute leukemia shows its true colors, thanks to St. Jude research.

 

By Jane Langille; Photos by Seth Dixon

 
 

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.”

Jeffrey Rubnitz, MD, PhD, and Thomas Alexander, MD talk in the hallway.

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.

Patient Graham Robertson laughs with Dave Cervi, DO, PhD.

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.
 
 

From Promise, Winter, 2019

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