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Serious about AML

While one little boy dons wacky hats and dreams of four-wheelers and mud pits, scientists and clinicians at St. Jude search for new ways to vanquish high-risk acute myeloid leukemia.

Patient Aiden

To look at Aiden Walley—with his constellation of freckles and silly hats—it’s hard to fathom that this 7-year-old is locked in a battle with an aggressive case of acute myeloid leukemia.

Ask 7-year-old Aiden Walley about his interests, and you’re in for an earful. He loves riding four-wheelers. Hunting with his daddy. Playing in the dirt. But for the past few years, he has had to limit those activities in lieu of other pursuits: Traveling to medical appointments. Enduring chemotherapy and radiation treatments. Undergoing three—yes, three—bone marrow transplants.

This rough-and-tumble boy with an ever-present smile and a silly disposition has been locked in a battle with an aggressive form of acute myeloid leukemia (AML).

In January of 2013—just four months after Aiden completed his initial treatment—the leukemia returned with a vengeance. The cancer persisted through two transplants, the second using blood stem cells from his mom. In October of 2014, Aiden had a third transplant. This time, his immune system was wiped out and replaced with stem cells from his grandmother.

 “It’s hard to understand how some leukemias can survive chemotherapy, radiation therapy and a new immune system,” says oncologist Jeffrey Rubnitz, MD, PhD, of St. Jude Children’s Research Hospital. “When leukemia survives transplant, you know it’s extremely resistant to treatment.”


After nearly three years at St. Jude, Aiden continues his battle with AML.


“The mutations would sneak up.”

Something had to be done.

Hiroto Inaba, PhD, St. Jude oncologist

Inspired by St. Jude patients like Aiden, Rubnitz and his colleagues are working to find a cure for AML that has either failed to go into remission after treatment or has returned after therapy.

A novel approach

AML is generally more difficult to treat than the most common childhood cancer, acute lymphoblastic leukemia (ALL). The survival rates reflect that dichotomy. AML has a 70 percent survival, compared to 94 percent for ALL. About 30 percent of children with AML relapse or have disease that is refractory (resistant to treatment). For those children, the prognosis is grim.

Before his third transplant, Aiden took part in a clinical trial designed to find out if a new drug called selinexor is safe and if it can benefit young AML patients. Selinexor is combined with two chemotherapy drugs with equally cumbersome names: fludarabine and cytarabine.

“Selinexor works by a mechanism that is totally different than any other drug used for cancer,” Rubnitz says.

Cancer is caused by the uncontrolled growth of cells. One way these cells flourish is by getting rid of tumor suppressor proteins—molecules that would normally cause cancer cells to die. Selinexor traps those proteins inside the nucleus of each cell, which may cause the cancer cell to stop growing or die.

 “This drug restores the leukemia cell to a more normal state, which, we hope, will make those cells more susceptible to standard chemotherapy,” Rubnitz explains.

The triple-drug combo is one of three new approaches developed at St. Jude for children with high-risk AML.

Taking aim at a mutated gene

A second clinical trial is designed for children who have a mutation, or change, in a gene called FLT3. Ten to 15 percent of children with AML have this mutation, which helps leukemia cells thwart the effects of standard AML chemotherapy.

 “This mutation makes leukemia cells grow rapidly,” explains St. Jude oncologist Hiroto Inaba, MD, PhD.

“For years, we gave chemo, chemo, chemo, and the disease would come back even after transplant,” Inaba says. “In our previous St. Jude protocol, we found that a drug called sorafenib is effective against leukemia cells that have this mutation.”

Jeffrey Rubnitz, MD, with a patient

Jeffrey Rubnitz, MD, PhD, of St. Jude Oncology, talks with John Michael Martinez, as the 11-year-old prepares for his third transplant. John Michael took part in a new clinical trial designed to find out if a drug called selinexor is safe and if it can benefit patients with AML.

However, six months to a year after taking sorafenib, children with the FLT3 mutation would often acquire more genetic changes.

“The mutations would sneak up,” Inaba says.

Something had to be done.

Inaba teamed with Sharyn Baker, PharmD, PhD, and Eric Zimmerman, PhD, both of St. Jude Pharmaceutical Sciences. They found that an experimental drug called crenolanib prevents the growth and survival of AML cells with the mutation. Scientists suspect that crenolanib also blocks leukemia cells that aquire additional mutations after exposure to sorafenib.

Crenolanib has been used to treat pediatric brain tumors, but it has never before been used against pediatric AML. The current clinical trial combines crenolanib with sorafenib to deliver what Inaba and his colleagues hope is a one-two punch to leukemia in children with the FLT3 mutation.

Tanja Gruber, MD, PhD

Tanja Gruber, MD, PhD, of St. Jude Oncology is developing a clinical trial for relapsed AML. In the lab, she discovered a drug combo that is effective for AML patients with rearrangements of the MLL gene.

New options on the horizon

Two new options are in the works for children with relapsed or refractory AML.

One clinical trial involves a process called micro-transplantation, in which chemotherapy is followed by an infusion of peripheral blood stem cells from a donor.

“When the patient mounts an immune response to reject those stem cells, the activation of the immune system may attack the leukemia cells, as well,” Rubnitz says. “So you’re activating the patient’s own immune system as well as the donor’s immune system. It seems to have a very potent anti-leukemic effect.”

Research indicates that response rates to micro-transplantation are good, the toxicity is low, and the patients rebound more quickly than in regimens that include chemotherapy alone.

“We’re very excited about it,” Rubnitz says.

Tanja Gruber, MD, PhD, of St. Jude Oncology is also working on a clinical trial for relapsed AML based on research in her lab. Gruber’s work suggests that, when given along with chemotherapy, two drugs called bortezomib and vorinostat are effective for AML patients who have rearrangements of a gene called MLL.

“It will be nice to have four options for patients with relapsed AML,” Rubnitz says. He emphasizes, however, that stem cell transplantation remains the gold standard for treating relapsed AML.

Hiroto Inaba, MD, PhD; Eric Zimmerman, PhD; Sharyn Baker, PharmD, PhD

Hiroto Inaba, MD, PhD (at left), of St. Jude Oncology has teamed up with Eric Zimmerman, PhD, and Sharyn Baker, PharmD, PhD, of Pharmaceutical Sciences to develop new options for children with AML who have a mutation in the FLT3 gene. 

We want to get these patients to transplant safely with very low levels of disease.

Jeffrey Rubnitz, MD, PhD, St. Jude oncologist

“Our goal in all of these therapies is to safely get these patients into remission so they can then receive stem cell transplants and be cured,” Rubnitz says. “In general, the more leukemia a child has going into transplant, the higher the chance of relapse afterward. So we want to get these patients to transplant safely with very low levels of disease.”

Seize the day

After nearly three years at St. Jude, Aiden continues his battle with AML.

The most challenging part of their journey has not been the distance from home—though it has been difficult. It has not been the treatment—though the therapy has been grueling at times.

“The most difficult thing you go through,” Anna says, “is just knowing your child has cancer. If Aiden weren’t bald, you’d probably never know he had cancer. He tires out now more than he did in the beginning, but if you give him a nap and he catches his second wind, he’s good to go.

“You have to just take it as you go,” she continues. “You take your good days and run with ’em.”

Abridged from Promise, Spring 2015

Editor's note: Aiden lost his battle with AML November 2015.

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