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Research
They’ve boosted AML survival to an all-time high, but St. Jude investigators hunger for even sweeter statistics.
Amid the organized chaos of a hospital emergency room, Nate Litchfield and Lindsey Martin perched on uncomfortable plastic chairs. Cradling their feverish infant, the couple glanced upward at a movie on TV.
Through the din of conversations and clattering equipment, they listened as Forrest Gump shared his familiar park-bench philosophy.
“My momma always said, ‘Life was like a box of chocolates,’” Gump drawled. “‘You never know what you’re gonna get.’”
Seemingly on cue, a doctor strode into the cubicle and informed the couple that their daughter did not have the urinary tract infection they originally suspected. She had leukemia.
Five months later, Lindsey still winces at the timing of the announcement. “It seemed so unreal,” she recalls.
During the preceding weekend, 3-month-old Adele Litchfield had exhibited a mild eye infection, a worrisome rash and a fever that would peak and then recede. “Every time her temperature went down, we’d think, ‘OK, it’s passing,’” Nate recalls.
In reality, it would be their first taste of an extremely serious illness. Adele had acute myeloid leukemia (AML), a cancer of the blood and bone marrow. Although nearly 12,000 new cases of AML occur in the United States each year, only about 500 of those are in children and adolescents.
AML originates in cells that normally develop into white blood cells. Healthy infants have fewer than 15,000 white blood cells per microliter of blood. Adele had more than 250,000. “We need to act fast,” the ER physician told the family. “We’re going to get you in an ambulance and send you to St. Jude Children’s Research Hospital.”
Soon after Adele arrived in Memphis, the hospital announced the results of its most recent AML clinical trial. In a study conducted at St. Jude and six other hospitals, investigators had pushed the pediatric AML survival rate to 71 percent three years after diagnosis—a rate 20 percent higher than previously reported U.S. rates.
During the preceding years, the overall survival of St. Jude AML patients had risen from 33 percent in the 1980s to 55 percent in the 1990s. In 2000, scientists began designing a clinical trial that they hoped would boost the rates even further.
Known as AML02, the study became the hospital’s first multi-institutional leukemia trial. In addition to obtaining large amounts of patient data, the collaboration allowed St. Jude clinicians and laboratory scientists to create and enhance relationships with their peers at other cancer centers.
One chief limitation in planning AML02 was the scarcity of new medications to fight AML. Drug development is a slow and laborious process—a fact that is exacerbated by the rarity of the disease in children.
“We were limited in what we could do in terms of new therapies, because only one new agent had been developed that we felt comfortable using in children,” recalls Jeffrey Rubnitz, MD, PhD, of St. Jude Oncology.
The team optimized the use of conventional drugs and added a new medication for certain patients who did not respond to traditional therapy. Investigators also evaluated genetic information to determine the risk factors for each child.
After each child completed the first or second course of chemotherapy, Dario Campana,
MD, PhD, of St. Jude Oncology and Pathology and his colleagues assessed the patient’s response to therapy based on the presence of minimal residual disease, or MRD. If scientists found even one leukemic cell among 1,000 normal bone marrow cells, clinicians immediately adjusted treatment in an effort to prevent relapse. In previous trials, clinicians had looked at MRD retrospectively, but in this study, samples were sent to Campana’s lab and the results were used to make treatment decisions. As a result, this was the first AML trial to use MRD in real time.
Worldwide, many children have succumbed because of the intensive therapy required to eradicate AML. In the St. Jude clinical trial, investigators focused on improving and optimizing supportive care in hopes of decreasing toxicity, infection rates and inpatient stays. One tactic they used was to administer antibiotics after each course of chemotherapy. In the past, patients had received these medications only after developing fever or other signs of infection.
“This is the first time preventive antibiotics and antifungal agents have been used in a pediatric AML trial,” Rubnitz says. “We found that it decreased admissions to the ICU, decreased infection rates and improved quality of life. We’re very happy with how well it worked. As a result, we’re also using this technique with some of our children after they undergo intensive rounds of chemotherapy for acute lymphoblastic leukemia.”
Tasting success, St. Jude investigators immediately began hungering for even higher survival rates.
AML is difficult to eradicate because it begins with an immature cell known as a stem cell. Originating in the bone marrow, stem cells are designed to survive throughout a person’s lifetime. Because the cells grow slowly, they are unaffected by drugs that disrupt the cell cycle and cell division. These hardy cells are also resistant to natural toxins. AML stem cells share these attributes; they divide slowly and are adept at pumping out toxins and drugs.
“It’s hard to kill leukemic stem cells,” Rubnitz says. “Intense therapy designed to kill them may also kill the healthy stem cells. So we need to devise ways to kill the leukemic stem cell but not the normal stem cell.” Rubnitz says researchers are making progress.
The hospital’s newest protocol, AML08, compares a new drug combination with the conventional medley of medications used to combat AML. Scientists hope the new chemotherapy regimen will enable them to avoid using one particular conventional chemotherapy agent that can cause heart damage. The new protocol is also exploring new markers and methods for detecting MRD.
AML is a disease with many different subtypes. Ideally, scientists would like to devise a specific therapy for each. For instance, some St. Jude patients have mutations in a gene called FLT3, which carries a survival rate of about 30 percent. The new St. Jude clinical trial uses a drug that has been shown to inhibit the FLT protein. “It’s early, but thus far the drug seems to be effective for this particular subtype of leukemia,” Rubnitz says.
The AML08 protocol also incorporates a new form of cellular therapy. In the previous clinical trial, high-risk patients underwent stem cell transplantation. Although this treatment greatly reduces the risk of relapse, it is potentially toxic and depends on donor availability. Currently, St. Jude clinicians recommend transplant only for high-risk AML patients. For some other patients, investigators are now using another form of cellular therapy called natural killer (NK) cell therapy. Scientists have discovered that NK cells are particularly effective at killing AML cells.
St. Jude recently conducted a pilot study testing the safety of NK cell therapy. Clinicians used this treatment on 10 children who were in remission from AML. The therapy consisted of a mild conditioning regimen to suppress the immune system and an infusion of natural killer cells from a parent.
“There was very little toxicity; actually it was much milder therapy than a course of AML chemotherapy,” Rubnitz says.
All 10 patients responded well and are still in remission. As a result, a standard-risk AML patient may now receive chemotherapy as well as an infusion of natural killer cells from a parent. Investigators hope this technique will eliminate any leukemia cells that might be resistant to chemotherapy.
Rubnitz attributes the success of the hospital’s AML studies to a seamless collaboration between the laboratory and the clinic, as well as the treatment team’s expertise. “Everybody in this institution is an expert in taking care of children with cancer,” he says. “From data managers to nurses and nurse practitioners, from postdocs to physicians, this hospital is devoted to pediatric cancer. Our supportive care here is excellent. Our transplant team is outstanding. We have great people and great resources.”
Children like little Adele Litchfield are the direct beneficiaries of that specialization. As soon as she and her parents arrived at St. Jude, the staff leapt into action.
“Everything happened so fast,” Nate recalls. “Almost immediately, they started doing amazing things—replacing her entire blood count twice and starting treatment the next day.”
As they contemplate the past few months—beginning with Forrest Gump’s dogma and continuing through Adele’s remission—Lindsey and Nate are thankful that their box of chocolates has included St. Jude.
“The AML protocol is tough,” Nate admits, “But it has been like a miracle. St. Jude saved her life.”
Reprinted from Promise Autumn 2010
