Dr. Jean Sanders has treated children with cancer for 30 years, long enough to know a success story when she sees it. She also knows that it takes awhile to change people's minds about what works.
What works, Sanders announced in a recently published study, is treating infants with acute lymphoblastic leukemia (ALL) in first remission with total-body irradiation followed by a bone-marrow transplant. She and her Clinical Research Division team achieved an unprecedented success rate of 76 percent disease-free survival, reported in the Jan. 6 edition of the journal Blood.
Sanders, director of Fred Hutchinson's pediatric stem-cell transplantation program, tracked the outcomes of 40 children diagnosed with ALL under the age of 12 months who were treated at the center from 1982 to 2003. The children were then followed to determine any long-term effects of treatment on learning, growth and hormones.
Although cancer is rare in children, ALL — a cancer of the blood — is the most common malignancy in this population. Over the past 35 years, the improvement in survival for children with ALL is one of the great oncology success stories. In the 1960s, less than 5 percent of children with ALL survived for more than five years. Cure rates today approach 80 percent for children between the ages of 1 and 9.
But the prognosis for infants with cancer is often worse than in older children, even with the same diagnosis. For children with ALL under 1 year of age treated with chemotherapy — the most common approach at cancer centers today — the survival rate is only around 30 percent.
"They're tough to treat," Sanders said of this high-risk group. "These are fragile individuals. Transplanting individuals at either end of age spectrum is challenging because they have unique medical reactions to the therapy. But we're experienced, and we pay attention to a lot of little details, so perhaps that made the difference in our results."
Radiation therapy for babies remains an unconventional approach because doctors fear the long-term repercussions on health. "The general opinion of most pediatric hematologists and oncologists is that radiation should not be used in infants because it will result in devastating, unacceptable late effects. That's not what we've observed," she said.
The researchers found radiation therapy caused growth-rate and growth-hormone deficiencies, so the patients needed to take growth hormones and/or other hormone medications. But according to Sanders, the babies proved resilient. "The fascinating thing about the infants is that, yes, they develop growth-hormone deficiency, but despite the fact that the blood tests tell you that they haven't got the ability to grow, they just go right ahead and grow anyway — which is perfectly fine," she said. "We'll take that any day of the week!"
Infants also experienced dental problems from the irradiation. The patients' permanent teeth failed to develop as the children matured or were damaged in other ways.
No long-term impact on IQ
Contrary to popular medical opinion that total-body irradiation causes learning problems in children, Fred Hutchinson's clinicians found no long-term impact on intelligence from the ALL treatment. "Babies who are sick stop developing, and then when they get well, they begin developing and catch up," Sanders said. "By the time they get to be 5, they're going to school and they're learning and doing just what they ought to. We've tested some of the patients' IQs, and they're perfectly normal and they're in normal classes."
There are many different kinds (subtypes) of ALL. Research indicates that a patient's subtype of ALL has a major impact on survival. Infants commonly have a subtype of ALL in which a specific gene, MLL, is modified. This chromosomal abnormality makes the leukemia very resistant to conventional chemotherapy, which explains why less than 20 percent of infants with this ALL subtype survive with that approach.
Sanders, also a professor of pediatrics at the University of Washington, found the MLL-gene rearrangement didn't have an impact on the success of the bone-marrow transplants. "Most of the children in first remission were MLL-gene rearrangement positive and survived extremely well," she said. "Transplantation can overcome the negative impact on survival of the MLL gene. It's not a prognostic factor at all in terms of outcome after transplantation." Similar success has been achieved through transplantation in adult leukemia patients with chromosomal abnormalities that make them difficult to treat.
Despite Sanders' unparalleled success with infants, she doesn't expect a sudden shift in clinical practice. "Change does not happen overnight," she said. "It's going to take years. We will continue to do what we're doing, and we'll continue to follow these patients."
Fred Hutchinson's findings are supported by data released last year by researchers at Hyogo Children's Hospital in Japan. In their five-year study of 44 infants with ALL, the patients received either chemotherapy or radiation before transplantation. About 64 percent of the patients were leukemia-free three years after transplantation. "Our study is the only one where everybody got the same total-body irradiation, and it's the only one that gives long-term side effects," Sanders said.
Children's Oncology Group, a prominent national research consortium, has not convened since Sanders' paper and the Japanese study results were published. The group is highly opposed to transplantation in infants; their opinion, based on previous findings, is that infants with ALL fare no better with transplantation than chemotherapy.
"The rest of the studies involve very small numbers of children and are less rigorous. That's why there have been mixed outcomes," Sanders said. "With this article, it remains to be seen whether that body of researchers can be persuaded that radiation does not cause devastating problems and that transplanting some of these children is a reasonable thing to do."
Fred Hutchinson co-authors included Paul Hoffmeister and Drs. Ted Gooley, Ann Woolfrey, Paul Carpenter, Robert Andrews, Eileen Bryant and Fred Appelbaum. Dr. Ho Joon Im from the University of Ulsan College of Medicine in Seoul, South Korea, also contributed.
Sanders — who refers to her patients as "my babies" — is gratified by the study's results. "It's very satisfying for me to know that we're not causing irreparable damage, and we're saving children," she said. "It's so hard on parents to know their little babies — their pride and joy — are so sick. It's really a treasure to see them survive and grow up."