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INTENSIVE CHEMOTHERAPY INCREASES SURVIVAL OF OLDER TEENAGERS WITH ALL

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Historically, older teenagers (those aged 15 - 18 years) with acute lymphoblastic leukemia (ALL) have had a much worse prognosis than younger patients.

Now, however, physicians at St. Jude Children's Research Hospital in Memphis, Tennessee, report that most older adolescents with ALL can be cured with intensive chemotherapy that takes into account their individual risk profile — without stem cell transplantation and without radiation to the brain.

This report was published online December 20 in the Journal of Clinical Oncology.

"The contemporary clinical trials for ALL show 5-year survival rates of 83% to 94% in children and much lower rates — anywhere from 27% to 59% — for older teens and adults," said lead author Ching-Hon Pui, MD, chairman of oncology at St. Jude.

"But with our latest protocol, which uses more effective risk-adjusted chemotherapy and sophisticated patient monitoring, we were able to push the cure rates for older teens to nearly 88%, essentially closing the survival gap between older and younger patients," he told Medscape Medical News.

Older teenagers are difficult to cure because they tend to have more high-risk leukemia, suffer more toxic adverse effects from their treatment, and are less likely to be compliant with their therapy.

"Teens are well known to be less compliant. For example, if they're invited to a party, they won't take their medicine because they don't want to be sick. Or they forget, because they have to take pills 3 times a day," Dr. Pui said. "Teens with chronic illness are notorious for compliance issues. With younger children, it's easier. They are supervised by their parents, who make sure they take their medicine as prescribed."

Study Details

In this report, Dr. Pui and his team compared the long-term survival of 963 pediatric patients, including 89 older adolescents, treated between 1991 and 2007 who were enrolled in 4 consecutive Total Therapy studies — studies XIIA, XIIB, XIV, and XV — that used protocols developed at St. Jude.

In the first 3 studies, treatment selection was based on presenting clinical features and leukemic cell genetics. In study XV, measuring the level of minimal residual disease (MRD) either by flow cytometry or polymerase chain reaction, was used to monitor the patient's response to and compliance with treatment, which featured intensive methotrexate, glucocorticoid, vincristine, and asparaginase, as well as early triple intrathecal therapy for higher-risk ALL.

In the Total XV study, any patient with 1% or more bone marrow MRD on day 19 of remission induction, or 0.1% to 0.99% MRD after completion of induction therapy, was considered to have standard-risk ALL. Patients who were unable to achieve morphologic remission or who had presence of MRD 1% or greater after completion of induction therapy and persistence of MRD 0.1% or greater beyond week 7 of continuation treatment were deemed to have high-risk ALL and became candidates for allogeneic stem cell transplantation.

The Total XV regimen also replaced radiation of the brain with intrathecal chemotherapy. Patients with low-risk disease received 13 to 18 intrathecal treatments, and patients with standard-risk disease received 16 to 25 intrathecal treatments. Prophylactic cranial irradiation was not used, as per the protocol of Total XV.

Survival Rate Increased Significantly With XV Protocol

In the earlier studies, the 5-year event-free survival rate and the 5-year overall survival rate for the 44 older adolescents were both 59.1% (95% confidence interval [CI], 43% - 72%). This was "strikingly" inferior to the event-free survival rate of 82.6% (95% CI, 78.5% - 86%; P < .001) and the overall survival rate of 88.3% (95% CI, 84.7% - 91.1%) achieved in the 403 younger patients, the investigators reported.

In contrast, in study XV, the 5-year event-free survival rates were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7% for the 453 younger patients. The 5-year overall survival rates were 87.9% ± 5.1% for the older teenagers and 94.1% ± 1.2% for the younger patients.

In addition, patients treated in study XV were less likely to suffer serious late treatment effects, including second cancers and infertility. "Our patients had a good quality of life. We have followed them for over 10 years, and of the 500 patients, only one developed a secondary cancer," Dr. Pui noted. "This is the lowest for any protocol."

Dr. Pui also said that his study highlights the fact that good results in pediatric ALL can be achieved without the use of radiation. It also underlines the importance of personalizing therapy and being aware of compliance.

"We do not give everyone the same dose. Instead, we base the dose on individual pharmacokinetics and pharmacodynamics. We pay close attention to compliance. We monitor patients regularly, and we can tell who is not taking their oral medications. We counsel these patients until they become compliant, and we keep checking to make sure they stay compliant. This is very important, especially for the older teens," Dr. Pui said.

The study also reinforces the growing body of evidence that suggests older teenagers and even young adults with ALL do better on pediatric — as opposed to adult — protocols.

"Pediatric ALL specialists who treat adolescents love to see this kind of data get published," Susan Rheingold, MD, assistant professor of medicine at Children's Hospital of Philadelphia in Pennsylvania, told Medscape Medical News.

Studies have been showing since the early 2000s that older teenagers and young adults do better on pediatric protocols than adult protocols, she said. "In general, the pediatric protocols had a 65% 5-year cure rate, and the adult protocols had a 45% cure rate. When those results began to come out, pediatric oncologists started to say, 'We need to be treating these older adolescents. We need to be treating them like 10-year-olds, and not like 70-year-olds, so we can improve their cure rate. And when it's a 20% higher cure rate — that's significant," she said.

Dr. Rheingold noted that the protocols of the Children's Oncology Group are open to patients up to the age of 30 years.

"You don't stop being a child automatically at the age of 18. Our university hospital [University of Pennsylvania Medical Center] is hearing the message that pediatric oncologists are curing these young adult patients at higher rates with chemo and without transplants, and are sending us patients who are in their 20s," she said.

"The emergency rooms between the adult hospital and the pediatric hospital are probably no further than 100 feet apart. A 21-year-old can walk into either emergency room with a new diagnosis of leukemia, and you would hate to think that what door they chose to walk into could change their cure rate by 10% or 20%."

This research was supported in part by the National Institutes of Health, the American Cancer Society, and the American Lebanese Syrian Associated Charities. Dr. Pui and Dr. Rheingold have disclosed no relevant financial relationships.

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