Zosia Chustecka

June 05, 2012

June 5, 2012 (Chicago, Illinois) — Cure rates of childhood leukemia are one of cancer's best success stories, but when the disease strikes in adolescence or young adulthood, the outcomes are not quite as good.

This inferior outcome in adolescents and young adults (AYA), aged 16 to 30 years, has long been suspected from historic data, but it has now been confirmed by a major phase 3 trial. The new data, presented here at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO), shed light on why the outcomes are worse in this age group.

"The inferior outcome for AYA patients is the result of more resistant disease, resulting in higher rates of relapse and higher toxicity from treatment," said lead author Eric Larsen, MD, medical director of the Maine Children's Cancer Program in Scarborough.

"We have to find novel agents to better eradicate the leukemia," he added.

Largest Cohort of this Age Group

This study, known as ALLL0232, was conducted by the Children's Oncology Group and involved 2574 patients with acute lymphoblastic leukemia (ALL), 501 of whom (20%) were 16 to 30 years of age. "This is the largest cohort of this age group in a single cancer clinical trial," Dr. Larsen noted.

The trial tested 2 treatment approaches. During the induction phase of treatment, the more potent steroid dexamethasone was compared with the standard prednisolone; during the interim maintenance phase of treatment, upfront high-dose methotrexate was compared with escalating intravenous methotrexate (Capizzi regimen).

The main results from this trial were reported at last year's ASCO meeting, and have already had an impact on clinical practice. "We are already acting on the results from this trial," said Jennifer McNeal, MD, assistant professor of pediatrics at the University of Chicago, Illinois, who moderated the session at which the updated results were reported.

Dr. McNeal said that her clinic has already switched to dexamethasone for younger patients with ALL, and that they are now using high-dose methotrexate instead of the Capizzi regimen in younger patients and in AYA.

Worse Outcomes

Results showing worse outcomes in AYA are cause for concern, Dr. McNeal said in an interview with Medscape Medical News. This is a patient population that has unique challenges, she explained. They appear to have a different biology, with a higher frequency of chromosomal abnormalities than children. There might also be compliance issue, she noted; once the young person is no longer under parental control, they might not adhere to clinic visits and medications. Many of the drugs that are used for maintenance are taken orally, and these young people might forget or decide not to continue taking the drug when they are feeling well, she added.

AYA had lower 5-year event-free survival than younger patients (68.0% vs 80.9%; P < .0001), and lower 5-year overall survival (79.8% vs 88.4%; P < .0001).

The 5-year cumulative incidence of relapse was higher for AYA than for younger patients (21.3% vs 13.4%), largely because of a higher rate of marrow relapses (15.2% vs 9.0%); the rate of central nervous system relapses was similar in the 2 groups.

In addition, fewer AYA than younger patients achieved remission (97.2% vs 98.8%; P = .013), and there were significantly more toxic deaths after induction and remission in AYA at 5 years (5.5% vs 2.1%; P < .0001).

Dr. Larsen said that these results have spurred the Children's Oncology Group to consider a number of options to enhance leukemia control and reduce the toxicity of treatment.

Approached for outside comment, Eyal Attar, MD, assistant professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center in Boston, said that the treatment outcomes of young adults with ALL have been an intense area of research in the past decade, with emphasis on why this age group fares better when patients are treated by pediatric oncologists using pediatric regimens than when they are treated by adult oncologists using adult-based regimens. It is possible that pediatric protocols tend to avoid myelotoxic drugs and that treatment compliance is aided by rigid protocols and patients' mothers (the "mommy factor). Adult regimens tend to use more myelosuppressive agents, and patients treated by adult oncologists often have less parental involvement.

A separate question addressed by this study is why AYA do worse than younger children, he said. Because the same regimen was used in all ages in this study, the difference in outcomes must have another explanation. Specifically, this study shows that AYA have a lower remission frequency, higher toxic death rate, and decreased survival, relative to children. "These observations confirm what is believed about ALL and chemotherapy — that there are age-associated differences in the basic biology of the disease that, when extrapolated to older adults, explain the extremely poor outcomes and chances of survival in older adults. Another is that chemotherapy is less well tolerated with age, he told Medscape Medical News.

Dr. Attar reiterated the point made by Dr. Larsen — that the survival of AYA in this trial was higher than has been seen historically, in particular when they were treated with adult-based regimens. "We must tailor drug therapy to the specific biology of AYA disease to improve efficacy while lowering toxicity," he explained.

Dr. Larsen has disclosed no relevant financial relationships.

2012 Annual Meeting of the American Society of Clinical Oncology: Abstract CRA9508. Presented June 3, 2012.


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