Using MRD to Intensify Therapy in Patients With ALL

Veronica Hackethal, MD

June 26, 2014

Children with acute lymphoblastic leukemia (ALL) who test positive for minimal residual disease (MRD) could benefit from stronger postremission therapy, but they might also experience more toxicity, according to the randomized controlled UKALL 2003 trial.

"The study is the first and only randomized study to demonstrate that postremission intensification of treatment is of benefit to patients with persistent minimal residual disease at the end of induction," said first author Ajay Vora, MD, professor of pediatric hematology at the Sheffield Children's Hospital and chair of the National Cancer Research Institute Childhood Leukemia Clinical Trials subgroup in Sheffield, United Kingdom.

Results were published online June 10 in the Lancet Oncology.

MRD refers to the small number of leukemia cells that remain in the body after treatment. Children with persistent MRD at the end of remission are at higher risk for relapse than children with undetectable MRD, the researchers explain.

In previous UKALL 2003 studies, event-free survival has been "excellent" in low-risk MRD patients who received reduced-intensity postremission therapy on the basis of a good MRD response, Dr. Vora reported.

The new UKALL 2003 results indicate that MRD response provides the "optimal strategy" when choosing the intensity of postremission therapy for ALL, he explained.

The study, conducted from October 2003 to June 2011, involved 46 centers in Ireland and the United Kingdom. Participants were 1 to 24 years of age, had been diagnosed with ALL, and were considered high risk because they had MRD of at least 0.01% on day 29 of induction therapy.

In all, 266 patients were randomized to receive standard treatment and 267 were randomized to receive augmented treatment, which consisted of 8 extra doses of asparaginase, 18 extra doses of vincristine, and escalated-dose intravenous methotrexate.

Event-free survival was defined as time from diagnosis to relapse, the development of a secondary tumor, or death.

At a follow-up of about 70 months, 5-year event-free survival was better with augmented therapy than with standard therapy (89.6% vs 82.8%; odds ratio [OR], 0.61; P = .04). The researchers attribute this improvement to a "substantially" decreased risk for relapse in the augmented group.

Overall 5-year survival was also better with augmented therapy than with standard therapy, although not significantly (92.9% vs 88.9%; OR, 0.67; P = .16).

Risk for death did not differ between the 2 groups. In the augmented group, 7 patients died and 1 developed a secondary tumor; in the standard group, 9 patients died.

The augmented group had higher rates of toxicity than the standard group (45% vs 34%; P = .02), but Dr. Vora emphasized that these were not linked to excess mortality or worsened quality of life. Toxicities included asparaginase hypersensitivity, pancreatitis, mouth sores, and inflammation or ulceration of the lining of the digestive tract.

These types of toxicity are regularly encountered in children being treated for ALL, according to Michael Rytting, MD, associate professor in pediatrics at The Children's Cancer Hospital at the University of Texas M.D. Anderson Cancer Center in Houston.

He discusses the study in an accompanying comment.

Although the augmented group experienced more toxicity, it was "still pretty tolerable," he told Medscape Medical News.

Children who received augmented therapy had a significantly better chance of event-free survival at 5 years, but Dr. Rytting noted that children who did not receive augmentation also had a "pretty good cure rate."

"It's not that all of those children are going to relapse," he said. "The majority of them will be cured, but you can improve their odds if you augment their treatment."

The MRD test is a "powerful predictor" of how patients will do, Dr. Rytting explained. However, although MRD is widely used in Europe and the United States, it has been problematic.

When MRD results are good, the test can be an indicator that current treatment is working. When MRD results are poor, doctors have few evidence-based therapeutic options to offer.

"That's what's really interesting about this study. It's the first published randomized study saying we're going to use MRD to change treatment," Dr. Rytting explained.

"The other important thing is that they were able to do it with standard chemotherapy that's widely available and that's not experimental or extremely expensive," he said. The researchers "showed that you can change treatment in a practical manner and improve outcomes."

This study might have already changed clinical practice in the United Kingdom, at least for children treated with the protocol used in this study, Dr. Rytting reported. However, the findings might not apply to children receiving other treatment protocols.

Dr. Vora and Dr. Rytting have disclosed no relevant financial relationships.

Lancet Oncol. Published online on June 10, 2014. Abstract, Comment

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