INDIVIDUALIZED TREATMENT FOR ALL

December 16, 2009 (New Orleans, Louisiana) — Two conclusions from the 5-year results of a trial in childhood acute lymphoblastic leukemia (ALL), which were presented at the American Society of Hematology (ASH) 51st Annual Meeting, are potentially practice-changing, according to program cochair Richard Van Etten, MD, PhD, chief of hematology/oncology and director of the Cancer Center at Tufts Medical Center, in Boston, Massachusetts.

In an interview with Medscape Oncology, he said the results show that individualizing the dose of asparaginase on the basis of pharmacokinetic measurements produced superior results to those seen with a fixed-dose regimen, and "everybody should now start doing this."

In addition, the trial showed superior results with dexamethasone, compared with prednisone, when added to asparaginase, he noted.

The findings come from the Dana-Farber Cancer Institute Protocol 00-01, and 5-year results were presented at the meeting by Lynda M. Vrooman, MD, from the Dana-Farber Cancer Institute in Boston. The protocol was designed with the overall goal of improving the efficacy of therapy and minimizing treatment-related toxicity.

To that end, explained Dr. Vrooman, the researchers evaluated an alternative dosing method for asparaginase, which is associated with toxicities such as allergy, thrombosis, and pancreatitis. They also studied the use of dexamethasone in postinduction therapy, because both preclinical and clinical data have suggested that, compared with prednisone, dexamethasone has a higher antileukemia effect, although a greater degree of toxicity has been noted.

The cohort consisted of 492 children from 10 institutions, between the ages of 1 and 18 years, and who were recruited between 2000 and 2004. All patients were newly diagnosed with ALL, and 282 were classified as standard risk and 210 were classified as high risk. Postinduction treatment for all study participants included 30 weeks of intramuscular Escherichia coli asparaginase (beginning at week 7) and vincristine/corticosteroid pulses every 3 weeks for 24 months.

Of this group, 473 achieved complete remission and were then eligible for a randomized comparison.

Asparaginase Results

In the asparaginase section of the trial, 384 (of 473) patients (81%) were assigned to 1 of 2 treatments for 30 weeks: 195 received a fixed dose of asparaginase (25,000 IU/m²); and 189 received an individualized dose, with a starting dose of 12,500 IU/m². The nadir serum asparaginase activity (NSAA) was evaluated every 3 weeks, and doses in patients receiving individualized therapy were adjusted to maintain NSAA between 0.10 and 0.14 IU/mL.

Patients randomized to individualized dosing demonstrated better 5-year event-free survival than fixed dosing (± standard error, 90 ± 2% vs 82 ± 3%; P = .04); this was observed across all subgroups.

Event-Free Survival at 5 Years: Individualized vs Fixed-Dose Asparaginase

ALL Population	Individualized Dose (± Standard Error)	Fixed Dose (± Standard Error)
Overall	90 ± 2%	82 ± 3%
Standard-risk group	89 ± 3%	86 ± 4%
High-risk group	93 ± 3%	78 ± 5%
1–10 year age group	90 ± 3%	85 ± 3%
10–18 year age group	90 ± 5%	72 ± 7%

The frequency of asparaginase-related allergy, pancreatitis, and thrombosis were similar between the 2 groups and on multivariable analysis, explained Dr. Vrooman, and both dexamethasone and individual-dose asparaginase were independent predictors of a favorable outcome (hazard ratio [HR] for dexamethasone, 0.49 [P = .02]; HR for individual-dose asparaginase, 0.52 [P = .04]), with no indication of interaction.

"We found that individualizing dosing with asparaginase was feasible in a multi-institution study," said Dr. Vrooman.

Although individualized dosing was associated with a superior outcome, she pointed out that this was not because of a reduction in toxicity or improved tolerability. "We are currently analyzing the association of asparaginase levels and asparaginase antibody formation with outcome in greater detail," she said.

Dexamethasone Superior to Prednisone

The steroid part of the trial was conducted in a cohort of 408 (of 473) children (86%) who were randomized to receive either dexamethasone (n = 201) or prednisone (n = 207) as 5-day pulses every 3 weeks.

Using dexamethasone in the postinduction phase resulted in one third fewer relapses than prednisone, Dr. Vrooman reported. In addition, the 5-year event-free survival (± standard error) for patients who received dexamethasone (n = 201) was 90 ± 2%, and for patients who received prednisone (n = 207) was 81 ± 3%.

Event-Free Survival at 5 Years: Dexamethasone vs Prednisone

ALL Population	Dexamethasone (± Standard Error)	Prednisone (± Standard Error)
Overall	90 ± 2%	81 ± 3%
Standard-risk group	89 ± 3%	84 ± 4%
High-risk group	91 ± 4%	78 ± 5%
1–10 year age group	91 ± 3%	82 ± 3%
10–18 year age group	88 ± 5%	77 ± 6%

Another trial, presented at ASH 2008, showed that dexamethasone is more effective in childhood ALL. In that study, dexamethasone decreased the risk for relapse by one third when given early in the treatment cycle, compared with prednisone. However, there were no differences in long-term survival in that trial.

Increase in Toxicity

In the latest study, Dr. Vrooman reported that dexamethasone was associated with more bone and infectious toxicities than prednisone, especially in older children and adolescents.

Although there was a significant increase in the rate of osteonecrosis in older patients receiving dexamethasone, the researchers did not observe a difference in the 5-year cumulative index of osteonecrosis in younger patients (aged 1 to 10 years); for dexamethasone it was 2.6% and for prednisone it was 4.3% (P = .43).

Fractures were more common among patients 10 to 18 years old who received dexamethasone than among those who received prednisone (P = .06), but this increased incidence was not observed in the younger group (P = .25). There was also a higher rate of infection in the dexamethasone group (n = 38; 18.8%) than in the prednisone group (n = 22; 10.6%).

No difference in the rate of death in remission was observed between the groups; it was 0% for dexamethasone and 2% for prednisone (P = .5).

"There was a very high rate of osteonecrosis in the older patients," said Nicola Gökbuget, MD, from the Goethe University Hospital, in Frankfurt, Germany. "If we use this regimen in adults, then we need to follow patients closely and monitor them for this complication."

It isn't certain that these findings would extrapolate to adults, explained Dr. Gökbuget, who was not involved in the study but was approached by Medscape Oncology for independent comment. "But we saw that this complication was higher in older children, so it could be even higher in adults," she said. "It could also be that this population is the most vulnerable."

Dr. Gökbuget also noted that, at the current time, little is known about prophylaxis for osteonecrosis. "We need to think about preventing it from occurring in the first place, as this can significantly affect the patient's quality of life," she said. "We also need to think about treating it. There are new approaches being investigated, but there is a lot of work left to do in this field."

Of the 92 patients who were randomized to both dexamethasone and individual-dose asparaginase, only 5 (5%) experienced an event.

Dr. Vrooman concluded that although dexamethasone is associated with superior event-free survival, the toxicity was higher. "Future studies should focus on minimizing dexamethasone toxicity in older pediatric patients without compromising efficacy," she said.

Dr. Vrooman has disclosed no relevant financial relationships. Study coauthors Jeffrey G. Supko, PhD, from Massachusetts General Hospital in Boston, and Stephen E. Sallan, MD, from the Dana-Farber Cancer Institute in Boston, report receiving research funding from Enzon, Inc.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 321. Presented December 7, 2009.