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Dexamethasone-based protocol improves ALL survival without cranial radiation

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – A dexamethasone-based protocol can cut the risk of relapse and improve survival in high-risk children with acute lymphoblastic leukemia (ALL), with fewer side effects, new research shows.

The regimen, designated the Dutch Childhood Oncology Group (DCOG) ALL-9 protocol, achieved 5-year event-free survival rates of 84% for non-high risk patients and 72% for high-risk patients, according to a report in the September 10th online issue of The Lancet Oncology.

High-risk patients were those with white blood cell counts of 50,000/microliter or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement.

By comparison, the ALL-6 protocol against which ALL-9 was tested achieved a similar 5-year event free survival of 83% in its non-high-risk group in the late 1980s, but this rate was only 53% among high-risk patients. Lead author Dr. Anjo J. Veerman from VU University Medical Center, Amsterdam, The Netherlands, and colleagues explain that while ALL-9 is identical to ALL-6 for non-high risk patients, changes were made for high-risk patients, in the hopes of improving outcomes.

They emphasize that the improvement in the high-risk group was achieved without cranial irradiation and without the use of such toxic drugs as anthracyclines, cyclophosphamide, or epipodophyllotoxins.

The ALL-9 trial involved 859 children, ages 1 to 18 years, with de novo disease who were recruited between January 1997 and November 2004. Median follow up was 72.2 months.

In the non-high risk group, 601 children received induction with dexamethasone, vincristine, and L-asparaginase for 6 weeks, then medium-dose methotrexate for 3 weeks, and then maintenance therapy. The 258 high-risk patients received the same three drugs plus daunorubicin for induction for 6 weeks, then high-dose methotrexate for 8 weeks, and two intensification courses before maintenance therapy.

Triple intrathecal medication was given 13, 15, and 17 times in non-high risk, high risk, and central nervous system-affected patients, respectively.

In all patients, maintenance therapy – consisting of mercaptopurine and methotrexate alternating with dexamethasone and vincristine — was continued until 109 weeks.

The complete remission rates in the non-high risk and high risk groups were 98.5% and 96.9%, respectively. Five deaths in the non-high risk group and four in the high risk group occurred during induction therapy. Isolated central nervous system relapses were noted in 2.6% of patients.

On multivariate analysis, the strongest predictor of outcomes was the DNA index, followed by age, and then the white blood cell count, the authors note.

“The most radical feature of (the ALL-9) protocol is the omission of prophylactic cranial irradiation in all patients,” Dr. Ching-Hon Pui, from St Jude Children’s Research Hospital in Memphis, Tennessee writes in a related editorial. “Not surprisingly, (the researchers) have reported only a few cases of osteonecrosis and only two cases of second malignancy.”

“The vast majority of their patients are expected to survive with an excellent quality of life,” Dr. Pui added.

Reference:
Lancet Oncology 2009.