SURVIVAL BENEFIT WITH MITOXANTRONE IN RELAPSED ALL

The survival rate for children with acute lymphoblastic leukemia (ALL) has dramatically increased over the past few decades, from about 50% to more than 80%. Despite these advances, patients who relapse often do poorly, and ALL remains a leading cause of death in children.

However, a new study has found that in patients in first relapse, mitoxantrone confers a significant benefit in progression-free and overall survival, compared with idarubicin. In fact, randomization was halted early by the Data and Safety Monitoring Committee because of differences in progression-free and overall survival between the 2 treatment groups.

The study was presented here at the American Society of Hematology 52nd Annual Meeting, and was published in the December 11 issue of the Lancet.

Vaskar Saha, MBBS, PhD, professor of pediatric oncology at the University of Manchester, United Kingdom, and colleagues found that the estimated 3-year progression-free survival was 35.9% (95% confidence interval [CI], 25.9 - 45.9) in children who received idarubicin, compared with 64.6% (95% CI, 54.2 - 73.2) in those who received mitoxantrone (P = .0004).

Similarly, 3-year overall survival was 45.2% (95% CI, 34.5 - 55.3) for idarubicin and 69.0% (95% CI, 58.5 - 77.3; P = .004) for mitoxantrone. "Mitoxantrone almost halved the hazard of an event at any given timepoint for both progression-free and overall survival," the authors note.

Suitable End Points for Drug Assessment

In an accompanying editorial, Martin Schrappe, MD, PhD, from the University Medical Center Schleswig-Holstein, Kiel, Germany, points out that the difference between the 2 regimens "translated into a clear survival advantage of more than 20%, which is one of the largest improvements ever achieved by a single modification of treatment."

Dr. Schrappe notes that another finding of this study concerns end points for drug assessment. The quantitative detection of minimal residual disease has major prognostic importance in both adult and pediatric leukemia, he explains. In the current study, however, minimal residual disease was measured in intermediate-risk patients at the completion of treatment, but no difference could be detected between the 2 study groups.

"On the basis of minimal residual disease as a surrogate end point, this highly efficacious combination of drugs would not have been considered for further assessment," he writes. This finding is relevant "for ongoing discussions on suitable end points for drug assessment."

Lower Toxicity With Mitoxantrone

In the trial, Dr. Saha and colleagues randomized 216 patients from 1 to 18 years of age with first relapse of ALL to receive either idarubicin or mitoxantrone during induction. The trial was undertaken in 22 centers in the United Kingdom and Ireland and 9 in Australia and New Zealand; neither the patients nor the healthcare workers were masked.

All high-risk patients and intermediate-risk patients with postinduction high minimal residual disease underwent allogenic stem cell transplantation after 3 blocks of therapy. Standard-risk patients and the remaining intermediate-risk patients continued with chemotherapy.

Median follow-up was 41 months in both groups, and the estimated 3-year progression-free survival of the entire cohort was 50.3% (95% CI, 42.9 - 57.3); overall survival was 57.1% (49.5 - 63.9). The adjusted hazard ratio for progression-free survival was 0.54 (95% CI, 0.36 - 0.82; P = .003), and for overall survival was 0.56 (95% CI, 0.36 - 0.87, P = .01).

Of 212 evaluable patients, 108 (51%) remain in second complete remission (45 of 109 [41%] in the idarubicin group and 63 of 103 [61%] in the mitoxantrone group).

A third complete remission was achieved in 6 of 38 patients in the idarubicin group and in 3 of 18 in the mitoxantrone group. A total of 49 patients underwent transplantation in each study group, after which 16 (33%) in the idarubicin group and 2 (4%) in the mitoxantrone group relapsed.

The authors note that throughout the trial, grade 3 or higher toxic effects were significantly lower with mitoxantrone than with idarubicin (incidence rate ratio mitoxantrone/idarubicin, 0.86; 95% CI, 0.75 - 0.98; P = .02). The toxic effects during the first 2 phases of the study were significantly higher with idarubicin than with mitoxantrone. These events were primarily hepatic and gastrointestinal.

Cytotoxics Still Have Role

Mitoxantrone has only been infrequently used in therapeutic trials in pediatric ALL, the researchers write. "A perception that optimization has been reached with available drugs has shifted focus towards newer drugs and targeted therapy."

They note that these newer agents will be prohibitively expensive for many patients (whereas mitoxantrone is a cheap and readily available), and clearly need further clinical assessment in this population.

"Our results suggest that, while we wait for targeted therapies to become a reality, conventional cytotoxics still have a role in treatment of acute lymphoblastic leukemia," they conclude.

The study was funded by Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation. Dr. Saha reports participating in speaker bureaus and advisory boards for EUSA Pharma, Genzyme, Medac, Kyowa-Hakko, and Novartis. Coauthor Philip Ancliff, MA, MRCP, MRCPath, from Great Ormond Street Hospital, London, United Kingdom, reports receiving travel support from Genzyme and Gilead. Coauthor Nicholas Goulden, MB, ChB, MRCP, FRCPath, PhD, also from Great Ormond Street Hospital, reports participating in advisory boards for Enzon. Dr. Schrappe has disclosed no relevant financial relationships