Reduced-intensity delayed intensification does not benefit standard-risk children with ALL

SAN DIEGO — Reduced-intensity delayed intensification of chemotherapy did not benefit standard-risk children with acute lymphoblastic leukemia, according to results of an international randomized trial presented during the plenary session at the ASH Annual Meeting and Exposition.

Researchers reported 50% more relapses in patients assigned the less intensive regimen.

“Any treatment modification of patients with excellent prognosis should be carried out with large caution under controlled conditions,” Martin Schrappe, MD, of the department of general pediatrics at Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein in Germany, said during a presentation.

The analysis included 1,163 patients (age range, 1 to 17 years) from the AIEOP-BFM-ALL 2000 trial who had standard-risk ALL.

Investigators defined standard risk as patients who were minimal residual disease negative by two polymerase chain reaction markers for immunoglobulin heavy chain and T-cell receptor rearrangements at week 5 after induction therapy and at week 12 after consolidation therapy.

Marker sensitivity was at least 10^-4, and no patients had clinical or biological high-risk criteria, such as poor response to induction or certain genetic features. Infants and patients with Philadelphia chromosome–positive leukemia were excluded.

Schrappe and colleagues performed a randomized comparison of two treatment protocols for delayed reintensification. They sought to assess the impact of reduced treatment burden in patients with the best treatment response and lowest risk for relapse.

Investigators assigned 579 patients to protocol II, which consisted of standard-intensity delayed intensification. The other 584 patients were assigned to protocol III.

Protocol III was shorter (duration, 29 days vs. 49 days), and it included a 30% lower dexamethasone dose and 50% lower doses of vincristine, doxorubicin and cyclophosphamide.

Investigators sought to prove noninferiority of the reduced-intensity regimen.

Median follow-up was 8.6 years.

Results from the intent-to-treat population showed no significant difference in EFS at 5 years between treatment groups at 5 years, although researchers observed a trend patients assigned the standard regimen fared better (94.7% vs. 90.7%).

However, an analysis by treatment given showed a statistically significant difference in 5-year EFS favoring the standard protocol (94.9% vs. 90.6%; P = .041).

Among patients aged 10 years and older, considered a critical age group among those with standard-risk disease, researchers reported a significantly higher cumulative incidence of relapse among those assigned the less intensive regimen (P = .02).

Researchers reported no significant difference in OS at 5 years; however, more patients assigned the less intensive protocol had died by 5 years (22 vs. 11). When researchers limited the OS analysis to patients with B-precursor disease, the most frequent subtype in the standard-risk group, they reported 58 events in patients assigned the reduced-intensity regimen and 38 among those assigned the regular-intensity regimen (P = .043).

More patients assigned the standard regimen developed grade III or grade 4 infections (26 vs. 18). However, more patients assigned the less intensive regimen died during complete remission (5 vs. 4) and developed second malignancies (7 vs. 4).

“Our study underlines the importance of well-designed, sufficiently powered studies for prospective evaluation of treatment reduction in childhood ALL, a major challenge for developing future therapy strategies,” Schrappe and colleagues wrote. – by Mark Leiser

Reference: Schrappe M, et al. Abstract 4. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosure: The researchers report honoraria and travel support from Jazz Pharmaceuticals, as well as advisory committee or board of directors roles with Bristol-Myers Squibb, Celgene and Novartis.