Induction therapy toxicities in children with Acute Lymphoblastic Leukemia

Tiphaine Adam de Beaumais1, Anne Uyttebroeck2, Séraphine Rossi2, Stefan Suciu2, Evelyne Jacqz-Aigrain1. 1Robert Debré hospital, Pediatric Clinical Pharmacology 75019, France, 2European Organisation for Research and Treatment of Cancer (EORTC), headquarters and 1200, Belgium

Background:

Optimization of childhood acute lymphoblastic leukemia (ALL) therapy allowed improving survival rates that reach today 90%. The goal of the aggressive Induction therapy is to bring the disease into a clinical and biological remission.

Methods:

This study was conducted in 408 children (54.2% boys; mean age: 6.9 ± 4.5 years) with ALL including in EORTC 58951 protocol from 1998 to 2008. Patients have received a 7-day Prephase followed by 28-days Induction therapy that consisted in daily 21-days Corticosteroids, 4 Vincristine administrations, 8 L-Asparaginase administrations and according to their risk group 2 to 4 Daunorubicin administrations, 2 intrathecal Methotrexate or Methotrexate-Aracytine-Hydrocortisone administrations, 0 to 1 Cyclophosphamide administration and 0 to 1 high-dose Methotrexate administration.

Adverse events (AE) were classified in thirteen classes: blood/bone marrow hemorrhage; cardiovascular (arterial/venous), gastrointestinal (stomatitis-mucositis/other), infection, allergy to asparaginase, hepatic, metabolic, neurological (personality change/cortical/motor) and other major complications of grade ≥ 3. The grading scale used for AE evaluation was assessed using the National Cancer Institute Common Terminology Criteria version 3 (Grade 1, mild AE; Grade2, moderate AE; Grade 3, severe AE; Grade 4, life-threatening or disabling AE and grade 5, death related to AE).

Results:

No patient had grade 5 AE and only 15.5% had no AE.

The most frequent grade 1-4 toxicities were hepatic toxicities (65.0%), infections (37.4%), metabolic toxicities (37.0%), stomatitis-mucositis (30.0%) and others gastrointestinal toxicities (29.2%).

We focused on grade 3-4 AE which may have consequences on the following treatment phases and long-term effects.

49.0% of patients had at least one grade 3-4 AE. The number of AE occurring in each patient ranged from 1 to 5 in 26.0, 13.2, 6.3, 2.8 and 0.5% respectively. The major grade 3-4 complications were hepatic toxicities (29.0%), infection (17.2%) and stomatitis-mucositis (10.6%).

Only three patients had more than 5% leukemic blasts in bone marrow at the end of Induction therapy and one patient died during this treatment phase.

Conclusion:

Nowadays, research on ALL treatment should also focus on reducing toxicities and sequellae as well as obtaining remission and long-term cure. Pharmacogenetic study is undertaken as it is a great promise for improving event-free survival in children with ALL while maintaining high cure rates.