Long Term Results of the AIEOP-All-95 Trial for Childhood Acute Lymphoblastic Leukemia. An Insight on the Prognostic Value of Dna Index in the Frame of BFM-Based Chemotherapy.

Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) conducted the ALL-95 study for risk-directed, BFM-oriented therapy of childhood acute lymphoblastic leukemia (ALL), aimed at exploring treatment reduction in standard risk (SR) and intensification during continuation therapy in intermediate risk (IR) as randomized questions and treatment intensification in high risk (HR). The prognostic value of DNA index was explored in this setting. 1,744 patients were enrolled, 115 SR, 1,385 IR, and 244 HR risk. SR patients (DNA index ≥1.16 and <1.60, age 1–5 and WBC<20K, non-T, no high risk features), received a reduced induction therapy (no anthracyclines); IR patients were randomized to receive or not vincristine-dexamethasone (VCR-DEXA) pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by double reinduction phase. The event-free-survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE 1.3) and 83.6% (0.9); 85.0% (3.4) and 95.5% (2.0) in SR, 75.1% (1.5) and 87.5% (0.9) in IR, 51.0% (3.2) and 57.2% (3.3) in HR patients, respectively. Patients with favorable DNA index had superior EFS in both IR [83.8(2.7) versus 73.9(1.7)] and in HR [67.8(9.4) and 49.6(3.5)]. Of the 6 patients with DNA index. <0.8 only 1 remained in remission. As for treatment burden there was no difference between SR patients, receiving only 3 drugs, and others in Induction IA. Highest treatment burden was reported during consolidation in HR patients. In reinduction, first protocol II had figures similar to those reported during protocol II given to non-HR patients, while second protocol II in HR patients was associated with higher treatment burden Treatment reduction, although appealing, should be applied with great caution not to endanger outstanding cure rate achieved with over 80% of patients in Italy during the second half of the 90s having been cured. Contribution of HSCT in front-line therapy remains limited. In this study, favorable DNA index was associated with better prognosis in IR and HR patients defined by clinical criteria and treated with BFM-oriented chemotherapy. Continuous effort put in the genetic studies could provide novel insights for treatment of subsets of childhood ALL refractory to modern chemotherapy.