Treatment reduction in highly selected standard-risk childhood acute lymphoblastic leukemia. The AIEOP ALL-9501 study.

BACKGROUND AND OBJECTIVES: Treatment of childhood standard-risk (SR) acute lymphoblastic leukemia (ALL) is generally successful. However, intensive chemotherapy regimens may be associated with severe treatment sequelae. Efforts are therefore being made to identify those patients in whom less intensive treatment would be equally successful but cause fewer long-term sequelae. The aim of this study was to evaluate the efficacy of treatment reduction in a subset of children with ALL at minimal risk of failure. DESIGN AND METHODS: The population of patients with SR ALL included children aged between 1 and 6 years with less than 20,000 WBC/mm3, non-T immunophenotype, DNA index between 1.16 and 1.6, absence of t(9;22) and t(4;11) clonal translocations, no extramedullary leukemia, good response to prednisone and complete remission (CR) at the end of induction therapy. A reduced-intensity, BFM-type treatment schedule (AIEOP-ALL 9501 protocol) was used. Induction therapy was based on vincristine, prednisone, L-asparaginase and intrathecal methotrexate only; high-dose-methotrexate (2 g/m2) was given x4. The BFM Protocol II was given as reinduction therapy; thus the total dose of anthracyclines was 120 mg/m2 and no epipodophyllotoxins or cranial irradiation were employed. RESULTS: Between May 1995 and December 1999, 123 patients were identified as having SR-ALL (7.8% of the ALL-95 population), of whom 102 received the SR protocol. After a median follow-up of 5.9 years, 11 patients in the SR protocol had relapsed, 1 had died in remission, and 1 had developed a second malignant neoplasm. The probabilities (standard errors) of survival and event-free survival (EFS) were, respectively, 97.0% (1.7) and 86.7% (3.5) at 5 years, and 95.3% (2.4) and 86.7% (3.5) at 7 years. INTERPRETATION AND CONCLUSIONS: Although most of the relapsed patients were rescued, the long-term EFS probability in this small, highly selected group of patients remains inferior to expectation. Thus, alternative selection criteria, such as treatment response measured by minimal residual disease, should be considered to address the issue of treatment reduction.

Osteonecrosis: An emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVES: Osteonecrosis (ON) is a potentially disabling complication of combination chemotherapy including high doses of steroids. The incidence and main risk factors for symptomatic ON have been investigated in a large group of children treated with high-dose steroids, prednisone and dexamethasone for childhood acute lymphoblastic leukemia (ALL). DESIGN AND METHODS: From May 1995 to December 1999, 1421 patients <18 years old, with newly diagnosed non-B ALL, were registered in the AIEOP-ALL 95 study. Their data were reviewed to identify patients who developed symptomatic ON. For those who were positively identified additional data were requested concerning ON-related symptoms, treatment and outcome. RESULTS: Overall, 15 of the 1421 patients developed symptomatic ON (1.1%) in a total of 29 sites. The estimated 5-year cumulative risk for clinically diagnosed ON was 1.6% (SE 0.4). The incidence was significantly higher among females (p=0.01) and older patients, with a peak rate of 7.4% (2.3) among those aged 10 to 17 years (p<0.0001). When the two factors, i.e. age and gender were combined, there was a striking increase in the risk among female patients aged 10 to 17 years. The median time between the diagnosis of ALL and that of ON was 17 months (range 8-45). The hip was the most frequently involved (19/29) site. INTERPRETATION AND CONCLUSIONS: Symptomatic ON occurred in only 1.1% of patients treated with BFM-type, intensive chemotherapy for childhood ALL. Female adolescents appear to be the subset of patients with the highest risk of ON, especially when categorized as having high risk leukemia and thus administered higher cumulative doses of dexamethasone.