CLINICO-BIOLOGIC CHARACTERIZATION OF 5203 ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS ENROLLED IN THE ITALIAN AIEOP AND GIMEMA PROTOCOLS, STRATIFIED IN AGE-COHORTS FROM SMALL CHILDREN TO YOUNG ELDERLY

Background. Acute lymphoblatic leukemia (ALL) shows marked differences in clinical outcome between children and adults. Several factors account for this different scenario, including the variable incidence of molecular aberrations. It is likely that other factors differ between the two cohorts. Overall, there is limited information on the distribution of the clinico-biologic variables in the various age-cohorts, ranging from small children to young elderly. Aims. To define the clinico-biologic profile of newly-diagnosed ALL patients, stratified in 9 age-cohorts: 1-5, 5-10, 10-14, 14-18, 18-25, 25-30, 30-40, 40-50, 50-60 years. Methods. Overall, 5203 patients were evaluated: 3754 children enrolled in the AIEOP protocols and 1449 adults recruited in the GIMEMA protocols. Clinical features included WBC (>50¥109/L) and Plt (<100¥109/L) counts, Hb levels (<10 g/dL), liver, spleen, mediastinum enlargement and CNS involvement. Biological features comprised immunophenotypic and molecular analyses. Differences among groups were evaluated using non-parametric tests (Chi-squared and Fisher-Exact test). Results. There were 2890 males and 2313 females (M/F=1.25).The highest incidence was recorded in the age-cohorts 1-5 and 5-10 (36.6% and 21.4%, respectively), with a progressive decrease from 10 to 30 years and an increase from 30 years onwards. Gender distribution highlighted a lower incidence of females: this phenomenon was remarkable between 14-50 years and disappeared in the 50-60 age-cohort (P<.0001). Hyperleukocytosis was less frequent in the age-cohorts 1-5 and 5-10 (P<.0001); spleen, liver and mediastinum enlargement were present in 28.8%, 19.5% and 7% of cases, respectively: there was a constant decrease of organ involvement in older patients (P=0.0276, P<.0001, P<.0001). CNS involvement was recorded in 2.1% of cases, most frequently between 1-14 years. A T-lineage affiliation was rarer among the 1-5 and 5-10 age-cohorts (5.1%, and 15.7%, respectively), increased in patients between 10 and 40 years (average=25%), and decreased in the elderly (40-50=11.9%, 50-60=12.2%). There was a significant association between gender and immunophenotype, T-ALL being more frequent in males (P<.0001) up to the 4th decade. A B-lineage derivation was found in 85.8% of patients: an increased incidence of pro-B ALL, sustained by ALL1/AF4 positivity, was recorded in the age-cohorts from 10 to 50 years. Molecular screening highlighted a progressive increase in BCR/ABL+ cases (P<.0001), detected in 52.7% of B-lineage cases in the 6th decade, and in ALL1/AF4+ cases with age (P<.0001) and a constant decrease in ETV6/RUNX1+ cases (P<.0001), whereas E2A/PBX1+ cases showed a consistent distribution among age-cohorts. Conclusions. Stratification in 9 age-cohorts confirms a high incidence of ALL in small children and shows a lower occurrence of ALL in females, particularly significant between 14-50 years, suggestive of a protective effect of fertility. Organ involvement declines with age, possibly reflecting a progressive, physiological atrophy, that may result in a lesser efficient immunologic control of the disease, ultimately translating in a worse outcome Finally, we conclusively quantify the decrease of ETV6/RUNX1 and progressive increase of ALL1/AF4 and BCR/ABL with age. This results in an increase with age of unfavorable prognostic markers that may be managed by targeted therapies, bearing in mind that in the 50-60 age-cohort BCR/ABL positivity accounts for over 50% of B-lineage cases. Figure 1. Molecular aberrations incidence among age-cohorts.