CLINICAL AND BIOLOGICAL CHARACTERISTICS OF ADULT DE-NOVO AND SECONDARY ACUTE MYELOID-LEUKEMIA WITH BALANCED 11Q23 CHROMOSOMAL ANOMALY OR MLL GENE REARRANGEMENT COMPARED TO CASES WITH UNBALANCED 11Q23 ANOMALY -CONFIRMATION OF THE EXISTENCE OF DIFFERENT ENTITIES WITH 11Q23 BREAKPOINT

Although the presence of a chromosome 11q23 breakpoint is of recognize d poor prognosis in acute lymphoblastic leukemia, its prognostic signi ficance in acute myeloid leukemia (AML) has been the object of conflic ting reports, perhaps reflecting the possibility of different entities . It has been found that only typical and generally balanced 11q23 chr omosomal anomalies involve the MLL gene while atypical and generally u nbalanced do not. To determine whether these two categories of AML pat ients had different initial characteristics and evolution, supporting different pathogenetic mechanisms, we analyzed clinical and biologic c haracteristics of newly diagnosed AML patients with balanced 11q23 bre akpoint and/or MLL rearrangement seen over a 10-year period in our ins titution and compared them to cases with unbalanced 11q23 anomaly seen over the same period. These two categories of patients were compared with newly diagnosed patients with normal karyotype and no MLL rearran gement when tested, seen over the same period of time and treated simi larly. Over this period, 442 newly diagnosed adult (>15 years) AML see n in our institution had a successful karyotype performed before any t herapy. Thirty-six cases (8%) had a chromosome 11q23 breakpoint includ ing 19 cases with a balanced translocation or inversion and 17 cases w ith an unbalanced anomaly. Eighty-seven recently diagnosed cases of AM L, for whom frozen cellular material was available, were analyzed by S outhern blot for the presence of MLL gene rearrangement, Fourteen case s (16% of the tested cases) had a rearrangement of the MLL gene, inclu ding seven cases with an apparently successful karyotype not showing a ny 11q23 breakpoint and two cases with no available karyotype. The onl y case with unbalanced 11q23 chromosomal anomaly which was tested had no MLL rearrangement. There was a clear-chit clinical difference betwe en the 28 patients having a balanced 11q23 anomaly/MLL rearrangement a nd the 17 patients having an unbalanced chromosomal anomaly: AML with unbalanced 11q23 anomalies occurred in older patients (P = 0.07), tend ed to be less frequently associated with previous exposure to topoisom erase II-active drugs and with M4/M5 FAB cytological subtypes, were al ways associated with other chromosomal anomalies (P < 0.0001), express ed more frequently the CD34 antigen (P = 0.05) and were of considerabl y poorer prognosis for achievement of CR (P = 0.005) and survival (P = 0.005). When compared to the control population, patients with balanc ed anomalies had more frequent history of toxic exposure (P = 0.0003) particularly to topoisomerase II-active drugs, tended to be more frequ ently of M4/M5 FAB subtypes (P = 0.07), expressed more frequently HLA- DR antigen (P = 0.02) and had shorter DFS (P = 0.02). Patients with un balanced anomalies had more frequent splenomegaly (P = 0.009), lower W BC count (P = 0.04), and much poorer prognosis for CR achievement (P = 0.0001), survival (P < 0.0001) and DFS (P = 0.01). This study confirm s the high frequency of 11q23 chromosomal breakpoint/MLL rearrangement in adult AML and the probable existence of two different entities wit h different clinical features according to the presence of a balanced or unbalanced cytogenetic abnormality, the latter being not associated with MLL rearrangement.