Acute Lymphoblastic Leukemia (ALL) with Low-Hypodiploid/near Triploid Karyotype Is a Specific Clinical Entity with Poor Outcome

Abstract

Abstract 1429 Background:Besides the immunophenotype, the karyotype is an important prognostic factor in ALL. In contrast to other leukemias, in ALL cytogenetic entities can be defined based on the number of chromosomes as so-called ploidy groups. A small subgroup with low-hypodiploid/near triploid karyotype was described, which seems to be associated with adverse outcome (Charrin et al, Blood 2004), but was poorly characterized so far. Aim:Characterize the subset of ALL with low-hypodiploid/near triploid karyotype with respect to the patterns of chromosomal gains and losses and additional structural abnormalities and prognosis. Patient and Methods:In total, 561 adult ALL patients with cytogenetic analysis at diagnosis were studied (median age: 52.5 yrs, range: 16–90 yrs). All cases were analyzed in addition by interphase FISH for the presence of BCR-ABL1- and MLL-rearrangements. Further, 16 patients (pts) with low-hypodiploidy/near triploidy and 18 pts with normal karyotype were evaluated by array-CGH (Human CGH 12×270K Whole-Genome Tiling Array; Roche NimbleGen, Madison, WI). Results:Near-haploidy (25–29 chromosomes) was observed in 2 (0.3%) and low-hypodiploidy (30–39 chromosomes) in 11 (1.9%) pts. 52 pts (9.3%) showed between 40 and 45 chromosomes and 356 pts (63.5%) 46 chromosomes. In 88 pts (15.7%) the chromosome number was between 47 and 50. 36 patients (6.4%) belonged to the high-hyperdiploid subset (51–65 chromosomes), 6 (1.1%) pts showed near-triploidy (66–79 chromosomes), and 10 (1.8%) near-tetraploidy (84–100 chromosomes). ALL with near-haploid/low-hypodiploid/near-triploid karyotype (n=19):This ALL subtype comprises ALL with near-haploid/low-hypodiploid karyotype (n=13) and ALL with near-triploid karyotype (n=6). A typical pattern of lost chromosomes was observed. Whilst chromosomes 3 and 7 were lost in all pts, chromosomes 1, 5 and 21 were retained in the majority of pts (n=18). 6/13 pts with near-haploidy or low-hypodiploidy showed a subclone with doubling of the aberrant chromosome set. In 6 pts with near-triploid karyotype the pattern of gained and lost chromosomes suggested that this near-triploid clone most probably evolved from the doubling of a near-haploid/low-hypodiploid clone with a comparable pattern of lost and retained chromosomes as observed in ALL with near-haploid/low-hypodiploid karyoytpe. Thus, in total 19/561 (3.4%) showed a low-hypodiploid/near-triploid karyotype with a typical pattern of lost and retained chromosomes. This genetic subgroup occurred only in B-cell precursor ALL (c-ALL and Pro-B-ALL) and showed a median age of 68.8 yrs (range: 15.7–77.9 yrs). In none of these pts a BCR-ABL1- or MLL-rearrangement was present. Structural abnormalities in addition to chromosome losses were found in 11/19 pts by chromosome banding analysis, the only recurrent one was a deletion 9p observed in 2 pts. In 16 of these 19 pts array CGH analyses were performed and revealed cytogenetically cryptic gains (n=9) and losses (n=18) in 11 pts. 13/16 pts showed a 9p21 deletion including the CDKN2A locus (10 pts due to monosomy 9 or cytogenetically visible 9p deletion and 3 due to a small cytogenetically cryptic deletion), this was homozygous in 3 pts. Additional recurrent losses were found in 6p22-6p25 (n=2) and 5q23.3-5q31.1 (n=2). Further, 18 pts (17 B-ALL, 1 T-ALL) with normal karyotype were evaluated by array CGH. 5 of these (27.8%) demonstrated a pattern of gains and losses resembling the pattern observed in the low-hypodiploid/near-triploid ALL cases demonstrating that some pts of this entity escape detection by cytogenetics, most probably due to low proliferation in vitro. Further, we confirmed a short median overall survival of only 6.1 months in this adult cohort of low-hypodiploid/near-triploid ALL. Conclusions:1. ALL with a low-hypodiploid/near-triploid karyotype is a rare entity accounting for 3.4% of adult ALL. It is observed only in B-lineage ALL and shows a typical pattern of lost and retained chromosomes and no BCR-ABL1- or MLL-rearrangement. 2. The only recurrent abnormalities in addition to loss of whole chromosomes were deletions of 6p22-6p25, 5q23.3-5q31.1, and 9p21 including the CDKN2A locus. 3. Array CGH or interphase FISH with centromere specific probes for chromosomes 1, 3, 5, 7, and 21 allows the identification of this specific entity and may be considered in cases with ALL and normal karyotype. Disclosures:Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.