Monosomal karyotype in Philadelphia chromosome-negative acute lymphoblastic leukemia

A monosomal karyotype (MK) is defined by the presence of two or more autosomal monosomies or one autosomal monosomy and one or more structural abnormality. MK has been shown to have a negative impact on survival in patients with acute myeloid leukemia, primary myelofibrosis and myelodysplastic syndromes. In several studies, the negative prognostic significance of MK in myeloid neoplasms persisted after treatment with allogeneic stem cell transplantation. A recent analysis from Spain failed to demonstrate an independent prognostic significance of MK in myelodysplastic syndromes. Multiple recurring chromosomal alterations have been identified in acute lymphoblastic leukemia (ALL). The World Health Organization 2008 classification recognizes the following recurring genetic abnormalities: t(9;22)(q34;q11.2);BCR-ABL, t(v;11q23); MLL rearrangement, t(12;21)(p13;q22); TEL-AML1(ETV6RUNX1), hyperdiploidy, hypodiploidy, t(5;14)(q31;q32) IL3-IGH and t(1;19)(q23;p13.3);TCF3-PBX1. Several cytogenetic risk classifications in adult ALL were introduced during the last decade. Although there are subtle differences between these, the overall assignment to favorable or unfavorable risk categories is concordant. Most analyses demonstrated a negative prognostic value for karyotypes with hypodiploidy, t(9;22), t(4;11), t(8;14), MLL translocations and for complex karyotypes (defined as the presence of five or more chromosomal abnormalities, excluding those with established translocations). In a large cytogenetic analysis of 1522 adult patients treated in the Medical Research Council UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial, four prognostic karyotype categories were identified: standard risk ALL (hyperdiploid karyotype), intermediate risk ALL (11q abnormalities (other than MLL), del(17p), del(6q), del(9p), del(12p), -13, t(14q32), t(10;14), low hyperdiploidy (47–50 chromosomes), tetraploidy, normal and all others), high-risk ALL ( 7, þ 8, MLL rearrangements, t(1;19), t(17;19), t(5;14)) and very-high-risk ALL (t(4;11), t(8;14), complex karyotype (X 5 abnormalities), low hypodiploidy and near triploidy). MK in ALL has not been evaluated thus far. The goal of this study was to evaluate the incidence, clinical characteristics and prognosis of a MK in Philadelphia chromosome-negative ALL (Ph Neg ALL). This study was approved by the Mayo Clinic Institutional Review Board. The Mayo Clinic leukemia database was used to identify consecutive patients with newly diagnosed ALL. Patients were stratified by cytogenetic risk categories using the four-karyotype risk model proposed by the MCR UKALLXII/ECOG 2993 analysis. All cytogenetic results were reviewed to identify patients with a MK. Outcomes analyzed included overall survival (OS) calculated from the date of diagnosis, leukemia-free survival (LFS) and relapse rates. Chi-square test was used to compare the variables. Survival was estimated and compared by using the Kaplan–Meier Method and the log-rank test, respectively. Multivariate analysis was performed using the Cox regression model. Between 1998 and 2010, a total of 175 consecutive patients with ALL (63 (36%) with the Philadelphia chromosome) were identified. Patients with Phþ ALL were excluded from further analysis. In the study set of patients with Ph Neg ALL (112 patients), the median age was 39 years (16–88). Seventy-four (66%) were male patients. Cytogenetic risk stratification revealed standard risk cytogenetics in 5 (4.4%), intermediate risk in 70 (62.5%), high risk in 8 (7.1%) and very-high risk in 29 (25.9%) patients. Twenty-two patients (20.9%) presented with extramedullary disease (13 patients with central nervous system disease; 12%). Six had prior exposure to chemotherapy. Complete blood counts at presentation were as follows: median hemoglobin 10 g/dl (4.1–18.5), median platelet count 61 10/l (3–523) and median white blood cell count 7.2 10/l(0.8–377). Thirty-four (39.3%) patients underwent allogeneic stem cell transplantation. The median OS for the whole cohort was 41 months (0–206). The median LFS was 29 months (0–193). Ninety-one patients (81.3%) achieved an initial complete response and 44 (39.3%) had a subsequent relapse after achieving an initial complete remission, with a median time to relapse of 15 (2–73) months. Out of these 112 patients with Ph Neg ALL, MK was identified in 19 patients (16.9%). The median age at presentation in these 19 patients was 39 (16–81) years. Twelve patients (63.2%) were male