Genetic Instability and RAS Mutations Characterize Leukemic Progression in t(9;11)-Bearing Acute Myeloid Leukemia
P Chandra, R Luthra, G Garcia-Manero, D Jones. UT MD Anderson Cancer Center, Houston, TX
Background: Acute myeloid leukemias (AML) harboring translocation of the mixed-lineage-leukemia (MLL) gene at chromosome 11q23 have a poor prognosis. Genetic factors that may synergize with MLL to produce this aggressive phenotype are poorly studied. To identify interacting factors in leukemic progression, we compared the flow cytometric, cytogenetic and molecular features at diagnosis and relapse in 61 patients with t(9;11)(p21-22;q23) AML.
Design: Patients included 22 men and 39 women, with a median age of 50 years (range 1-81), including 32 de novo and 29 therapy related (t-AML) t(9;11) cases, with 0.2 to 87.5 months followup (median 12.2). Flow cytometric (FC) phenotype, G-banded karyotype and MLL-FISH analysis, were compared with codon 12, 13, and 61 KRAS and NRAS mutation status performed by PCR-based pyrosequencing, and codon 835/836 FLT3-ITD mutation status mostly determined by PCR-based methods.
Results: FAB subtypes at diagnosis were M5 (41%), M4 (26%), M2 (13%), M1 (15%), and M0 (5%). Most patients displayed some degree of monocytic differentiation by cytochemistry or FC phenotype. RAS mutations were found at diagnosis in 32% (14/44), with FLT3 alterations in 9% (4/43) and were mutually exclusive; RAS mutations were more frequent in t(9;11)-AML as compared to t(6;11)-bearing AML from our database (1/17, p = 0.04). Fifty-one patients (84%) had relapsed/refractory disease, with 45 deaths due to disease (median survival 11.8 months), 7 alive with disease, and 9 in complete remission. t-AML patients (p = 0.023) and those with cytochemical evidence of monocytic differentiation did worse (p = 0.05), by Kaplan-Meier analysis. Only 6 cases (10%) had t(9;11) as the sole cytogenetic aberration throughout disease. High rates of aneuploidy (48% overall, +8 in 18%), and/or structural chromosomal changes (43%) were common at diagnosis or upon relapse. Shifts in FC phenotype were also noted in 7/19 cases. Changes in HLA-DR, CD34, CD52, and CD64 correlated with increasing aneuploidy and disease progression.
Conclusions: AML with t(9;11) (p21-22;q23) often shows complex cytogenetic changes including shifting patterns of aneuploidy and genomic progression upon relapse, factors which may contribute to its extremely poor outcome. Frequency of RAS mutation is similar to other leukemias with monocytic differentiation. Therefore, strategies targeting RAS pathway activation may be helpful in treatment of this aggressive AML subtype.
Tuesday, March 10, 2009 1:30 PM
Platform Session: Section D, Tuesday Afternoon