Acute Myeloid Leukemia (AML) with Monosomal Karyotype Is Characterized by Absence of NPM1 and FLT3 Mutations, Worse Clinical Outcome and Usually Falls within AML with Myelodysplasia-Related Changes (MRC)
OK Weinberg, M Seetharam, L Ren, L Ma, K Seo, J Zehnder, J Gotlib, DA Arber. Stanford University Medical Center, Stanford, CA
Background: The importance of cytogenetics and complex karyotype in prognosis of AML is now widely recognized, but less is known about chromosomal monosomy. The goal of this study is to characterize patients with monosomal karyotype by mutation status and clinicopathological features.
Design: One-hundred forty AML patients, including 77 males and 63 females diagnosed at Stanford University, were tested for NPM1, FLT3 (ITD and D835) and CEBPA mutations. Diagnostic cytogenetic findings were reviewed and patients stratified into cytogenetic risk groups. Overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined and compared using Kaplan-Meier and multivariate Cox proportional hazards regression.
Results: Monosomal karyotype (MK) was present in 18/130 (14%) patients and the most common loses were 7, 5, 17, 21, 20, 22 and 18. Patients with MK were significantly older (83 vs 59 years, p=0.0125) and presented with lower WBC (34 vs 66 K/uL, p=0.0006), lower platelets (41 vs 64 K/uL, p=0.0111), and lower marrow blasts (38% vs 65%, p=0.0030) as compared to the other AML patients. In addition, patients with MK were more frequently diagnosed with AML-MRC (16/18 vs 48/107, p=0.0034) with a decreased frequency of NPM1 (0/18 vs 28/107, p=0.0138) and FLT3-ITD mutation (0/18 vs 29/107, p=0.0117) and more frequent blast expression of CD4 (12/14 vs 46/86, p=0.0235). Clinical outcome data showed that patients with MK had a significantly worse OS, PFS and CR compared to other AML patients (p=0.001, 0.002, 0.0262). Dividing patients by number of monosomies showed that patients with 2 or more monosomies had a significantly worse OS (p=0.0001) and PFS (p=0.0045) than those with no monosomies. Within the AML-MRC group, MK correlated with lower WBC (17 vs 37 K/uL, p=0.0005), lower platelets (21 vs 35 K/uL, p=0.0095), lower marrow blasts (19% vs 36%, p=0.0015) and shorter OS and PFS (p=0.0322 and 0.0084). Multivariate Cox proportional hazard analysis identified risk groups, monosomy and age >60y and as predictors of worse OS (hazard ratio: 2.49, 2.41, 2.35).
Conclusions: AML patients with monosomal karyotype are characterized by significant absence of NPM1 and FLT3-ITD mutations, most fall within the newly defined AML-MRC group and exhibit a significantly worse OS, PFS and lower CR as compared to other AML patients.
Tuesday, March 23, 2010 11:30 AM
Platform Session: Section B, Tuesday Morning