• In intermediate-risk AML,effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio.• Combined evaluation of NPM1 mutation and FLT3-ITD burden might contribute to identify patients who benefit from early allogeneic HSCT.Risk associated to FLT3 internal tandem duplication (FLT3-ITD) in patients with acute myeloid leukemia (AML) may depend on mutational burden and its interaction with other mutations. We analyzed the effect of FLT3-ITD/FLT3 wild-type (FLT3wt) ratio depending on NPM1 mutation (NPM1mut) in 303 patients with intermediate-risk cytogenetics AML treated with intensive chemotherapy. Among NPM1mut patients, FLT3wt and low ratio (<0.5) subgroups showed similar overall survival, relapse risk, and leukemia-free survival, whereas high ratio ( ‡0.5) patients had a worse outcome. In NPM1wt AML, FLT3-ITD subgroups showed a comparable outcome, with higher risk of relapse and shortened overall survival than FLT3wt patients. Allogeneic stem cell transplantation in CR1 was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD. In conclusion, effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio. (Blood. 2013;121(14): 2734-2738) IntroductionThe presence of FLT3 internal tandem duplication (FLT3-ITD) is associated with an increased risk of relapse (RR) and inferior overall survival (OS) in patients with normal karyotype acute myeloid leukemia (AML), arising as one of the main prognostic factors in this group of patients. 1-4 However, the risk conferred by this mutation has been related to specific characteristics, such as the allelic burden, length of the mutation, or specific sequence. [4][5][6][7] Thus, the proportion of the mutant allele among leukemic population is considered one of the most important features modulating the prognostic impact of the mutation.6,7 Nonetheless, the resulting effect of the FLT3-ITD is not only a consequence of intrinsic characteristics of the mutation but can also depend on the interaction with other mutations, such as WT1 or DNMT3A, which seem to add an adverse effect in patients with FLT3-ITD AML. [8][9][10] Moreover, FLT3-ITD, considered as a secondary mutation involving signaling cell pathways that confer a proliferation advantage to the leukemic clone (type I mutation), is frequently observed in patients harboring NPM1 mutations, associated to a favorable prognosis.11-14 Therefore, the effect of FLT3-ITD burden might depend on the presence or absence of an underlying NPM1 mutation, as recently suggested. [15][16][17] To test this hypothesis we analyzed a large series of patients with a long follow-up from the Spanish cooperative group CETLAM (Grupo cooperativo para el estudio y tratamiento de las leucemias agudas mieloblásticas). Study designPatients and treatment The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solel...

CTLA-4 is an inhibitory molecule that

We retrospectively assessed whether normalized bone marrow WT1 levels could be used for risk stratification in a consecutive series of 584 acute myeloid leukemia (AML) patients. A cutoff value of 5065 copies at diagnosis identified two prognostic groups (overall survival (OS): 44 ± 3 vs 36 ± 3%, P=0.023; leukemia-free survival (LFS): 47 ± 3 vs 36 ± 4%, P=0.038; and cumulative incidence of relapse (CIR): 37 ± 3 vs 47 ± 4%, P=:0.043). Three groups were identified on the basis of WT1 levels post-induction: Group 0 (WT1 between 0 and 17.5 copies, 134 patients, OS: 59 ± 4%, LFS:59 ± 4% and CIR: 26 ± 4%); Group 1 (WT1 between 17.6 and 170.5 copies, 160 patients, OS: 48 ± 5%, LFS:41 ± 4% and CIR: 45 ± 4%); and Group 2 (WT1 >170.5 copies, 71 patients, OS: 23 ± 6%, LFS: 19 ± 7% and CIR: 68 ± 8%) (P<0.001). Post-intensification samples distinguished three groups: patients with WT1 >100 copies (47 patients, 16%); an intermediate group of patients with WT1 between 10 and 100 copies (148 patients, 52%); and a third group with WT1 <10 copies (92 patients, 32%). Outcomes differed significantly in terms of OS (30 ± 7%, 59 ± 4%, 72 ± 5%), LFS (24 ± 7%, 46 ± 4%, 65 ± 5%) and relapse probability (CIR 72 ± 7%, 45 ± 4%, 25 ± 5%), all P<0.001. WT1 levels in bone marrow assayed using the standardized ELN method provide relevant prognostic information in de novo AML.