Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy

Abstract

• 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...

Prognostic factors for acute myeloid leukaemia in adults - biological significance and clinical use

“…(Kottaridis et al, 2001;Whitman et al, 2001;Frohling et al, 2002;Thiede et al, 2002;Gale et al, 2008). In patients with intermediate cytogenetic risk, the negative prognostic impact is evident in patients with concomitant Nucleophosmin 1 (NPM1) mutation only when present with a high allelic mutant to wt ratio, while in patients with wt NPM1, the presence of a FLT3-ITD itself confers a negative prognosis (de Jonge et al, 2011;Schnittger et al, 2011a;Schneider et al, 2012;Pratcorona et al, 2013). The ITD size highly correlated with the ITD location within the FLT3 gene ).…”

Post-remission therapy for acute myeloid leukemia

“…An exemption may be AML with a FLT3-ITD in the presence of an NPM1 mutation and a low FLT3-ITD mutant to wild-type ratio (<0.5) with a reported favorable outcome also after intensive chemotherapy. 47 However these results need further confirmation. Furthermore, FLT3-inhibitors are in clinical evaluation, 48 where maintenance after intensive consolidation therapy but also after allogeneic HSCT has been evaluated in ongoing clinical trials (e.g.…”

Impact of FLT3-ITD diversity on response to induction chemotherapy in patients with acute myeloid leukemia

“…6 The allelic burden of FLT3-ITD was equally distributed between the two subgroups (median: 0.60 versus 0.61, not significant). Figure S1.…”