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Prognostic significance of high-level FLT3 expression in MLL-rearranged infant acute lymphoblastic leukemia

Ronald W. Stam, Pauline Schneider, Paola de Lorenzo, Maria G. Valsecchi, Monique L. den Boer and Rob Pieters

To the editor:

Recently, we have demonstrated that in primary MLL-rearranged infant acute lymphoblastic leukemia (ALL) samples, high-level expression of wild-type FLT3 is associated with FLT3 phosphorylation (ie, constitutive activation) and sensitivity toward the small-molecule FLT3 inhibitor PKC412.1,2 Similarly, Brown et al reported that MLL-rearranged ALL cells with high-level FLT3 expression are selectively killed by the FLT3 inhibitor CEP-701.3

These findings suggest the existence of a threshold level of FLT3 expression above which activated FLT3 becomes apparent and “targetable.” Exploring this possibility, we have analyzed the prognosis of our recently published cohort of patients with MLL-rearranged infant ALL2 in relation to FLT3 expression. For 32 of 41 samples for which the level of FLT3 expression was determined using quantitative RT-PCR, clinical data were available. All of these samples tested negative for the presence of activating FLT3/tyrosine kinase domain (TKD) mutations or FLT3/internal tandem duplications (ITDs). Among these 32 patients with MLL-rearranged infant ALL, FLT3 expression relative to the housekeeping gene GAPDH ranged from 0.46% to 17.4%, with a median and mean expression level of 1.8% and 3.5%, respectively. Moreover, all patients were uniformly treated according the Interfant-99 protocol.

Using the mean FLT3 expression as the cut-off value to divide patients into 2 groups expressing low or high levels of FLT3, we found that high-level FLT3 expression is likely associated with a poor treatment outcome (Figure 1) within this subtype of ALL that is already characterized by a poor prognosis.46 The 1-year event-free survival (EFS) estimate is 71% for patients expressing low levels of FLT3, compared with 36% for patients displaying high-level FLT3 expression. These data are in concordance with data published by Ozeki et al,7 who showed that high-level expression of wild-type FLT3 is an unfavorable prognostic factor for overall survival in acute myeloid leukemia (AML).

Figure 1

EFS for patients with MLL-rearranged infant ALL expressing high (n = 11) or lower (n = 21) levels of FLT3 as determined by quantitative rt. PCR. The 1-year EFS estimate is 71% and 36% for patients expressing low or high levels of FLT3, respectively.

We conclude that constitutively activated FLT3 as a result of increased expression may contribute to the dismal prognosis of MLL-rearranged infant ALL. However, this should be confirmed in a larger prospective study. Targeting FLT3 overexpression in MLL-rearranged infant ALL using the FLT3 inhibitors PKC412 and CEP-701 has been shown to be effective in vitro and in vivo in a mouse model.13 Based upon these findings, The Childhood Oncology Group in the United States, and the Interfant Study Group worldwide are planning clinical studies including these FLT3 inhibitors. The finding we present here emphasizes the value of these clinical trials, as we show that the patients that are most likely to respond to FLT3 inhibitors are patients at very high risk of treatment failure.

Authorship

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Ronald W. Stam, Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children's Hospital, Dr Molenwaterplein 50, 3015 GE Rotterdam, the Netherlands; e-mail: r.stam{at}erasmusmc.nl.

References