Identification of Partial Tandem Duplications of the MLL Gene in Acute Myeloid Leukemia: Prospective Analysis within the Multicenter Treatment Trial AML HD98-A

Abstract

At the cytogenetic level clonal chromosome aberrations are identified in approximately 50% of all patients (pts) with de novo acute myeloid leukemia (AML). To identify subgroups of pts with different risk for relapse within the population of pts who have normal cytogenetics molecular markers are warranted. Partial tandem duplication (PTD) of theMLL gene has been identified in 5–10% of AML patients with normal cytogenetics. First studies of heterogeneously treated pts suggest thatMLL PTD is associated with an unfavorable prognosis. Recently, we reported our results from the multicenter treatment trial AML HD93. In this study pretreatment samples were examined for PTD of theMLL gene. The incidence for PTD ofMLL was 8% in the group with normal cytogenetics and pts with PTD had a significantly shorter disease free survival compared to the PTD negative pts. None of the pts of the low risk group defined by t(15;17), t(8;21) and inv(16) exhibited a PTD, whereas PTD of theMLL gene was detected in 6% of the high risk group defined by all other chromosomal aberrations.

Based on these data we initiated a prospective analysis for the detection ofMLL PTD within the ongoing AML HD98-A trial for adult pts (16–60 years) with AML. Aim of this study is to continue evaluation of incidence and clinical significance ofMLL PTD in a homogeneously treated patient population. Up to now 326 pts are enrolled in the multi- center treatment trial. The preliminary results presented here are focused on the cases with normal cytogenetics from whom enough pretreatment material for Southern blot analysis was available (n=99). In case of the detection ofMLL rearrangements by Southern blot analysis the intragenic duplication was confirmed by single round RT-PCR and sequencing of the PCR-product. Based on the current results the incidence ofMLL PTD is 7/99 (7%). First data of clinical outcome underline the results of our recent study and show that PTD of theMLL gene is associated with a short disease free survival. If the negative prognostic impact ofMLL PTD in AML pts with normal cytogenetics will be confirmed in this study, this molecular marker should be used to stratify these pts for more intensive treatment regimens.