Slow fusion gene transcript clearance predicts poor outcome in infants with MLL-rearranged acute lymphoblastic leukemia
Grigory A. Tsaur1,2, Tatyana V. Nasedkina3, Alexander M. Popov1,2,4, Anna S. Ivanova1,2, Yulia A. Yakovleva1,2, Tatyana O. Riger1,2, Egor V. Shorikov1,2, Leonid I. Saveliev1,2,4, Larisa G. Fechina1,2
1Regional Children Hospital 1, Ekaterinburg, Russia; 2Research Institute of Medical Cell Technologies, Ekaterinburg, Russia; 3Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; 4Ural State Medical Academy, Ekaterinburg, Russia
Correspondence
Grigory Tsaur, Regional Children Hospital №1, Pediatric Oncology & Hematology Center
S. Deryabina Street 32, 620149 Ekaterinburg, Russia, Phone: +7-343-216-2517, Fax: +7-343-216-2517
E-mail: grigory.tsaur@gmail.com
Summary
Objective
To find out a single time point (TP) for fusion gene transcript (FGt) monitoring by RT-PCR that clearly predicts the outcome in infants with MLL-rearranged ALL. All patients (pts) were treated by MLL-Baby protocol, containing all-trans retinoic acid (ATRA).
Methods
The monitoring of FGt was performed in 18 infants with defined MLL translocation partner genes and more than 4 follow-up samples. MRD-negativity was defined as an absence of FGt in nested RT-PCR with sensitivity of 1E-5. The median of follow-up was 25 months. There were
11 MLL-AF4-positive pts, 3 MLL-MLLT10-positive, 2 MLL-EPS15-positive, 1 MLL-MLLT1-positive patient, and 1 MLL-MLLT3-positive patient. Bone marrow samples were obtained at diagnosis, on day 15 of remission induction (TP1), end of remission induction (TP2), one week after first ATRA administration (TP3). In MLL-AF4-positive pts following TPs (TP4–TP9) were scheduled before each HR block. In all other pts the presence of FGt was estimated before each reinduction (TP4-TP6).
Results
FGt elimination speed does not correlate to any known prognostic factors. Retrospectively, patients were divided into 2 groups. The first group included 14 patients who achieved molecular remission by TP4, while 2 relapses occurred (MLL-AF4-positive and MLL-EPS15-positive). The second group consisted of 4 MLL-AF4-positive pts who did not achieve molecular remission by TP4; there were 3 relapses. The number of relapses in this group was significantly higher (p=0.04). The 70-month RFS in the first group was 0.84, in the second group 0.25 (p=0.02). The cumulative incidence of relapse in the first group was 0.15, in the second group 0.75 (p=0.02)
Conclusions
The presence of FGt by TP4 helps to identify pts with a high risk of relapse.
Keywords
ALL, infants, MLL rearrangements, fusion gene transcripts, MRD monitoring
