Prognostic Significance of Time to Achievement of Molecular Remission in Infants with Mll-Rearranged Acute Lymphoblastic Leukemia Treated by Mll-Baby Protocol

Clinical experience

Tsaur G.A., Popov A.M., Nasedkina T.V., Riger T.O., Streneva O.V.,

Shorikov E.V., Saveliev L.I., Fechina L.G.

Abstract.

Predictive value of early complete molecular remission (cMR) in infant acute lymphoblastic leukemia is not clear so far. Objective. To define a time point (TP) of fusion gene transcript (FGt) monitoring by reverse-transcriptase PCR (RT-PCR), that clearly predicts outcome in infants with MLL-rearranged ALL, enrolled onto MLL-Baby protocol where conventional chemotherapy is augmented by administration of all-trans retinoic acid (ATRA). Methods. Monitoring of FGt was performed in 18 infants with defined MLL translocation partner genes who had more than 4 follow-up samples. Median of follow-up in the observed group was 30 months. cMR was defined as absence of FGt at nested RT-PCR with sensitivity 5½10-5. Detection of FGt in bone marrow (BM) was performed by qualitative nested RT-PCR as previously described. Among 18 infants there were 11 MLL-AF4-positive patients (pts), 3 MLL-MLLT10-positive pts, 2 MLL-EPS15-positive pts, one MLL-MLLT1-positive patient and one MLL-MLLT3-positive patient. BM samples were obtained at diagnosis, at day 15 of remission induction (time point (TP) 1), at the end of remission induction (TP2) and after each course of ATRA administration (TP3-TP9). Informed consent was obtained in all cases. Results. FGt elimination speed did not correlate with any known prognostic factors such as initial WBC count, age at diagnosis, number of blast cells at day 8 of dexamethasone prophase, CNS status, type of MLL partner gene. Retrospectively, pts were divided into two groups. First group included 14 pts who achieved cMR by TP4, where two relapses occurred (in MLL-AF4-positive and MLL-EPS15-positive cases). The second group consisted of four MLL-AF4-positive pts, who had not achieved cMR by TP4. In this group there were 3 relapses. Number of relapses was significantly higher in the second group (odds ratio 18.00; 95% CI 1.19-271.47; p=0.044). Cumulative incidence of relapse in the first group was 0.15, in the second group 0.75 (p=0.022). 75-months event-free survival in the first group was 0.84, in the second group 0.25 (p=0.023). Conclusions. Slow achievement of cMR corresponds to poor outcome in infant ALL with MLL rearrangements. Persistence of FGt at TP4 allows defining patients with high risk of relapse.

Kew words:

acute lymphoblastic leukemia, infants, minimal residual disease, treatment response, MLL rearrangements, polymerase chain reaction

Аuthors:

Tsaur Grigory A.

e-mail: tsaur@mail.ru
Regional Children’s Hospital №1; Research Institute of Medical Cell Technologies
Russia, 620149, Ekaterinburg, S. Deryabina street, 32

Popov Alexander M.

e-mail: uralcytometry@gmail.com
Regional Children’s Hospital №1; Research Institute of Medical Cell Technologies
Russia, 620149, Ekaterinburg, S. Deryabina street, 32

Nasedkina Tatyana V.

e-mail: nased@eimb.ru
Engelgardt Institute of Molecular Biology RAS,
Doctor of sciences, Senior Researcher at Biochip Laboratory
Russia, GSP-1, 119991, Moscow, Vavilova street, 32

Riger Tatyana O.

e-mail: rigertati@mail.ru
Regional Children’s Hospital №1; Research Institute of Medical Cell Technologies
Russia, 620149, Ekaterinburg, S. Deryabina street, 32

Streneva Olga V. e-mail: dr_streneva@mail.ru
Regional Children’s Hospital №1; Research Institute of Medical Cell Technologies
Russia, 620149, Ekaterinburg, S. Deryabina street, 32

Shorikov Egor V.

e-mail: egor.shorikov@mail.ru
Regional Children’s Hospital №1; Research Institute of Medical Cell Technologies
Russia, 620149, Ekaterinburg, S. Deryabina street, 32

Saveliev Leonid I.

e-mail: sav7000@yandex.ru
Regional Children’s Hospital №1; Research Institute of Medical Cell Technologies
Ural State Medical University
Russia, 620149, Ekaterinburg, S. Deryabina street, 32

Fechina Larisa G.

e-mail: childrens_oncology@mail.ru
Regional Children’s Hospital №1; Research Institute of Medical Cell Technologies
Russia, 620149, Ekaterinburg, S. Deryabina street, 32