The Clinical Significance of Monitoring Expression Level of Sil-TAL1 Fusion Gene after Allogeneic Hematopoietic Stem Cell Transplantation

Objective SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL). However, whether this fusion gene could be used as a reliable marker of minimal residual disease (MRD) after allogeneic stem cell transplantation (allo-HSCT) remains unknown. This study purposed to investigate the clinical significance of monitoring level of SIL-TAL1 fusion gene in patients with T-ALL after allo-HSCT.

Methods Clinical data of consecutive 29 patients received allo-HSCT in Peking University Institute of Hematology from December 2009 to May 2016 were retrospectively collected. The SIL-TAL1 gene and Wilms tumor 1 (WT1) gene was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplant and the fixed time points after transplantation. The transcript level was calculated as target transcript copies/ABL copies in percentage. A WT1 transcript level more than 0.60% was defined as WT1+. At the same time, leukemia associated immunophenotype (LAIP) was examined by 8-color flow cytometry. Positive FCM was defined as >0.01% of cells with an LAIP phenotype in >1 bone marrow samples in patients. The correlation between its expression level and status of disease was analyzed.

Results The median follow-up was 217d(46d-1852d). There were 13 patients died and 11(84.6%) of them died of leukemia relapse. Total 14 (48.3%) patients underwent relapse at a median of 90 d(60d-540d) after transplant. The median expression level of SIL-TAL1 gene at the diagnosis was 7.5%(0.012%-20.1%). Except 6 patients, the SIL-TAL1 levels of other 23 patients at the diagnosis were available. Nine of them had a positive SIL-TAL1 expression with a median of 1.2%(0.035%-9.7%). However, among these 9 patients, only 6 cases were FCM+ and 3 cases were WT1+. After allo-HSCT, the SIL-TAL1 expression of 13 patients converted to positive after transplant at a time of 84 d (30d-600d) with a median expression level of 0.05%(0.0034%-20.4%). In the 14 relapsed patients, 10(71.4%) cases had an increased SIL-TAL1 expression 30d(15d-225d) earlier than hematological relapse. The immunophenotype changed at the time of relapse compared to that at the diagnosis in one patient. Though WT1 and FCM were positive, his SIL-TAL1 gene remained negative at the relapse. The SIL-TAL1 gene converted to positive at the same time of relapse in the last 3 patients. Among the 14 relapsed patients, 6 patients received chemotherapy followed by donor lymphocyte infusion (DLI), but none of them achieved complete remission (CR) and remained SIL-TAL1 positive. 6 patients abandoned further treatment after relapse. Only 2 patients returned to CR after DLI with a negative SIL-TAL1. The patients with positive SIL-TAL1 and without SIL-TAL1 had a 2-year cumulative incidence of relapse (CIR) of 86.1±12.7% and 40.8±14.1%, respectively (P=0.038). It showed that all patients who had a positive SIL-TAL1 after transplant underwent relapse. However, those whose SIL-TAL1 expression remained to be negative had a lower 2-year CIR of 17.0±11.2%. There was also significant difference in overall survival between patients with or without post positive SIL-TAL1 expression (P<0.001).

Conclusion Monitoring SIL-TAL1 fusion gene by RQ-PCR could be a more sensitive method to evaluate MRD status after allo-HSCT. Those whose SIL-TAL1 gene converts to positive at early stage of transplant will have a poor prognosis. Patients with this type of ALL would have little response to the current intervention towards relapse. Giving relapse intervention based on SIL-TAL1 gene expression might improve the outcomes of T-ALL patients with SIL-TAL1.