PB1655 GENOTYPE AND CLINICAL REPERCUSSIONS IN T LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN

Background: T lineage acute lymphoblastic leukemia (T‐ALL) accounts for approximately 15% of pediatric ALL. T‐ALL has a distinct clinical presentation characterized by high white cell counts, bulky disease and early relapses that are difficult to salvage. Elucidation of the genetic landscape of T‐ALL could pave the way for improving outcomes through better risk stratification and targeted therapy. Aims: To detect common genetic aberrations in children with T‐ALL and identify their clinical significance Methods: Children aged ≤ 12 years, and diagnosed with T‐ALL between September 2015 and December 2018 were included. RNA and DNA were isolated from the peripheral blood sample obtained at diagnosis. cDNA was prepared from RNA. Reverse‐transcriptase polymerase chain reaction (RT‐PCR) was performed to detect oncogenic transcripts: TLX‐1, TLX‐3 and SIL‐TALI. RT‐PCR followed by bidirectional sequencing was used to detect NOTCH1 mutations. Multiplex Ligation‐dependent Probe Amplification was performed with a T‐ALL probemix for identifying copy number variations (CNV). Clinical details were obtained retrospectively till September 2016 and prospectively subsequently. Treatment was administered as per the Indian Collaborative Childhood Leukemia protocol (ICICLE). The study was funded by the Council of Scientific and Industrial Research, India. Results: Thirty‐three children with T‐ALL were diagnosed in the study period.. The mean age was 6.7 ± 2.7 years (range: 1.1‐11.5) and 27 (82%) were boys. The mean white cell count was 235.69 × 10 3 /μL (range: 1.3 – 785.43). A partial exchange transfusion for hyperleukocytosis was performed in 8 (24%) patients. Radiological evidence of mediastinal adenopathy and superior mediastinal syndrome were evident in 16(48%) and 7 (21%) patients. Bulky lymphadenopathy and hepatosplenomegaly were observed in 11(33%) patients. One (3%) patient had central nervous system involvement at presentation. Two (6%) patients had an immunophenotype that was consistent with early‐T‐precursor ALL. TLX1 and TLX‐3 overexpression were detected in 1 (3%) and 7 (21%) patients. The SIL‐TAL1 fusion transcript was identified in 8 (27%) patients. Of the 19 patients in whom the NOTCH1 gene could be adequately assessed, 16 (84%) had evidence of mutations. The NOTCH1 mutations identified were point mutations in the HD domain, frameshift mutations in the PEST domain and multiple domain mutations in 11 (69%), 3 (19%) and 2 (12%) patients. The commonest CNVs were detected in the cell cycle genes CDKN2A (90%) and CDKN2B (80%), followed by the epigenetic regulator gene PHF6 (87%). Figure 1 illustrates the genetic aberrations detected in the study. Two (6%) patients refused therapy. Relapse occurred in 8 (25%) patients and induction failure occurred in 2 (6%) patients. One patient developed therapy related myelodysplasia. Twelve of the 31 treated patients, (39%) were poor prednisolone responders. The median follow‐up duration was 14 months (range: 0.5‐36). The mean time to relapse was 16.2 months (95% CI: 9.7‐22.8). A greater proportion of relapses were observed in patients with NOTCH1 mutations in the PEST/multiple domains when compared to patients with mutations in the HD domain (80% vs. 18%, P = 0.036). Summary/Conclusion: NOTCH1 mutations were identified in 84% of T‐ALL patients. Mutations in PEST/multiple domains of NOTCH1 were associated with greater proportion of relapses. The commonest copy number variations were identified in the cell cycle and epigenetic regulator genes. This is an avenue for targeted therapy research.