Highly aggressive T-cell acute lymphoblastic leukemia with t(8;14)(q24;q11): extensive genetic characterization and achievement of early molecular remission and long-term survival in an adult patient

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) originates from multiple gene alterations occurring in normal precursor T cells, and represents 20% of adult ALL cases. Several recurrent cytogenetic abnormalities, cryptic cytogenetic aberrations, micro-deletions and other genomic changes were described using fluorescence in situ hybridization (FISH) arrays and gene expression and mutation analysis. Among the alterations affecting cell growth and differentiation mechanisms, 1,2 a key pathogenetic role was demonstrated for NOTCH1-activating mutation, detectable in about 60% of the cases, with or without associated FBXW7 gene inactivation. Other frequent findings are CDKN2A/2B deletions and T-cell receptor (TCRB, TCRA-TCRD) gene translocations involving transcription factor (TAL1, TAL2, LYL1, LMO1, LMO2, LMO3, TLX1, TLX3, NKX2.1, NKX2.2, HOXA, MYC), tumor suppressor (WT1, LEF1, ETV6, RUNX1, GATA3) and signal transduction (PTEN, ABL1, NRAS, JAK1, JAK3) genes. Variously combined, these abnormalities concur to identify distinct molecular and prognostic subsets that could be targeted by new biology response modifiers to enhance the probability of cure. Translocation t(8;14)(q24;q11), first reported in pediatric patients and detectable in about 1% of TALL cases, is the hallmark of an extremely aggressive syndrome characterized by hyperleukocytosis, lymphoma-like presentation, rapid neurological progression and poor response to chemotherapy. 3 In t(8;14)(q24;q11), the MYC proto-oncogene, which is also a target of NOTCH1 activation and maps at 8q24, is activated and fused to TCRA/D genes, exerting transcriptional repression of cell cycle inhibitors p27 and p21. Because of its rarity, t(8;14) þ TALL is almost unknown (or under-recognized) in adults. In the MRC-ECOG study recruiting 782 successfully karyotyped patients, no t(8;14) þ TALL was recognized, although there were 102 patients with unspecified abnormal karyotypes, 4 and no t(8;14) þ TALL was identified in two large series from the same group (n ¼ 356) and GIMEMA (n ¼ 90). 5,6 We identified an adult patient with t(8;14) þ TALL in whom a thorough clinico-laboratoristic investigation was performed, including the combined interphase (CI) FISH study of several genes potentially involved in TALL pathogenesis and the molecular evaluation of minimal residual disease (MRD). This 44-year-old male suffering from backache and malaise for 3 days before referral presented with a white blood cell (WBC) count of 251 Â 10 9 /l (100% lymphoblasts), hemoglobin 16.4 g/dl, platelets 159 Â 10 9 /l, modest diffuse lymphadenopathies, and enlarged spleen and liver palpable 5 and 3 cm below the costal margin, respectively. The chest film showed a mediastinal mass (34% of the transverse chest diameter), while routine biochemistry indicated liver involvement (aspartate transaminase 216 U/l, alanine transaminase 188 U/l, alkaline phosphatase 493 U/l, gamma glutamyl-trasferase 303 U/l, bilirubin 0.7 mg/dl), preserved renal function (urea 36 mg/dl, creatinine 1.28 mg/dl, creatinine clearance 99 ml/min, sodium 144 mmol/l, potassium 3.8 mmol/l, chloride 104 mmol/l, calcium 10.4 mmol/l), and high risk for tumor lysis syndrome (lactate dehydrogenase 5079 U/l, uric acid 9.1 mg/dl). Flow cytometry analysis confirmed TALL with late cortical immunophenotype: cyCD3 94%, CD7 97%, CD2 92%, CD5 95%, CD4 70%, CD8 94%, CD1a 82%, sCD3 92%; nuclear TdT was poorly expressed (11%), CD56 was 3% and myeloid/stem cell antigens were CD33 7%, CD117 70% and CD34 70% (CD13 not assessed). The cytogenetic analysis, performed according to Quinacrine-banding of 24 and 48 h unstimulated cell cultures, showed a 46 XY, t(8;14)(q24;q11)[13]/46 XY[3] karyotype (Figure 1a). The concurrent involvement of MYC proto-oncogene and TCRA/D genes was confirmed by FISH on metaphases exposed to LSI MYC/IGH/CEP8 tricolor dual fusion and LSI MYC and TCRA/D break apart Vysis probes: t(8;14)(D8Z1 þ ,5 0 MYC þ ,3 0 TCRA/D þ ;5 0 TCRA/D þ ,3 0