Early T-cell Precursor Leukemia Research Articles

Early T-cell precursor leukemia: questions of diagnosis, treatment and description of own clinical case

Early T-cell precursor leukemia (early T-cell precursor, ETP-ALL) is a new subvariant of acute lymphoblastic leukemia (ALL). Tumor blasts have a unique phenotype, including signs of both stem and myeloid cells. This fact significantly complicates differential diagnosis. Cytogenetic and molecular biological features of cells in ETP-ALL are the most important diagnostic criteria. Nowadays the leading scientific international groups of pediatric leukemia conduct researches to develop new treatment protocols for ETP-ALL or to optimize existing chemotherapy regimens by including targeted drugs (bortezomib, ruxolitinib, venetoclax). Currently, hematopoietic stem cell transplantation is a mandatory option in the treatment of ETP-ALL. Targeted drugs and CAR-T-cell (chimeric antigen receptor of T-cells) therapy are the most perspective ways of posable treatment. In this article there are summarized data on diagnosis and therapy and a description of a successful treatment of a patient with ETP-ALL.

Early T-Cell Precursor Leukemia Has a Higher Risk of Induction-Related Infection among T-Cell Acute Lymphoblastic Leukemia in Adult.

Background Infections are an important cause of morbidity and mortality for acute lymphoblastic leukemia (ALL). However, the reports regarding risk factors of induction-related infection are roughly unknown/limited in adult T-ALL during induction chemotherapy. Methods We performed a retrospective cohort study for the prevalence and risk predictors of induction-related infection among consecutive T-ALL patients (N = 97) enrolled in a PDT-ALL-LBL clinical trial. Of 97 patients with T-ALL enrolled in the trial, 46 were early T-cell precursor (ETP) ALL and 51 were non-ETP ALL. Results When compared with non-ETP, ETP ALL subtype was characterized with lower neutrophil count (1.35 × 109/L vs. 8.7 × 109/L, P < 0.001) and lower myeloid percentage in the bone marrow (13.35% vs. 35.31%, P = 0.007). Additionally, ETP ALL had longer neutropenia before diagnosis (P < 0.001), as well as during induction chemotherapy (P < 0.001). Notably, the ETP cohort experienced higher cumulative incidence of clinically documented infections (CDI; 33.33%, P = 0.001), microbiologically documented infections (MDI; 45.24%, P = 0.006), resistant infection (11.9%, P = 0.013), and mixed infection (21.43%, P = 0.003), respectively, than those of the non-ETP cohort. Furthermore, multivariable analysis revealed that T-ALL mixed infection was more likely related to chemotherapy response (OR, 0.025; 95% CI 0.127-0.64; P = 0.012) and identified myeloid percentage as a predictor associated with ETP-ALL mixed infection (OR, 0.915; 95% CI 0.843-0.993; P = 0.033), with ROC-defined cut-off value of 2.24% in ETP cohorts. Conclusions Our data for the first time demonstrated that ETP-ALL characterized with impaired myelopoiesis were more susceptible to induction-related infection among T-ALL populations.

Outcome of 126 adolescent and adult T-cell acute leukemia/lymphoma patients and the prognostic significance of early T-cell precursor leukemia subtype

目的分析我国急性T淋巴细胞白血病/淋巴瘤（T-ALL/LBL）患者的临床特征，探究急性早期前体T淋巴细胞白血病/淋巴瘤（ETP-ALL/LBL）分型的预后意义。方法回顾性分析2008年1月至2014年12月间在四川大学华西医院就诊的126例T-ALL/LBL患者临床资料，基于白血病细胞的免疫表型将其分为三组：ETP-ALL/LBL（CD1a−，CD8−，CD5−/dim以及一种或多种干细胞和髓系相关抗原表达）、近似ETP-ALL/LBL（除CD5+外其他同ETP-ALL表型特征）及非ETP-ALL/LBL（non-ETP-ALL/LBL）组，对患者的实验室指标及预后相关因素进行分析。结果126例T-ALL/LBL患者中男女比例为2.5∶1，中位年龄为25（14~77）岁，ETP-ALL/LBL亚型的比例高达47.6%。T-ALL患者首次化疗完全缓解（CR1）率显著高于T-LBL患者（64.4%对30.8%，P=0.032）；初诊外周血WBC>50×109/L的患者CR1率显著高于WBC ≤ 50×109/L的患者（78.4%对50.9%，P=0.010）。相较于non-ETP-ALL/LBL组，ETP-ALL/LBL组患者发病年龄更大（P<0.001）、外周血WBC更低（P<0.001）、病程中中枢神经系统浸润率更低（10.0%对30.2%，P=0.009）。ETP-ALL/LBL组患者CR1率显著低于non-ETP-ALL/LBL组（37.3%对84.6%，P<0.001）；ETP-ALL/LBL组患者较non-ETP-ALL/LBL组患者总生存期短，但差异无统计学意义（P=0.073）。T系抗原CD1a+组、CD8+组、CD4+组的CR1率均比相应的阴性组高（P值分别为0.002、0.000、0.001），而髓系抗原CD33+组、CD56+组CR1率均比相应的阴性组低（P值分别为0.035、0.035）。结论中国青少年和成人T-ALL患者中ETP-ALL/LBL亚型比例高，ETP-ALL/LBL属于成人ALL的高危亚型，需要更精确的诊断及新的治疗策略来改善预后。

Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia includes T-cell acute lymphoblastic leukemia (T-ALL) and B-cell acute lymphoblastic leukemia (B-ALL). In children, T-ALL usually has a worse prognosis than B-ALL, although childhood T-ALL prognoses have improved remarkably. The varying outcomes among T-ALL cases suggest that an unrecognized biological heterogeneity may contribute to chemo-resistance. Deep exploration of T-lymphocyte development in recent years has found a subgroup of patients with a phenotype that resembles early T-cell precursor, which confers a much poorer prognosis than any other form of T-ALL. This novel subtype of T-ALL was called early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Flow cytometry data from T-ALL patients enrolled in Shanghai Children's Medical Center between July 2002 and October 2010 were assessed according to Dr. Campana's protocol. Among total 89 T-ALL cases, 74 cases had enough immunophenotype data available to differentiate between ETP (CD1a(-), CD8(-), CD5(dim), at least one marker of stem cell or myeloid lineage) and non-ETP. From these 74 subjects, 12 ETP-ALL cases (16.2%) were identified. The event-free survival (EFS) rate at 66.8 months was 11.1% ± 10.1% for ETP-ALL and 57.6% ± 5.6% for non-ETP-ALL (P = 0.003). The overall survival rates were 13.3% ± 11.0% for ETP-ALL and 64.7% ± 6.3% for non-ETP-ALL (P = 0.002). Our findings demonstrate that early T-cell precursor leukemia is a very high-risk subtype of acute lymphoblastic leukemia with poor prognosis.

Clinical and molecular characterization of early T-cell precursor leukemia: a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations

A subgroup of pediatric acute T-lymphoblastic leukemia (T-ALL) was characterized by a gene expression profile comparable to that of early T-cell precursors (ETPs) with a highly unfavorable outcome. We have investigated clinical and molecular characteristics of the ETP-ALL subgroup in adult T-ALL. As ETP-ALL represents a subgroup of early T-ALL we particularly focused on this cohort and identified 178 adult patients enrolled in the German Acute Lymphoblastic Leukemia Multicenter studies (05/93–07/03). Of these, 32% (57/178) were classified as ETP-ALL based on their characteristic immunophenotype. The outcome of adults with ETP-ALL was poor with an overall survival of only 35% at 10 years, comparable to the inferior outcome of early T-ALL with 38%. The molecular characterization of adult ETP-ALL revealed distinct alterations with overexpression of stem cell-related genes (BAALC, IGFBP7, MN1, WT1). Interestingly, we found a low rate of NOTCH1 mutations and no FBXW7 mutations in adult ETP-ALL. In contrast, FLT3 mutations, rare in the overall cohort of T-ALL, were very frequent and nearly exclusively found in ETP-ALL characterized by a specific immunophenotype. These molecular characteristics provide biologic insights and implications with respect to innovative treatment strategies (for example, tyrosine kinase inhibitors) for this high-risk subgroup of adult ETP-ALL.

MEF2C as Novel Oncogene for Early T-Cell Precursor (ETP) Leukemia

AbstractAbstract 9To identify novel oncogenic pathways in T-cell acute lymphoblastic leukemia (T-ALL), we combined expression profiling of 117 pediatric patient samples and detailed molecular cytogenetic analyses. Using unsupervised and supervised analyses, we identified a T-ALL cluster that was associated with an immature immunophenotype (CD1−, CD4−, CD8−), frequent expression of CD34 and co-expression of the myeloid markers CD13/CD33. Patients in this cluster lacked any of the known oncogenic rearrangements, but ectopically expressed MEF2C, which was recently demonstrated as an important transcription factor for T-cell development1. Molecular-cytogenetic analyses including the Chromatine Conformation Capture on Chip (4C) method revealed novel rearrangements of the MEF2C locus at 5q14, rearrangement of transcription factors that target MEF2C (PU.1, NKX2-5, RUNX1) or MEF2C-associated cofactors (NCOA2/GRIP1) in about half of the patients in this cluster. Four out of the 6 rearrangements identified have never been observed before in human cancer. Nearly all of these patients in this cluster could be predicted by the early T-cell precursor (ETP) signature2 using PAM statistics. This indicates that MEF2C may represent the oncogene for ETP T-ALL, an entity that has been associated with poor outcome2. Inhibition of MEF2C in a cell line model system provoked relieve of developmental arrest, indicating that ectopic MEF2C expression blocks T-cell development at an early stage. We demonstrated that MEF2C is a transcriptional regulator for many differentially expressed genes that were associated with the immature cluster including LYL1 and LMO2. Although LYL1 has been suggested as potential oncogene for immature T-ALL cases3, oncogenic rearrangements were never identified in T-ALL cases with immature immunophenotype. Our data therefore imply that high expression of LYL1 (and LMO2) is part of a pathogenic pathway for immature T-ALL that is regulated by the MEF2C oncogene.1 Stehling-Sun, S., Dade, J., Nutt, S. L., DeKoter, R. P. & Camargo, F. D. Regulation of lymphoid versus myeloid fate ‘choice’ by the transcription factor Mef2c. Nat Immunol 10, 289–296, (2009).2 Coustan-Smith, E. et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 10, 147–156, (2009).3 Ferrando, A. A. et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75–87 (2002). Disclosures:No relevant conflicts of interest to declare.

Pediatric early T-cell precursor leukemia with NF1 deletion and high-sensitivity in vitro to tipifarnib

Pediatric early T-cell precursor leukemia with NF1 deletion and high-sensitivity in vitro to tipifarnib