Diagnosis and Treatment of Early T-Cell Precursor Acute Lymphoblastic Leukaemia (ETP-ALL)
Authors: Maharaj Carolyn Nicole , Kaffo Eleanor , Vitasaras Evangelos , Orfinada Karen , Baker Robert , Nacheva Elisabeth , Wilson Andrew J. , O'Nions Jenny , Gupta Rajeev , Xu Ke 
Published: December 2024

Background: ETP-ALL is regarded as high-risk T-ALL subgroup. ETP cells derive from a subset of immature thymocytes that retain the ability to differentiate into both T-cell and myeloid lineages. ETP-ALL blasts are typically CD8− and CD1a−, CD5weak, and express one or more myeloid or stem cell marker (Swerdlow SH, 2017, WHO 4th edition). ETP-ALL shares significant molecular and genomic similarities to T/myeloid mixed phenotype acute leukaemia (MPAL) and is distinct from non-ETP-ALL. Currently, there are no established consensus guidelines on optimum treatment.

Aims: We sought to characterise the phenotypic, genetic and treatment outcomes of our cohort.

Methods: A retrospective analysis was performed of all ETP-ALL patients diagnosed and treated at our single centre between February 2015 & April 2023. The diagnosis of ETP-ALL was made in accordance with the WHO 4th edition diagnostic criteria. We reviewed bone marrow flow cytometry, myeloid next generation sequencing (NGS) (Archer Pan-Heme VariantPlex), fluorescence in situ hybridization (FISH), and molecular karyotyping (8x60K oligonucleotide arrays, Agilent) results, patients' treatment regimen and outcome.

Results: A total of sixteen ETP-ALL cases were identified, with a median follow up of 29 months (range 8 days to 85 months). Of the sixteen patients, nine patients were male and seven were female. Median age was 43 years old (range 16-77 years). In all cases, blast populations showed cytoplasmic or surface CD3 expression by flow cytometry or immunohistochemistry, and 94% (15/16) were positive for CD34 (or cCD34). Myeloid antigens CD117, CD13, and CD33 were positive in 50% (8/16), 38% (6/16) and 63% (10/16) respectively. Of those T lymphoid antigens tested: CD2, CD5, CD7 were positive in 38% (6/16), 63% (10/16) and 94% (15/16) respectively; CD1a and CD8 T cell markers were negative in all 16 patients (100%) and CD5 was negative or weakly positive in 75% (12/16). The most common molecular abnormalities detected were NOTCH1 (37.5%, 6/16), with DNMT3A (25%, 4/16), IDH1/2 (25%, 4/16) NRAS/KRAS (25%, 4/16), WT1 (25%, 4/16) and TP53 (25%, 4/16) and ASXL1 (25%, 4/16). Additional mutations detected were FLT3, PHF6, EZH2, U2AF1, JAK3, ETV6, ARID1A, ELANE, GATA2, KMT2D, RUNX1, SETD2, SH2B3 and IKZF1. All sixteen samples underwent FISH analysis using probes against TCRA/D, KMT2A, BCR:ABL1, TP53. Molecular karyotyping via chromosomal microarray was performed on eleven patients' samples. Six patients' samples had G-banding. Eleven patients' samples had abnormal karyotype; the remaining five had a normal karyotype. The cytogenetic abnormalities identified were loss of TRB1, KMT2A rearrangement, TRA/TRD rearrangement, 5q deletion, monosomy 5, TP53 loss, ABL1 loss, ATM loss, ETV6 loss, t(7;14), ABL1 amplification, NUP214 amplification, NUP214 fusion, 9q34 deletion, complex genome.

One patient was unfit for chemotherapy. Fifteen patients received ALL-directed induction regimens (UKALL14, UKALL60+, UKALL 2011 or UKALL 2019). Morphological complete remission (CR), was obtained in 75% (12/16) patients. One patient left the country after induction. Two patients required a salvage regimen with Fla-Ida (fludarabine, cytarabine, idarubicin) or mini-Fla-Ida prior to achieving complete remission. Six proceeded to receive allogeneic haematopoietic stem cell transplantation (alloHSCT). Six patients who achieved CR did not proceed to alloHSCT. Three were unfit for transplant. Three were physicians' and patients' choice; all three were MRD negative post induction. The 2-year overall survival (OS) rate was 100% (6/6) and 83% (5/6) of patients with or without allo-SCT at CR1/CR2, respectively.

Summary/Conclusion: Our data identified genetic mutations in NOTCH1, DNMT3A, IDH1/2 NRAS/KRAS, WT1, PHF6, ASXL1, FLT3, EZH2, TP53, U2AF1, JAK3, ETV6, ARID1A, ELANE, GATA2, KMT2D, RUNX1, SETD2, SH2B3 and IKZF1, with NOTCH1 as the most common mutation in our cohort of ETP-ALL patients. ETP-ALL patients treated with standard UKALL-style induction, followed by allo-SCT at CR1/CR2 showed 100% 2-year OS in our cohort.