Understanding and clinical approach to early T-cell precursor acute lymphoblastic leukemia

Abstract

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct biological subtype of T-cell acute lymphoblastic leukemia (T-ALL) that was first described in 2009 based on a gene expression profile resembling that of early T-cell precursors in the thymus. ETP-ALL is characterized by an immature immunophenotype featuring positivity for CD7 and cytoplasmic CD3, with co-expression of myeloid/stem cell markers, and absence of CD1a, CD8, with weak or absent CD5 expression. ETP-ALL accounts for 5.5%–17.1% of pediatric and 15.8%–47.3% of adult T-ALL cases. Early studies identified ETP-ALL as a high-risk entity associated with induction failure and poor outcomes. However, subsequent prospective clinical trials demonstrated that outcomes with contemporary intensive chemotherapy were not significantly inferior to those of non-ETP T-ALL, challenging its designation as a uniformly high-risk disease. Recent large-scale genomic studies have identified molecularly defined subtypes that supersede immunophenotypic classifications, including ETP-like, BCL11B-rearranged, and SPI1-rearranged subtypes, with markedly different prognostic implications. Minimal residual disease (MRD) response remains the most robust prognostic indicator for guiding treatment intensification. Allogeneic hematopoietic stem cell transplantation (HSCT) is recommended for patients with persistent MRD positivity after consolidation. For relapsed/refractory disease, novel agents, including daratumumab, venetoclax, and bortezomib, have demonstrated promising activity, with allogeneic HSCT in the second complete remission remaining the treatment goal. This review provides an overview of the definitions, genomic classifications, clinical outcomes, and evolving treatment approaches for ETP-ALL.

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the malignant transformation of T-cell progenitors and accounting for approximately 10%–15% of pediatric and 20%–25% of adult ALL cases [1, 2]. Historically, T-ALL has been considered a biologically heterogeneous disease associated with relatively inferior outcomes compared with B-cell precursor ALL, particularly in relapsed setting [3]. Advances in intensive multi-agent chemotherapy protocols have substantially improved outcomes over recent decades, with 5-year event-free survival (EFS) rates reaching 75%–85% in pediatric trials [4].

Within this heterogeneous landscape, early T-cell Precursor ALL (ETP-ALL) was first described in 2009 as a biologically distinct subtype defined by a gene expression profile closely resembling that of normal early T-cell precursors (ETPs)—immature thymocytes that have recently emigrated from the bone marrow and retain hematopoietic stem cell-like characteristics. This original report from St. Jude Children's Research Hospital and the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) identified ETP-ALL as a high-risk entity associated with markedly inferior outcomes, generating substantial interest in understanding its unique biology and developing risk-adapted treatment strategies [5].

Over the subsequent decade, extensive multi-institutional data have shown that outcomes in patients with ETP-ALL treated with contemporary intensive regimens are more favorable than those initially described. Recent reports have shown similar outcomes for ETP-ALL and non-ETP, challenging the perception that ETP-ALL is a uniformly high-risk subtype [6, 7].

Nevertheless, ETP-ALL remains a clinically challenging entity because of its high rate of induction failure, distinct molecular landscape, and relative resistance to certain cytotoxic agents, including nelarabine [7]. More recently, comprehensive genomic studies have revealed that immunophenotypic classification alone is insufficient to capture the prognostic heterogeneity of ETP-ALL, prompting the development of genomically defined subtypes that more accurately stratify patients according to risk [8, 9].

This review summarizes the current understanding of ETP-ALL, from its immunophenotypic definition and genomic classification to its clinical outcomes and evolving treatment approaches, with particular emphasis on evidence from major prospective clinical trials and recent genomic studies.

Immunophenotypic definition of ETP-ALL

Historical background

The concept of ETP-ALL was established by Coustan-Smith et al. in 2009 using gene expression profiling of 139 consecutive patients with T-ALL enrolled in the St. Jude Children’s Research Hospital Total Therapy Studies XIII, XIV, and XV from 1992 to 2006, with independent validation in 100 consecutive patients enrolled in the AIEOP ALL-2000 protocol [5]. Within this cohort, a cluster of 13 cases was identified with gene expression profiles that strongly resembled those of normal ETPs—thymocytes at the earliest stage of T-cell development—that co-expressed hematopoietic stem cell and myeloid markers.

The ETP gene signature is characterized by overexpression of genes associated with stem cell and myeloid programs, including CD44, CD34, KIT, GATA2, CEBPA, SPI1, ID2, and MYB, and underexpression of T-lineage commitment genes, such as CD1, CD3, CD4, CD8, RAG1, NOTCH3, PTCRA, LEF1, TCF12, LAT, LCK, TCF7, and ZAP70 [4]. This molecular profile reflected the incomplete T-lineage commitment of ETP-ALL cells and their close relationship to hematopoietic stem and progenitor cells.

Immunophenotypic criteria

Based on these gene expression data, a practical immunophenotypic definition of ETP-ALL was established using routinely available flow cytometry markers. ETP-ALL is defined by the following criteria: positivity for T-cell markers, including CD2, cCD3, and CD7; absence of CD1a and CD8 expression; absent or dim CD5 expression (< 75% compared with normal T cells); and positivity for at least one myeloid or stem cell marker (HLA-DR, CD13, CD33, CD34, or CD117) [5, 10]. This immunophenotype differs from those of typical thymocytes and conventional T-ALL, reflecting the immature and undifferentiated nature of ETP-ALL cells.

Subsequent refinement of the classification introduced the category of "near-ETP" T-ALL, recognizing an intermediate subgroup between classic ETP-ALL and conventional (non-ETP) T-ALL. Near-ETP was defined as cases that otherwise met the immunophenotypic criteria for ETP-ALL but expressed higher CD5 levels [11]. ETP-ALL accounts for 5.5%–17.1% of all T-ALL cases in children and 15.8%–47.3% in adults, with the near-ETP category comprising an additional 14%–16% of all T-ALL [7, 11].

Limitations of immunophenotypic classification

Despite its widespread use, the immunophenotypic classification of ETP-ALL has significant limitations. Recent genomic studies have demonstrated substantial discordance between immunophenotypic and genomic definitions. Notably, only approximately 70% of immunophenotypically defined ETP-ALL cases carry an ETP-like genomic signature, whereas approximately 28% of genomically defined ETP-like cases have a non-ETP immunophenotype [8].

An updated genomics-based classification of T-ALL and ETP-ALL

WHO and ICC classifications

The 2022 WHO Classification of Haematolymphoid Tumors recognizes ETP-ALL as a distinct entity within T-ALL and subclassifies it as either ETP-ALL or non-ETP T-ALL based on immunophenotype [12]. The 2022 International Consensus Classification (ICC) subdivides ETP-ALL into early T-cell precursor ALL with BCL11B-activated or not otherwise specified, and eight other provisional genomic entities or T-ALL based on clonal drivers and transcriptomics [13]. The WHO and ICC classifications are presented in Table 1.

Table 1.

WHO and ICC classifications on T-ALL

WHO [12] (Diagnosis based on immunophenotype)	ICC [13] (Diagnosis based on genotype)
T-lymphoblastic leukaemia/lymphoma, NOS	Early T-cell precursor ALL, BCL11B-activated
Early T-precursor lymphoblastic leukaemia/lymphoma	Early T-cell precursor ALL, NOS
	T-ALL, NOS
	Provisional entities - TAL1/2-R - TLX1-R - TLX3-R - HOXA - LMO1/2-R - NKX2-R - SPI1-R - BHLH, other

Emerging genomics-based classification of T-ALL

In 2024, Pölönen et al. presented a gene expression– and genetic alteration–based classification of T-ALL derived from comprehensive whole-genome sequencing (WGS), whole-exome sequencing (WES), and whole-transcriptome sequencing (WTS) of a cohort of 1,309 patients treated in the Children’s Oncology Group (COG) AALL0434 trial [8].

Using uniform manifold approximation and projection (UMAP) and Leiden algorithms, WTS gene expression data were presented in two dimensions, delineating 15 T-ALL subtypes with distinct drivers and patterns of oncogene expression. This classification includes the following genomic subtypes: ETP-like, BCL11B, TAL1 DP-like, TAL1 αβ-like, TLX1, TLX3, NKX2−1, NKX2−5, SPI1, LMO2 γδ-like, STAG2/LMO2, NUP98, NUP214, KMT2A, MLLT10, HOXA9-TCR, and TME-enriched. This analysis demonstrated that the immunophenotypic ETP status was distributed across multiple genomic subtypes, confirming that immunophenotype alone is suboptimal for T-ALL classification.

The study by Pölönen et al. refined the classification of subtypes such as TAL1-DP-like (~ 25%) and TAL1-αβ-like (~ 16.7%), and linked genomic profiles with prognosis. Among the 15 subtypes, two high-risk groups were newly defined: “ETP-like” (~ 18%) and “LMO2 γδ-like” (0.7%). The γδ T-ALL with LMO2/STAG2 rearrangement has been suggested to be vulnerable to DNA repair pathways from LMO2 activation and STAG2 loss, making them vulnerable to PARP inhibition [14]. ETP-like cases carry diverse drivers (e.g., KMT2A, MLLT10, NUP98, ETV6, HOXA13, ZFP36L2), with distinct transcriptional phenotypes and variable risks.

In addition, discordance between genotype and immunophenotype was observed. The genomically defined ETP-like group comprised nearly equal distributions of ETP, near-ETP, and non-ETP immunophenotypic cases. Cases with ETP-immunophenotype comprised 70% of the ETP-like genomic group and nearly 30% of ETP cases with BCL11B and TLX3 subtypes. This study proposed that the immunophenotypically defined entity of ETP-ALL be superseded by a broader category of “ETP-like” leukemia, defined by its gene expression profile and heterogenous driver alterations [8].

Genomic subtypes showed markedly different prognostic implications independent of immunophenotype. The ETP-like and SPI1-rearranged subtypes are associated with the highest rates of MRD positivity at the end of induction and inferior event-free survival, whereas TAL1-, TLX1-, BCL11B-, and KMT2A-rearranged subtypes generally have favorable outcomes [8].

The overlap between these genetic and immunophenotypic categories of T-ALL is depicted schematically in Fig. 1.

Fig. 1.

Overlap among the genetic and immunophenotypic categories of T-ALL, modified from Pölönen et al. [15]. IP, immunophenotype

BMP pathway signature as a novel prognostic biomarker

Recently, a bone marrow progenitor (BMP)-like leukemia subpopulation that is highly enriched in refractory ETP-ALL was reported as a distinct type of T-ALL. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcomes across multiple T-ALL subtypes and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state [9].

Integrated risk stratification

The ICC Classification can overlap with the provisional genomic entities suggested from the genomic data of the specimen study of AALL0434 [8]. The provisional genomic entities of T-ALL are as follows (superscript text indicates the genetic subtype):

• Very high risk (5-year EFS, 45% when MRD-positive vs. 58% when MRD-negative): ETP-like^KMT2A, SPI1, LMO2 γδ-like

• High risk (5-year EFS, 60% when MRD-positive vs. 78% when MRD-negative): ETP-like^{MLLT10, NUP98, Rare}, TAL1 αβ-like^Other, NKX2-5

• Low risk (5-year EFS, 78% when MRD-positive vs. 89% when MRD-negative): ETP-like^{HOXA13, MED12, ETV6, NUP214}, TAL1 DP-like^{JAK, LEF1/LYL1, Other}, TAL1 αβ-like^{NOTCH WT, Loss 6q}, TLX3^Immature, BCL11B, MLLT10, STAG2/LMO2, NUP98, TME-enriched

• Very low risk (5-year EFS, 91% when MRD-positive vs. 98% when MRD-negative): NKX2-1, TLX1, TLX3^DP−like, KMT2A, NUP214, HOXA9 TCR, TAL1 DP-like^RPL10, ETP-like^ZFP36L2 [8]

This integrated framework demonstrates that ETP-like status per se is insufficient to define risk; rather, the specific of genomic alteration subtype determines prognosis. Genomic subtypes provided prognostic information independent of MRD; the BCL11B-rearranged T-ALL and ZFP36L2 ETP-like subtypes had a poor MRD response yet favorable outcomes, whereas the SPI1-rearranged subtype and the group of patients with PI3K pathway gene mutations had favorable MRD responses yet resulted in poorer survival [8]. However, these subtypes were derived from a single cohort without independent validation. Further studies using independent cohorts are required to confirm the robustness and clinical relevance of these subtypes.

Clinical outcomes of ETP-ALL

Initial reports–ETP-ALL as a high-risk disease

The landmark 2009 study from St. Jude Children's Research Hospital and AIEOP reported markedly inferior outcomes for ETP-ALL compared with non-ETP T-ALL. In the St. Jude cohort, the 10-year OS for ETP-ALL was 19% (95% CI, 0%–92%) versus 84% (95% CI, 72%–96%) for non-ETP T-ALL (p < 0.0001), while 10-year EFS was 22% (CI, 5%–49%) versus 69% (CI, 53%–84%) (p < 0.0001), respectively. The AIEOP cohort similarly showed 5-year OS of 45% (95% CI, 0%–90%) and EFS of 22% for ETP-ALL versus 90% and 71%, respectively, for non-ETP T-ALL [5]. ETP-ALL is characterized by high rates of induction failure and post-induction relapse.

The Tokyo Children's Cancer Study Group (TCCSG) L99-15 study further corroborated these findings, reporting a 4-year EFS of 40% in ETP-ALL (n = 5) compared with 70% in non-ETP T-ALL (p = 0.014), although OS did not differ significantly, likely due to successful salvage with allogeneic hematopoietic stem cell transplantation (HSCT) in three of four relapsed patients [16].

Contemporary trials–reconsidering risk of ETP-ALL

Subsequent prospective trials using more intensive treatment regimens challenged the notion that ETP-ALL is a uniformly high-risk entity. In the UKALL 2003 trial, which included 222 patients with T-ALL, ETP-ALL patients (n = 35, 16%) showed a non-significantly inferior 5-year EFS (76.7% vs. 84.6%, p = 0.2) and OS (82.4% vs. 90.9%, p = 0.1) than patients with non-ETP T-ALL. The authors concluded that ETP-ALL had an intermediate-risk outcome that did not warrant experimental treatment or allogeneic transplantation in first-remission [17].

The largest prospective trial of pediatric T-ALL, COG AALL0434, enrolled 1,256 patients, including 145 ETP (11.5%), 209 near-ETP (16.6%), and 902 non-ETP (71.8%) patients [7, 18]. In this study, ETP (6.2%) and near-ETP (6.2%) had higher rates of induction failure than non-ETP T-ALL (1.2%) (p < 0.0001). Despite the high induction failure rate of ETP-ALL, the three groups had comparable EFS and OS: ETP (80.4% ± 3.9% and 86.8% ± 3.4%), near-ETP (81.1% ± 3.3% and 89.6% ± 2.6%), and non-ETP (85.3% ± 1.4% and 90.0% ± 1.2%), with no significant differences observed (p = 0.1679 and p = 0.3297, respectively).

Role of MRD in ETP-ALL

MRD monitoring during treatment is the most powerful prognostic tool for ETP-ALL. However, its interpretation requires careful consideration. In the AALL0434 analysis, no significant differences in EFS or OS were observed between patients with day-29 MRD < 0.01% and those with 0.01%–0.1%; however, day-29 MRD ≥ 0.1% was associated with inferior outcomes for near-ETP and non-ETP patients, but not in ETP patients. End-of-consolidation (EOC) MRD ≥ 0.01% was also highly predictive of treatment failure in the overall cohort (5-year EFS, 52.4% vs. 80.9% for EOC MRD < 0.01%; p = 0.0001) and within the non-ETP group, but not within the ETP and near-ETP groups. Within the ETP group, day-29 MRD ≥ 10% was the sole MRD threshold predictive of inferior outcome, suggesting that ETP blasts may clear more slowly during induction and that conventional MRD cutoffs derived from non-ETP T-ALL may not directly apply to ETP-ALL. These MRD dynamics likely reflect the biological features of ETP-ALL, including relative glucocorticoid resistance and slower cytoreduction kinetics during induction, rather than ultimate treatment failure [7].

An important consideration is that MRD assessment based on T-cell receptor (TCR) rearrangements may be challenging in ETP-ALL. Because ETP-ALL blasts originate from immature progenitors, they may lack or have incomplete TCR rearrangements, potentially limiting the sensitivity of PCR- or NGS-based MRD assessments targeting TCR rearrangements [19]. The AALL0434 study used flow cytometry-based MRD assessment [8], whereas the AIEOP-BFM ALL 2009 [20], UKALL2003 [21], DCOG ALL11 [22], and NOPHO ALL2008 [23] studies incorporated quantitative PCR-based IG/TR MRD approaches. Further studies are needed to determine the optimal approach to MRD assessment in ETP-ALL.

Treatment of newly diagnosed ETP-ALL

Induction therapy

Patients with ETP-ALL experience higher rates of induction failure (approximately 6%) than patients with non-ETP T-ALL [24], but this alone does not mandate immediate escalation or alteration of the initial therapeutic plan. Dexamethasone-based multi-agent induction (Berlin-Frankfurt-Münster [BFM] protocol-type induction incorporating vincristine, dexamethasone, L-asparaginase, and an anthracycline) is the standard approach for ETP-ALL treatment [25].

Generally, T-ALL is considered to benefit from dexamethasone rather than prednisone, owing to its superior CNS penetration and greater lymphocytotoxic potency [6, 26]. This advantage has not been formally tested in ETP-ALL-specific studies; however, preclinical data suggest that relative glucocorticoid resistance in ETP-ALL is mediated through IL-7/JAK/STAT5 signaling, leading to upregulation of BCL-2 and reduced pro-apoptotic activity of glucocorticoids [27]. Therefore, dexamethasone-based induction is preferred, with targeting of the JAK/STAT and BCL-2 pathways proposed as a strategy to restore steroid sensitivity.

Consolidation–role of nelarabine and capizzi methotrexate

The COG AALL0434 trial evaluated two key intensification strategies for T-ALL. The first was nelarabine, a purine nucleoside prodrug with selective T-cell lymphocytotoxic activity. In the COG AALL0434 study, patients at intermediate and high risk were randomized to receive nelarabine, Which improved outcomes in patients with non-ETP and showed a trend toward benefit in patients with near-ETP. Patients with ETP did not show significant benefit from the addition of nelarabine (no significant improvement in EFS or OS); however, because patients with ETP were more frequently removed from the study and underwent allogeneic HSCT, the efficacy of nelarabine should be interpreted with caution [7]. In the COG AALL0434 study, escalating-dose methotrexate without leucovorin rescue (Capizzi methotrexate) showed benefits across T-ALL, regardless of ETP status [7].

Role of allogeneic HSCT in newly diagnosed ETP-ALL

The role of allogeneic HSCT in the first complete remission (CR1) of ETP-ALL has been debated. Early studies suggested allogeneic HSCT in CR1 given the poor outcomes reported in the 2009 landmark study. However, contemporary data from UKALL 2003 and AALL0434 suggest that patients with ETP-ALL who achieve good MRD response do not require allogeneic HSCT in CR1 and can be managed with chemotherapy alone [7, 17].

The COG AALL1231 trial, a successor to the AALL0434 trial, was designed to assess the addition of bortezomib to BFM-based treatment through randomization. This study included 9% (n = 84) of ETP-ALL patients, but outcomes specific to ETP-ALL were not reported separately. Patients classified as very high risk in AALL1231 (MRD ≥ 0.1% after consolidation or induction failure) received three BFM high-risk blocks, but their 4-year EFS and OS were both below 35%, indicating poor outcomes [28]. Based on these findings, allogeneic HSCT is recommended for patients with persistent MRD.

Several previous studies have also supported allogeneic HSCT in patients with chemotherapy-refractory ETP-ALL, with transplantation in first CR associated with significantly superior post-transplant survival [16, 29].

Based on these data, treatment for newly diagnosed ETP-ALL is recommended with dexamethasone-based induction, augmented BFM (aBFM) consolidation with nelarabine (nelarabine added owing to benefit for overall T-ALL, even if the ETP-specific benefit is uncertain), and risk stratification by MRD at the end of consolidation. If the MRD at the end of consolidation is < 0.01%, Capizzi MTX, followed by delayed intensification and maintenance along with nelarabine, is recommended. In case of MRD 0.1% or more at end of consolidation, allogeneic HSCT after Capizzi MTX is recommended. If MRD is 0.01%–0.099%, re-evaluation of MRD after Capizzi MTX is needed to determine the need for allogeneic HSCT [25].

Treatment of relapsed/refractory ETP-ALL

Relapsed or refractory ETP-ALL remains a major clinical challenge associated with poor prognosis. The general approach involves comprehensive genomic profiling at relapse, enrollment in clinical trials (if available), reinduction with novel agents, and consolidation with allogeneic HSCT in MRD-negative second complete remission (CR2) [25].

Bortezomib (proteasome inhibitor)

Bortezomib, a proteasome inhibitor approved for multiple myeloma, has demonstrated efficacy against relapsed/refractory T-ALL. In the COG AALL07P1 pilot study, incorporation of bortezomib into reinduction regimens resulted in a CR2 rate of approximately 68% in patients with relapsed/refractory T-ALL [30]. However, the COG AALL1231 trial found no benefit from adding bortezomib to frontline therapy for newly diagnosed T-ALL, suggesting that its role may be limited to relapsed settings [28].

Daratumumab (anti-CD38 monoclonal antibody)

Daratumumab, an FDA-approved human IgG1κ anti-CD38 monoclonal antibody established for the treatment of multiple myeloma, has demonstrated activity in relapsed/refractory T-ALL based on preclinical and early clinical data. Preclinical studies testing daratumumab in 15 different T-ALL patient-derived xenograft (PDX) models, including an ETP-ALL PDX, demonstrated antileukemic efficacy in 14 of the 15 models, supporting clinical development [31].

A phase II DELPHINUS study combining daratumumab and backbone chemotherapy reported an overall response rate (ORR) of approximately 82.8% (CR + CR with incomplete marrow recovery) in pooled T-cell ALL (n = 29) at the end of cycle 2, with a manageable toxicity profile [32]. The median EFS was approximately 8.9 months in childhood T-ALL. Daratumumab serves as a bridge to allogeneic HSCT in patients achieving MRD-negative remission and represents a promising salvage option for ETP-ALL.

BH3 pathway inhibition: venetoclax and navitoclax

Venetoclax, a highly selective oral BCL-2 inhibitor, and navitoclax, an oral BCL-XL/BCL-2 dual inhibitor, exploit the dependence of ETP-ALL on anti-apoptotic signaling through BCL-2 and related proteins. A phase I study of navitoclax-based reinduction in 47 patients with relapsed/refractory ALL and lymphoblastic lymphoma reported an overall CR rate of 60% among all patients and 75.0% in 12 pediatric patients. Among the seven patients with ETP-ALL, five achieved CR, one had stable disease, and one had progressive disease [33]. Another trial of venetoclax and homoharringtonine in relapsed/refractory ETP-ALL reported 100% of CR or CR with incomplete hematological recovery (CRi) in the total 18 patients enrolled [34].

Preclinical data from the BMP-17 signature study further demonstrated that ETP-like T-ALL with high BMP pathway activity is preferentially sensitive to venetoclax and navitoclax [33], supporting the biological rationale for BCL-2 inhibition in this subgroup.

Resistance to dasatinib

Although preclinical studies have suggested that the sensitivity of T-ALL to tyrosine kinase inhibitors depends on lymphocyte-specific protein tyrosine kinase activation, ETP-ALL samples demonstrated resistance to dasatinib in ex vivo models, likely because of the stem cell-like epigenetic state of ETP blasts and their reduced LCK dependency [35]. Therefore, dasatinib is not recommended as a salvage strategy for ETP-ALL outside the context of specific molecular alterations.

Other emerging targets

Several additional therapeutic targets are under active investigation:

• Ruxolitinib (JAK inhibitor): Frequent JAK/STAT pathway activation in ETP-ALL, particularly through IL-7Rα/JAK1/JAK3 mutations and as the mechanism of glucocorticoid resistance, provides a rationale for JAK inhibitor therapy [36]. A randomized controlled trial (NCT03117751) evaluated the efficacy of ruxolitinib in combination with reinduction chemotherapy for relapsed/refractory T-ALL.

• FLT3 inhibitors: Acute leukemias with aberrant BCL11B (BCL11B-a) expression have been reported to show high expression levels of the tyrosine receptor kinase gene FLT3, elevated transcript levels, and dependency on the antiapoptotic protein BCL2. In a preclinical study, the combination of the FLT3 inhibitor gilteritinib and the BCL2 inhibitor venetoclax showed efficacy in PDX models, suggesting potential activity of FLT3 inhibitors in T-ALL [37]. FLT3 inhibitors have been evaluated clinically in patients with relapsed ALL (NCT03132454 and NCT01620216).

• CDK4/6, MEK, and mTOR inhibitors: RAS pathway mutations are more prevalent in ETP-ALL than in non-ETP T-ALL, making RAS-directed agents, such as MEK inhibitors and downstream mTOR inhibitors, biologically relevant. CDK4/6 inhibitors may also be effective given the proliferative signature of ETP-ALL.

• Anti-CD123 and anti-CD33 (gemtuzumab ozogamicin): Given the co-expression of myeloid antigens (CD123 and CD33) in ETP-ALL blasts, antibody-based therapies targeting these antigens may be effective (NCT04681105).

• CAR-T cell therapy: CD7- and CD5-directed CAR-T cells have entered early-phase trials for T-ALL (NCT03081910, NCT03690011, and NCT04004637). Given the universal CD7 expression in ETP-ALL, CD7-directed CAR-T therapy holds promise, although fratricide of normal T cells requires technical solutions such as deletion of the target antigen from CAR-T cells. Studies of autologous or allogeneic CAR T-cell therapy for relapsed T-ALL have reported successful results [38–40]. Several other surface markers, including CD1a, CD2, CD3, CD4, and CD38, are currently being investigated as targets for cellular therapies in preclinical studies.

Recommended approach for relapsed/refractory ETP-ALL

Based on the available evidence, the recommended stepwise approach for relapsed/refractory ETP-ALL is as follows: comprehensive tumor sequencing at relapse is recommended to identify actionable mutations and therapeutic targets. ETP-ALL has a distinct genomic landscape compared with non-ETP T-ALL, including frequent mutations in RAS pathway genes, FLT3, JAK/STAT pathway genes, and epigenetic regulators [8, 25]. This molecular characterization can support the selection of targeted therapies and inform eligibility for biomarker-enriched clinical trials.

Therefore, clinical trial enrollment should be considered if feasible. Reinduction with novel agents, including nelarabine (if not previously used), daratumumab, venetoclax, and bortezomib, or molecularly targeted therapy based on genomic profiling could be considered. Allogeneic HSCT in MRD-negative CR2 remains the primary goal for patients achieving remission. Transplantation in CR1 is associated with significantly better post-transplant outcomes than transplantation in CR2 or later remission [25].

Conclusion

ETP-ALL is a biologically distinct subtype of T-ALL, defined by an immature immunophenotype characterized by co-expression of myeloid and stem cell markers and associated with higher rates of induction failure than conventional T-ALL.

The field is undergoing a fundamental paradigm shift from immunophenotypic to genomic classification of T-ALL. Large-scale WTS studies have identified molecularly defined subtypes with markedly different prognostic implications, demonstrating that the ETP immunophenotype encompasses heterogeneous genomic entities. The ETP-like genomic subtype with co-occurring KMT2A, SPI1, or LMO2 γδ-like features constitutes a very high-risk group requiring treatment intensification, whereas BCL11B-rearranged ETP-ALL may be associated with lower risk. Integrating genomic subtypes with MRD monitoring should form the basis of future risk stratification for patients with T-ALL.

While early studies identified ETP-ALL as a high-risk entity with a poor prognosis, contemporary intensive chemotherapy protocols, including dexamethasone-based induction, aBFM consolidation, and nelarabine, have substantially improved outcomes, with 5-year EFS of 75%–86% in prospective pediatric trials. In addition, MRD response remains the most important prognostic determinant in deciding the treatment.

Daratumumab and venetoclax/navitoclax have demonstrated the most promising early clinical activity against relapsed/refractory ETP-ALL, with response rates supporting their potential use as bridging strategies in allogeneic HSCT. The unique molecular landscape of ETP-ALL, which includes frequent FLT3, JAK/STAT, and RAS pathway mutations, offers multiple opportunities for targeted therapy. Achieving MRD-negative CR2 followed by allogeneic HSCT remains the standard treatment approach for patients with relapsed disease.

Prospective validation of genomically defined risk stratification in T-ALL, biomarker-enriched trials of targeted agents (FLT3 inhibitors, JAK inhibitors, and BCL-2 inhibitors) in molecularly defined ETP-ALL subtypes, optimization of MRD thresholds for HSCT allocation specifically in ETP-ALL, and further development of CAR T-cell strategies for T-ALL are needed. Collaboration across oncology groups will be essential to accrue sufficient data on this relatively rare entity and generate evidence capable of informing clinical practice.

Author’s contributions

Ju HY wrote and reviewed the manuscript.

Funding

This study was not supported by any funding sources.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.