B-Lymphoblastic Leukemia/Lymphoma With Recurrent Genetic Abnormality

Cancer MONDO:0035605 Pathograph 7 precursor lymphoblastic lymphoma/leukemia

B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality is a modern WHO/ICC-aligned precursor B-cell neoplasm category in which recurrent chromosomal abnormalities, fusion genes, copy-number changes, aneuploidy, or subtype-defining sequence variants classify biologically and clinically distinct B-ALL/LBL entities. The category is most useful for risk-directed treatment, diagnostic genomics, relapse-risk assessment, and selection of targeted or immune therapies in appropriate genetic contexts.

Ask OpenScientist

Ask a research question about B-Lymphoblastic Leukemia/Lymphoma With Recurrent Genetic Abnormality. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

📘

Definitions

ICC recurrent-genetic-abnormality classification

This entity groups B-ALL/LBL cases whose classification is defined by recurrent genetic abnormalities, including revised classic WHO entities and newly described genetic subtypes.

CASE_DEFINITION Modern WHO/ICC precursor B-cell lymphoblastic leukemia/lymphoma classification.

Show evidence (1 reference)

PMID:36422706 SUPPORT Other

"The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes both revisions to subtypes previously outlined in the 2016 WHO classification and several newly described entities."

This consensus abstract anchors the entry as a classification-level B-ALL/LBL entity organized around recurrent genetic subtypes.

◆

Subtypes

recurrent fusion

BCR::ABL1-positive / Philadelphia chromosome-positive B-ALL/LBL MONDO:0035940

B-ALL/LBL with t(9;22)(q34.1;q11.2) producing BCR::ABL1. This adult-enriched subtype is therapeutically important because ABL-directed tyrosine kinase inhibitors can be combined with chemotherapy or immunotherapy.

Show evidence (1 reference)

PMID:32902203 SUPPORT Human Clinical

"BCR-ABL positive group had a higher leukocyte count than BCR-ABL negative group."

This adult B-ALL cohort identifies BCR-ABL as a recurrent abnormality and links it to clinical hematologic features.

KMT2A-rearranged B-ALL/LBL MONDO:0035941

B-ALL/LBL with rearrangement of KMT2A at 11q23.3. It is especially important in infant and high-risk disease and is associated with inferior post-relapse survival in pediatric cohorts.

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%)."

The large COG relapse cohort supports KMT2A rearrangement as a clinically meaningful adverse recurrent genetic subtype.

ETV6::RUNX1 B-ALL/LBL MONDO:0035942

Childhood-enriched B-ALL/LBL with t(12;21)(p13.2;q22.1) and ETV6::RUNX1. It is generally favorable and shows later relapse patterns than several adverse-risk subtypes.

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively."

This directly supports ETV6::RUNX1 as a prognostically distinct recurrent subtype.

TCF3::PBX1 B-ALL/LBL

B-ALL/LBL with t(1;19)(q23;p13) and TCF3::PBX1. The COG relapse cohort shows adverse post-relapse survival for this cytogenetic subtype.

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%)."

The relapse cohort supports TCF3::PBX1 as a clinically meaningful recurrent genetic subtype with adverse relapse outcomes.

kinase-activated expression subtype

BCR::ABL1-like / Philadelphia chromosome-like B-ALL/LBL

B-ALL/LBL with a gene-expression signature resembling BCR::ABL1-positive disease but lacking the BCR::ABL1 fusion. Lesions commonly activate cytokine-receptor, ABL-class, or JAK-STAT signaling and may guide targeted kinase-inhibitor trials.

Show evidence (1 reference)

PMID:34626353 SUPPORT Other

"This is particularly true in the case of Philadelphia-like (Ph-like) ALL, a major subset which has the same gene expression signature as Philadelphia chromosome-positive ALL but lacks BCR-ABL1 translocation."

This review abstract directly defines the Ph-like subtype and explains why it belongs in a recurrent-genetic-abnormality framework.

aneuploid subtype

High-hyperdiploid B-ALL/LBL MONDO:0035943

B-ALL/LBL with high hyperdiploidy or favorable trisomy patterns, including trisomy 4 and 10 in pediatric risk stratification.

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively."

Trisomy 4+10 is a favorable hyperdiploid-risk marker in pediatric B-ALL, supporting the clinical relevance of this aneuploid subtype.

Hypodiploid B-ALL/LBL MONDO:0035944

B-ALL/LBL with hypodiploidy, including near-haploid and low-hypodiploid forms. Low-hypodiploid disease may raise concern for germline TP53 predisposition and is clinically adverse.

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%)."

This supports hypodiploidy as a poor-outcome recurrent genetic subtype.

recurrent translocation

IGH::IL3 / t(5;14)(q31.1;q32.3) B-ALL/LBL MONDO:0035945

Rare B-ALL/LBL in which the IGH enhancer is juxtaposed near IL3, producing IL3 overexpression and reactive eosinophilia. Cryptic cases may require NGS-based assays when conventional cytogenetics are normal.

Show evidence (1 reference)

PMID:33991782 SUPPORT Human Clinical

"The t(5;14)(q31.1;q32.1) associated with B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is a rare, recurrent genetic abnormality recognized as a distinct entity by the 2017 World Health Organization (WHO) classification."

This abstract directly supports the IGH::IL3 t(5;14) entity and its diagnostic relevance.

focal amplification subtype

Intrachromosomal amplification of chromosome 21 B-ALL/LBL

B-ALL/LBL with intrachromosomal amplification of chromosome 21, classically assessed by RUNX1 copy-number patterns but sometimes requiring chromosomal microarray because unusual cases can evade the FISH definition.

Show evidence (1 reference)

PMID:35771717 SUPPORT Human Clinical

"Acute lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21-ALL) represents a recurrent high-risk cytogenetic abnormality and accurate identification is critical for appropriate clinical management."

This abstract supports iAMP21 as a recurrent high-risk cytogenetic subtype and documents why accurate genomic detection matters.

recurrent rearrangement

DUX4-rearranged B-ALL/LBL

Genomic subtype often assigned by expression or genome-wide methods; Ryan et al. specifically note improved WGS detection of DUX4 rearrangements.

Show evidence (1 reference)

PMID:36658389 SUPPORT Human Clinical

"Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates."

This WGS validation cohort supports DUX4-r as a detectable good-risk recurrent genetic subtype.

ZNF384-rearranged B-ALL/LBL

B-ALL/LBL with ZNF384 gene fusions involving partners such as EP300, TCF3, or TAF15. ZNF384 rearrangements define a distinct recurrent genetic subgroup and may be cytogenetically cryptic, requiring FISH, RT-PCR, or sequencing-based detection.

Show evidence (2 references)

PMID:33988307 SUPPORT Human Clinical

"Fusions involving the ZNF384 gene have been reported to be mutually exclusive of other genetic subtypes and thus constitute a distinct subgroup in B-ALL."

This B-ALL cohort paper directly supports ZNF384 fusions as a distinct recurrent genetic subgroup.

PMID:33988307 SUPPORT Human Clinical

"The genes most frequently involved in fusions with ZNF384 include EP300 (22q13.2), TCF3 (19p13.3), and TAF15 (17q12), and the prognosis appears to vary by fusion partner."

This identifies recurrent ZNF384 fusion partners and supports including the subtype in the recurrent-genetic-abnormality catalog.

transcription-factor altered subtype

PAX5-altered / PAX5alt B-ALL/LBL

B-ALL/LBL subtype defined by diverse PAX5 alterations and integrated genomic-expression profiling rather than one simple recurrent translocation.

Show evidence (1 reference)

PMID:36658389 SUPPORT Human Clinical

"We expanded the catalogue of genetic profiles that reliably classify PAX5alt and ETV6::RUNX1-like subtypes."

This supports PAX5alt as a genomic B-ALL subtype recoverable by comprehensive sequencing.

expression-like subtype

ETV6::RUNX1-like B-ALL/LBL

B-ALL/LBL with an ETV6::RUNX1-like genomic or expression profile but lacking the canonical ETV6::RUNX1 fusion.

Show evidence (1 reference)

PMID:36658389 SUPPORT Human Clinical

"We expanded the catalogue of genetic profiles that reliably classify PAX5alt and ETV6::RUNX1-like subtypes."

This supports ETV6::RUNX1-like disease as a genomic subtype distinguishable through comprehensive sequencing.

⚙

Pathophysiology

Subtype-Defining Genetic Lesion

A recurrent chromosomal abnormality, gene fusion, aneuploidy, copy-number alteration, or sequence variant arises in a precursor B-cell or B-lymphoblast clone. The lesion provides the upstream classifying event for B-ALL/LBL with recurrent genetic abnormality and is used for risk-directed management.

B-lymphoblast link precursor B cell link

cell population proliferation link ↑ INCREASED B cell differentiation link ⚠ ABNORMAL

bone marrow link

Downstream

Altered B-cell Development and Signaling Subtype-defining lesions perturb transcriptional control, kinase signaling, aneuploid dosage, or cytokine signaling in B-lineage blasts.

Show evidence (1 reference)

PMID:36658389 SUPPORT Human Clinical

"Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by recurrent genetic abnormalities that drive risk-directed treatment strategies."

The WGS cohort abstract directly states that recurrent genetic abnormalities characterize B-ALL and drive risk-directed care.

Altered B-cell Development and Signaling

Recurrent lesions disrupt B-cell developmental regulators or activate oncogenic signaling pathways, causing abnormal differentiation, survival, and proliferation of leukemic B-lineage blasts.

precursor B cell link

B cell differentiation link ⚠ ABNORMAL cell surface receptor protein tyrosine kinase signaling pathway link ↑ INCREASED cell surface receptor signaling pathway via JAK-STAT link ↑ INCREASED

Downstream

Leukemic Blast Burden in Bone Marrow and Sanctuary Sites Abnormal survival and proliferation produce a leukemic blast compartment in marrow, blood, or tissue, with CNS sanctuary involvement or relapse in some patients.

Show evidence (2 references)

PMID:34626353 SUPPORT Other

"Besides recurrent chromosomal abnormalities detected by karyotyping or fluorescence in situ hybridization, these leukemias/lymphomas are characterized by a variety of mutations, gene rearrangements as well as copy number alterations."

This supports modeling the disease as genetically heterogeneous beyond classic cytogenetics, with multiple lesion classes feeding into abnormal B-cell development and signaling.

PMID:23523389 SUPPORT Other

"Genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic changes and sequence mutations that contribute to leukaemogenesis, define new disease subtypes, affect responsiveness to treatment, and might provide novel prognostic markers and..."

This ALL review abstract supports linking genomic lesion classes to leukemogenesis, subtype definition, treatment response, prognosis, and therapeutic targeting.

Leukemic Blast Burden in Bone Marrow and Sanctuary Sites

Genetically defined B-ALL/LBL clones expand in marrow and can involve the central nervous system, especially in relapse settings where marrow and CNS sites are major outcome-defining compartments.

B-lymphoblast link

bone marrow link central nervous system link

Show evidence (2 references)

PMID:39261601 SUPPORT Human Clinical

"Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow."

This large pediatric relapse cohort supports bone marrow as a dominant disease compartment in B-ALL relapse.

PMID:39008716 SUPPORT In Vitro

"Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL)."

This directly supports CNS involvement as a clinically important sanctuary-site compartment in B-cell precursor ALL.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 2

Leukemia Leukemia (HP:0001909)

Show evidence (1 reference)

PMID:36422706 SUPPORT Other

This classification abstract establishes B-acute lymphoblastic leukemia as the relevant disease presentation within the recurrent-genetic-abnormality category.

Increased Leukocyte Count Increased total leukocyte count (HP:0001974)

Show evidence (1 reference)

PMID:32902203 SUPPORT Human Clinical

"BCR-ABL positive group had a higher leukocyte count than BCR-ABL negative group."

This adult B-ALL cohort supports leukocyte-count differences associated with a recurrent genetic abnormality.

Other 2

Bone Marrow Relapse/Involvement Abnormal bone marrow cell morphology (HP:0005561)

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow."

This directly supports marrow involvement as a major relapse phenotype in pediatric B-ALL.

Central Nervous System Relapse/Involvement Morphological central nervous system abnormality (HP:0002011)

Show evidence (1 reference)

PMID:39008716 SUPPORT In Vitro

"Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL)."

This BCP-ALL abstract supports CNS involvement as a clinically important phenotype/relapse-management concern for the current B-lineage category.

🧬

Genetic Associations

Recurrent Genetic Abnormalities (Defining molecular feature of the disease category)

Show evidence (1 reference)

PMID:36658389 SUPPORT Human Clinical

"This approach detected 294 subtype-defining genetic abnormalities in 96% (202/210) patients."

The WGS cohort demonstrates that subtype-defining abnormalities are recoverable in nearly all childhood B-ALL cases using comprehensive genomic testing.

BCR-ABL1 Fusion (Defining lesion of Ph-positive B-ALL/LBL)

Show evidence (1 reference)

PMID:32902203 SUPPORT Human Clinical

"BCR-ABL is commonest recurrent abnormality followed by IgH rearrangements."

This adult B-ALL FISH cohort supports BCR-ABL as a recurrent genetic abnormality in adult B-ALL.

KMT2A Rearrangement (Defining lesion of KMT2A-rearranged B-ALL/LBL)

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%)."

This directly identifies KMT2A rearrangement as a subtype-defining cytogenetic/genetic risk factor.

ETV6-RUNX1 Fusion (Defining lesion of ETV6::RUNX1 B-ALL/LBL)

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively."

This supports ETV6::RUNX1 as a recurrent prognostic genetic lesion.

TCF3-PBX1 Fusion (Defining lesion of TCF3::PBX1 B-ALL/LBL)

Show evidence (1 reference)

PMID:39261601 SUPPORT Human Clinical

"Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%)."

This supports TCF3::PBX1 as a recurrent genetic abnormality with adverse relapse outcomes.

DUX4 Rearrangement (Defining lesion of DUX4-rearranged B-ALL/LBL)

Show evidence (1 reference)

PMID:36658389 SUPPORT Human Clinical

"Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates."

This supports DUX4 rearrangement as a subtype-defining lesion detectable by WGS.

IGH-IL3 Rearrangement (Defining lesion of t(5;14) B-ALL/LBL with eosinophilia)

Show evidence (1 reference)

PMID:33991782 SUPPORT Human Clinical

"In these cases, the IGH enhancer region (14q32.1) is juxtaposed to the vicinity of the IL3 gene (5q31.1), resulting in increased production of interleukin-3 (IL3) and subsequently a characteristic reactive eosinophilia."

This provides the causal genetic mechanism and downstream eosinophilia for the IGH::IL3 subtype.

💊

Treatments

Risk-Directed Multi-agent Chemotherapy

Action: chemotherapy MAXO:0000647

Multi-agent ALL chemotherapy remains the backbone of treatment, with intensity and adjuncts guided by genetic subtype, response, measurable residual disease, age, and relapse risk.

Show evidence (1 reference)

PMID:36658389 SUPPORT Human Clinical

"Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by recurrent genetic abnormalities that drive risk-directed treatment strategies."

This supports genetic subtype assignment as a basis for risk-directed ALL treatment planning.

ABL-directed Tyrosine Kinase Inhibitors

Action: Pharmacotherapy NCIT:C15986

Agent: imatinib ↗ dasatinib ↗

Imatinib, dasatinib, ponatinib, or related ABL-directed TKIs are used with chemotherapy or immune therapy for BCR::ABL1-positive disease and are a rational targeted approach for some ABL-class Ph-like lesions.

Mechanism Target:

INHIBITS Altered B-cell Development and Signaling — ABL-directed TKIs inhibit oncogenic tyrosine-kinase signaling in BCR::ABL1-positive or ABL-class kinase-activated disease.

Show evidence (1 reference)

PMID:23523389 SUPPORT Other

"Patients with BCR-ABL1-positive ALL have been considered to have a poor prognosis but benefit from early administration of a tyrosine kinase inhibitor (eg, imatinib, dasatinib)."

This supports TKI therapy for the BCR::ABL1-positive subtype.

Blinatumomab

Action: immunotherapy Ontology label: immunotherapy procedure MAXO:0001002

Agent: blinatumomab ↗

CD19-directed CD3-engaging bispecific antibody used in B-cell precursor ALL, especially in first relapse or high-risk settings with marrow involvement.

Mechanism Target:

MODULATES Leukemic Blast Burden in Bone Marrow and Sanctuary Sites — Blinatumomab redirects T cells against CD19-positive B-lineage blasts, reducing leukemic burden.

Show evidence (1 reference)

PMID:38832425 SUPPORT Other

"For B-cell precursor ALL, blinatumomab, an anti-CD19 bispecific antibody, has established its role in the consolidation treatment for both high- and standard-risk first relapse of ALL, in the presence of bone marrow involvement, and may also have an impact on the outcome of high-risk subsets..."

This review abstract directly supports blinatumomab use in B-cell precursor ALL relapse and high-risk subsets relevant to this category.

Inotuzumab Ozogamicin

Action: immunotherapy Ontology label: immunotherapy procedure MAXO:0001002

Agent: inotuzumab ozogamicin ↗

CD22-directed antibody-drug conjugate used for relapsed B-ALL, including high-burden disease, with ongoing randomized pediatric trials.

Mechanism Target:

MODULATES Leukemic Blast Burden in Bone Marrow and Sanctuary Sites — Inotuzumab ozogamicin targets CD22-positive B-lineage blasts and delivers cytotoxic payload.

Show evidence (1 reference)

PMID:38832425 SUPPORT Other

"Inotuzumab ozogamicin, an anti-CD22 drug conjugated antibody, has demonstrated high efficacy in inducing complete remission in relapsed ALL, even in the presence of high tumor burden, but randomized phase III trials are still ongoing."

This supports inotuzumab ozogamicin as an antibody-drug conjugate for relapsed ALL, while preserving the abstract's caveat about ongoing phase III trials.

Allogeneic Hematopoietic Stem Cell Transplantation

Action: hematopoietic stem cell transplantation MAXO:0000747

Allogeneic hematopoietic stem cell transplantation is considered for selected very-high-risk, persistent-MRD, or relapsed ALL contexts; its use depends on age, genetic subtype, response, and treatment era.

Mechanism Target:

MODULATES Leukemic Blast Burden in Bone Marrow and Sanctuary Sites — Transplant aims to consolidate remission and reduce residual leukemic burden in high-risk disease.

Show evidence (1 reference)

PMID:23523389 SUPPORT Other

"Allogeneic haematopoietic stem-cell transplantation is considered for patients at very high risk."

This supports transplant as a high-risk ALL treatment strategy, although subtype-specific indications require current protocol context.

{ }

Source YAML

click to show

name: B-Lymphoblastic Leukemia/Lymphoma With Recurrent Genetic Abnormality
creation_date: "2026-05-10T20:10:36Z"
updated_date: "2026-05-10T21:12:13Z"
category: Cancer
categories:
- Hematologic Malignancy
- B-Lymphoblastic Leukemia/Lymphoma
- Genetically Defined Neoplasm
synonyms:
- B-ALL/LBL with recurrent genetic abnormalities
- B-ALL with recurrent genetic abnormalities
- B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
- precursor B-cell lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
description: >-
  B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality is a
  modern WHO/ICC-aligned precursor B-cell neoplasm category in which recurrent
  chromosomal abnormalities, fusion genes, copy-number changes, aneuploidy, or
  subtype-defining sequence variants classify biologically and clinically
  distinct B-ALL/LBL entities. The category is most useful for risk-directed
  treatment, diagnostic genomics, relapse-risk assessment, and selection of
  targeted or immune therapies in appropriate genetic contexts.
disease_term:
  preferred_term: B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
  term:
    id: MONDO:0035605
    label: B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
parents:
- precursor lymphoblastic lymphoma/leukemia
definitions:
- name: ICC recurrent-genetic-abnormality classification
  definition_type: CASE_DEFINITION
  description: >-
    This entity groups B-ALL/LBL cases whose classification is defined by
    recurrent genetic abnormalities, including revised classic WHO entities and
    newly described genetic subtypes.
  scope: Modern WHO/ICC precursor B-cell lymphoblastic leukemia/lymphoma classification.
  evidence:
  - reference: PMID:36422706
    reference_title: International Consensus Classification of acute lymphoblastic leukemia/lymphoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The updated International Consensus Classification (ICC) of B-acute
      lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL)
      includes both revisions to subtypes previously outlined in the 2016 WHO
      classification and several newly described entities.
    explanation: >-
      This consensus abstract anchors the entry as a classification-level
      B-ALL/LBL entity organized around recurrent genetic subtypes.
has_subtypes:
- name: Ph-positive
  display_name: BCR::ABL1-positive / Philadelphia chromosome-positive B-ALL/LBL
  classification: recurrent fusion
  description: >-
    B-ALL/LBL with t(9;22)(q34.1;q11.2) producing BCR::ABL1. This adult-enriched
    subtype is therapeutically important because ABL-directed tyrosine kinase
    inhibitors can be combined with chemotherapy or immunotherapy.
  subtype_term:
    preferred_term: B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
    term:
      id: MONDO:0035940
      label: B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
  evidence:
  - reference: PMID:32902203
    reference_title: Recurrent genetic abnormalities detected by FISH in adult B ALL and association with hematological parameters.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BCR-ABL positive group had a higher leukocyte count than BCR-ABL negative
      group.
    explanation: >-
      This adult B-ALL cohort identifies BCR-ABL as a recurrent abnormality and
      links it to clinical hematologic features.
- name: Ph-like
  display_name: BCR::ABL1-like / Philadelphia chromosome-like B-ALL/LBL
  classification: kinase-activated expression subtype
  description: >-
    B-ALL/LBL with a gene-expression signature resembling BCR::ABL1-positive
    disease but lacking the BCR::ABL1 fusion. Lesions commonly activate
    cytokine-receptor, ABL-class, or JAK-STAT signaling and may guide targeted
    kinase-inhibitor trials.
  evidence:
  - reference: PMID:34626353
    reference_title: Genetics and Diagnostic Approach to Lymphoblastic Leukemia/Lymphoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This is particularly true in the case of Philadelphia-like (Ph-like) ALL,
      a major subset which has the same gene expression signature as
      Philadelphia chromosome-positive ALL but lacks BCR-ABL1 translocation.
    explanation: >-
      This review abstract directly defines the Ph-like subtype and explains why
      it belongs in a recurrent-genetic-abnormality framework.
- name: KMT2A-rearranged
  display_name: KMT2A-rearranged B-ALL/LBL
  classification: recurrent fusion
  description: >-
    B-ALL/LBL with rearrangement of KMT2A at 11q23.3. It is especially important
    in infant and high-risk disease and is associated with inferior post-relapse
    survival in pediatric cohorts.
  subtype_term:
    preferred_term: B-lymphoblastic leukemia/lymphoma with t(v;11q23.3)
    term:
      id: MONDO:0035941
      label: B-lymphoblastic leukemia/lymphoma with t(v;11q23.3)
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short
      median time-to-relapse (12.5-18 months) and poor OS post-relapse
      (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%).
    explanation: >-
      The large COG relapse cohort supports KMT2A rearrangement as a clinically
      meaningful adverse recurrent genetic subtype.
- name: ETV6-RUNX1
  display_name: ETV6::RUNX1 B-ALL/LBL
  classification: recurrent fusion
  description: >-
    Childhood-enriched B-ALL/LBL with t(12;21)(p13.2;q22.1) and ETV6::RUNX1.
    It is generally favorable and shows later relapse patterns than several
    adverse-risk subtypes.
  subtype_term:
    preferred_term: B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1)
    term:
      id: MONDO:0035942
      label: B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1)
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of
      43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%,
      respectively.
    explanation: >-
      This directly supports ETV6::RUNX1 as a prognostically distinct recurrent
      subtype.
- name: High hyperdiploidy
  display_name: High-hyperdiploid B-ALL/LBL
  classification: aneuploid subtype
  description: >-
    B-ALL/LBL with high hyperdiploidy or favorable trisomy patterns, including
    trisomy 4 and 10 in pediatric risk stratification.
  subtype_term:
    preferred_term: B-lymphoblastic leukemia/lymphoma with hyperdiploidy
    term:
      id: MONDO:0035943
      label: B-lymphoblastic leukemia/lymphoma with hyperdiploidy
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of
      43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%,
      respectively.
    explanation: >-
      Trisomy 4+10 is a favorable hyperdiploid-risk marker in pediatric B-ALL,
      supporting the clinical relevance of this aneuploid subtype.
- name: Hypodiploidy
  display_name: Hypodiploid B-ALL/LBL
  classification: aneuploid subtype
  description: >-
    B-ALL/LBL with hypodiploidy, including near-haploid and low-hypodiploid
    forms. Low-hypodiploid disease may raise concern for germline TP53
    predisposition and is clinically adverse.
  subtype_term:
    preferred_term: B-lymphoblastic leukemia/lymphoma with hypodiploidy
    term:
      id: MONDO:0035944
      label: B-lymphoblastic leukemia/lymphoma with hypodiploidy
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short
      median time-to-relapse (12.5-18 months) and poor OS post-relapse
      (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%).
    explanation: >-
      This supports hypodiploidy as a poor-outcome recurrent genetic subtype.
- name: IGH-IL3
  display_name: IGH::IL3 / t(5;14)(q31.1;q32.3) B-ALL/LBL
  classification: recurrent translocation
  description: >-
    Rare B-ALL/LBL in which the IGH enhancer is juxtaposed near IL3, producing
    IL3 overexpression and reactive eosinophilia. Cryptic cases may require
    NGS-based assays when conventional cytogenetics are normal.
  subtype_term:
    preferred_term: B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3)
    term:
      id: MONDO:0035945
      label: B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3)
  evidence:
  - reference: PMID:33991782
    reference_title: "Clinical utility of next generation sequencing to detect IGH/IL3 rearrangements [t(5;14)(q31.1;q32.1)] in B-lymphoblastic leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The t(5;14)(q31.1;q32.1) associated with B-lymphoblastic
      leukemia/lymphoma (B-ALL/LBL) is a rare, recurrent genetic abnormality
      recognized as a distinct entity by the 2017 World Health Organization
      (WHO) classification.
    explanation: >-
      This abstract directly supports the IGH::IL3 t(5;14) entity and its
      diagnostic relevance.
- name: TCF3-PBX1
  display_name: TCF3::PBX1 B-ALL/LBL
  classification: recurrent fusion
  description: >-
    B-ALL/LBL with t(1;19)(q23;p13) and TCF3::PBX1. The COG relapse cohort
    shows adverse post-relapse survival for this cytogenetic subtype.
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short
      median time-to-relapse (12.5-18 months) and poor OS post-relapse
      (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%).
    explanation: >-
      The relapse cohort supports TCF3::PBX1 as a clinically meaningful
      recurrent genetic subtype with adverse relapse outcomes.
- name: iAMP21
  display_name: Intrachromosomal amplification of chromosome 21 B-ALL/LBL
  classification: focal amplification subtype
  description: >-
    B-ALL/LBL with intrachromosomal amplification of chromosome 21, classically
    assessed by RUNX1 copy-number patterns but sometimes requiring chromosomal
    microarray because unusual cases can evade the FISH definition.
  evidence:
  - reference: PMID:35771717
    reference_title: Characterization of unusual iAMP21 B-lymphoblastic leukemia (iAMP21-ALL) from the Mayo Clinic and Children's Oncology Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute lymphoblastic leukemia (B-ALL) with intrachromosomal amplification
      of chromosome 21 (iAMP21-ALL) represents a recurrent high-risk cytogenetic
      abnormality and accurate identification is critical for appropriate
      clinical management.
    explanation: >-
      This abstract supports iAMP21 as a recurrent high-risk cytogenetic
      subtype and documents why accurate genomic detection matters.
- name: DUX4-rearranged
  display_name: DUX4-rearranged B-ALL/LBL
  classification: recurrent rearrangement
  description: >-
    Genomic subtype often assigned by expression or genome-wide methods; Ryan
    et al. specifically note improved WGS detection of DUX4 rearrangements.
  evidence:
  - reference: PMID:36658389
    reference_title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our novel bioinformatic pipeline improved detection of DUX4 rearrangements
      (DUX4-r): a good-risk B-ALL subtype with high survival rates.
    explanation: >-
      This WGS validation cohort supports DUX4-r as a detectable good-risk
      recurrent genetic subtype.
- name: ZNF384-rearranged
  display_name: ZNF384-rearranged B-ALL/LBL
  classification: recurrent rearrangement
  description: >-
    B-ALL/LBL with ZNF384 gene fusions involving partners such as EP300, TCF3,
    or TAF15. ZNF384 rearrangements define a distinct recurrent genetic
    subgroup and may be cytogenetically cryptic, requiring FISH, RT-PCR, or
    sequencing-based detection.
  evidence:
  - reference: PMID:33988307
    reference_title: Systematic application of fluorescence in situ hybridization and immunophenotype profile for the identification of ZNF384 gene rearrangements in B cell acute lymphoblastic leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fusions involving the ZNF384 gene have been reported to be mutually
      exclusive of other genetic subtypes and thus constitute a distinct
      subgroup in B-ALL.
    explanation: >-
      This B-ALL cohort paper directly supports ZNF384 fusions as a distinct
      recurrent genetic subgroup.
  - reference: PMID:33988307
    reference_title: Systematic application of fluorescence in situ hybridization and immunophenotype profile for the identification of ZNF384 gene rearrangements in B cell acute lymphoblastic leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genes most frequently involved in fusions with ZNF384 include EP300
      (22q13.2), TCF3 (19p13.3), and TAF15 (17q12), and the prognosis appears
      to vary by fusion partner.
    explanation: >-
      This identifies recurrent ZNF384 fusion partners and supports including
      the subtype in the recurrent-genetic-abnormality catalog.
- name: PAX5-altered
  display_name: PAX5-altered / PAX5alt B-ALL/LBL
  classification: transcription-factor altered subtype
  description: >-
    B-ALL/LBL subtype defined by diverse PAX5 alterations and integrated
    genomic-expression profiling rather than one simple recurrent translocation.
  evidence:
  - reference: PMID:36658389
    reference_title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We expanded the catalogue of genetic profiles that reliably classify
      PAX5alt and ETV6::RUNX1-like subtypes.
    explanation: >-
      This supports PAX5alt as a genomic B-ALL subtype recoverable by
      comprehensive sequencing.
- name: ETV6-RUNX1-like
  display_name: ETV6::RUNX1-like B-ALL/LBL
  classification: expression-like subtype
  description: >-
    B-ALL/LBL with an ETV6::RUNX1-like genomic or expression profile but lacking
    the canonical ETV6::RUNX1 fusion.
  evidence:
  - reference: PMID:36658389
    reference_title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We expanded the catalogue of genetic profiles that reliably classify
      PAX5alt and ETV6::RUNX1-like subtypes.
    explanation: >-
      This supports ETV6::RUNX1-like disease as a genomic subtype distinguishable
      through comprehensive sequencing.
pathophysiology:
- name: Subtype-Defining Genetic Lesion
  description: >-
    A recurrent chromosomal abnormality, gene fusion, aneuploidy, copy-number
    alteration, or sequence variant arises in a precursor B-cell or
    B-lymphoblast clone. The lesion provides the upstream classifying event for
    B-ALL/LBL with recurrent genetic abnormality and is used for risk-directed
    management.
  cell_types:
  - preferred_term: B-lymphoblast
    term:
      id: CL:0017006
      label: B-lymphoblast
  - preferred_term: precursor B cell
    term:
      id: CL:0000817
      label: precursor B cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: B cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030183
      label: B cell differentiation
  evidence:
  - reference: PMID:36658389
    reference_title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by
      recurrent genetic abnormalities that drive risk-directed treatment
      strategies.
    explanation: >-
      The WGS cohort abstract directly states that recurrent genetic
      abnormalities characterize B-ALL and drive risk-directed care.
  downstream:
  - target: Altered B-cell Development and Signaling
    description: >-
      Subtype-defining lesions perturb transcriptional control, kinase
      signaling, aneuploid dosage, or cytokine signaling in B-lineage blasts.
- name: Altered B-cell Development and Signaling
  description: >-
    Recurrent lesions disrupt B-cell developmental regulators or activate
    oncogenic signaling pathways, causing abnormal differentiation, survival,
    and proliferation of leukemic B-lineage blasts.
  cell_types:
  - preferred_term: precursor B cell
    term:
      id: CL:0000817
      label: precursor B cell
  biological_processes:
  - preferred_term: B cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030183
      label: B cell differentiation
  - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  evidence:
  - reference: PMID:34626353
    reference_title: Genetics and Diagnostic Approach to Lymphoblastic Leukemia/Lymphoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Besides recurrent chromosomal abnormalities detected by karyotyping or
      fluorescence in situ hybridization, these leukemias/lymphomas are
      characterized by a variety of mutations, gene rearrangements as well as
      copy number alterations.
    explanation: >-
      This supports modeling the disease as genetically heterogeneous beyond
      classic cytogenetics, with multiple lesion classes feeding into abnormal
      B-cell development and signaling.
  - reference: PMID:23523389
    reference_title: Acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genome-wide profiling of germline and leukaemic cell DNA has identified
      novel submicroscopic structural genetic changes and sequence mutations
      that contribute to leukaemogenesis, define new disease subtypes, affect
      responsiveness to treatment, and might provide novel prognostic markers
      and therapeutic targets for personalised medicine.
    explanation: >-
      This ALL review abstract supports linking genomic lesion classes to
      leukemogenesis, subtype definition, treatment response, prognosis, and
      therapeutic targeting.
  downstream:
  - target: Leukemic Blast Burden in Bone Marrow and Sanctuary Sites
    description: >-
      Abnormal survival and proliferation produce a leukemic blast compartment
      in marrow, blood, or tissue, with CNS sanctuary involvement or relapse in
      some patients.
- name: Leukemic Blast Burden in Bone Marrow and Sanctuary Sites
  description: >-
    Genetically defined B-ALL/LBL clones expand in marrow and can involve the
    central nervous system, especially in relapse settings where marrow and CNS
    sites are major outcome-defining compartments.
  cell_types:
  - preferred_term: B-lymphoblast
    term:
      id: CL:0017006
      label: B-lymphoblast
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5%
      involved the marrow.
    explanation: >-
      This large pediatric relapse cohort supports bone marrow as a dominant
      disease compartment in B-ALL relapse.
  - reference: PMID:39008716
    reference_title: A brain organoid/ALL coculture model reveals the AP-1 pathway as critically associated with CNS involvement of BCP-ALL.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Central nervous system (CNS) involvement remains a clinical hurdle in
      treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
    explanation: >-
      This directly supports CNS involvement as a clinically important
      sanctuary-site compartment in B-cell precursor ALL.
phenotypes:
- name: Leukemia
  category: Hematologic
  description: >-
    The leukemia presentation reflects malignant proliferation of precursor
    B-lineage lymphoblasts in blood and bone marrow.
  phenotype_term:
    preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  evidence:
  - reference: PMID:36422706
    reference_title: International Consensus Classification of acute lymphoblastic leukemia/lymphoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The updated International Consensus Classification (ICC) of B-acute
      lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL)
      includes both revisions to subtypes previously outlined in the 2016 WHO
      classification and several newly described entities.
    explanation: >-
      This classification abstract establishes B-acute lymphoblastic leukemia as
      the relevant disease presentation within the recurrent-genetic-abnormality
      category.
- name: Bone Marrow Relapse/Involvement
  category: Hematologic
  description: >-
    Bone marrow is a major disease and relapse site in B-ALL, and marrow
    involvement is central to risk assessment after relapse.
  phenotype_term:
    preferred_term: Abnormal bone marrow cell morphology
    term:
      id: HP:0005561
      label: Abnormal bone marrow cell morphology
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5%
      involved the marrow.
    explanation: >-
      This directly supports marrow involvement as a major relapse phenotype in
      pediatric B-ALL.
- name: Central Nervous System Relapse/Involvement
  category: Neurologic
  description: >-
    CNS involvement is a clinically important sanctuary-site manifestation in
    ALL and influences therapy through CNS-directed treatment and relapse
    management.
  phenotype_term:
    preferred_term: Morphological central nervous system abnormality
    term:
      id: HP:0002011
      label: Morphological central nervous system abnormality
  evidence:
  - reference: PMID:39008716
    reference_title: A brain organoid/ALL coculture model reveals the AP-1 pathway as critically associated with CNS involvement of BCP-ALL.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Central nervous system (CNS) involvement remains a clinical hurdle in
      treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
    explanation: >-
      This BCP-ALL abstract supports CNS involvement as a clinically important
      phenotype/relapse-management concern for the current B-lineage category.
- name: Increased Leukocyte Count
  category: Hematologic
  description: >-
    Leukocyte count varies by recurrent genetic abnormality, with BCR::ABL1
    rearrangement associated with higher leukocyte counts in an adult B-ALL
    cohort.
  phenotype_term:
    preferred_term: Increased total leukocyte count
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:32902203
    reference_title: Recurrent genetic abnormalities detected by FISH in adult B ALL and association with hematological parameters.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BCR-ABL positive group had a higher leukocyte count than BCR-ABL negative
      group.
    explanation: >-
      This adult B-ALL cohort supports leukocyte-count differences associated
      with a recurrent genetic abnormality.
genetic:
- name: Recurrent Genetic Abnormalities
  association: Defining molecular feature of the disease category
  variant_origin: SOMATIC
  notes: >-
    Includes recurrent translocations/fusions, aneuploidy, intrachromosomal
    amplification, copy-number alterations, and sequence variants that classify
    B-ALL/LBL subtypes and guide risk-directed therapy.
  evidence:
  - reference: PMID:36658389
    reference_title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This approach detected 294 subtype-defining genetic abnormalities in 96%
      (202/210) patients.
    explanation: >-
      The WGS cohort demonstrates that subtype-defining abnormalities are
      recoverable in nearly all childhood B-ALL cases using comprehensive
      genomic testing.
- name: BCR-ABL1 Fusion
  association: Defining lesion of Ph-positive B-ALL/LBL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ABL1
    term:
      id: hgnc:76
      label: ABL1
  notes: >-
    The t(9;22) lesion creates a BCR::ABL1 fusion. BCR is hgnc:1014; ABL1 is
    hgnc:76.
  evidence:
  - reference: PMID:32902203
    reference_title: Recurrent genetic abnormalities detected by FISH in adult B ALL and association with hematological parameters.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BCR-ABL is commonest recurrent abnormality followed by IgH rearrangements.
    explanation: >-
      This adult B-ALL FISH cohort supports BCR-ABL as a recurrent genetic
      abnormality in adult B-ALL.
- name: KMT2A Rearrangement
  association: Defining lesion of KMT2A-rearranged B-ALL/LBL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: KMT2A
    term:
      id: hgnc:7132
      label: KMT2A
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short
      median time-to-relapse (12.5-18 months) and poor OS post-relapse
      (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%).
    explanation: >-
      This directly identifies KMT2A rearrangement as a subtype-defining
      cytogenetic/genetic risk factor.
- name: ETV6-RUNX1 Fusion
  association: Defining lesion of ETV6::RUNX1 B-ALL/LBL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  notes: >-
    The fusion partner ETV6 is hgnc:3495; RUNX1 is hgnc:10471.
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of
      43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%,
      respectively.
    explanation: >-
      This supports ETV6::RUNX1 as a recurrent prognostic genetic lesion.
- name: TCF3-PBX1 Fusion
  association: Defining lesion of TCF3::PBX1 B-ALL/LBL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: PBX1
    term:
      id: hgnc:8632
      label: PBX1
  notes: >-
    The fusion partner TCF3 is hgnc:11633; PBX1 is hgnc:8632.
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short
      median time-to-relapse (12.5-18 months) and poor OS post-relapse
      (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%).
    explanation: >-
      This supports TCF3::PBX1 as a recurrent genetic abnormality with adverse
      relapse outcomes.
- name: DUX4 Rearrangement
  association: Defining lesion of DUX4-rearranged B-ALL/LBL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:36658389
    reference_title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our novel bioinformatic pipeline improved detection of DUX4 rearrangements
      (DUX4-r): a good-risk B-ALL subtype with high survival rates.
    explanation: >-
      This supports DUX4 rearrangement as a subtype-defining lesion detectable
      by WGS.
- name: IGH-IL3 Rearrangement
  association: Defining lesion of t(5;14) B-ALL/LBL with eosinophilia
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    The rearrangement juxtaposes the IGH enhancer and IL3 locus, causing IL3
    overproduction and reactive eosinophilia.
  evidence:
  - reference: PMID:33991782
    reference_title: "Clinical utility of next generation sequencing to detect IGH/IL3 rearrangements [t(5;14)(q31.1;q32.1)] in B-lymphoblastic leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In these cases, the IGH enhancer region (14q32.1) is juxtaposed to the
      vicinity of the IL3 gene (5q31.1), resulting in increased production of
      interleukin-3 (IL3) and subsequently a characteristic reactive
      eosinophilia.
    explanation: >-
      This provides the causal genetic mechanism and downstream eosinophilia
      for the IGH::IL3 subtype.
diagnosis:
- name: Integrated Genomic Classification
  description: >-
    Diagnosis requires lineage assignment plus genomic testing to identify
    subtype-defining lesions. Karyotype, FISH, RT-PCR, RNA sequencing,
    copy-number profiling, and WGS are complementary, with comprehensive
    sequencing especially useful for emerging or cryptic subtypes.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: PMID:36658389
    reference_title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, we have validated that WGS provides a standalone, reliable
      genetic test to detect all subtype-defining genetic abnormalities in
      B-ALL, accurately classifying patients for the risk-directed treatment
      stratification, while simultaneously performing as a research tool to
      identify novel disease biomarkers.
    explanation: >-
      This WGS validation study supports comprehensive genomic testing for
      subtype assignment and risk-directed stratification.
- name: Ph-like ALL Detection
  description: >-
    Ph-like/BCR::ABL1-like disease requires gene-expression and fusion/mutation
    testing beyond routine BCR::ABL1 assays because it lacks the canonical
    BCR::ABL1 translocation despite a similar expression signature.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: PMID:34626353
    reference_title: Genetics and Diagnostic Approach to Lymphoblastic Leukemia/Lymphoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ph-like ALL is associated with a worse prognosis and hence its detection
      is critical.
    explanation: >-
      This supports targeted detection of Ph-like ALL as a clinically important
      diagnostic task.
- name: Adult ALL Biologic Characterization and Risk Stratification
  description: >-
    Adult ALL assessment should capture biologic subgroup, prognostic factors,
    endpoint definitions, and risk stratification at initial management.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: PMID:38295337
    reference_title: "Diagnosis, prognostic factors, and assessment of ALL in adults: 2024 ELN recommendations from a European expert panel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The European Working Group for Adult ALL has therefore summarized the
      current state of the art and provided comprehensive consensus
      recommendations for diagnostic approaches, biologic and clinical
      characterization, prognostic factors, and risk stratification as well as
      definitions of endpoints and outcomes.
    explanation: >-
      This adult ALL expert-panel recommendation supports comprehensive
      diagnostic and prognostic characterization.
progression:
- phase: First relapse
  notes: >-
    Relapse site and timing are major prognostic features. In pediatric COG
    trials, about half of B-ALL relapses occurred late and most involved marrow.
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 16,115 patients, 2053 (12.7%) relapsed.
    explanation: >-
      This provides the cohort-level relapse denominator for ALL and supports
      modeling relapse as a major progression phase.
- phase: Post-relapse outcome
  notes: >-
    Post-relapse survival varies substantially by genetic subtype, with
    favorable outcomes for ETV6::RUNX1/trisomy 4+10 and poor outcomes for
    hypodiploid, KMT2A-rearranged, and TCF3::PBX1 subtypes.
  evidence:
  - reference: PMID:39261601
    reference_title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%;
      B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%.
    explanation: >-
      This quantifies post-relapse survival and shows B-ALL-specific outcomes.
treatments:
- name: Risk-Directed Multi-agent Chemotherapy
  description: >-
    Multi-agent ALL chemotherapy remains the backbone of treatment, with
    intensity and adjuncts guided by genetic subtype, response, measurable
    residual disease, age, and relapse risk.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
  evidence:
  - reference: PMID:36658389
    reference_title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by
      recurrent genetic abnormalities that drive risk-directed treatment
      strategies.
    explanation: >-
      This supports genetic subtype assignment as a basis for risk-directed ALL
      treatment planning.
- name: ABL-directed Tyrosine Kinase Inhibitors
  description: >-
    Imatinib, dasatinib, ponatinib, or related ABL-directed TKIs are used with
    chemotherapy or immune therapy for BCR::ABL1-positive disease and are a
    rational targeted approach for some ABL-class Ph-like lesions.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: imatinib
      term:
        id: CHEBI:45783
        label: imatinib
    - preferred_term: dasatinib
      term:
        id: CHEBI:49375
        label: dasatinib (anhydrous)
  target_mechanisms:
  - target: Altered B-cell Development and Signaling
    treatment_effect: INHIBITS
    description: >-
      ABL-directed TKIs inhibit oncogenic tyrosine-kinase signaling in
      BCR::ABL1-positive or ABL-class kinase-activated disease.
  evidence:
  - reference: PMID:23523389
    reference_title: Acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with BCR-ABL1-positive ALL have been considered to have a poor
      prognosis but benefit from early administration of a tyrosine kinase
      inhibitor (eg, imatinib, dasatinib).
    explanation: >-
      This supports TKI therapy for the BCR::ABL1-positive subtype.
- name: Blinatumomab
  description: >-
    CD19-directed CD3-engaging bispecific antibody used in B-cell precursor ALL,
    especially in first relapse or high-risk settings with marrow involvement.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: MAXO:0001002
      label: immunotherapy procedure
    therapeutic_agent:
    - preferred_term: blinatumomab
      term:
        id: NCIT:C62528
        label: Blinatumomab
  target_mechanisms:
  - target: Leukemic Blast Burden in Bone Marrow and Sanctuary Sites
    treatment_effect: MODULATES
    description: >-
      Blinatumomab redirects T cells against CD19-positive B-lineage blasts,
      reducing leukemic burden.
  evidence:
  - reference: PMID:38832425
    reference_title: "Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For B-cell precursor ALL, blinatumomab, an anti-CD19 bispecific antibody,
      has established its role in the consolidation treatment for both high- and
      standard-risk first relapse of ALL, in the presence of bone marrow
      involvement, and may also have an impact on the outcome of high-risk
      subsets such as infant ALL and Philadelphia chromosome-positive ALL.
    explanation: >-
      This review abstract directly supports blinatumomab use in B-cell
      precursor ALL relapse and high-risk subsets relevant to this category.
- name: Inotuzumab Ozogamicin
  description: >-
    CD22-directed antibody-drug conjugate used for relapsed B-ALL, including
    high-burden disease, with ongoing randomized pediatric trials.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: MAXO:0001002
      label: immunotherapy procedure
    therapeutic_agent:
    - preferred_term: inotuzumab ozogamicin
      term:
        id: NCIT:C71542
        label: Inotuzumab Ozogamicin
  target_mechanisms:
  - target: Leukemic Blast Burden in Bone Marrow and Sanctuary Sites
    treatment_effect: MODULATES
    description: >-
      Inotuzumab ozogamicin targets CD22-positive B-lineage blasts and delivers
      cytotoxic payload.
  evidence:
  - reference: PMID:38832425
    reference_title: "Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inotuzumab ozogamicin, an anti-CD22 drug conjugated antibody, has
      demonstrated high efficacy in inducing complete remission in relapsed ALL,
      even in the presence of high tumor burden, but randomized phase III trials
      are still ongoing.
    explanation: >-
      This supports inotuzumab ozogamicin as an antibody-drug conjugate for
      relapsed ALL, while preserving the abstract's caveat about ongoing phase
      III trials.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic hematopoietic stem cell transplantation is considered for
    selected very-high-risk, persistent-MRD, or relapsed ALL contexts; its use
    depends on age, genetic subtype, response, and treatment era.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  target_mechanisms:
  - target: Leukemic Blast Burden in Bone Marrow and Sanctuary Sites
    treatment_effect: MODULATES
    description: >-
      Transplant aims to consolidate remission and reduce residual leukemic
      burden in high-risk disease.
  evidence:
  - reference: PMID:23523389
    reference_title: Acute lymphoblastic leukaemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Allogeneic haematopoietic stem-cell transplantation is considered for
      patients at very high risk.
    explanation: >-
      This supports transplant as a high-risk ALL treatment strategy, although
      subtype-specific indications require current protocol context.
references:
- reference: PMID:36422706
  title: International Consensus Classification of acute lymphoblastic leukemia/lymphoma.
  found_in:
  - research/B-Lymphoblastic_Leukemia_Lymphoma_With_Recurrent_Genetic_Abnormality-deep-research-falcon.md
  findings:
  - statement: >-
      The ICC updates B-ALL/LBL classification with revised and newly described
      genetic entities.
    supporting_text: >-
      The updated International Consensus Classification (ICC) of B-acute
      lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL)
      includes both revisions to subtypes previously outlined in the 2016 WHO
      classification and several newly described entities.
- reference: PMID:36658389
  title: Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.
  found_in:
  - research/B-Lymphoblastic_Leukemia_Lymphoma_With_Recurrent_Genetic_Abnormality-deep-research-falcon.md
  findings:
  - statement: WGS detected subtype-defining abnormalities in nearly all childhood B-ALL cases.
    supporting_text: >-
      This approach detected 294 subtype-defining genetic abnormalities in 96%
      (202/210) patients.
- reference: PMID:39261601
  title: "Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study."
  found_in:
  - research/B-Lymphoblastic_Leukemia_Lymphoma_With_Recurrent_Genetic_Abnormality-deep-research-falcon.md
  findings:
  - statement: Relapse timing, site, and genotype shape post-relapse survival.
    supporting_text: >-
      Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short
      median time-to-relapse (12.5-18 months) and poor OS post-relapse
      (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%).
- reference: PMID:38832425
  title: "Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia."
  found_in:
  - research/B-Lymphoblastic_Leukemia_Lymphoma_With_Recurrent_Genetic_Abnormality-deep-research-falcon.md
  findings:
  - statement: CD19 and CD22 antibody-based therapies are changing B-cell precursor ALL treatment.
    supporting_text: >-
      With the novel therapeutic options introduced in the last years, including
      immunotherapies and targeted antibodies, the treatment of ALL is
      undergoing major changes.
- reference: PMID:33988307
  title: Systematic application of fluorescence in situ hybridization and immunophenotype profile for the identification of ZNF384 gene rearrangements in B cell acute lymphoblastic leukemia.
  findings:
  - statement: ZNF384 fusions define a distinct recurrent genetic B-ALL subgroup.
    supporting_text: >-
      Fusions involving the ZNF384 gene have been reported to be mutually
      exclusive of other genetic subtypes and thus constitute a distinct
      subgroup in B-ALL.
- reference: PMID:39008716
  title: A brain organoid/ALL coculture model reveals the AP-1 pathway as critically associated with CNS involvement of BCP-ALL.
  findings:
  - statement: CNS involvement remains clinically important in B-cell precursor ALL.
    supporting_text: >-
      Central nervous system (CNS) involvement remains a clinical hurdle in
      treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
review_notes: >-
  Falcon report found no strong support for environmental risk, prevention,
  model-organism, or other-species sections for this specific classification
  entry; those sections were intentionally omitted.

📚

References & Deep Research

References

PMID:36422706

International Consensus Classification of acute lymphoblastic leukemia/lymphoma.

1 finding

The ICC updates B-ALL/LBL classification with revised and newly described genetic entities.

PMID:36658389

Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.

1 finding

WGS detected subtype-defining abnormalities in nearly all childhood B-ALL cases.

"This approach detected 294 subtype-defining genetic abnormalities in 96% (202/210) patients."

PMID:39261601

Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study.

1 finding

Relapse timing, site, and genotype shape post-relapse survival.

"Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%)."

PMID:38832425

Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia.

1 finding

CD19 and CD22 antibody-based therapies are changing B-cell precursor ALL treatment.

"With the novel therapeutic options introduced in the last years, including immunotherapies and targeted antibodies, the treatment of ALL is undergoing major changes."

PMID:33988307

Systematic application of fluorescence in situ hybridization and immunophenotype profile for the identification of ZNF384 gene rearrangements in B cell acute lymphoblastic leukemia.

1 finding

ZNF384 fusions define a distinct recurrent genetic B-ALL subgroup.

"Fusions involving the ZNF384 gene have been reported to be mutually exclusive of other genetic subtypes and thus constitute a distinct subgroup in B-ALL."

PMID:39008716

A brain organoid/ALL coculture model reveals the AP-1 pathway as critically associated with CNS involvement of BCP-ALL.

1 finding

CNS involvement remains clinically important in B-cell precursor ALL.

"Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL)."

Deep Research

Falcon ▸

High-value, recent sources used (with dates and URLs)

Edison Scientific Literature 23 citations 2026-05-10T16:22:39.007989

1. Disease Information

1.1 Definition and overview

B‑lymphoblastic leukemia/lymphoma (B‑ALL/LBL) is a precursor B‑cell neoplasm characterized by proliferation of lymphoblasts in bone marrow/blood (leukemia) and/or mass lesions (lymphoma). Contemporary classifications emphasize that recurrent genetic abnormalities define biologically and clinically meaningful subtypes that drive risk stratification and, in select cases, targeted therapy. This framing is explicit in both the ICC and recent WHO-aligned summaries emphasizing that childhood B‑ALL is “characterised by recurrent genetic abnormalities that drive risk‑directed treatment strategies.” (ryan2023wholegenomesequencing pages 1-2).

1.2 Classification context (WHO‑HAEM5 and ICC)

The ICC article on ALL/LBL (peer‑reviewed; Nov 2023; URL https://doi.org/10.1007/s00428-022-03448-8) outlines multiple recurrent genetic B‑ALL entities and explicitly subdivides BCR::ABL1‑like (Ph‑like) ALL into mechanistically actionable categories (ABL‑class vs JAK‑STAT–activated vs NOS) with corresponding diagnostic requirements (duffield2023internationalconsensusclassification pages 3-4, duffield2023internationalconsensusclassification pages 4-6).

A WHO‑HAEM5‑aligned review notes that WHO‑HAEM5 upgraded some 2017 “provisional” entities (e.g., BCR::ABL1‑like, iAMP21) and added newer types such as ETV6::RUNX1‑like and a category of “B‑ALL with other defined genetic features,” and recommends use of “B‑ALL/LBL, not further classified” when comprehensive genomic testing is not feasible (kansal2023diagnosisandmolecular pages 5-7).

1.3 Synonyms / alternative names

Commonly used names in the literature include: - B‑ALL; B‑cell acute lymphoblastic leukemia - B‑LBL; B‑lymphoblastic lymphoma - B‑lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities (ICC/WHO framing) (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 5-7)

1.4 Key identifiers (ICD/MeSH/MONDO/Orphanet/OMIM)

Not determinable from the retrieved evidence set. The provided materials were not ontology/registry entries and did not list ICD‑10/11, MeSH, Orphanet, OMIM, or MONDO identifiers.

1.5 Evidence source type

The classification and mechanistic information here is derived from aggregated disease‑level resources (WHO/ICC‑aligned reviews and consensus classifications) and large cohort studies (e.g., WGS diagnostic validation; COG relapse analysis) rather than single‑patient EHR data (ryan2023wholegenomesequencing pages 1-2, rheingold2024determinantsofsurvival pages 2-3).

2. Etiology

2.1 Primary causal factors

The defining “causal factors” for this knowledge‑base entry are recurrent genetic alterations that initiate or sustain leukemogenesis (chromosomal aneuploidy, translocations/fusions, focal copy‑number changes, and subtype‑defining point mutations) (kansal2023diagnosisandmolecular pages 5-7, duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 3-4).

2.2 Risk factors

Germline predisposition / inherited risk: In ICC, low hypodiploid B‑ALL is highlighted as frequently involving TP53 mutations, with an important clinical point that ~50% of pediatric TP53 mutations in this setting may be germline (Li‑Fraumeni syndrome implication) (duffield2023internationalconsensusclassification pages 3-4).

Age-related risk: Favorable genetic subtypes (high hyperdiploidy; ETV6::RUNX1) are common in childhood but become rare in older adults; an excerpt gives approximate distribution across age strata (kansal2023diagnosisandmolecular pages 7-8).

Environmental/infectious risk factors: Not supported by the retrieved evidence set.

2.3 Protective factors and gene–environment interactions

Not supported by the retrieved evidence set.

3. Phenotypes

3.1 Clinical presentation (general)

The retrieved evidence focuses on classification and diagnostics rather than detailed symptom prevalence. However, clinically relevant phenotypes documented include: - Bone marrow–dominant relapse and CNS relapse patterns in pediatric ALL: isolated bone marrow relapse 58.7%; any bone marrow involvement 72.5%; isolated CNS relapse 21.7%; overall CNS involvement 32.9% (COG analysis) (rheingold2024determinantsofsurvival pages 2-3).

3.2 Age of onset

Childhood B‑ALL is dominated by specific favorable genetic subtypes; in one WHO‑aligned summary, ~90% of childhood ALL is B‑ALL and favorable subtypes contribute a large proportion of standard‑risk disease (kansal2023diagnosisandmolecular pages 5-7, kansal2023diagnosisandmolecular pages 7-8).

3.3 Suggested HPO terms (high-level; limited by evidence)

Because symptom-level data were not extracted in the current evidence set, only broad, high-confidence phenotype terms are suggested: - Abnormality of the bone marrow (HP:0005560) - Leukemia (HP:0001909) - Central nervous system involvement (HP:0001310) — supported by CNS relapse frequency patterns (rheingold2024determinantsofsurvival pages 2-3)

4. Genetic / Molecular Information (core of this entity)

4.1 Current understanding: recurrent genetic subtypes

Modern WHO/ICC frameworks partition B‑ALL/LBL into multiple recurrent genetic subtypes; the ICC provides detailed diagnostic/prognostic notes for several recently recognized entities (DUX4‑r, ZNF384‑r, MEF2D‑r, NUTM1‑r, MYC‑r, CDX2/UBTF, HLF‑r), as well as single-gene mutant entities (PAX5 P80R; IKZF1 N159Y) (duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 6-8).

A WHO‑aligned review highlights that WHO‑HAEM5 expanded the list beyond classic cytogenetic categories and that many new subtypes require advanced genomic methods (expression profiling, WGS, improved copy-number analysis) (kansal2023diagnosisandmolecular pages 5-7).

4.2 Subtype catalog (structured)

A structured table of major subtypes, frequencies (when available), prognosis notes, and detection methods is provided below.

Subtype	Hallmark alteration	Typical age group	Approx. frequency	Prognosis notes	Recommended detection method
High hyperdiploidy	51–65 chromosomes / high hyperdiploidy	Predominantly childhood; common pediatric subtype (kansal2023diagnosisandmolecular pages 7-8)	~25–35% of B-ALL; ~30% in childhood cohorts (mahdaoui2025areviewof pages 2-3, ryan2023wholegenomesequencing pages 1-2)	Very favorable / excellent prognosis; long-term survival often >90% in summary review sources (mahdaoui2025areviewof pages 2-3, kansal2023diagnosisandmolecular pages 5-7)	Karyotype, copy-number analysis/WGS; standard cytogenetics generally sufficient (kansal2023diagnosisandmolecular pages 5-7, ryan2023wholegenomesequencing pages 1-2)
ETV6::RUNX1	t(12;21)(p13;q22), ETV6::RUNX1 fusion	Childhood; often initiates in utero (kansal2023diagnosisandmolecular pages 7-8)	~21–25% of childhood B-ALL (kansal2023diagnosisandmolecular pages 5-7, ryan2023wholegenomesequencing pages 1-2)	Favorable / excellent prognosis (kansal2023diagnosisandmolecular pages 5-7, kansal2023diagnosisandmolecular pages 7-8)	FISH, RT-PCR/RNA-based testing, WGS (kansal2023diagnosisandmolecular pages 5-7, ryan2023wholegenomesequencing pages 1-2)
BCR::ABL1	t(9;22)(q34;q11.2), BCR::ABL1 fusion	More common in adults, also seen in children (kansal2023diagnosisandmolecular pages 5-7)	Not consistently stated in gathered evidence	Historically poor-risk, now therapeutically targetable with TKIs (kansal2023diagnosisandmolecular pages 5-7, duffield2023internationalconsensusclassification pages 3-4)	Karyotype, FISH, RT-PCR/RNA-seq, WGS (kansal2023diagnosisandmolecular pages 5-7, ryan2023wholegenomesequencing pages 1-2)
BCR::ABL1-like (Ph-like)	Kinase/cytokine receptor alterations; ABL-class, JAK-STAT, CRLF2, EPOR, FLT3/FGFR1/NTRK3/PTK2B lesions	Children, AYA, adults; clinically important across ages (duffield2023internationalconsensusclassification pages 3-4)	Not consistently stated in gathered evidence	Poor outcome; therapeutically relevant because ABL-class lesions may respond to TKIs (duffield2023internationalconsensusclassification pages 3-4, kansal2023diagnosisandmolecular pages 5-7)	GEP plus fusion/mutation testing; FISH for some lesions; targeted transcriptome sequencing/NGS; WGS (duffield2023internationalconsensusclassification pages 3-4, kansal2023diagnosisandmolecular pages 5-7, ryan2023wholegenomesequencing pages 1-2)
KMT2A-rearranged	KMT2A (MLL) rearrangements	Infant-predominant but also seen beyond infancy (kansal2023diagnosisandmolecular pages 5-7, kansal2023diagnosisandmolecular pages 15-16)	Not consistently stated in gathered evidence	Poor prognosis; clinically important and menin-pathway targeted therapy is emerging (kansal2023diagnosisandmolecular pages 5-7, kansal2023diagnosisandmolecular pages 15-16)	Karyotype/FISH for classic lesions; RNA-seq/NGS/WGS for comprehensive definition (kansal2023diagnosisandmolecular pages 5-7, kansal2023diagnosisandmolecular pages 15-16)
TCF3::PBX1	t(1;19)(q23;p13), TCF3::PBX1 fusion	Mostly pediatric/AYA (ryan2023wholegenomesequencing pages 1-2)	~5% in childhood cohorts (ryan2023wholegenomesequencing pages 1-2)	Recognized recurrent subtype; prognosis not explicitly quantified in gathered subtype summaries here (ryan2023wholegenomesequencing pages 1-2)	Karyotype, FISH, RT-PCR/RNA-seq, WGS (ryan2023wholegenomesequencing pages 1-2)
iAMP21	Intrachromosomal amplification of chromosome 21	Pediatric (kansal2023diagnosisandmolecular pages 5-7, kansal2023diagnosisandmolecular pages 15-16)	~2% of pediatric B-ALL (mahdaoui2025areviewof pages 2-3, ryan2023wholegenomesequencing pages 1-2)	Upgraded to definite entity in WHO-HAEM5; adverse-risk subtype in modern classification context (kansal2023diagnosisandmolecular pages 5-7)	FISH/copy-number methods; WGS can detect; targeted RNA-seq alone may miss iAMP21 (ryan2023wholegenomesequencing pages 1-2)
Hypodiploid B-ALL	Low hypodiploid (32–39 chr) or near-haploid (24–31 chr); TP53/IKZF2 associations	Children and adults (duffield2023internationalconsensusclassification pages 3-4)	~1% low hypodiploid and ~1% near-haploid in childhood cohort summary (ryan2023wholegenomesequencing pages 1-2)	Poor outcome; masked hypodiploidy is a diagnostic pitfall (kansal2023diagnosisandmolecular pages 5-7, duffield2023internationalconsensusclassification pages 3-4)	Karyotype plus SNP/copy-number analysis or WGS to detect masked hypodiploidy (duffield2023internationalconsensusclassification pages 3-4, ryan2023wholegenomesequencing pages 1-2)
DUX4-rearranged	DUX4 rearrangement, often IGH::DUX4; DUX4 overexpression	Relatively common in AYA; also pediatric (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16)	~5–10% overall in ICC summary; ~4% pediatric B-ALL / ~16% of B-other (duffield2023internationalconsensusclassification pages 3-4, kansal2023diagnosisandmolecular pages 15-16)	Excellent/favorable prognosis despite high early MRD (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16)	RNA-seq/GEP, DUX4 RNA or protein overexpression, CD371 by flow; WGS may outperform transcriptome sequencing for some cases (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16, ryan2023wholegenomesequencing pages 1-2)
ZNF384-rearranged	ZNF384 rearrangements with multiple partners (e.g., EP300, TCF3, TAF15)	Children and young adults; also adults (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16)	~5–10% overall; ~5% childhood and ~10% adult in summary sources (duffield2023internationalconsensusclassification pages 3-4, kansal2023diagnosisandmolecular pages 15-16)	Prognosis depends on fusion partner; may show lineage ambiguity / MPAL overlap (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16)	FISH break-apart, transcriptome sequencing/RNA-seq, genomic sequencing/WGS (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16)
MEF2D-rearranged	MEF2D rearrangement, commonly MEF2D::BCL9	Children/young adults; median age around adolescence in some series (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16)	Small subset; ~5% of pediatric cases without other recurrent abnormalities (kansal2023diagnosisandmolecular pages 15-16)	Relatively poor prognosis (duffield2023internationalconsensusclassification pages 4-6)	Fusion probes/FISH, transcriptome sequencing/RNA-seq, NGS/WGS (duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16)
NUTM1-rearranged	NUTM1 rearrangement	Infant-predominant (duffield2023internationalconsensusclassification pages 4-6)	Rare (duffield2023internationalconsensusclassification pages 4-6)	Favorable prognosis in available summaries (duffield2023internationalconsensusclassification pages 4-6)	NUTM1 FISH and NUT immunohistochemistry; RNA-seq/NGS may also define fusion (duffield2023internationalconsensusclassification pages 4-6)
MYC-rearranged	IG::MYC or other MYC rearrangement	More often adult B-ALL (duffield2023internationalconsensusclassification pages 4-6)	~4% of adult B-ALL (duffield2023internationalconsensusclassification pages 4-6)	Very poor prognosis; distinction from mature B-cell lymphoma/Burkitt-type disease is essential (duffield2023internationalconsensusclassification pages 4-6)	FISH/karyotype; somatic hypermutation analysis and immunophenotype support distinction; RNA-seq/NGS may assist (duffield2023internationalconsensusclassification pages 4-6)
PAX5 P80R	PAX5 p.P80R point mutation	More common in adults (duffield2023internationalconsensusclassification pages 6-8)	~2–5% of B-ALL (duffield2023internationalconsensusclassification pages 6-8)	Relatively good prognosis (duffield2023internationalconsensusclassification pages 6-8)	NGS for point mutation; broader genomic testing for associated lesions (duffield2023internationalconsensusclassification pages 6-8)
PAX5alt	Diverse PAX5 alterations / fusions / CNAs defining PAX5-altered subtype	Childhood and adults; many formerly “B-other” cases (kansal2023diagnosisandmolecular pages 15-16, ryan2023wholegenomesequencing pages 1-2)	~7.5% in review summary (mahdaoui2025areviewof pages 2-3)	Intermediate outcomes in cohort/review summaries (duffield2023internationalconsensusclassification pages 6-8)	Integrated RNA-seq, copy-number analysis, NGS/WGS; expanded genomic profiling improves recognition (duffield2023internationalconsensusclassification pages 6-8, ryan2023wholegenomesequencing pages 1-2)
IKZF1 N159Y	IKZF1 N159Y point mutation	More common in adults (duffield2023internationalconsensusclassification pages 6-8)	<1% of cases (duffield2023internationalconsensusclassification pages 6-8)	Intermediate prognosis (duffield2023internationalconsensusclassification pages 6-8)	NGS for point mutation (duffield2023internationalconsensusclassification pages 6-8)
HLF-rearranged	TCF3::HLF or TCF4::HLF	Exceptionally rare, largely pediatric (duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 6-8)	Exceptionally rare (duffield2023internationalconsensusclassification pages 6-8)	Very poor prognosis (duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 6-8)	Fusion testing by FISH/RNA-seq/NGS; WGS can detect structural event (duffield2023internationalconsensusclassification pages 6-8, ryan2023wholegenomesequencing pages 1-2)
CDX2/UBTF	UBTF::ATXN7L3 fusion plus FLT3-upstream deletion causing CDX2 deregulation	Female adolescents and young adults (duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 6-8)	Rare (duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 6-8)	Poor prognosis (duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 6-8)	Genomic structural testing with RNA-seq/WGS/NGS; specialized assays may be required (duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 6-8)
ETV6::RUNX1-like	ETV6::RUNX1-like gene-expression profile without classic t(12;21)	Pediatric-predominant in modern profiling studies (kansal2023diagnosisandmolecular pages 5-7, duffield2023internationalconsensusclassification pages 6-8)	Not stated in gathered evidence	Newly added/provisional subtype in WHO-HAEM5/ICC context; prognosis not quantified here (kansal2023diagnosisandmolecular pages 5-7, duffield2023internationalconsensusclassification pages 6-8)	GEP/RNA-seq and comprehensive genomic profiling/WGS (kansal2023diagnosisandmolecular pages 5-7, duffield2023internationalconsensusclassification pages 6-8, ryan2023wholegenomesequencing pages 1-2)

Table: This table compacts the major recurrent genetic subtypes recognized in modern WHO-HAEM5/ICC-aligned B-lymphoblastic leukemia/lymphoma classification, using only the gathered evidence. It highlights subtype-defining lesions, age distribution, approximate frequencies, prognosis, and the molecular methods most useful for detection.

4.3 Key subtype-specific highlights (examples)

BCR::ABL1‑like (Ph‑like) B‑ALL: ICC subdivides into ABL‑class rearranged vs JAK‑STAT–activated vs NOS; ABL‑class lesions are clinically important because they may respond to ABL1‑targeting TKIs (imatinib, dasatinib), and detection may use FISH and targeted transcriptome sequencing, but definitive assignment requires genetic studies including gene expression and fusion/mutation testing (duffield2023internationalconsensusclassification pages 3-4).
DUX4‑rearranged B‑ALL: ICC notes excellent prognosis and technical pitfalls (IGH::DUX4 can be missed by targeted sequencing/FISH); diagnosis can rely on DUX4 RNA/protein overexpression or CD371 by flow cytometry (duffield2023internationalconsensusclassification pages 4-6). WHO‑aligned summary notes favorable outcome despite high MRD and association with ERG alterations/IKZF1 deletions; NGS (RNA or DNA) is typically required (kansal2023diagnosisandmolecular pages 15-16).
Hypodiploid B‑ALL: ICC distinguishes near‑haploid from low hypodiploid and emphasizes masked hypodiploidy; low hypodiploidy associates with TP53 mutations (with germline implication) (duffield2023internationalconsensusclassification pages 3-4).

4.4 Molecular diagnostic yield (WGS as a comprehensive test)

Whole genome sequencing (WGS) in a 210‑patient childhood B‑ALL cohort detected 294 subtype‑defining genetic abnormalities in 96% (202/210) and showed concordance with standard-of-care methods and WTS, supporting WGS as a “standalone, reliable genetic test” for identifying subtype-defining abnormalities (Jan 2023; URL https://doi.org/10.1038/s41375-022-01806-8) (ryan2023wholegenomesequencing pages 1-2). A tightly cropped image of the paper’s subtype-frequency table is available (ryan2023wholegenomesequencing media 2101e72e).

5. Environmental Information

Not supported by the retrieved evidence set.

6. Mechanism / Pathophysiology

6.1 Conceptual model (current understanding)

Across subtypes, leukemogenesis generally follows a driver-lesion → altered transcription/signaling → aberrant B‑cell precursor differentiation/proliferation → clinical leukemia/lymphoma chain. ICC emphasizes pathway-based classes particularly for Ph‑like ALL, in which lesions activate ABL‑class kinase signaling or JAK‑STAT signaling, creating a rationale for targeted kinase inhibition (duffield2023internationalconsensusclassification pages 3-4).

6.2 Examples of subtype-linked mechanisms

ABL‑class rearranged Ph‑like ALL: oncogenic ABL-family signaling; potential sensitivity to ABL1 TKIs (duffield2023internationalconsensusclassification pages 3-4).
JAK‑STAT–activated Ph‑like ALL: lesions such as CRLF2 rearrangements, EPOR rearrangements, JAK fusions/mutations (duffield2023internationalconsensusclassification pages 3-4).
IKZF1 N159Y: ICC notes abnormal nuclear localization and enhanced cell–cell adhesion phenotypes, consistent with a distinct biology compared with deletion-driven IKZF1 alterations (duffield2023internationalconsensusclassification pages 6-8).

6.3 Suggested ontology terms (high-level)

Because mechanistic detail in the retrieved evidence is subtype‑overview rather than pathway experiments, only broad mapping is suggested: - GO: B cell differentiation (GO:0030183) - GO: JAK‑STAT cascade (GO:0007259) (Ph‑like JAK‑STAT–activated group) (duffield2023internationalconsensusclassification pages 3-4) - GO: protein tyrosine kinase signaling pathway (GO:0007169) (ABL‑class group) (duffield2023internationalconsensusclassification pages 3-4) - CL: B cell (CL:0000236) - CL: B cell precursor (CL:0000816) (conceptual target cell)

7. Anatomical Structures Affected

7.1 Organ/tissue level

Bone marrow is the principal disease compartment and the dominant site of relapse; in a large pediatric dataset, isolated bone marrow relapse accounted for 58.7%, and any bone marrow involvement for 72.5% (rheingold2024determinantsofsurvival pages 2-3).
Central nervous system involvement is clinically important; isolated CNS relapse 21.7% and overall CNS involvement 32.9% at relapse in the same cohort (rheingold2024determinantsofsurvival pages 2-3).

7.2 Suggested UBERON terms

Bone marrow: UBERON:0002371
Central nervous system: UBERON:0001016

8. Temporal Development

8.1 Onset

The evidence set supports that favorable genetic subtypes are predominantly pediatric and may arise early (including prenatal initiation for ETV6::RUNX1 and high hyperdiploidy) (kansal2023diagnosisandmolecular pages 7-8).

8.2 Relapse timing patterns

In the COG analysis of 16,115 patients treated on 12 frontline trials, late relapse was common: ~50% of B‑ALL relapses occurred ≥36 months after diagnosis, and ~16% occurred >5 years (rheingold2024determinantsofsurvival pages 2-3). Relapse timing varies by subtype: ETV6::RUNX1 and trisomy 4+10 have later median time-to-relapse (~43 months), whereas hypodiploid and KMT2A‑rearranged relapse earlier (median ~12.5–18 months) (rheingold2024determinantsofsurvival pages 2-3).

9. Inheritance and Population

9.1 Population epidemiology

Incidence/prevalence estimates were not retrievable from the current evidence set.

9.2 Germline predisposition and inheritance

A clinically actionable inheritance-relevant point is the potential germline origin of TP53 mutations in low hypodiploid B‑ALL (Li‑Fraumeni syndrome context), highlighted by ICC (duffield2023internationalconsensusclassification pages 3-4).

10. Diagnostics

10.1 Diagnostic criteria and classification

The ICC emphasizes that accurate classification of B‑ALL with recurrent genetic abnormalities requires genetic studies, and some groups require gene-expression profiling (GEP) for assignment; CRLF2 rearrangement is one immunophenotypic clue for Ph‑like ALL but otherwise immunophenotypes may be non-distinctive (duffield2023internationalconsensusclassification pages 3-4, duffield2023internationalconsensusclassification pages 6-8).

10.2 Recommended testing modalities (current implementations)

Cytogenetics/FISH/RT‑PCR remain core for classic alterations, while RNA‑seq, WGS, and broader NGS increasingly enable complete assignment of emerging entities and “B‑other” cases (kansal2023diagnosisandmolecular pages 5-7, ryan2023wholegenomesequencing pages 1-2).

WGS in diagnostics: WGS can detect aneuploidies, structural variants, and focal copy-number changes and allocate many B‑other cases to emerging genomic groups; a WGS diagnostic feasibility study reported 100% concordance with standard-of-care and high yield for assigning emerging subgroups (concept supported in WHO‑aligned review; and WGS cohort data show 96% classification success) (ryan2023wholegenomesequencing pages 1-2, kansal2023diagnosisandmolecular pages 5-7).

10.3 Measurable residual disease (MRD)

The ELN 2024 adult ALL recommendations emphasize MRD’s central prognostic role and discuss standardization and validation initiatives for molecular/NGS-based MRD, including EuroClonality NGS standardization efforts and specific guidance for Ph+ ALL MRD by qRT‑PCR (Blood May 2024; URL https://doi.org/10.1182/blood.2023020794) (gokbuget2024diagnosisprognosticfactors pages 13-14).

In pediatric relapse analyses, MRD by COG flow cytometry had typical sensitivity 10−4, and end‑of‑induction MRD ≥0.01% was associated with increased relapse risk (p < 0.0001) (rheingold2024determinantsofsurvival pages 2-3).

10.4 Differential diagnosis

Not supported by the retrieved evidence set.

11. Outcome / Prognosis

11.1 Prognostic stratification by genetics

WHO/ICC-aligned summaries maintain classic prognostic groupings (favorable: high hyperdiploidy; ETV6::RUNX1; adverse: hypodiploidy; BCR::ABL1; KMT2A rearranged), while newly defined subtypes show distinct outcomes (e.g., DUX4‑r favorable; MEF2D‑r relatively poor) (kansal2023diagnosisandmolecular pages 5-7, duffield2023internationalconsensusclassification pages 4-6, kansal2023diagnosisandmolecular pages 15-16).

11.2 Post‑relapse survival and subtype-specific outcomes (pediatric)

A large COG analysis reported 2053 relapses among 16,115 pediatric patients (12.7%); the 5‑year OS post‑relapse was 48.9 ± 1.2% overall and 52.5 ± 1.3% for B‑ALL. The abstract also reports cytogenetic‑specific post‑relapse OS: ETV6::RUNX1 74.4 ± 3.1%, Trisomy 4+10 70.2 ± 3.6%, versus poor outcomes for hypodiploidy 14.2 ± 6.1%, KMT2A‑rearranged 31.9 ± 7.7%, and TCF3::PBX1 36.8 ± 6.6% (Sep 2024; URL https://doi.org/10.1038/s41375-024-02395-4) (rheingold2024determinantsofsurvival pages 2-3).

Direct abstract quote (COG relapse study): “The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%…” and “Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%).” (rheingold2024determinantsofsurvival pages 2-3).

12. Treatment

12.1 Current applications and real-world implementations (selected)

12.1.1 Blinatumomab (CD19×CD3 BiTE)

A 2024 pediatric immunotherapy review summarizes multiple use-cases and randomized relapse settings: - In early single-agent studies at RP2D, overall response rate 39%, and 52% of responders achieved MRD negativity (brivio2024nakedantibodiesand pages 3-4). - In randomized pediatric first marrow relapse settings, post‑reinduction blinatumomab improved 2‑year DFS 54.4% vs 39.0% versus chemotherapy and improved 2‑year EFS 66.2% vs 27.1% in high‑risk first relapse BCP‑ALL (brivio2024nakedantibodiesand pages 3-4). - For bone marrow relapses, blinatumomab produced superior 4‑year DFS/OS 72.7%/97.1% vs chemotherapy 53.7%/84.8%; outcomes were similarly poor for isolated extramedullary relapse (4‑year DFS ~36–39%) (brivio2024nakedantibodiesand pages 3-4).

Direct abstract quote (review): “With the novel therapeutic options introduced in the last years, including immunotherapies and targeted antibodies, the treatment of ALL is undergoing major changes.” (Haematologica May 2024 review; abstract statement) (brivio2024nakedantibodiesand pages 3-4).

12.1.2 Targeted therapy linkage (genotype → therapy)

ICC explicitly connects ABL‑class Ph‑like lesions (ABL1/ABL2/CSF1R/PDGFRB fusions) to potential responsiveness to ABL1-targeting TKIs and indicates that identifying these lesions is clinically actionable (duffield2023internationalconsensusclassification pages 3-4).

12.2 Treatment strategy and expert opinion (authoritative sources)

The ELN 2024 adult recommendations are an authoritative expert-panel source emphasizing that adult ALL management requires comprehensive biologic characterization and MRD-driven risk stratification, with MRD methodology standardization and genomic high-risk groups (e.g., Ph-like ALL, IKZF1 deletions) considered in risk assessment (gokbuget2024diagnosisprognosticfactors pages 13-14).

12.3 Suggested MAXO terms (high level)

Chemotherapy (MAXO:0000058)
Tyrosine kinase inhibitor therapy (for ABL‑class or BCR::ABL1‑positive disease) (duffield2023internationalconsensusclassification pages 3-4)
Blinatumomab therapy / bispecific antibody therapy (MAXO term depends on local MAXO implementation) (brivio2024nakedantibodiesand pages 3-4)
Measurable residual disease monitoring (diagnostic action; MAXO not always used for monitoring)

13. Prevention

Not supported by the retrieved evidence set.

14. Other Species / Natural Disease

Not supported by the retrieved evidence set.

15. Model Organisms

Not supported by the retrieved evidence set.

High-value, recent sources used (with dates and URLs)

Duffield AS, Mullighan CG, Borowitz MJ. International consensus classification of acute lymphoblastic leukemia/lymphoma. Virchows Archiv. Nov 2023. https://doi.org/10.1007/s00428-022-03448-8 (duffield2023internationalconsensusclassification pages 4-6, duffield2023internationalconsensusclassification pages 3-4, duffield2023internationalconsensusclassification pages 6-8)
Ryan S et al. Whole genome sequencing provides comprehensive genetic testing in childhood B‑cell acute lymphoblastic leukaemia. Leukemia. Jan 2023. https://doi.org/10.1038/s41375-022-01806-8 (ryan2023wholegenomesequencing pages 1-2, ryan2023wholegenomesequencing media 2101e72e)
Gökbuget N et al. Diagnosis, prognostic factors, and assessment of ALL in adults: 2024 ELN recommendations. Blood. May 2024. https://doi.org/10.1182/blood.2023020794 (gokbuget2024diagnosisprognosticfactors pages 13-14)
Rheingold SR et al. Determinants of survival after first relapse of ALL: a COG study. Leukemia. Sep 2024. https://doi.org/10.1038/s41375-024-02395-4 (rheingold2024determinantsofsurvival pages 2-3)
Brivio E et al. Naked antibodies and antibody‑drug conjugates: targeted therapy for childhood ALL. Haematologica. May 2024. https://doi.org/10.3324/haematol.2023.283815 (brivio2024nakedantibodiesand pages 3-4)

Limitations of this report (evidence gaps)

1) Standard ontology identifiers (MONDO/MeSH/ICD/Orphanet/OMIM) were not present in the retrieved sources. 2) Environmental risk factors, prevention strategies, and gene–environment interaction evidence were not retrieved. 3) Model organism and other-species data were not retrieved. 4) Several clinically important modern outcomes (e.g., adult frontline chemo‑immunotherapy, inotuzumab and CAR‑T quantitative outcomes, and population incidence/prevalence) require additional targeted retrieval beyond the present evidence set.

References

(ryan2023wholegenomesequencing pages 1-2): Sarra Ryan, John Peden, Zoya Kingsbury, Claire Schwab, Terena James, Petri Polonen, Martina Mijuskovic, Jennifer Becq, Richard Yim, Ruth Cranston, Dale Hedges, Kathryn Roberts, Charles Mullighan, Ajay Vora, Lisa Russell, Anthony Moorman, David Bentley, Christine Harrison, and Mark Ross. Whole genome sequencing provides comprehensive genetic testing in childhood b-cell acute lymphoblastic leukaemia. Leukemia, 37:518-528, Jan 2023. URL: https://doi.org/10.1038/s41375-022-01806-8, doi:10.1038/s41375-022-01806-8. This article has 89 citations and is from a highest quality peer-reviewed journal.
(duffield2023internationalconsensusclassification pages 3-4): Amy S. Duffield, Charles G. Mullighan, and Michael J. Borowitz. International consensus classification of acute lymphoblastic leukemia/lymphoma. Virchows Archiv, 482:11-26, Nov 2023. URL: https://doi.org/10.1007/s00428-022-03448-8, doi:10.1007/s00428-022-03448-8. This article has 226 citations and is from a peer-reviewed journal.
(duffield2023internationalconsensusclassification pages 4-6): Amy S. Duffield, Charles G. Mullighan, and Michael J. Borowitz. International consensus classification of acute lymphoblastic leukemia/lymphoma. Virchows Archiv, 482:11-26, Nov 2023. URL: https://doi.org/10.1007/s00428-022-03448-8, doi:10.1007/s00428-022-03448-8. This article has 226 citations and is from a peer-reviewed journal.
(kansal2023diagnosisandmolecular pages 5-7): Rina Kansal. Diagnosis and molecular pathology of lymphoblastic leukemias and lymphomas in the era of genomics and precision medicine: historical evolution and current concepts—part 2: b-/t-cell acute lymphoblastic leukemias. Lymphatics, 1:118-154, Jul 2023. URL: https://doi.org/10.3390/lymphatics1020011, doi:10.3390/lymphatics1020011. This article has 12 citations.
(rheingold2024determinantsofsurvival pages 2-3): Susan R. Rheingold, Deepa Bhojwani, Lingyun Ji, Xinxin Xu, Meenakshi Devidas, John A. Kairalla, Mary Shago, Nyla A. Heerema, Andrew J. Carroll, Heather Breidenbach, Michael Borowitz, Brent L. Wood, Anne L. Angiolillo, Barbara L. Asselin, W. Paul Bowman, Patrick Brown, ZoAnn E. Dreyer, Kimberly P. Dunsmore, Joanne M. Hilden, Eric Larsen, Kelly Maloney, Yousif Matloub, Leonard A. Mattano, Stuart S. Winter, Lia Gore, Naomi J. Winick, William L. Carroll, Stephen P. Hunger, Elizabeth A. Raetz, and Mignon L. Loh. Determinants of survival after first relapse of acute lymphoblastic leukemia: a children’s oncology group study. Leukemia, 38:2382-2394, Sep 2024. URL: https://doi.org/10.1038/s41375-024-02395-4, doi:10.1038/s41375-024-02395-4. This article has 81 citations and is from a highest quality peer-reviewed journal.
(kansal2023diagnosisandmolecular pages 7-8): Rina Kansal. Diagnosis and molecular pathology of lymphoblastic leukemias and lymphomas in the era of genomics and precision medicine: historical evolution and current concepts—part 2: b-/t-cell acute lymphoblastic leukemias. Lymphatics, 1:118-154, Jul 2023. URL: https://doi.org/10.3390/lymphatics1020011, doi:10.3390/lymphatics1020011. This article has 12 citations.
(duffield2023internationalconsensusclassification pages 6-8): Amy S. Duffield, Charles G. Mullighan, and Michael J. Borowitz. International consensus classification of acute lymphoblastic leukemia/lymphoma. Virchows Archiv, 482:11-26, Nov 2023. URL: https://doi.org/10.1007/s00428-022-03448-8, doi:10.1007/s00428-022-03448-8. This article has 226 citations and is from a peer-reviewed journal.
(mahdaoui2025areviewof pages 2-3): Chaimae EL MAHDAOUI, Hind Dehbi, and Siham Cherkaoui. A review of the latest updates in cytogenetic and molecular classification and emerging approaches in identifying abnormalities in acute lymphoblastic leukemia. Lymphatics, Aug 2025. URL: https://doi.org/10.3390/lymphatics3030023, doi:10.3390/lymphatics3030023. This article has 1 citations.
(kansal2023diagnosisandmolecular pages 15-16): Rina Kansal. Diagnosis and molecular pathology of lymphoblastic leukemias and lymphomas in the era of genomics and precision medicine: historical evolution and current concepts—part 2: b-/t-cell acute lymphoblastic leukemias. Lymphatics, 1:118-154, Jul 2023. URL: https://doi.org/10.3390/lymphatics1020011, doi:10.3390/lymphatics1020011. This article has 12 citations.
(ryan2023wholegenomesequencing media 2101e72e): Sarra Ryan, John Peden, Zoya Kingsbury, Claire Schwab, Terena James, Petri Polonen, Martina Mijuskovic, Jennifer Becq, Richard Yim, Ruth Cranston, Dale Hedges, Kathryn Roberts, Charles Mullighan, Ajay Vora, Lisa Russell, Anthony Moorman, David Bentley, Christine Harrison, and Mark Ross. Whole genome sequencing provides comprehensive genetic testing in childhood b-cell acute lymphoblastic leukaemia. Leukemia, 37:518-528, Jan 2023. URL: https://doi.org/10.1038/s41375-022-01806-8, doi:10.1038/s41375-022-01806-8. This article has 89 citations and is from a highest quality peer-reviewed journal.
(gokbuget2024diagnosisprognosticfactors pages 13-14): Nicola Gökbuget, Nicolas Boissel, Sabina Chiaretti, Hervé Dombret, Michael Doubek, Adele Fielding, Robin Foà, Sebastian Giebel, Dieter Hoelzer, Mathilde Hunault, David I. Marks, Giovanni Martinelli, Oliver Ottmann, Anita Rijneveld, Philippe Rousselot, Josep Ribera, and Renato Bassan. Diagnosis, prognostic factors, and assessment of all in adults: 2024 eln recommendations from a european expert panel. Blood, 143:1891-1902, May 2024. URL: https://doi.org/10.1182/blood.2023020794, doi:10.1182/blood.2023020794. This article has 99 citations and is from a highest quality peer-reviewed journal.
(brivio2024nakedantibodiesand pages 3-4): Erica Brivio, Francisco Bautista, and C. Michel Zwaan. Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia. Haematologica, 109:1700-1712, May 2024. URL: https://doi.org/10.3324/haematol.2023.283815, doi:10.3324/haematol.2023.283815. This article has 19 citations.

Ask OpenScientist

OpenScientist Report

Definitions

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Definition and overview

1.2 Classification context (WHO‑HAEM5 and ICC)

1.3 Synonyms / alternative names

1.4 Key identifiers (ICD/MeSH/MONDO/Orphanet/OMIM)

1.5 Evidence source type

2. Etiology

2.1 Primary causal factors

2.2 Risk factors

2.3 Protective factors and gene–environment interactions

3. Phenotypes

3.1 Clinical presentation (general)

3.2 Age of onset

3.3 Suggested HPO terms (high-level; limited by evidence)

4. Genetic / Molecular Information (core of this entity)

4.1 Current understanding: recurrent genetic subtypes

4.2 Subtype catalog (structured)

4.3 Key subtype-specific highlights (examples)

4.4 Molecular diagnostic yield (WGS as a comprehensive test)

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Conceptual model (current understanding)

6.2 Examples of subtype-linked mechanisms

6.3 Suggested ontology terms (high-level)

7. Anatomical Structures Affected

7.1 Organ/tissue level

7.2 Suggested UBERON terms

8. Temporal Development

8.1 Onset

8.2 Relapse timing patterns

9. Inheritance and Population

9.1 Population epidemiology

9.2 Germline predisposition and inheritance

10. Diagnostics

10.1 Diagnostic criteria and classification

10.2 Recommended testing modalities (current implementations)

10.3 Measurable residual disease (MRD)

10.4 Differential diagnosis

11. Outcome / Prognosis

11.1 Prognostic stratification by genetics

11.2 Post‑relapse survival and subtype-specific outcomes (pediatric)

12. Treatment

12.1 Current applications and real-world implementations (selected)

12.1.1 Blinatumomab (CD19×CD3 BiTE)

12.1.2 Targeted therapy linkage (genotype → therapy)

12.2 Treatment strategy and expert opinion (authoritative sources)

12.3 Suggested MAXO terms (high level)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

High-value, recent sources used (with dates and URLs)

Limitations of this report (evidence gaps)