Clonal expansion of lymphoid blasts — most common pediatric cancer; CNS sanctuary and Philadelphia chromosome subtype distinctive.
Also known as: ALL, acute lymphoblastic leukemia, acute lymphocytic leukemia, T-ALL, B-ALL, Ph+ ALL
Overview
Hematologic malignancy of immature lymphoid cells (B-cell or T-cell lineage) accumulating in bone marrow, blood, and extramedullary sites. Diagnosis requires ≥20% lymphoblasts in marrow or peripheral blood, with B-cell (most common) or T-cell immunophenotype.
Epidemiology
Most common childhood cancer (~25% of pediatric cancers); peak incidence ages 2-5 years. Less common but more lethal in adults. Adult ALL has higher rate of Philadelphia chromosome (BCR-ABL1) — up to 25%. Slight male predominance.
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Ionizing radiation, prior chemotherapy (alkylators, topoisomerase II inhibitors)
Prenatal X-ray exposure
Environmental: benzene; possibly pesticides
Greaves' delayed-infection hypothesis: limited early infectious exposure followed by later immune challenge may contribute in childhood B-ALL
Pathophysiology
Acquired chromosomal translocations and mutations arrest lymphoid differentiation at an immature stage, leading to clonal expansion. B-ALL recurrent abnormalities: t(9;22) BCR-ABL1 (Philadelphia chromosome), t(12;21) ETV6-RUNX1 (favorable, common in children), t(1;19) E2A-PBX1, MLL/KMT2A rearrangements (infant ALL, poor prognosis), hyperdiploidy (>50 chromosomes, favorable), hypodiploidy. T-ALL: NOTCH1 mutations, deletions of CDKN2A. CNS and gonads serve as sanctuary sites with poor drug penetration.
Pertussis, parvovirus — Lymphocytosis without blasts
ITP — Isolated thrombocytopenia, no blasts, normal other lineages
Diagnostic workup
Diagnostic criteria
≥20% lymphoblasts in bone marrow or peripheral blood with lymphoid immunophenotype (B-cell or T-cell precursor markers, TdT positive) — distinct from mature B-cell neoplasms (Burkitt) which lack TdT.
Labs
CBC — anemia, thrombocytopenia; WBC variable (high, normal, or low); lymphoblasts on smear
Peripheral smear — lymphoblasts (small to medium, scant cytoplasm, fine chromatin, indistinct nucleoli); NO Auer rods (rules out AML)
Cytochemistry — MPO negative (distinguishes from AML); PAS positive
Cytogenetics and FISH: Philadelphia chromosome t(9;22) BCR-ABL1, t(12;21), MLL rearrangements, hyperdiploidy, hypodiploidy
Molecular: BCR-ABL1, IKZF1 deletions, Ph-like signature; NOTCH1 in T-ALL
Lumbar puncture with cytospin and intrathecal chemotherapy at diagnosis (CNS staging and prophylaxis)
Tumor lysis labs (uric acid, K, PO4, Ca, Cr, LDH)
HLA typing for potential allogeneic HSCT
Echocardiogram before anthracycline
Imaging
Chest X-ray and CT chest — mediastinal mass especially in T-ALL (do BEFORE sedation/anesthesia to assess airway compression risk)
Testicular ultrasound if suspected involvement
MRI brain/spine for symptomatic CNS disease
Diagnostic algorithm
flowchart TD
A[Pancytopenia +<br/>circulating blasts<br/>Bone pain, lymphadenopathy] --> B[Bone marrow + flow cytometry]
B --> C{Blast lineage}
C -->|TdT+, MPO-,<br/>lymphoid markers| D[ALL]
C -->|TdT-, MPO+,<br/>Auer rods, myeloid| E[AML]
D --> F{Subtype}
F -->|B-ALL CD19+ CD10+| G[B-ALL]
F -->|T-ALL CD3+ CD7+,<br/>mediastinal mass| H[T-ALL]
G --> I{BCR-ABL1?}
I -->|Positive| J[Ph+ ALL:<br/>add TKI imatinib/dasatinib/<br/>ponatinib, consider HSCT]
I -->|Negative| K[Pediatric-style induction:<br/>vincristine + steroid +<br/>anthracycline + asparaginase<br/>+ IT methotrexate]
H --> K
K --> L[Consolidation +<br/>maintenance 2-3y]
L --> M{MRD?}
M -->|Positive| N[Intensify; consider HSCT;<br/>blinatumomab/CAR-T<br/>for relapse]
ALL diagnostic and treatment pathway — lineage assignment, BCR-ABL1 status, and MRD-directed therapy.
Treatment
First-line
Induction (4 weeks): vincristine + corticosteroid (prednisone/dexamethasone) + anthracycline (daunorubicin) + asparaginase (PEG-asparaginase or Erwinia); achieves remission in >95% of pediatric ALL, ~80% of adult ALL
Allogeneic HSCT — for high-risk or relapsed disease; matched sibling preferred
MRD-directed therapy: minimal residual disease assessment at end of induction and consolidation directs intensification (positive MRD = worse prognosis; HSCT often considered)
Newer TKIs (ponatinib) for T315I-mutated Ph+ ALL
Complications
Tumor lysis syndrome — common at presentation given high tumor burden
ALL cure rates: children ~90%; adolescents/young adults ~70-80%; adults ~40-50%. Age and biology dominate prognosis.
Auer rods ABSENT in ALL — their presence indicates AML.
Mediastinal mass + lymphoblasts in an adolescent male = T-ALL until proven otherwise; secure airway before sedation.
CNS prophylaxis with intrathecal chemotherapy is mandatory — CNS is a sanctuary site with poor drug penetration. Cranial radiation has largely been replaced by IT methotrexate to reduce neurocognitive toxicity.
Philadelphia-positive ALL (BCR-ABL1) — historically very poor prognosis — now markedly improved with TKI addition (imatinib, dasatinib, ponatinib).
Adolescents and young adults (16-39) treated with pediatric-style regimens have substantially better outcomes than with adult regimens.
Blinatumomab and CAR-T cell therapy have transformed outcomes for relapsed/refractory B-ALL.
MRD (minimal residual disease) by flow or PCR at end of induction is the strongest prognostic factor — drives intensification decisions including HSCT.
References
NCCN 2024 — NCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukemia (NCCN.org)
CALGB 10403 — Pediatric-inspired therapy in adolescents and young adults with ALL (Stock et al., Blood 2019)
Maude et al. — Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia (NEJM 2018)
Kantarjian et al. — Blinatumomab versus Chemotherapy for Advanced ALL (NEJM 2017)
Foà et al. — Dasatinib-blinatumomab for Ph+ Acute Lymphoblastic Leukemia (NEJM 2020)
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