Acute lymphoblastic leukemia

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acute lymphoblastic leukemia pathophysiology classification diagnosis

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acute lymphoblastic leukemia treatment prognosis risk stratification

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Acute Lymphoblastic Leukemia (ALL)

Overview

ALL is a malignant clonal proliferation of lymphoid progenitor cells (lymphoblasts) that accumulate in the bone marrow, peripheral blood, and extramedullary sites. It is the most common childhood cancer (~80% of pediatric leukemias) but also occurs in adults, where prognosis is considerably worse.

Classification

ALL is classified by lineage and cytogenetics/molecular features (Harrison's, p. 3175):

Category	Subtype	Key Features
B-cell lineage	B-ALL	~85% of cases; CD19+, CD10+/-
T-cell lineage	T-ALL	~15%; CD3+, CD7+; mediastinal mass common

Key Cytogenetic/Molecular Subtypes

Subtype	Frequency	Prognosis
t(12;21) ETV6-RUNX1	~25% pediatric	Favorable
Hyperdiploidy (>50 chromosomes)	~25% pediatric	Favorable
t(9;22) BCR-ABL1 (Ph+)	~25–30% adults	Poor (improved with TKIs)
Ph-like ALL	~15–20% adults	Poor (targetable kinase lesions)
t(4;11) MLL-AF4 (KMT2A)	Infants	Poor
Hypodiploidy (<44 chromosomes)	~1–2%	Poor
iAMP21	~2% pediatric	Intermediate-poor

Ph-like (BCR-ABL1–like) ALL carries a gene expression profile similar to Ph+ ALL without the BCR-ABL1 fusion, harbors targetable kinase lesions (JAK2, CRLF2, ABL-class fusions), and is associated with minimal residual disease (MRD) persistence and poor outcomes (Management of Adult ALL, p. 25).

Pathophysiology

Lymphoblasts arise from committed lymphoid progenitors due to acquired genetic alterations:

Chromosomal translocations creating fusion oncoproteins (e.g., BCR-ABL1, ETV6-RUNX1)
Copy number alterations (e.g., IKZF1/Ikaros deletion — independently associated with poor prognosis)
Gene expression dysregulation driving uncontrolled proliferation and block in differentiation
Blast accumulation suppresses normal hematopoiesis → cytopenias

Clinical Presentation

Symptoms of bone marrow failure:

Fatigue, pallor (anemia)
Fever, infections (neutropenia)
Bleeding, petechiae, bruising (thrombocytopenia)
Bone pain (especially in children)

Extramedullary involvement:

Hepatosplenomegaly, lymphadenopathy
CNS involvement — headache, cranial nerve palsies, meningism (more common in T-ALL and high-risk B-ALL)
Anterior mediastinal mass — classic for T-ALL; may cause SVC syndrome or respiratory compromise

Diagnosis

Per Harrison's (p. 3175), diagnosis requires:

Peripheral blood smear — circulating blasts (variable; may be absent in aleukemic presentations)
Bone marrow aspirate/biopsy — ≥20% lymphoblasts (WHO criteria); typically hypercellular with monotonous lymphoblast infiltrate

Bone marrow aspirate showing dense infiltration by lymphoblasts — uniform small-to-medium cells with finely dispersed chromatin, scant cytoplasm, and minimal residual erythroid/myeloid precursors, consistent with ALL (Webpathology)

Immunophenotyping (flow cytometry) — essential for B vs. T lineage assignment; key markers:
- B-ALL: CD19, CD10, CD22, CD79a, TdT
- T-ALL: CD3 (cytoplasmic), CD7, CD2, CD5, TdT
Cytogenetics (karyotype + FISH) — identifies prognostic translocations
Molecular studies — BCR-ABL1 PCR, Ph-like gene expression panel, IKZF1 deletion
CSF analysis — lumbar puncture for CNS staging (CNS1/2/3)
CBC, LFTs, uric acid, LDH — baseline labs; high LDH reflects tumor burden

Risk Stratification

Pediatric (COG risk groups)

Group	Criteria
Standard risk	Age 1–9.99 yrs, WBC <50,000/µL, B-ALL, favorable cytogenetics
High risk	Age ≥10 or WBC ≥50,000/µL
Very high risk	Ph+, Ph-like, hypodiploidy, MLL rearrangement, poor MRD response

Adults

Risk factors for poor prognosis include:

Age >35–60 (worsens progressively)
WBC >30,000 (B-ALL) or >100,000 (T-ALL)
Ph+ or Ph-like genotype
IKZF1 deletion
Persistent MRD after induction

Treatment

General Framework

Treatment is delivered in 3 phases:

1. Induction (4–8 weeks)

Goal: achieve complete remission (CR) — <5% blasts in marrow

Pediatric regimens (e.g., AALL0434, DFCI):

Vincristine + corticosteroid (dexamethasone preferred) + asparaginase ± anthracycline

Adult regimens (e.g., HyperCVAD, BFM-inspired):

Vincristine, daunorubicin/doxorubicin, cyclophosphamide, corticosteroids, asparaginase
CR rates: ~85–95% in pediatric, ~80–90% in adults

Ph+ ALL: Add a TKI (imatinib, dasatinib, or ponatinib) to chemotherapy backbone from day 1.

2. Consolidation / Intensification

Multiple cycles of high-dose methotrexate (HD-MTX), cytarabine, 6-mercaptopurine
CNS prophylaxis: intrathecal MTX ± cytarabine ± hydrocortisone (cranial irradiation largely abandoned)
Allogeneic SCT in high-risk adults achieving CR1 (Ph+, MRD+, adverse cytogenetics)

3. Maintenance (~2–3 years)

Daily 6-mercaptopurine + weekly methotrexate ± monthly vincristine/corticosteroid pulses
MRD monitoring guides intensification

Targeted / Novel Agents

Agent	Indication
Imatinib / Dasatinib / Ponatinib	Ph+ ALL (TKIs)
Blinatumomab (CD19×CD3 BiTE)	Relapsed/refractory B-ALL; MRD+ disease
Inotuzumab ozogamicin	Relapsed/refractory CD22+ B-ALL
Tisagenlecleucel (CAR-T)	Pediatric/young adult r/r B-ALL
Nelarabine	T-ALL (nucleoside analog)
Venetoclax	Emerging role, especially in elderly

Blinatumomab + ponatinib combinations have shown activity in relapsed/refractory Ph+ ALL (Management of Adult ALL, p. 25).

CNS Disease

Prophylaxis is mandatory for all patients (intrathecal chemotherapy)
CNS3 (blasts in CSF + symptoms) requires intensified IT therapy ± cranial radiation
CNS relapse carries poor prognosis

Complications

Complication	Cause
Tumor lysis syndrome	Rapid cell death at induction
Infections	Prolonged neutropenia, immunosuppression
Osteonecrosis	Corticosteroids (especially adolescents)
Pancreatitis / hepatotoxicity	Asparaginase
Cardiotoxicity	Anthracyclines
Neuropathy	Vincristine
Secondary malignancy	Late effect of therapy

Prognosis

Population	5-Year OS
Pediatric (standard risk)	~90–95%
Pediatric (high risk)	~75–85%
Adults <40 years	~40–60%
Adults >60 years	~20–30%
Ph+ ALL (TKI era)	~50–60% (improving)
Relapsed/refractory	~30–40% (with novel agents)

Minimal residual disease (MRD) — detected by flow cytometry or PCR — is the single most important prognostic marker post-induction. MRD negativity predicts sustained remission; MRD positivity should prompt treatment intensification.

Special Populations

Infants (<1 year): Often KMT2A-rearranged; very poor prognosis; experimental protocols
Adolescents & young adults (AYA): Pediatric-inspired regimens (with asparaginase) outperform adult regimens
Elderly (>65): Reduced-intensity regimens; blinatumomab-based approaches gaining ground
Down syndrome: Hypersensitive to methotrexate; modified protocols required

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