Acute Lymphoblastic Leukemia (ALL)

Risk factors

• Down syndrome (10-20x increased risk)
• Genetic syndromes: Li-Fraumeni, neurofibromatosis 1, ataxia-telangiectasia, Bloom syndrome, Klinefelter
• 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.

Clinical presentation

Differential diagnosis

• Acute myeloid leukemia (AML) — MPO positive, myeloid markers (CD13, CD33, CD117); Auer rods; differs in age distribution and therapy
• Aplastic anemia — Hypocellular marrow without blasts; pancytopenia without circulating blasts
• Lymphoma (lymphoblastic lymphoma) — Same cell of origin (typically T-cell precursor); mass-forming with <20% marrow blasts; treated similarly
• EBV infection / infectious mononucleosis — Atypical lymphocytes (reactive), positive Monospot/EBV serology, no marrow blasts
• Pertussis, parvovirus — Lymphocytosis without blasts
• ITP — Isolated thrombocytopenia, no blasts, normal other lineages

Diagnostic workup

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]

Treatment

Complications

• Tumor lysis syndrome — common at presentation given high tumor burden
• Infection — febrile neutropenia, opportunistic (Pneumocystis prophylaxis with TMP-SMX, fungal prophylaxis)
• Bleeding — DIC, thrombocytopenia
• CNS relapse — most common extramedullary relapse site
• Testicular relapse (boys)
• Asparaginase toxicity: pancreatitis, thrombosis (especially CNS sinus), hyperglycemia, hyperammonemia, hypofibrinogenemia, hypersensitivity
• Anthracycline cardiotoxicity, vincristine neuropathy
• Late effects of cranial radiation: neurocognitive impairment, secondary CNS tumors, endocrine dysfunction
• Steroid-related: avascular necrosis, hyperglycemia, osteoporosis, behavioral changes
• CAR-T related: cytokine release syndrome, ICANS (neurotoxicity)

PANCE pearls

• 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)