Leukemias — ALL, AML, CLL, CML

Non-modifiable (host/genetic)

• **Constitutional trisomy 21 (Down syndrome)**: markedly increased risk of both ALL and AML; transient abnormal myelopoiesis in the neonate and later acute megakaryoblastic leukemia (GATA1 mutations) are the classic associations.
• Chromosomal instability/DNA-repair syndromes: Fanconi anemia, Bloom syndrome, ataxia-telangiectasia (ATM), Li-Fraumeni (germline TP53), Nijmegen breakage — defective repair permits accumulation of leukemogenic lesions, typically AML/MDS.
• Germline predisposition to myeloid neoplasms: RUNX1, CEBPA, GATA2, and DDX41 variants; also neurofibromatosis type 1 (juvenile myelomonocytic leukemia) and Noonan syndrome.
• Antecedent clonal hematopoiesis, MDS, or a myeloproliferative neoplasm (PV, ET, primary myelofibrosis) evolving to secondary AML — worse prognosis than de novo AML.
• Age and sex: ALL peaks in children 2–5 years; AML, CLL, and CML rise with age. CLL is the leukemia with the strongest family history signal and is rare in East Asian populations.

Modifiable/environmental

• Ionizing radiation: atomic-bomb and radiotherapy data link exposure to AML, ALL, and CML; CLL is characteristically not radiation-associated.
• Benzene and petrochemical solvents: occupational exposure causes marrow aplasia then AML/MDS.
• Cigarette smoking: a recognized modifiable AML risk factor.
• Prior cytotoxic chemotherapy (therapy-related myeloid neoplasm):
• Alkylating agents/radiation — latency roughly 5–7 years, preceded by MDS, with –5/del(5q), –7/del(7q) and TP53 lesions.
• Topoisomerase II inhibitors (etoposide, anthracyclines) — shorter latency of a few years, no MDS phase, KMT2A (MLL) rearrangement at 11q23, often monocytic.
• HTLV-1 causes adult T-cell leukemia/lymphoma (endemic Japan, Caribbean) — a distinct entity from the four leukemias above but a frequent distractor.

Common mechanisms across all leukemias

• Acquired genetic mutations in stem or progenitor cells causing loss of differentiation control and constitutive proliferation
• Impaired apoptosis via overexpression of anti-apoptotic proteins (e.g., BCL-2) or inactivation of tumor suppressors (p53, RB)
• Progressive bone marrow replacement by malignant blasts leading to cytopenias (anemia, thrombocytopenia, neutropenia) and functional bone marrow failure

ALL-specific pathophysiology

• Malignant transformation of B-cell or T-cell precursors in lymphoid tissue
• Common cytogenetic abnormalities: t(9;22) Philadelphia chromosome (BCR-ABL fusion gene, found in ~25% of adult ALL and ~5% of pediatric ALL), t(12;21) ETV6-RUNX1 (favorable in children), t(1;19) E2A-PBX1, complex karyotype, and hyperdiploidy
• Lymphoblasts are typically TdT-positive (terminal deoxynucleotidyl transferase), CD34+, and express B-cell or T-cell markers depending on lineage

AML-specific pathophysiology

• Malignant transformation of myeloid progenitor cells with arrested differentiation
• Common cytogenetic abnormalities: t(15;17) PML-RARA (acute promyelocytic leukemia or APL—favorable prognosis), t(8;21) RUNX1-RUNX1T1, inv(16) CBFB-MYH11 (core binding factor leukemias—favorable), and complex/abnormal karyotype (unfavorable)
• Myeloblasts express MPO (myeloperoxidase), CD33, CD34, and myeloid markers; APL blasts are abnormal promyelocytes filled with Auer rods (pathognomonic)
• FLT3-ITD (internal tandem duplication) and TP53 mutations associated with worse prognosis

CLL-specific pathophysiology

• B-cell lineage malignancy typically arising from mature lymphocytes
• Abnormality: del(13q) (most favorable), trisomy 12 (intermediate), del(11q) involving ATM (unfavorable), del(17p) involving TP53 (worst prognosis)
• Cells express CD5, CD19, CD23 (coexpression of CD5 on B cells is key); typically light chain restricted (either κ or λ)
• Slow growth rate with intact differentiation capability; may transform to aggressive lymphoma (Richter transformation)

CML-specific pathophysiology

• Mutation in hematopoietic stem cell creating the Philadelphia chromosome t(9;22) producing BCR-ABL fusion gene
• BCR-ABL constitutively activates tyrosine kinase, driving uncontrolled proliferation while maintaining some capacity for normal differentiation
• Results in increased granulopoiesis with left shift and presence of mature myeloid cells (unlike acute leukemias)
• Three phases: chronic phase (>90% blasts <5%), accelerated phase (blasts 5-19%, basophilia, other cytogenetic abnormalities), and blast crisis (≥20% blasts—transforms to AML or ALL)

ALL

• Acute onset (days to weeks) with symptoms related to bone marrow failure and leukostasis
• Bleeding manifestations: petechiae, ecchymosis, epistaxis, intracranial hemorrhage (ICH) due to severe thrombocytopenia
• Anemia-related: fatigue, dyspnea, tachycardia, pallor
• Infections: fever, opportunistic infections (due to non-functional leukocytes despite high WBC)
• Lymphadenopathy, hepatosplenomegaly, mediastinal mass (T-cell ALL more commonly has anterior mediastinal involvement)
• CNS involvement: headache, mental status changes, cranial nerve palsies (ALL has higher propensity than AML)
• Bone pain and lytic lesions, particularly in children

AML

• Acute presentation (days to weeks) with manifestations of bone marrow failure
• Bleeding: gingival bleeding and infiltration (especially in monocytic subtypes), DIC with hemorrhage (particularly in APL)
• Infection: fever, pneumonia, perirectal cellulitis, sepsis (immature neutrophils cannot respond to infection)
• Anemia: fatigue, dyspnea, pallor
• Leukostasis syndrome: respiratory distress, visual changes, confusion (more common in AML than ALL despite lower WBC counts due to larger, less deformable blasts)
• Hepatosplenomegaly, lymphadenopathy (less prominent than ALL)
• APL-specific: DIC with severe bleeding, abnormal promyelocytes with Auer rods; extremely high risk of early hemorrhagic death without prompt all-trans retinoic acid (ATRA)

CLL

• Insidious onset; often discovered incidentally on routine labs (asymptomatic in ~50% at diagnosis)
• Lymphocytosis: fatigue, weakness (may be asymptomatic for years)
• Lymphadenopathy (non-tender, rubbery nodes)
• Hepatosplenomegaly (less common than in other leukemias)
• B-symptoms: fever, night sweats, weight loss (uncommon at presentation; suggest advanced disease or transformation)
• Autoimmune complications: AIHA (autoimmune hemolytic anemia), immune thrombocytopenia (ITP), pure red cell aplasia—due to autoreactive T cells
• Infections: recurrent due to hypogammaglobulinemia and impaired T-cell function
• Richter transformation (5-10% of patients): sudden acceleration to aggressive lymphoma with massive lymphadenopathy, high LDH, B-symptoms

CML

• Chronic phase (first 3-5 years): often asymptomatic; discovered on routine CBC with leukocytosis
• Splenomegaly (70-90% of patients—often massive and tender)
• Abdominal fullness, early satiety, left upper quadrant pain
• Constitutional symptoms: fatigue, weight loss, night sweats, fever (from hypermetabolism and cytokine release)
• Leukostasis uncommon despite very high WBC due to mature cell morphology
• Bleeding and bruising: from thrombocytosis with platelet dysfunction
• Accelerated phase/Blast crisis: sudden deterioration with fever, severe leukocytosis, blasts ≥20%, similar symptoms to acute leukemias

ALL

• Complete blood count (CBC): leukocytosis (variable, 10,000-500,000/μL) with lymphoblasts, anemia, thrombocytopenia
• Peripheral blood smear: medium-sized blasts with high nuclear-to-cytoplasmic ratio, fine chromatin, visible nucleoli, scant cytoplasm; some may contain Auer rods (rare in ALL, more common in AML)
• Bone marrow aspiration and biopsy: ≥20% blasts defines acute le

Immediate stabilization (before definitive therapy)

• Tumor lysis prophylaxis: aggressive IV isotonic fluids plus a xanthine oxidase inhibitor (allopurinol); rasburicase (recombinant urate oxidase) for high tumor burden or established hyperuricemia — contraindicated in G6PD deficiency (hemolysis, methemoglobinemia).
• Leukostasis: cytoreduction with hydroxyurea ± leukapheresis; avoid unnecessary RBC transfusion until the count falls, since it raises viscosity.
• Febrile neutropenia is an emergency: cultures then empiric antipseudomonal beta-lactam (cefepime or piperacillin-tazobactam) within an hour, per IDSA.
• Suspected APL: start ATRA immediately on morphologic suspicion — do not wait for confirmatory PML-RARA — and support DIC with cryoprecipitate/fibrinogen and platelets.

Disease-directed first line (NCCN)

• ALL: multiagent induction (vincristine + corticosteroid + anthracycline ± asparaginase), then consolidation and 2–3 years of maintenance (6-mercaptopurine + methotrexate). CNS prophylaxis with intrathecal methotrexate is mandatory — systemic chemotherapy does not cross the blood–brain barrier. Ph-positive ALL adds a BCR-ABL1 TKI (imatinib, dasatinib).
• AML: intensive induction with cytarabine plus an anthracycline ("7+3"); add midostaurin for FLT3 mutations, gemtuzumab ozogamicin for CD33+ core-binding-factor disease. Unfit/older adults: hypomethylating agent (azacitidine) plus venetoclax. APL is chemotherapy-sparing: ATRA + arsenic trioxide.
• CLL: observation for asymptomatic early-stage disease — treating early does not prolong survival. Treat for progressive cytopenias, bulky/symptomatic adenopathy, B-symptoms, or rapid lymphocyte doubling. First line is a covalent BTK inhibitor (acalabrutinib) or venetoclax + obinutuzumab. del(17p)/TP53 disease responds poorly to chemoimmunotherapy — avoid it.
• CML: lifelong BCR-ABL1 TKI (imatinib or a second-generation agent) with quantitative BCR-ABL1 PCR on the International Scale against ELN/NCCN milestones; ponatinib for the T315I gatekeeper mutation.

Emergencies at presentation

• Tumor lysis syndrome: massive blast turnover releases intracellular contents — hyperkalemia, hyperphosphatemia, hyperuricemia, secondary hypocalcemia, urate/calcium-phosphate nephropathy with oliguric AKI. Highest risk in ALL and Burkitt-type disease and after venetoclax initiation (hence dose ramp-up). Signaled by rising potassium/phosphate with falling calcium in the first days of therapy.
• Leukostasis/hyperviscosity: bulky, non-deformable myeloblasts plug the pulmonary and cerebral microvasculature — dyspnea/hypoxemia and confusion or visual change with a very high blast count. More common in AML than CML despite lower WBC because mature CML granulocytes deform.
• DIC in APL: promyelocyte granules release tissue factor and annexin II–driven hyperfibrinolysis — prolonged PT/aPTT, low fibrinogen, high D-dimer, and fatal intracranial or pulmonary hemorrhage.
• **Febrile neutropenia and neutropenic enterocolitis (typhlitis)**: fever with right lower quadrant pain and bowel wall thickening on CT.

Treatment-related

• Differentiation syndrome (ATRA or arsenic): cytokine release from maturing promyelocytes — fever, weight gain, hypotension, pulmonary infiltrates, pleuropericardial effusions; treat promptly with dexamethasone. An emergency.
• Anthracycline cardiomyopathy (dose-dependent, falling LVEF), cyclophosphamide hemorrhagic cystitis (acrolein; mesna prevents), vincristine peripheral neuropathy, asparaginase pancreatitis and thrombosis, high-dose cytarabine cerebellar ataxia and conjunctivitis, methotrexate mucositis and leukoencephalopathy.
• Arsenic trioxide QT prolongation; ponatinib arterial occlusive events; imatinib periorbital edema and myelosuppression.
• Allogeneic HSCT: graft-versus-host disease, veno-occlusive disease, CMV reactivation; secondary malignancies years later.

Disease evolution

• CML blast crisis (≥20% blasts) — abrupt clinical deterioration, treat as acute leukemia.
• CLL: autoimmune hemolytic anemia/ITP, hypogammaglobulinemia with encapsulated-organism infection, and Richter transformation — sudden nodal enlargement, B-symptoms, and a steeply rising LDH.
• CNS relapse, especially in ALL: cranial neuropathy or headache with blasts in CSF.

• Suspected APL is the single most time-sensitive vignette: a young adult with fever, bruising, low fibrinogen, and *Auer rod*–laden promyelocytes — the best next step is start ATRA now, before PML-RARA confirmation, because early hemorrhagic death, not chemoresistance, is what kills.
• Auer rods = myeloid lineage (MPO-positive); TdT positivity = lymphoblast. Both blast types share ≥20% marrow blasts, so lineage is settled by flow cytometry and cytochemistry, not morphology alone.
• t(9;22) means opposite things by disease: in CML it defines the disease and predicts excellent TKI response; in ALL it is an adverse marker requiring a TKI added to chemotherapy.
• Smudge (basket) cells on smear with CD5+/CD19+/CD23+ lymphocytosis is CLL. CD5 coexpression on B cells is the tested association — the distractor is mantle cell lymphoma, which is also CD5+ but CD23-negative with t(11;14)/cyclin D1.
• Low leukocyte alkaline phosphatase (LAP) favors CML; a high LAP with toxic granulation and Döhle bodies favors a leukemoid reaction from infection. Confirm CML with BCR-ABL1, not the LAP score.
• ALL demands intrathecal CNS prophylaxis and, in T-ALL, look for an anterior mediastinal mass with superior vena cava syndrome in an adolescent male.
• Do not give rasburicase in G6PD deficiency — hydrogen peroxide generated by urate oxidase precipitates hemolysis and methemoglobinemia.
• Asymptomatic early-stage CLL is observed, not treated; the ordering of therapy is driven by symptoms, cytopenias, and doubling time (NCCN). Choosing chemotherapy for an incidentally found lymphocytosis is the classic wrong answer, as is chemoimmunotherapy in del(17p)/TP53 disease.