Acute Leukemias: AML, APL & ALL

Acute Leukemia: Definition and Presentation

Definition. An acute leukemia is a clonal neoplasm in which hematopoietic precursors stop maturing and accumulate as blasts. By convention, at least 20% blasts in the marrow or blood define acute leukemia; certain recurrent translocations, such as t(8;21), inv(16), and t(15;17), establish AML even below that count. Blasts are large cells with fine chromatin, prominent nucleoli, and scant cytoplasm.

Marrow failure. Blasts crowd out normal hematopoiesis, so symptoms come from what is missing: anemia (fatigue, pallor, dyspnea), neutropenia (fever and infections), and thrombocytopenia (petechiae, mucosal bleeding). Marrow expansion causes bone pain, which in young children appears as limping or refusing to walk. The WBC count may be high with circulating blasts, normal, or low, so a normal count does not exclude leukemia.

Acute Myeloid Leukemia

Morphology. Myeloblasts may contain Auer rods: needle-shaped, pink-red cytoplasmic inclusions formed by fused azurophilic granules rich in myeloperoxidase. Their presence proves myeloid lineage. Myeloperoxidase or Sudan black B cytochemistry and flow cytometry (CD13, CD33, CD117, CD34) confirm the diagnosis.

Risk factors. Most AML arises without a known cause, but recognized risks include benzene, smoking, ionizing radiation, prior myelodysplastic syndrome or myeloproliferative neoplasm (including CML in blast phase), and Down syndrome. Therapy-related AML comes in two patterns. Alkylating agents and radiation cause AML after 5–10 years, usually after a myelodysplastic phase, with losses of chromosomes 5 and 7 (−5/−7 or 5q/7q deletions). Topoisomerase II inhibitors such as etoposide and anthracyclines cause AML after 1 to 3 years, without a myelodysplastic phase, typically with balanced KMT2A (11q23) translocations.

Down syndrome. Trisomy 21 increases the risk of acute leukemia about 10- to 20-fold, both ALL and AML. Before age 5, the characteristic AML is acute megakaryoblastic leukemia, whose blasts express the platelet glycoproteins CD41 (GPIIb) and CD61 (GPIIIa) and carry GATA1 mutations. It is often preceded in the newborn by transient abnormal myelopoiesis, which usually resolves without treatment.

Monocytic differentiation. Acute monocytic and myelomonocytic leukemias, often KMT2A-rearranged, infiltrate the gingiva, skin (leukemia cutis), and CNS. Their blasts are nonspecific esterase-positive and may stain weakly for MPO. Gingival hypertrophy also follows phenytoin, cyclosporine, and calcium channel blockers such as nifedipine, while scurvy produces swollen, bleeding gums. A myeloid sarcoma (chloroma) is a tumor mass of myeloblasts outside the marrow.

Genetics and prognosis. Core-binding factor leukemias, t(8;21) RUNX1::RUNX1T1 and inv(16) CBFB::MYH11 (which features abnormal marrow eosinophils), and NPM1-mutated AML without FLT3-ITD respond best to cytarabine-based chemotherapy. FLT3 internal tandem duplication constitutively activates a receptor tyrosine kinase, producing high blast counts and a higher relapse risk; FLT3 inhibitors (midostaurin with induction, gilteritinib at relapse) are added. Complex karyotype (three or more abnormalities), TP53 mutation, and −5/−7 are adverse.

Treatment. Intensive induction is "7+3": cytarabine, a pyrimidine analog active in S phase, for 7 days plus an anthracycline (daunorubicin or idarubicin) for 3 days, followed by consolidation. High-risk disease proceeds to allogeneic stem cell transplant. Older or unfit patients receive venetoclax, a BCL-2 inhibitor, with the hypomethylating agent azacitidine.

Acute Promyelocytic Leukemia

Mechanism. APL is defined by t(15;17), which fuses PML to the retinoic acid receptor-α gene (RARA). The PML::RARA protein represses genes required for granulocytic maturation, freezing cells at the promyelocyte stage. The hypergranular promyelocytes may contain bundles of Auer rods (faggot cells). Patients are typically younger adults.

DIC at presentation. Promyelocyte granules release tissue factor, and the cells express annexin II, which enhances plasmin generation. The result is DIC with hyperfibrinolysis: low platelets and fibrinogen, high D-dimer, and a prolonged PT. Intracranial or pulmonary hemorrhage is the main cause of early death.

Start ATRA as soon as APL is suspected from the smear and coagulation profile; do not wait for genetic confirmation. Support with fibrinogen (cryoprecipitate) and platelets.

Differentiation therapy. All-trans retinoic acid, a vitamin A derivative given at pharmacologic doses, overcomes PML::RARA repression and promotes its degradation, so promyelocytes mature. Arsenic trioxide degrades the fusion protein through its PML portion and prolongs the QT interval, so the ECG, potassium, and magnesium are monitored. ATRA plus arsenic cures more than 90% of standard-risk APL, making it the most curable AML.

Differentiation syndrome. Days to weeks into therapy, maturing myeloid cells release cytokines and infiltrate tissues, causing fever, dyspnea, pulmonary infiltrates and effusions, weight gain, hypotension, and renal failure, often with a rising WBC. Dexamethasone is started promptly, and ATRA or arsenic is held if severe. Also called retinoic acid syndrome, it can also complicate IDH inhibitors (ivosidenib, enasidenib), another differentiating therapy for AML.

Acute Lymphoblastic Leukemia

B-ALL. ALL is the most common cancer of childhood, peaking at 2–5 years. Lymphoblasts are TdT-positive (terminal deoxynucleotidyl transferase, a template-independent DNA polymerase of immature lymphocytes), MPO-negative, and often PAS-positive. About 85% of childhood cases are B-lineage (CD10/CALLA, CD19, CD22, CD79a). Children present with marrow failure, bone pain, lymphadenopathy, and hepatosplenomegaly. TdT separates precursor neoplasms from mature ones: Burkitt lymphoma, a mature B-cell tumor, is TdT-negative.

T-ALL. T-ALL arises from thymic precursors (TdT+, CD2, CD3, CD5, CD7) and classically affects adolescent males with an anterior mediastinal mass and a very high WBC. The mass can cause SVC syndrome or airway compression. T-lymphoblastic lymphoma is the same disease with fewer than 25% marrow blasts.

Philadelphia-positive ALL. The t(9;22) BCR::ABL1 fusion is uncommon in children but frequent in adults, which partly explains poorer adult outcomes; a tyrosine kinase inhibitor is added to chemotherapy.

Sanctuary sites. Lymphoblasts shelter behind the blood–brain and blood–testis barriers. Every ALL regimen therefore includes CNS-directed therapy with intrathecal methotrexate (sometimes with cytarabine and hydrocortisone) and systemic high-dose methotrexate. Painless testicular enlargement in a child in remission suggests relapse. Methotrexate inhibits dihydrofolate reductase; leucovorin (folinic acid) bypasses the block and rescues normal cells after high-dose therapy.

Oncologic Emergencies of Acute Leukemia

Tumor lysis syndrome. Starting therapy for bulky, rapidly dividing tumors (ALL, Burkitt lymphoma, AML with a high WBC) releases intracellular contents. Potassium causes arrhythmias; phosphate precipitates calcium, causing hypocalcemia with cramps or tetany; nucleic acid purines are metabolized to uric acid. Urate and calcium phosphate crystals obstruct renal tubules and cause acute kidney injury.

Rasburicase is contraindicated in G6PD deficiency because its hydrogen peroxide byproduct causes hemolysis and methemoglobinemia.

Leukostasis. Very high blast counts (often above 100,000/μL), especially of large, sticky myeloblasts, sludge in small vessels of the lungs and brain, causing hypoxia, confusion, and visual changes. It requires urgent cytoreduction.