Acute Leukemias: Diagnosis, APL & Induction Complications
From the first smear to day 28 — where speed saves lives
Clinical presentation
Marrow failure. Acute leukemia replaces normal hematopoiesis over days to weeks. Anemia causes fatigue, pallor, and dyspnea; neutropenia causes fevers and infections even when the total WBC is high; thrombocytopenia causes petechiae, gum bleeding, epistaxis, and bruising. The WBC may be low, normal, or very high.
Tissue infiltration. Children with ALL often have bone pain or a limp from marrow expansion, plus lymphadenopathy and hepatosplenomegaly. Monocytic AML infiltrates the gums (gingival hypertrophy) and skin (leukemia cutis) and can form a myeloid sarcoma. T-ALL classically affects adolescent males with an anterior mediastinal mass, a very high WBC, and CNS involvement; the CNS and testes are sanctuary sites for ALL relapse.
Bone pain, limp, and cytopenias in a child suggest ALL. Review a smear before giving corticosteroids for presumed arthritis, which can mask the diagnosis.
Coagulopathy and hyperleukocytosis. Bleeding out of proportion to the platelet count suggests DIC, classically from APL. A WBC above 100,000/μL (hyperleukocytosis) raises the risk of leukostasis and tumor lysis.
Initial evaluation and diagnosis
- CBC with differential and smearcirculating blasts; Auer rods (needle-shaped, MPO-positive inclusions) establish myeloid lineage
- Coagulation panelPT/INR, aPTT, fibrinogen, and D-dimer to detect DIC
- Tumor lysis labsuric acid, potassium, phosphate, calcium, creatinine, LDH
- Bone marrow aspirate and biopsymorphology, flow cytometry, karyotype/FISH, molecular panel
- Pretreatment studiestype and screen, HLA typing, hepatitis B and HIV serologies, pregnancy test, echocardiogram; lumbar puncture in ALL
Defining the disease. Blasts making up at least 20% of marrow or blood cells define acute leukemia; AML with t(15;17), t(8;21), or inv(16) is diagnosed even below that threshold. Flow cytometry assigns the lineage.
| Feature | AML | B-ALL | T-ALL |
|---|---|---|---|
| Markers | MPO, CD13, CD33, CD117 (± CD34; CD14/CD64 if monocytic) | CD10, CD19, CD22, TdT | Cytoplasmic CD3, CD7, CD2, CD5, TdT |
| Morphology | Granules, Auer rods | Scant agranular cytoplasm | Scant agranular cytoplasm |
| Typical patient | Older adult (median age about 68) | Child aged 2–5; Down syndrome | Adolescent male, mediastinal mass |
Genetics drive risk. Cytogenetic and molecular results set prognosis, add targeted drugs, and decide whether transplant is pursued in first remission.
| Group | AML | ALL |
|---|---|---|
| Favorable | t(15;17) PML::RARA, t(8;21), inv(16), NPM1 mutation | Hyperdiploidy, t(12;21) ETV6::RUNX1 (children) |
| High risk | Complex karyotype, −5/−7, TP53 mutation (FLT3-ITD is relapse-prone but now graded intermediate, ELN 2022) | BCR-ABL1 t(9;22) (about a quarter of adults), KMT2A rearrangement, hypodiploidy |
| Treatment impact | FLT3 → midostaurin; t(15;17) → ATRA + arsenic | BCR-ABL1 → add a TKI (imatinib, dasatinib) |
Acute promyelocytic leukemia
Recognition. APL shows abnormal hypergranular promyelocytes, often packed with bundles of Auer rods (faggot cells). Their granules trigger DIC with hyperfibrinolysis: low fibrinogen, prolonged PT, high D-dimer, and hemorrhage. Intracranial or pulmonary bleeding is the leading cause of early death.
- Start ATRA on suspicionsmear plus coagulopathy is enough; do not wait for PML::RARA confirmation
- Replace aggressivelyplatelets >30,000–50,000/μL, cryoprecipitate for fibrinogen >100–150 mg/dL, FFP for a prolonged PT; heparin and antifibrinolytics are not routine; defer central lines and lumbar puncture
- ConfirmFISH or PCR for PML::RARA
- Complete inductionATRA + arsenic trioxide; add an anthracycline or gemtuzumab when WBC >10,000/μL
Differentiation syndrome. ATRA and arsenic force blasts to mature and release cytokines, causing fever, dyspnea and hypoxemia, pulmonary infiltrates, pleural or pericardial effusions, weight gain and edema, hypotension, and AKI, usually within the first weeks. Give dexamethasone 10 mg IV every 12 hours at the first sign; hold ATRA or arsenic only when severe. Rising WBC during induction is controlled with hydroxyurea.
Arsenic trioxide prolongs the QTc and can cause torsades de pointes. Obtain baseline and at least weekly ECGs, keep potassium >4.0 mEq/L and magnesium >1.8 mg/dL, avoid other QT-prolonging drugs (fluoroquinolones, azoles, ondansetron), and hold arsenic if QTc exceeds 500 ms.
Outcome. With prompt ATRA plus arsenic, most patients who survive the first weeks are cured, making APL the most curable adult AML.
Hyperleukocytosis and leukostasis
Mechanism. Large, rigid myeloblasts plug the microcirculation, typically in AML with WBC above 100,000/μL (monocytic AML at lower counts; rarely in ALL). Leukostasis is pulmonary (dyspnea, hypoxemia, diffuse infiltrates), neurologic (confusion, headache, stroke, intracranial hemorrhage), or retinal (hemorrhages), and occasionally causes priapism or limb ischemia.
Management. Cytoreduce urgently with hydroxyurea and prompt induction chemotherapy; leukapheresis is an option for selected patients but is avoided in APL, where it worsens the coagulopathy. Start tumor lysis prophylaxis. Avoid red cell transfusion, which raises viscosity; transfuse slowly only if essential.
Blasts consume oxygen in the ABG syringe and lyse in clotted tubes, producing a falsely low PaO2 (trust pulse oximetry) and spurious hyperkalemia.
Induction and post-remission therapy
AML. Fit patients receive "7+3": continuous-infusion cytarabine for 7 days plus daunorubicin or idarubicin for 3 days, after a baseline echocardiogram because anthracyclines are cardiotoxic. Midostaurin is added for FLT3 mutations, and gemtuzumab ozogamicin (anti-CD33) helps favorable core-binding factor AML. Older or unfit patients receive venetoclax with azacitidine or decitabine. Complete remission means <5% marrow blasts with count recovery, usually assessed near day 28. Favorable-risk disease is consolidated with high-dose cytarabine (watch for cerebellar toxicity); adverse-risk and many intermediate-risk, refractory, or relapsed cases go to allogeneic stem cell transplant.
ALL. Induction combines vincristine, a corticosteroid, and asparaginase, with or without an anthracycline, followed by consolidation and 2–3 years of maintenance with daily 6-mercaptopurine and weekly methotrexate (check TPMT/NUDT15 before 6-mercaptopurine). Every patient receives CNS prophylaxis with intrathecal methotrexate; cranial irradiation has largely been abandoned for prophylaxis. BCR-ABL1–positive disease adds a TKI. Measurable residual disease (MRD) after induction guides intensification, and persistent MRD, high-risk genetics, or relapse lead to blinatumomab (CD19-directed), CAR T cells, or allogeneic transplant.
Supportive care during induction
Tumor lysis syndrome. Begin vigorous IV hydration and allopurinol before chemotherapy, and check potassium, phosphate, calcium, uric acid, and creatinine every 6–12 hours in high-risk patients. Give rasburicase (recombinant urate oxidase) for high risk — WBC ≥100,000/μL, preexisting hyperuricemia, or renal impairment — only after confirming normal G6PD activity, since deficiency leads to hemolysis and methemoglobinemia. Send uric acid samples on ice, because rasburicase keeps working in the tube.
Neutropenic fever. A temperature ≥38.3°C once, or ≥38.0°C sustained for an hour, with ANC <500/μL (or expected to fall below it) requires blood cultures, including from any central line, and an antipseudomonal β-lactam (cefepime, piperacillin–tazobactam, or meropenem) within 60 minutes. Add vancomycin for instability, catheter or skin infection, pneumonia, or MRSA colonization, and add a mold-active antifungal if fever persists beyond 4–7 days.
Blood products and prophylaxis. Use leukoreduced products (fewer febrile reactions, HLA alloimmunization, and CMV transmission) that are irradiated to prevent transfusion-associated GVHD. Transfuse platelets below 10,000/μL (higher with bleeding, fever, or APL) and red cells below 7 g/dL. During prolonged neutropenia give levofloxacin, a mold-active azole (posaconazole during AML induction), and acyclovir for HSV-seropositive patients; ALL regimens add TMP-SMX against Pneumocystis because of heavy corticosteroid exposure.