7.6 Acute Leukemias, Chronic Leukemias & Myeloproliferative Neoplasms
Key Takeaways
- Acute leukemia, chronic leukemia and marrow infiltration disorders appear under both leukocyte disorders and hematologic malignancies.
- Acute promyelocytic leukemia is a medical emergency in which all-trans retinoic acid is started on clinical suspicion before cytogenetic confirmation.
- Chronic myeloid leukemia is defined by the BCR-ABL1 fusion and treated with a tyrosine kinase inhibitor.
- Asymptomatic early-stage chronic lymphocytic leukemia is observed rather than treated, since early therapy does not improve survival.
- Differentiation syndrome during all-trans retinoic acid therapy presents with fever, dyspnea, infiltrates and weight gain and is treated with dexamethasone.
Last updated: August 2026
Hematologic neoplasms arise from the malignant transformation of myeloid, lymphoid, or plasma cell lineages at various stages of differentiation. Board certification requires precise understanding of molecular cytogenetics, risk stratification, targeted antineoplastic pharmacology, and oncologic complications.
1. Acute Leukemias
Acute leukemias are characterized by the rapid clonal proliferation of poorly differentiated, immature hematopoietic progenitor cells (blasts) in the bone marrow, resulting in bone marrow failure (anemia, neutropenia, thrombocytopenia) and tissue infiltration.
| Acute Leukemia Subtype | Hallmark Morphology & Flow Cytometry | Characteristic Cytogenetics / Molecular | Clinical Features & Board Pearls | Evidence-Based Therapy |
|---|---|---|---|---|
| Acute Myeloid Leukemia (AML) | ≥ 20% myeloblasts in marrow or blood; delicate Auer rods (fused azurophilic granules, peroxidase+); CD13+, CD33+, CD34+, CD117+, MPO+ | Favorable: $t(8;21)$, $inv(16)$, NPM1 or biallelic CEBPA without FLT3-ITD.<br/>Adverse: FLT3-ITD, TP53, complex karyotype, del(5q), del(7) | Pancytopenia, gingival hyperplasia (monocytic AML-M5), leukemia cutis, myeloid sarcoma | Induction: "7+3" Regimen (Cytarabine 7-day continuous infusion + Daunorubicin x 3 days). Add Midostaurin for FLT3 mutations. Consolidation: High-dose Cytarabine (HiDAC) or Allogeneic HCT for intermediate/poor risk |
| Acute Promyelocytic Leukemia (APL / AML M3) | Hypergranular promyelocytes with bundles of multiple Auer rods ("faggot cells"); CD33+, CD13+, CD34-negative, HLA-DR-negative | Translocation $t(15;17)(q24;q21)$ creating the PML-RARA fusion transcript | MEDICAL EMERGENCY: Consumptive coagulopathy / severe DIC (hyperfibrinolysis, fatal intracranial/pulmonary hemorrhage) | EMERGENCY THERAPY: Immediate All-trans Retinoic Acid (ATRA) + Arsenic Trioxide (ATO) upon suspicion. Monitor for Differentiation Syndrome (treat with IV Dexamethasone 10 mg BID) |
| Acute Lymphoblastic Leukemia (ALL) | Lymphoblasts with high nuclear-to-cytoplasmic ratio; TdT+; B-ALL: CD19+, CD20+, CD22+; T-ALL: CD3+, CD5+, CD7+ | $t(9;22)(q34;q11.2)$ BCR-ABL1 (Philadelphia chromosome) in 25–30% of adults; $t(4;11)$ KMT2A rearrangement | B-ALL: Bone pain, hepatosplenomegaly, testicular enlargement.<br/>T-ALL: Adolescent male with anterior mediastinal mass (stridor, SVC syndrome) | Multi-agent induction (Vincristine, Corticosteroids, Anthracycline, PEG-asparaginase). If Ph+ ALL: Add BCR-ABL TKI (Dasatinib/Ponatinib). Intrathecal Chemotherapy (Methotrexate) is mandatory for CNS prophylaxis |
2. Chronic Leukemias & Myeloproliferative Neoplasms (MPNs)
Chronic Myeloid Leukemia (CML)
- Pathophysiology: Clonal myeloproliferative disorder driven by the balanced translocation $t(9;22)(q34;q11.2)$, which fuses the BCR gene on chromosome 22 with the ABL1 tyrosine kinase gene on chromosome 9 (Philadelphia Chromosome). This creates the constitutively active BCR-ABL1 oncoprotein kinase, driving uncontrolled granulopoiesis.
- Clinical Presentation: Marked leukocytosis (WBC often 50,000–250,000/mcL) with the complete spectrum of myeloid differentiation (myeloblasts, promyelocytes, myelocytes, metamyelocytes, bands, neutrophils), absolute basophilia and eosinophilia, and massive splenomegaly. Leukocyte Alkaline Phosphatase (LAP) score is low/zero (differentiates CML from a reactive leukemoid reaction where LAP is elevated).
- Disease Phases:
- Chronic Phase: < 10% blasts in marrow/blood (85–90% of presentations).
- Accelerated Phase: 10–19% blasts, persistent thrombocytopenia (< 100k) or thrombocytosis (> 1,000k), progressive splenomegaly.
- Blast Crisis: ≥ 20% blasts in marrow/blood or extramedullary blast proliferation (acts as acute leukemia: 70% myeloid, 30% lymphoid).
- Targeted Management:
- First-line: Tyrosine Kinase Inhibitors (TKIs: Imatinib [1st gen], Dasatinib, Nilotinib, Bosutinib [2nd gen]).
- Monitoring: Quantitative Real-Time PCR (RT-qPCR) for BCR-ABL1 transcripts on the International Scale (IS) every 3 months. Milestone: Major Molecular Response (MMR / $MR^{3.0}$: BCR-ABL1 $\le 0.1%$ IS) at 12 months.
- Resistance / Mutations: The T315I gatekeeper mutation confers resistance to all 1st and 2nd generation TKIs; requires Ponatinib (3rd gen TKI) or Asciminib (allosteric STAMP inhibitor).
Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)
- Diagnostic Criteria: Sustained absolute monoclonal B-lymphocytosis ($\ge 5,000/\text{mcL}$) in peripheral blood for $\ge 3$ months. Flow cytometry reveals co-expression of CD5, CD19, CD20 (dim), CD23, and weak surface immunoglobulin light chain restriction (kappa or lambda). Smear shows mature small lymphocytes with fragile smudge cells (basket cells).
- Staging Systems:
- Rai System: Stage 0 (Lymphocytosis alone, low risk); Stage I (Lymphadenopathy); Stage II (Splenomegaly or hepatomegaly); Stage III (Anemia, Hb < 11.0 g/dL); Stage IV (Thrombocytopenia, Platelets < 100,000/mcL).
- Binet System: Stage A (< 3 lymph node areas); Stage B ($\ge 3$ lymph node areas); Stage C (Anemia Hb < 10 or Platelets < 100k).
- Indications for Treatment (iwCLL Criteria):
- Asymptomatic early-stage disease (Rai 0–II without active disease) is managed with active surveillance ("watch and wait"); early treatment does NOT prolong overall survival.
- Initiate treatment ONLY for active disease: Progressive marrow failure (worsening anemia/thrombocytopenia), massive/progressive splenomegaly ($\ge 6$ cm below costal margin), bulky/progressive lymphadenopathy ($\ge 10$ cm), progressive lymphocytosis with lymphocyte doubling time < 6 months, or severe disease-related B symptoms.
- Modern First-Line Targeted Therapies:
- BTK Inhibitors: Acalabrutinib or Zanubrutinib (preferred over ibrutinib due to lower rates of atrial fibrillation and bleeding) continuous daily therapy.
- BCL-2 Inhibitor Regimen: Fixed-duration Venetoclax + Obinutuzumab (anti-CD20) x 12 months (requires tumor lysis syndrome prophylaxis and stepped dose titration).
- High-risk genetics: Deletion 17p / TP53 mutation renders chemoimmunotherapy (FCR) ineffective; targeted therapy with BTK inhibitors or Venetoclax is mandatory.
Classical Myeloproliferative Neoplasms (MPNs)
| MPN Entity | Driver Mutations | Key Laboratory & Bone Marrow Findings | Classic Clinical Features | Evidence-Based Therapy |
|---|---|---|---|---|
| Polycythemia Vera (PV) | JAK2 V617F (> 95%) or JAK2 Exon 12 (3%) | Elevated Hct (> 49% men, > 48% women), Low serum Erythropoietin (EPO), panmyelosis on marrow | Aquagenic pruritus (severe itching after warm bath), erythromelalgia, splenoportal venous thrombosis, hyperuricemia/gout | Therapeutic Phlebotomy (Target Hct < 45% strictly) + Aspirin 81 mg daily.<br/>Add Hydroxyurea for High Risk (Age $\ge 60$ or prior thrombosis) |
| Essential Thrombocythemia (ET) | JAK2 V617F (55%), CALR (25%), MPL (4%) | Sustained Platelets $\ge 450,000/\text{mcL}$, large mature megakaryocytes in marrow | Microvascular vasomotor symptoms (headache, erythromelalgia), thrombosis, paradoxical bleeding (acquired vWS if Plt > 1 million) | Low-dose Aspirin.<br/>Add Hydroxyurea (or Anagrelide) for High-Risk patients (Age $\ge 60$ or prior thrombosis) |
| Primary Myelofibrosis (PMF) | JAK2 (60%), CALR (25%), MPL (5%) | Leukoerythroblastic blood smear, Teardrop erythrocytes (Dacrocytes), dry tap marrow (reticulin/collagen fibrosis) | Massive splenomegaly (extramedullary hematopoiesis), severe cachexia, constitutional B symptoms, bone pain | Ruxolitinib or Fedratinib (JAK1/2 inhibitors) to shrink spleen and relieve symptoms; Allogeneic HCT is the sole curative option |
Test Your Knowledge
A 46-year-old previously healthy woman is admitted with acute fatigue, gingival bleeding, epistaxis, and widespread ecchymoses. Laboratory evaluation reveals: WBC 2,800/mcL with 45% blasts/promyelocytes containing numerous Auer rods arranged in bundles, Hemoglobin 7.2 g/dL, and Platelets 18,000/mcL. Coagulation profile shows: PT 22.4 seconds, aPTT 48 seconds, Fibrinogen 78 mg/dL (low), and D-dimer markedly elevated (> 20 mcg/mL), consistent with severe disseminated intravascular coagulation. Cytogenetic analysis is pending. What is the most appropriate immediate medical intervention?
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Test Your Knowledge
A 72-year-old man presents for a routine annual physical examination. He is completely asymptomatic with no fevers, night sweats, fatigue, or weight loss. Physical examination reveals no palpable cervical, axillary, or inguinal lymphadenopathy, and no hepatosplenomegaly. Routine complete blood count reveals: WBC 38,500/mcL with 88% mature-appearing lymphocytes, Hemoglobin 14.2 g/dL, and Platelets 210,000/mcL. Peripheral blood smear demonstrates absolute lymphocytosis with numerous smudge cells. Flow cytometry confirms a clonal B-cell population co-expressing CD5, CD19, CD20 (dim), and CD23 with kappa light chain restriction. What is the most appropriate next step in management?
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