Leukemias ( AML,ALL,CML,CLL )

Summary

Leukemias are malignant clonal proliferations of white blood cell precursors in the bone marrow, leading to bone marrow failure (anemia, thrombocytopenia, neutropenia) and circulating abnormal cells.

They are classified by:

• Speed of onset → Acute (blasts > 20%) vs Chronic (mature cells).
• Cell lineage → Myeloid vs Lymphoid.

This gives the 4 classic types:

• ALL – Acute Lymphoblastic Leukemia → children.
• AML – Acute Myeloid Leukemia → adults (median ~65 y).
• CML – Chronic Myeloid Leukemia → middle-aged adults, Philadelphia chromosome.
• CLL – Chronic Lymphocytic Leukemia → elderly (> 60 y), most common adult leukemia in the West.

Diagnosis: CBC + peripheral smear + bone marrow biopsy + flow cytometry. Treatment differs sharply by type, ranging from chemotherapy and targeted agents (imatinib for CML) to watchful waiting (early CLL).

Overview and Classification

A clonal hematopoietic stem cell acquires a mutation → uncontrolled proliferation of one lineage → crowds out normal marrow.

• Acute leukemias → immature blasts (≥ 20% of marrow) → rapid course, marrow failure within weeks.
• Chronic leukemias → relatively mature cells → slow course, often picked up on routine CBC.

Shared clinical features (any leukemia):

• Anemia → fatigue, pallor.
• Thrombocytopenia → bleeding, petechiae, bruises.
• Neutropenia / dysfunctional WBCs → infections, fever.
• Organ infiltration → hepatosplenomegaly, lymphadenopathy, bone pain.

Acute Lymphoblastic Leukemia (ALL)

Definition: Acute leukemia of lymphoid blasts (B-cell >> T-cell). Most common childhood malignancy, peak age 2–5 years. Higher risk in Down syndrome.

Clinical features

• Marrow failure → anemia, bleeding, infections, fever.
• Bone pain, limp (kids).
• Lymphadenopathy + hepatosplenomegaly.
• CNS involvement → headache, cranial nerve palsies.
• T-cell ALL → anterior mediastinal mass in a teenage boy → may cause SVC syndrome.
• Testicular involvement = sanctuary site, common relapse location.

Diagnosis

• CBC: ↑↑ WBC with lymphoblasts; anemia + thrombocytopenia.
• Peripheral smear / marrow: blasts ≥ 20%; small cells, scant cytoplasm, no Auer rods.
• Flow cytometry / IHC: TdT (+) = hallmark of lymphoblasts.
  • B-ALL → CD10, CD19, CD20.
  • T-ALL → CD2–CD8.
• Cytogenetics: t(12;21) in children = good prognosis; t(9;22) Philadelphia = poor.
• LP for CNS staging.

ALL peripheral smear and ALL diagnostic features table.

Treatment

• Induction + consolidation + maintenance chemo (multi-drug, ~2–3 years total).
• Intrathecal methotrexate for CNS prophylaxis (mandatory).
• Imatinib / TKIs added if Ph+.

Prognosis in children: ~90% cure. Adults do worse.

Acute Myeloid Leukemia (AML)

Definition: Acute leukemia of myeloid blasts. Most common acute leukemia in adults (median age ~65 y).

Risk factors

• Prior chemotherapy (alkylating agents, topoisomerase II inhibitors).
• Radiation, benzene, smoking.
• Transformation from MDS or other myeloproliferative disorders.
• Down syndrome (especially < 5 y → AML M7, megakaryoblastic).

Clinical features

• Marrow failure symptoms (anemia, bleeding, infection).
• Leukostasis when WBC > 50,000–100,000 → headache, dyspnea, visual changes, priapism (medical emergency → leukapheresis).
• Gum hypertrophy and skin infiltration (leukemia cutis) → monocytic subtypes (M4, M5).
• DIC at presentation → APL (M3).

Diagnosis

• Marrow blasts ≥ 20%.
• Auer rods + myeloperoxidase (MPO) positive blasts.
• Flow: CD13, CD33, CD117.
• Key cytogenetics:
  • t(15;17) PML-RARα → APL (M3) → treat with ATRA + arsenic.
  • t(8;21), inv(16) → favorable prognosis.

AML blast with Auer rod.

Treatment

• "7 + 3" induction: cytarabine × 7 days + anthracycline × 3 days.
• APL exception: ATRA + arsenic trioxide (best-prognosis AML).
• Allogeneic stem cell transplant for high-risk or relapsed disease.

Chronic Myeloid Leukemia (CML)

Definition: Myeloproliferative disorder driven by the Philadelphia chromosome → t(9;22) → BCR-ABL fusion → constitutively active tyrosine kinase. Median age ~45–55 y.

Clinical features

• Often asymptomatic → found on routine CBC.
• Massive splenomegaly (LUQ fullness, early satiety).
• Fatigue, night sweats, weight loss.
• Hyperviscosity / leukostasis if WBC very high.

Three phases

1. Chronic phase (~85% at diagnosis) → high WBC, < 10% blasts.
2. Accelerated phase → 10–19% blasts, worsening symptoms.
3. Blast crisis → ≥ 20% blasts, behaves like acute leukemia (2/3 myeloid, 1/3 lymphoid).

Diagnosis

• CBC: WBC often > 100,000, all stages of granulocytes, basophilia & eosinophilia.
• LAP score ↓ (vs ↑ in leukemoid reaction).
• Confirm with BCR-ABL by FISH / PCR or cytogenetic t(9;22).

CML peripheral smear · Clinical phases of CML · Leukemoid reaction vs CML.

Treatment

• Imatinib (and other TKIs: dasatinib, nilotinib) → first-line, excellent response.
• Allogeneic stem cell transplant → for TKI failure or blast crisis.

Chronic Lymphocytic Leukemia (CLL)

Definition: Monoclonal proliferation of mature but functionally incompetent B-lymphocytes. Most common leukemia in adults in the West; age usually > 60 y. Considered the same disease as small lymphocytic lymphoma (SLL).

Clinical features

• Often asymptomatic → incidental absolute lymphocytosis.
• Painless lymphadenopathy, hepatosplenomegaly.
• Fatigue, B symptoms in advanced disease.
• Recurrent infections due to hypogammaglobulinemia.
• Autoimmune complications: warm AIHA (Coombs +), ITP.

Diagnosis

• Absolute lymphocyte count ≥ 5,000/µL of clonal mature-appearing B-cells.
• Smudge cells on smear (fragile lymphocytes crushed during slide prep).
• Flow cytometry: CD5, CD19, CD20, CD23 positive (CD5 = T-cell marker aberrantly expressed on these B-cells).

CLL smear with smudge cells · CLL diagnosis & treatment indications.

Complications

• Richter transformation → diffuse large B-cell lymphoma (DLBCL); aggressive, poor prognosis.
• Recurrent infections (encapsulated organisms).
• Autoimmune cytopenias.

Treatment

• Early/asymptomatic → watchful waiting (no survival benefit from early treatment).
• Symptomatic / advanced → BTK inhibitors (ibrutinib), BCL-2 inhibitor (venetoclax), or anti-CD20 (rituximab) ± chemo (FCR).

Side-by-side Comparison

Use this comparison as your "must-memorize" backbone — most exam questions on leukemia test one of these rows.

Diagnostic Approach

Same workup for any suspected leukemia:

1. CBC + peripheral smear → look at WBC count, presence of blasts, smudge cells, Auer rods, basophilia.
2. Bone marrow aspiration & biopsy → required for acute leukemias and AML/ALL confirmation; ≥ 20% blasts = acute leukemia.
3. Flow cytometry / immunophenotyping → distinguishes lineage (myeloid vs lymphoid; B vs T).
4. Cytogenetics / FISH / PCR → translocations drive prognosis & therapy:
   • t(9;22) BCR-ABL → CML, Ph+ ALL.
   • t(15;17) PML-RARα → APL.
   • t(12;21) → favorable pediatric ALL.
   • t(8;21), inv(16) → favorable AML.
5. LDH, uric acid, electrolytes → baseline for tumor lysis risk.
6. LP if ALL (CNS staging) or any CNS symptoms.

Algorithm for blasts: immunophenotyping.

Quick smear pearls

• Auer rods → AML (especially APL).
• Smudge cells → CLL.
• Full myeloid spectrum + basophilia → CML.
• TdT-positive blasts → ALL.

Complications

Beyond marrow failure, three high-yield complications appear repeatedly on exams:

1. Tumor Lysis Syndrome (TLS)

• Massive cell death → release of intracellular contents.
• ↑ K⁺, ↑ phosphate, ↑ uric acid, ↓ Ca²⁺ → AKI, arrhythmias, seizures.
• Highest risk: ALL, Burkitt lymphoma, AML with high WBC.
• Prevention: aggressive IV fluids + allopurinol (or rasburicase for high-risk).

Tumor lysis syndrome: risk factors, prophylaxis, treatment.

2. Leukostasis

• WBC > 50,000–100,000 (AML or blast-crisis CML).
• Sludging in microvasculature → dyspnea, headache, blurred vision, AMS, priapism.
• Emergency: leukapheresis + hydroxyurea + start induction chemo.

3. CNS / Sanctuary-site involvement

• ALL spreads to CNS and testes → why intrathecal methotrexate is mandatory.

4. Disease-specific

• APL (M3) → DIC at presentation; bleeding can be fatal before treatment.
• CLL → AIHA, ITP, hypogammaglobulinemia, Richter transformation.
• CML → blast crisis (transformation to acute leukemia).

Mnemonics