Leukemias ( AML,ALL,CML,CLL )

Overview & Diagnostic Principles

Leukemias are malignant clonal proliferations of white-cell precursors arising in the bone marrow. A single hematopoietic stem/progenitor cell acquires a driver mutation, proliferates uncontrollably, and crowds out normal hematopoiesis → marrow failure + circulating abnormal cells.

Two classification axes

• Speed / maturity → Acute (immature blasts ≥ 20% of marrow; rapid, marrow failure in weeks) vs Chronic (relatively mature cells; indolent, often found incidentally on a routine CBC).
• Lineage → Myeloid vs Lymphoid.

Crossing these two axes yields the four classic leukemias:

(ملاحظة سريرية: عتبة الـ 20% من الأرومات (blasts) في نقي العظم أو الدم المحيطي هي الحد الفاصل الذي يُعرّف اللوكيميا الحادة عن المزمنة.)

Leukemia age groups — «ALL CALM»
ALL → kids (Children, 2–5 y) AML → Adults (~65 y) CML → Middle-aged (45–55 y) CLL → Late adulthood / elderly (> 60 y)	جملة تذكرية

Shared clinical features (any leukemia)

All four converge on the consequences of marrow replacement plus tissue infiltration:

• Anemia → fatigue, pallor, dyspnea.
• Thrombocytopenia → petechiae, easy bruising, mucosal bleeding.
• Neutropenia / dysfunctional WBCs → recurrent infections, fever.
• Organ infiltration → hepatosplenomegaly, lymphadenopathy, bone pain.

Universal diagnostic workup

The same stepwise workup applies to any suspected leukemia:

1. CBC + peripheral smear → WBC count, and morphologic clues: blasts, Auer rods, smudge cells, basophilia.
2. Bone marrow aspiration & biopsy → confirms diagnosis; ≥ 20% blasts = acute leukemia.
3. Flow cytometry / immunophenotyping → assigns lineage (myeloid vs lymphoid; B vs T).
4. Cytogenetics / FISH / PCR → translocations drive prognosis & therapy:
   • t(9;22) BCR-ABL → CML and 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, K⁺, phosphate, Ca²⁺, creatinine → baseline tumor-lysis risk.
6. Lumbar puncture → for ALL (CNS staging) or any CNS symptoms.

Quick smear pearls

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

Acute Leukemias: ALL vs. AML

Both are defined by ≥ 20% blasts and an aggressive course, but they split cleanly by age and lineage: ALL = lymphoid blasts in children; AML = myeloid blasts in adults.

Epidemiology & risk factors

• ALL — most common childhood malignancy; peak 2–5 years; B-cell ≫ T-cell. Strongly associated with Down syndrome.
• AML — most common acute leukemia in adults (median ~65 y). Risk factors: prior chemotherapy (alkylating agents, topoisomerase-II inhibitors), radiation, benzene, smoking, transformation from MDS/myeloproliferative disorders, and Down syndrome (especially AML M7, megakaryoblastic, in children < 5 y).

Clinical clues

• ALL: marrow failure + bone pain / limp, lymphadenopathy, hepatosplenomegaly, CNS involvement (headache, cranial-nerve palsies). T-ALL → anterior mediastinal mass in a teenage boy (may cause SVC syndrome). Testes = sanctuary site and common relapse location.
• AML: marrow failure + leukostasis (WBC > 50–100k → headache, dyspnea, visual changes, priapism), gum hypertrophy and leukemia cutis (monocytic subtypes M4/M5), and DIC at presentation in APL (M3).

Diagnosis & morphology

Both show marrow blasts ≥ 20%; the lineage is settled by morphology and flow cytometry:

• ALL: small blasts, scant cytoplasm, NO Auer rods; TdT-positive is the hallmark (ملاحظة سريرية: إنزيم الـ TdT النووي هو السمة المميزة للأرومات اللمفاوية ويغيب في اللوكيميا النقوية). B-ALL → CD10/CD19/CD20; T-ALL → CD2–CD8. Cytogenetics: t(12;21) = good (children); t(9;22) Philadelphia = poor.
• AML: Auer rods + myeloperoxidase (MPO)-positive blasts; flow CD13/CD33/CD117. Auer rods are myeloid-specific (ملاحظة سريرية: قضبان أوير (Auer rods) نوعية للنسيلة النقوية وتؤكد تشخيص AML وتستبعد ALL). Key cytogenetics: t(15;17) PML-RARα → APL (M3); t(8;21)/inv(16) → favorable.

See the ALL epidemiology, clinical features, and diagnosis reference for the full pediatric workup including CNS staging.

Treatment

• ALL: multi-phase chemotherapy — induction → consolidation → maintenance (~2–3 years total) + intrathecal methotrexate for CNS prophylaxis (mandatory). Add a TKI (imatinib) if Ph⁺. Childhood cure ~90%; adults do worse.
• AML: «7 + 3» induction — cytarabine × 7 days + an anthracycline × 3 days. APL exception: ATRA + arsenic trioxide (best-prognosis AML). Allogeneic stem cell transplant for high-risk or relapsed disease.

Acute leukemia buzzwords
Auer rods = AML (especially M3/APL); MPO-positive blasts. TdT⁺ blasts = ALL (lymphoid lineage). t(15;17) → APL → give ATRA («15 + 17 → ATRA»). Child + bone pain ± anterior mediastinal mass → think T-ALL.	جملة تذكرية

Chronic Leukemias: CML vs. CLL

Both are indolent, frequently asymptomatic, and often discovered on a routine CBC. They diverge by lineage: CML is a myeloproliferative neoplasm of mature granulocytes; CLL is an accumulation of mature but incompetent B-lymphocytes.

Pathogenesis & epidemiology

• CML — driven by the Philadelphia chromosome → t(9;22) → BCR-ABL fusion → constitutively active tyrosine kinase (ملاحظة سريرية: انتقال t(9;22) المنتج لجين BCR-ABL هو السمة الجزيئية المُعرِّفة لـ CML وهدف العلاج الموجَّه). Median age ~45–55 y.
• CLL — monoclonal proliferation of mature B-cells; most common adult leukemia in the West; age usually > 60 y. Considered the same disease as small lymphocytic lymphoma (SLL).

Clinical clues

• CML: massive splenomegaly (LUQ fullness, early satiety), fatigue, night sweats, weight loss; hyperviscosity if WBC very high.
• CLL: painless lymphadenopathy, hepatosplenomegaly, B symptoms when advanced; recurrent infections from hypogammaglobulinemia; autoimmune cytopenias — warm AIHA (Coombs⁺) and ITP.

CML — 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).

The clinical phases of CML by blast percentage lay out how the disease escalates from stable chronic phase to blast crisis.

Diagnosis & morphology

• CML: WBC often > 100,000 with all stages of granulocyte maturation, plus basophilia & eosinophilia. LAP score is LOW (ملاحظة سريرية: انخفاض إنزيم الفوسفاتاز القلوي للكريات البيض (LAP) هو السمة المميزة التي تفرق CML عن التفاعل الابيضاضي الشديد). Confirm with BCR-ABL by FISH/PCR or cytogenetic t(9;22).
• CLL: absolute B-lymphocyte count ≥ 5,000/µL of clonal, mature-appearing cells; smudge cells on smear (fragile lymphocytes crushed during slide prep) (ملاحظة سريرية: خلايا اللطخة (smudge cells) ناتجة عن هشاشة اللمفاويات وتُعدّ مؤشراً مميزاً لـ CLL). Flow cytometry: CD5⁺, CD19⁺, CD20⁺, CD23⁺ (CD5 = a T-cell marker aberrantly expressed on these B-cells).

Refer to the CLL diagnostic criteria and treatment indications for the flow-cytometry panel and the thresholds that trigger therapy.

Treatment

• CML: Imatinib (or dasatinib/nilotinib) — first-line TKI with excellent response; allogeneic stem cell transplant reserved for TKI failure or blast crisis.
• CLL: Early/asymptomatic → watchful waiting (no survival benefit from early treatment). Symptomatic/advanced → BTK inhibitor (ibrutinib), BCL-2 inhibitor (venetoclax), or anti-CD20 (rituximab) ± chemo (FCR).

Disease-specific complication

• CLL → Richter transformation: evolution to diffuse large B-cell lymphoma (DLBCL) — rapidly enlarging node, new B symptoms, aggressive course and poor prognosis.
• CML → blast crisis: transformation to acute leukemia.

Important – فكرة سؤال
CD5 is normally a T-cell antigen, yet it is aberrantly co-expressed (with CD19/CD20/CD23) on the malignant B-cells of CLL. The other classic CD5⁺ B-cell neoplasm is mantle cell lymphoma — separate them: mantle cell is CD23-negative with t(11;14) / cyclin D1 overexpression, whereas CLL is CD23-positive.	تذكر

Chronic leukemia buzzwords
Philadelphia = CML → «9 on top of 22» → t(9;22) → BCR-ABL. ↓ LAP score = CML (↑ LAP in leukemoid reaction). Smudge cells = CLL → «CLL crushes its cells». Massive splenomegaly + basophilia → CML.	جملة تذكرية

Master Comparison & Key Differentials

This is the must-memorize backbone of the topic — the single matrix that most exam questions test one row of. Read it across (one disease) and down (one feature) until each cell is automatic.

Key differential: CML vs leukemoid reaction

A reactive neutrophilia (severe infection, sepsis) can mimic CML on the smear. The decisive separators are the LAP score, BCR-ABL, and basophilia (ملاحظة سريرية: ارتفاع الـ LAP مع غياب BCR-ABL يرجّح التفاعل الابيضاضي، بينما انخفاض الـ LAP مع وجود BCR-ABL يؤكد CML).

See the library's leukemoid reaction vs CML comparison for the same differential framed around the low-vs-high LAP score and BCR-ABL status.

Urgent Complications

Beyond marrow failure, three time-critical emergencies dominate exam questions and must be recognized on sight: tumor lysis syndrome, leukostasis, and APL-associated DIC.

1. Tumor Lysis Syndrome (TLS)

• Mechanism: massive tumor cell death (spontaneous or with chemotherapy) dumps intracellular contents into the blood.
• Metabolic tetrad: ↑ K⁺, ↑ phosphate, ↑ uric acid, ↓ Ca²⁺ (calcium falls as it binds the released phosphate) → AKI, arrhythmias, tetany/seizures.
• Highest risk: ALL, Burkitt lymphoma, AML with high WBC / bulky, rapidly proliferating disease.
• Prevention: aggressive IV hydration + allopurinol (xanthine oxidase inhibitor) for standard risk; rasburicase for high risk.

The tumor lysis syndrome risk stratification and prophylaxis lays out the high/intermediate/low risk categories and the rasburicase-vs-allopurinol decision.

Important – فكرة سؤال
Rasburicase (recombinant urate oxidase) is contraindicated in G6PD deficiency — it generates hydrogen peroxide as it degrades uric acid, precipitating severe hemolysis and methemoglobinemia. In G6PD-deficient patients at risk of tumor lysis syndrome, use allopurinol + aggressive IV hydration instead.	تذكر

2. Leukostasis

• Trigger: WBC > 50,000–100,000 — typically AML or blast-crisis CML.
• Mechanism: sludging of bulky blasts in the microvasculature → tissue hypoxia.
• Features: dyspnea, headache, blurred vision, altered mental status, priapism.
• Emergency management: leukapheresis + hydroxyurea + prompt induction chemotherapy.

3. APL-associated DIC

• Acute promyelocytic leukemia (AML M3, t(15;17)) presents with disseminated intravascular coagulation — the malignant promyelocytes release procoagulant granules.
• Bleeding can be fatal before treatment even begins (ملاحظة سريرية: التخثر المنتشر داخل الأوعية (DIC) في APL هو حالة إسعافية؛ يجب البدء بالـ ATRA فور الاشتباه السريري قبل تأكيد الوراثيات الخلوية).
• Smear: abnormal promyelocytes with abundant cytoplasm and bundles of Auer rods.

Important – فكرة سؤال
In suspected APL (AML M3) — promyelocytes packed with bundles of Auer rods, t(15;17), and DIC at presentation — start ATRA (all-trans retinoic acid) IMMEDIATELY on clinical suspicion, before cytogenetic confirmation returns. ATRA differentiates the malignant promyelocytes and rapidly reverses the lethal coagulopathy; delaying therapy to await confirmation can be fatal from hemorrhage.	تذكر