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Acute Lymphoid (Lymphoblastic) Leukaemia (ALL)

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Definition

• ~85% are B-ALLs
• ~15-25% are T-ALLs

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Epidemiology

• Most common cancer in children, with a peak incidence at 3-4 years of age
• B-ALL peaks at ~3 years (paralleling the maximum number of normal bone marrow pre-B cells); T-ALL peaks in adolescence (when the thymus reaches maximum size)
• Slightly more frequent in boys than girls
• Hispanic/Latino children have the highest incidence of any ethnic group in the US
• Adult incidence: 0.7-1.8/100,000/year; rises again in the elderly
• Ph+ ALL accounts for ~50% of elderly B-lineage ALL patients

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Etiology & Risk Factors

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Pathogenesis & Molecular Biology

Key genetic alterations in B-ALL:

Key genetic alterations in T-ALL:

• NOTCH1 mutations: 50-70% of T-ALL (essential for T-cell development)
• Translocations at T-cell receptor enhancer regions (chromosomes 7 and 14)

"Ph-like ALL" lacks classic BCR-ABL1 but has kinase-activating mutations in the same signalling pathway - accounting for 20-25% of adult ALLs and carrying a poor prognosis.

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Classification

Immunophenotype (B-cell lineage, ~75% of ALL)

T-cell lineage (~25% of ALL)

The WHO now classifies ALL primarily on cytogenetic and molecular features rather than morphology alone.

FAB Morphology (historical)

• L1: Small blasts (common in children)
• L2: Large heterogeneous blasts (common in adults)
• L3: Vacuolated blasts = Burkitt leukaemia (mature B-ALL); ~5% of adults

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Clinical Features

• Anaemia - fatigue, pallor, headache, dyspnoea
• Thrombocytopenia - petechiae, ecchymoses, bleeding gums, epistaxis (~1/3 of patients have clinically evident bleeding at diagnosis)
• Granulocytopenia - bacterial infections (~1/3 have significant or life-threatening infections at presentation)

• Lymphadenopathy, hepatosplenomegaly - common at diagnosis
• Mediastinal mass - characteristic of T-ALL (thymic origin)
• Bone pain - from periosteal infiltration or marrow expansion; especially in children
• CNS involvement (leukemic meningitis) - headache, nausea, cranial nerve palsies
• Leukemia cutis - raised, non-pruritic rash
• Testicular infiltration (especially in relapsed childhood ALL)

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Diagnosis

Peripheral Blood

Bone Marrow

• 20% blasts required for diagnosis

• Morphology, cytochemistry (TdT+, Sudan black-, MPO- in ALL)

Immunophenotyping (flow cytometry) - essential

• B-lineage: CD19, CD22, CD10, CD20, cytoplasmic/surface Ig
• T-lineage: CD7, CD1a, CD3 (surface/cytoplasmic)
• A marker considered positive if >20% cells stain positive

Cytogenetics / Molecular

• Karyotype, FISH, PCR for BCR-ABL1, KMT2A rearrangements, etc.
• Identifies prognostic subgroups and therapy targets

CSF Examination (Lumbar Puncture)

• Essential in all ALL patients
• CNS involvement defined as ≥5 cells/μL or leukemic blasts on morphology
• Intrathecal methotrexate should be given at the first LP to eliminate any transferred blast cells
• Only in patients with adequate platelets (>20 × 10³/L) and without active haemorrhage

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Antigen Targets for Immunotherapy in B-ALL

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Treatment

1. Induction (3-4 weeks)

• CR achieved in 90% of children and 80-90% of adults
• Dexamethasone preferred over prednisone (better CNS penetration, acts on resting blasts)
• CD20-positive, Ph-negative ALL: add rituximab (375 mg/m²) - improves outcome
• Two widespread adult regimens:
  • BFM (Berlin-Frankfurt-Münster) protocol - common in Europe
  • Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) - common in North America

2. Post-remission Consolidation (6-8 courses)

• High-dose methotrexate (1-5 g/m²) and/or high-dose cytarabine (1-3 g/m²) - essential for sanctuary site penetration (CNS)
• Ph+ ALL: add a TKI (imatinib, dasatinib, ponatinib)
• Allogeneic stem cell transplantation (SCT) for high-risk patients in first CR

3. Maintenance Therapy (2-2.5 years)

• 6-mercaptopurine (daily) + methotrexate (weekly) + intrathecal therapy
• For Ph+ ALL: add a TKI throughout maintenance; continue 2-2.5 years guided by MRD
• Exception: Burkitt leukaemia requires only 6-12 months maintenance

CNS Prophylaxis and Treatment

• Intrathecal methotrexate is standard
• High-dose systemic methotrexate/cytarabine reaches CNS sanctuary sites
• Cranial irradiation now largely replaced by intrathecal chemotherapy to avoid neurocognitive side effects

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Ph+ ALL - Special Considerations

• BCR-ABL1 fusion (190 kD in ALL vs. 210 kD in CML)
• TKI (imatinib, dasatinib, ponatinib) added to chemotherapy - dramatically improves outcomes
• A chemotherapy-free induction with dasatinib + dexamethasone + blinatumomab achieves:
  • CR rate 98%
  • 2-year OS 95%, DFS 88%
• Blinatumomab eliminates Ph+ cells with TKI-resistant mutations

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Immunotherapy & Novel Agents

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Prognosis

Cure rates by age:

Favourable prognostic features:

• Age 1-10 years, WBC < 50 × 10⁹/L at diagnosis
• Hyperdiploidy (>50 chromosomes)
• t(12;21) (ETV6-RUNX1) in children
• CALLA-positive (CD10+) immunophenotype
• Rapid early response / early achievement of MRD negativity

Unfavourable prognostic features:

• Age <1 or >10 years (in children); all adult ALL
• WBC > 50 × 10⁹/L at diagnosis
• t(9;22) Ph+ without TKI therapy
• t(4;11) KMT2A rearrangement
• Hypodiploidy (<44 chromosomes)
• Ph-like ALL
• T-ALL with early T-cell precursor (ETP-ALL) phenotype
• CNS involvement at diagnosis
• Slow response to induction; failure to achieve MRD negativity

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Key Points Summary

1. ALL is the most common childhood cancer - peak at 3-4 years, B-cell type predominantly
2. T-ALL predominantly affects adolescent males and often presents with a mediastinal mass
3. Cytogenetics and molecular biology (not just morphology/immunophenotype) drive modern classification and risk stratification
4. The Philadelphia chromosome (BCR-ABL1) is the single most important cytogenetic abnormality to identify in adult ALL - it is found in ~25% and is treatable with TKIs
5. Treatment follows induction → consolidation → maintenance, with CNS prophylaxis throughout
6. Blinatumomab, inotuzumab, and CAR-T cells have transformed the management of relapsed/refractory ALL
7. MRD monitoring (minimal residual disease) guides treatment decisions and predicts relapse

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• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Chapter 111: Acute Lymphoid Leukemia
• Goldman-Cecil Medicine, International Ed., Chapter 168: Acute Lymphoblastic Leukemia
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 13: Lymphoid Neoplasms

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MCQs on Acute Lymphoid Leukaemia (ALL)

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Based on: Harrison's Principles of Internal Medicine 22nd Ed., Goldman-Cecil Medicine, Robbins & Cotran Pathologic Basis of Disease

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Chronic Myeloid Leukaemia (CML)

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Definition

• The Ph chromosome = elongated chromosome 9 + shortened chromosome 22
• BCR-ABL1 encodes a constitutively active p210 tyrosine kinase (in CML)
• This kinase drives uncontrolled granulocytic proliferation via RAS, JAK/STAT, and PI3K/AKT signalling pathways
• There is no BCR-ABL1-negative CML - cases without the Ph chromosome by cytogenetics still harbour BCR-ABL1 detectable by FISH or PCR

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Epidemiology

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Etiology

• No familial association - no increased risk in monozygotic twins or relatives
• No benzene, insecticide, fertilizer, or viral associations (unlike AML)
• Ionizing radiation is the only established risk factor:
  • Risk peaks 5-10 years after exposure
  • Dose-related
  • Mean time to CML development after atomic bomb exposure: 6.3 years

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Pathophysiology

• Constitutive tyrosine kinase activity → phosphorylation of downstream substrates
• Activation of RAS pathway (proliferation)
• Activation of JAK/STAT pathway (survival, inhibited apoptosis)
• BCR-ABL1 dimerisation (via BCR coiled-coil domain) is required for kinase activation
• Preferentially drives granulocytic and megakaryocytic progenitor expansion
• Causes abnormal release of immature granulocytes from marrow into blood
• Normal stem cells persist and can re-emerge with effective TKI therapy

Compare BCR-ABL1 fusion proteins:

Protein	Size	Associated condition
p210	210 kDa	CML (most); rare in Ph+ ALL
p190	190 kDa	Ph+ ALL (2/3 of cases)
p230	230 kDa	Rare CML/chronic neutrophilic leukaemia

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Phases of CML

1. Chronic Phase (CP) - ~90% at diagnosis

• Symptomatic but manageable
• Blasts < 10% (WHO) or < 15% (ELN) in peripheral blood/marrow
• Duration: average 3-6 years without treatment
• >75% of CML in developed world diagnosed in this phase

2. Accelerated Phase (AP)

Note: ELN criteria are used in clinical practice; WHO criteria are rarely used in trials.

3. Blast Phase (Blast Crisis) - BC

• 70% myeloid blast crisis (resembles AML)
• 30% lymphoid blast crisis (usually pre-B cell) - evidence CML originates from a pluripotent stem cell with both myeloid and lymphoid potential
• Blast crisis is triggered by acquisition of additional mutations in transcription factor genes (e.g., RUNX1, GATA2, WT1, TP53)
• Prognosis: median survival 5-7 months in blast crisis

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Morphology

Peripheral Blood:

• Leukocytosis, often exceeding 100,000 cells/μL
• Full granulocytic spectrum: neutrophils, band forms, metamyelocytes, myelocytes
• Eosinophilia and basophilia (characteristic)
• Blasts usually < 10% in chronic phase
• Thrombocytosis (sometimes marked)
• Low Leukocyte Alkaline Phosphatase (LAP) score - key differentiator from leukaemoid reaction

Bone Marrow:

• Markedly hypercellular - massively increased maturing granulocytic precursors
• Increased megakaryocytes (small, dysplastic forms)
• Sea-blue histiocytes (scattered macrophages with wrinkled green-blue cytoplasm) - characteristic
• Increased reticulin; overt fibrosis rare in chronic phase

Spleen:

• Greatly enlarged due to extensive extramedullary haematopoiesis
• Contains infarcts of varying age
• Mild hepatomegaly and lymphadenopathy also possible

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Clinical Features

Onset: insidious

• Fatigue, weakness, weight loss, anorexia (hypermetabolic state)
• Dragging sensation in the left upper abdomen from massive splenomegaly
• Acute left upper quadrant pain from splenic infarction
• Mild-to-moderate anaemia
• Symptoms of hyperviscosity at very high WBC counts
• ~25-50% diagnosed incidentally on routine FBC

Hepatosplenomegaly:

• Splenomegaly is the most prominent finding on examination
• Can be massive - extending to the pelvis in advanced disease

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Diagnosis

Step 1 - FBC + Peripheral Blood Film

• Leukocytosis with left shift (entire granulocytic series)
• Basophilia + eosinophilia
• Low/absent LAP score

Step 2 - Confirm BCR-ABL1

Step 3 - Bone Marrow Biopsy

• Confirms phase, assesses fibrosis
• Cytogenetics for clonal evolution
• Not always required for diagnosis in classical CML

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TKI Therapy - The Revolution

FDA-approved BCR-ABL1 TKIs:

• Nilotinib: ~30× more potent
• Bosutinib: 30-50× more potent
• Dasatinib: ~300× more potent; also inhibits SRC family kinases

Front-line Response Data (12-month milestones):

TKI Response Milestones (ELN 2020):

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Resistance & T315I Mutation

• Threonine → Isoleucine substitution at position 315 of ABL1
• Confers resistance to imatinib, dasatinib, nilotinib, and bosutinib
• Only ponatinib and asciminib retain activity against T315I
• Asciminib targets the ABL myristoyl pocket (allosteric site) rather than the ATP-binding site - unique mechanism among TKIs

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Treatment-Free Remission (TFR)

• Requires ≥4.5-log reduction in BCR-ABL1 (MR4.5) sustained for ≥2 years
• ~50% of carefully selected patients maintain molecular remission after stopping TKI
• The other ~50% relapse (usually within 6 months) but re-respond to TKI re-initiation
• TFR eliminates lifelong drug costs and toxicities

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Allogeneic SCT

• Was the only curative option pre-TKI era
• Now reserved for TKI failure (multiple TKIs) or blast crisis
• Risks include transplant-related mortality (10-30%), GvHD, infections
• Accelerated phase with TKIs: median survival now 88 months (vs 28 months pre-TKI)
• Blast crisis remains devastating: median survival only 5-7 months

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Sokal and ELTS Scoring - Risk Stratification at Diagnosis

• Age
• Spleen size
• Platelet count
• % blasts at diagnosis

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Key Differentials

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Summary - Key Points

1. CML is caused by t(9;22)(q34;q11) - the Philadelphia chromosome - present in >90% of cases; the rest have cryptic BCR-ABL1 detectable by FISH/PCR
2. The cell of origin is a pluripotent HSC - explains why blast crisis can be myeloid OR lymphoid
3. BCR-ABL1 produces p210 kDa protein in CML (vs p190 in Ph+ ALL)
4. Disease course: chronic → accelerated → blast crisis (the latter carrying very poor prognosis)
5. TKIs (especially imatinib and 2nd-gen TKIs) have transformed CML from a uniformly fatal disease to one with near-normal life expectancy
6. T315I mutation = pan-resistance to 1st/2nd gen TKIs; only ponatinib/asciminib work
7. MRD monitoring by qPCR (BCR-ABL1 on International Scale) drives all treatment decisions
8. Treatment-free remission is now an achievable goal in ~50% of patients with deep molecular response

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Acute Myeloid Leukaemia (AML)

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Definition

• Arrest of myeloid differentiation at an early precursor stage
• Accumulation of non-functional blast cells
• Resultant bone marrow failure (anaemia, thrombocytopenia, neutropenia)

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Epidemiology

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Aetiology & Risk Factors

1. Acquired / Environmental

2. Hereditary / Germline Predisposition

Anticancer drugs are the leading cause of therapy-related AML.

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Pathogenesis

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WHO 2022 Classification

Group 1: AML with Defining Genetic Abnormalities

Group 2: AML, Myelodysplasia-Related (AML-MR)

• Prior MDS or MDS/MPN history, OR
• Complex karyotype, specific chromosomal aberrations, OR
• Mutations in: ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2
• Carries adverse prognosis

Group 3: AML, Defined by Differentiation (NOS)

• AML with minimal differentiation (M0)
• AML without maturation (M1)
• AML with maturation (M2)
• Acute myelomonocytic leukaemia (M4)
• Acute monocytic leukaemia (M5)
• Acute erythroid leukaemia (M6)
• Acute megakaryoblastic leukaemia (M7)
• Acute basophilic leukaemia

Note: The 2022 WHO classification superseded the 2016 version. The older FAB (French-American-British) M0-M7 classification is now largely replaced but still used in some contexts.

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Morphology & Special Features

Auer Rods

• Pathognomonic of AML (never seen in ALL)
• Needle-shaped pink cytoplasmic inclusions = fused lysosomes
• Multiple Auer rods in a single cell = "faggot cells" - hallmark of APL (M3)

Key Morphologic-Genetic Correlations:

Immunophenotype (Flow Cytometry):

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Clinical Features

From Marrow Failure:

• Anaemia - fatigue, dyspnoea, decreased exercise tolerance
• Thrombocytopenia - petechiae, ecchymoses, bleeding from unusual sites, DIC (especially APL)
• Neutropenia - recurrent or life-threatening bacterial/fungal infections; fever is the most common presenting symptom

From Organ Infiltration:

• Gingival hypertrophy - characteristic of monocytic AML (M5) / KMT2A rearrangements
• Leukemia cutis (skin nodules/rash) - most common in monocytic subtypes
• Myeloid sarcoma (chloroma) - extramedullary tumour of myeloid blasts; green colour from myeloperoxidase; associated with t(8;21)
• Hepatosplenomegaly, lymphadenopathy (less prominent than in ALL)
• CNS involvement - headache, visual changes, cranial nerve palsies (rare in AML vs ALL)
• Back pain + lower extremity weakness - spinal granulocytic sarcoma; associated with t(8;21)
• DIC - characteristic of APL; ecchymoses, oozing from IV sites

Hyperleukocytosis (WBC > 100,000/μL):

• Occurs in ~5-10% of AML
• Leukostasis: slugging of blasts in capillaries → respiratory failure, stroke, priapism
• Medical emergency - requires emergent leukapheresis

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Diagnosis

Initial Workup:

1. CBC with differential - anaemia, thrombocytopenia, leukocytosis (or leukopenia); blasts on smear
2. Bone marrow aspirate + biopsy (essential):
   • Morphology (Auer rods, blast %)
   • Flow cytometry (immunophenotype)
   • Cytogenetics (karyotype) - standard
   • FISH - specific translocations
   • Molecular studies (NGS panel): NPM1, FLT3, IDH1/2, CEBPA, TP53, ASXL1, DNMT3A, etc.
3. Chemistry panel: LDH, uric acid (tumour lysis risk), electrolytes, renal/hepatic function, DIC screen (PT, aPTT, fibrinogen, d-dimer)
4. Cardiac function: echocardiogram or MUGA scan (before anthracyclines)
5. HLA typing: for potential allogeneic SCT
6. Viral serologies: CMV, HSV, VZV (reactivation risk)

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ELN 2022 Risk Stratification (Crucial for Treatment Decisions)

Favourable Risk:

• t(8;21)/RUNX1::RUNX1T1
• inv(16) or t(16;16)/CBFB::MYH11
• Mutated NPM1 without FLT3-ITD
• bZIP in-frame mutated CEBPA

Intermediate Risk:

• Mutated NPM1 with FLT3-ITD
• Wild-type NPM1 with FLT3-ITD (no adverse lesions)
• t(9;11)/MLLT3::KMT2A
• Other cytogenetic/molecular abnormalities

Adverse Risk:

• t(6;9)/DEK::NUP214
• t(v;11)/KMT2A-rearranged (most partners)
• t(9;22)/BCR::ABL1
• inv(3) or t(3;3)/GATA2,MECOM(EVI1)
• -5 or del(5q); -7; -17/abnl(17p)
• Complex karyotype (≥3 abnormalities)
• Monosomal karyotype (≥2 monosomies or 1 monosomy + structural abnormality)
• Wild-type NPM1 + FLT3-ITD high
• Mutated RUNX1, ASXL1, TP53

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Treatment

Overall Framework:

• Patient age and fitness
• ELN genetic risk category
• Availability of targeted agents

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Induction Chemotherapy

Standard-intensity ("7+3 regimen") - for fit patients:

• Cytarabine 100-200 mg/m² continuous IV infusion × 7 days
• Anthracycline (daunorubicin 60-90 mg/m² or idarubicin 12 mg/m²) × days 1, 2, 3
• CR rate: 60-80% in younger patients; lower in older/unfit

• Cytarabine: S-phase specific antimetabolite → inhibits DNA synthesis (phosphorylated to ara-CTP intracellularly)
• Anthracyclines: DNA intercalators → topoisomerase II inhibition → DNA strand breaks

• Gemtuzumab ozogamicin (anti-CD33 ADC) added in CBF-AML and CD33+ AML
• Midostaurin added for FLT3-mutated AML (first FDA approval in AML with a targeted agent)
• Gilteritinib (FLT3 inhibitor) for relapsed/refractory FLT3-mutated AML

Low-intensity regimens - for older/unfit patients:

• Venetoclax + azacitidine (or decitabine) - now standard of care for unfit elderly patients
  • Venetoclax = BCL-2 inhibitor → overcomes apoptosis resistance
  • CR rates ~65-70% in previously untreated elderly patients
• IDH1 inhibitor (ivosidenib) ± azacitidine - for IDH1-mutated AML
• IDH2 inhibitor (enasidenib) - for IDH2-mutated AML
• Low-dose cytarabine (LDAC) ± glasdegib

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Post-remission / Consolidation

• Key toxicity: cerebellar toxicity (ataxia, dysarthria) - monitor carefully

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Acute Promyelocytic Leukaemia (APL) - Special Case

• ATRA (all-trans retinoic acid) + ATO (arsenic trioxide) = standard of care for low-risk APL
  • ATRA: 45 mg/m²/day orally → induces differentiation of leukemic promyelocytes
  • ATO: 0.15 mg/kg/day IV
  • CR approaches 100%; long-term survival >90%
• High-risk APL (WBC >10,000/μL): add cytoreductive chemotherapy immediately due to risk of APL syndrome and DIC

• Occurs within first 3 weeks of ATRA/ATO therapy
• Features: fever, fluid retention, dyspnoea, chest pain, pulmonary infiltrates, pleural/pericardial effusions, hypoxaemia
• Mechanism: adhesion of differentiated neoplastic cells to pulmonary vasculature
• Treatment: dexamethasone ± cytoreduction; temporarily stop ATRA if severe
• Mortality: ~10% if unrecognised

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Targeted Agents in AML (Summary)

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Allogeneic SCT in AML

• Gold standard for adverse-risk AML in first CR
• Only potentially curative approach for many high-risk patients
• Requires HLA-matched sibling or unrelated donor (or haploidentical if no match)
• Main benefit: Graft-vs-Leukaemia (GvL) effect in addition to high-dose conditioning
• Main risks: transplant-related mortality, graft-vs-host disease (GvHD), infections
• Decision guided by ELN risk + MRD status after induction

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MRD (Minimal Residual Disease) Monitoring

• Flow cytometry MRD (leukemia-associated immunophenotype)
• Molecular MRD (NPM1, RUNX1-RUNX1T1, CBFB-MYH11 by PCR)
• MRD negativity after first consolidation = strong predictor of long-term remission
• MRD persistence → escalate therapy / proceed to SCT

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Prognosis

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Key Points Summary

1. AML is diagnosed by ≥20% blasts in marrow/blood (except APL, t(8;21), inv(16) - diagnosed by genetics)
2. Auer rods are pathognomonic of AML; faggot cells (multiple Auer rods) = APL
3. The two-hit model: Class I mutations (FLT3, RAS) drive proliferation; Class II mutations (NPM1, RUNX1 fusions) block differentiation
4. APL is a haematological emergency - DIC is the key early threat; ATRA + ATO achieves ~100% CR and >90% long-term survival
5. FLT3-ITD (~30%) = most common adverse mutation; NPM1 (~30%) = most common favourable mutation
6. Treatment: 7+3 induction → HiDAC consolidation for fit patients; venetoclax + azacitidine for unfit elderly patients
7. ELN risk stratification determines whether allogeneic SCT is needed in first CR
8. Targeted therapies (midostaurin, gilteritinib, ivosidenib, venetoclax) have significantly improved outcomes across AML subtypes

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