Acute and Chronic Leukaemias – A Clinical and Pathophysiological Guide 🩸

 Leukaemia refers to a group of blood cancers arising from abnormal proliferation of white blood cell precursors. The problem begins in the bone marrow, where mutations in haematopoietic stem or progenitor cells allow one clone to escape normal checks on growth and differentiation.

While the term leukaemia may sound singular, it actually encompasses a group of distinct diseases, each with its own biological behaviour, clinical features, and management principles. Chronic and acute leukemias are completely different diseases, and they progress at different speeds.

Over time — sometimes over days, sometimes years — these abnormal cells crowd out normal blood production, leading to anaemia, immunosuppression, and bleeding. Clinical presentations vary depending on which blood line is affected and how fast the disease progresses.

Classifying the chaos

Leukaemias are broadly classified based on:

Disease tempo:

• Acute: rapid accumulation of undifferentiated blast cells
• Chronic: slow build-up of more mature (but still abnormal) cells.

Cell lineage:

• Lymphoid: Derived from lymphoid precursors ( precursors to B, T, or NK cells)
• Myeloid: Derived from granulocyte/monocyte precursors (precursors to neutrophils, monocytes, erythrocytes, megakaryocytes)

This classification gives us the four major types (I am not covering everything in this blog, just the big ones !):

• Acute Lymphoblastic Leukaemia (ALL)
• Acute Myeloid Leukaemia (AML)
• Chronic Lymphocytic Leukaemia (CLL)
• Chronic Myeloid Leukaemia (CML)

Pathophysiology overview: How it all goes wrong

All leukaemias arise from genetic mutations in haematopoietic stem or progenitor cells, which lead to:

• Clonal proliferation of a single dysfunctional cell line
• Failure of normal haematopoiesis due to marrow overcrowding
• Impaired immune and coagulation function

Acute leukaemias 

In both AML and ALL, mutations arrest differentiation at the blast stage. These immature cells divide uncontrollably, fail to mature, and suppress normal bone marrow function. Acute leukaemias are typified by an accumulation of immature precursor cells (blasts) in the bone marrow, leading to marrow failure. These patients can present acutely unwell with pancytopenia or hyperleukocytosis complications.

In AML, myeloid progenitors (normally destined to become granulocytes, monocytes, erythrocytes, or platelets) become stuck in an immature state. 

• Genetic hits (e.g. FLT3-ITD, NPM1 mutations, t(15;17) in APL) arrest differentiation at the blast stage.
• Accumulation of >20% blasts in bone marrow.
• This leads to neutropaenia (infections), anaemia (fatigue) and thrombocytopaenia (bruising/bleeding)

In ALL, lymphoid precursors (mostly B-cells in children, T-cells in adolescents) are affected.

• Genetic events (e.g. t(12;21), hyperdiploidy, or t(9;22) in adult ALL) lead to uncontrolled proliferation of lymphoblasts.
• Blasts may infiltrate lymph nodes, CNS or mediastinum (especially in T-ALL)
• CNS involvement is common – headaches, cranial nerve palsies

Key microscopic features

1. Blasts (AML & ALL) 🔬

Definition: 

Large, immature cells with high nuclear-to-cytoplasmic ratio, prominent nucleoli, and open (euchromatic) chromatin.

Seen in: 

Acute leukaemias (AML & ALL).

Hallmarks:

• AML blasts → Myeloblasts may show cytoplasmic granules & specific inclusions like Auer rods.
• ALL blasts → Lymphoblasts are smaller, lack granules, and express TdT positivity.

Clinical relevance: 

High blast count (>20%) in marrow confirms acute leukaemia. 

Normal blood film (Left) and acute leukaemia (right) with predominance of blast cells

2. Auer rods (AML, particularly APL) 

Definition: 

Needle-like, reddish-staining cytoplasmic inclusions made of fused lysosomal granules.

Seen in: 

AML, especially Acute Promyelocytic Leukaemia (APL, t(15;17)).

Hallmarks:

• Found within myeloblasts and promyelocytes.
• Often abundant in APL and associated with high bleeding risk (DIC).

Clinical relevance: 

Presence of Auer rods supports AML or APL diagnosis and suggests differentiation into myeloid lineage. 

The presence or absence of Auer rods in residual blasts after treatment can be used to assess remission. 

3. Hyperleukocytosis & leucostasis features 🚨

Definition: 

Marked elevation in white cell count (often >100,000/µL), causing blood viscosity issues.

Seen in: 

Acute leukaemias with blast excess, particularly AML & ALL.

Hallmarks:

• Circulating blasts obstruct microvasculature, leading to organ damage.
• May cause dyspnoea, stroke-like symptoms, and retinal vessel abnormalities.

Peripheral blood with red cells far outnumbered by immature blasts

Clinical presentation

• Rapid onset over days to weeks

• Symptoms reflect bone marrow failure:
• Anaemia → fatigue, pallor, dyspnoea
• Neutropenia → infections (often bacterial/fungal) persistent, recurrent or severe
• Thrombocytopenia → petechiae, mucosal bleeding, easy bruising

• Organ infiltration: hepatosplenomegaly, lymphadenopathy (especially in ALL), CNS involvement (more common in T-cell ALL)

• Hyperleukocytosis/leucostasis: with very high levels of circulating WBS (and abnormal malignant ones that are more rigid), hyperviscosity and impaired blood flow can occur. Patients can present in organ failure, respiratory failure, stroke or DIC. Additionally tumour lysis syndrome can occur where the rapid destruction of leukaemic cells can increase uric acid in the bloodstream leading to acute kidney injury.

• In ALL, CNS or testicular involvement may be present at diagnosis. In AML, gingival hypertrophy and skin infiltration are sometimes seen (especially in monocytic subtypes).

Disease Course:

• Acute leukaemia without treatment is rapidly fatal (weeks)
• Requires urgent diagnosis and therapy: induction chemotherapy ± CNS prophylaxis (ALL), targeted agents (e.g. ATRA in APL), stem cell transplant in high-risk cases

Chronic Leukaemias 

CLL is a malignancy of mature B cells that have lost their ability to undergo apoptosis. They accumulate in blood, bone marrow, and lymph nodes, and produce inadequate antibodies. T-cell dysfunction may also develop. Malignancy of mature but functionally incompetent B lymphocytes.

• Accumulate due to defective apoptosis (e.g. overexpression of BCL2).
• Immunosuppression results from hypogammaglobulinaemia and dysfunctional T cell interactions.
• Hypogammaglobulinaemia → recurrent infections
• Autoimmune haemolytic anaemia or ITP (in ~20%)

CML: CML results from the Philadelphia chromosome [t(9;22)], creating the BCR-ABL fusion gene.

• This leads to constitutive tyrosine kinase activity and uncontrolled myeloid proliferation.
• Though the white cells look mature, they behave abnormally and dominate the marrow.

Key microscopic features 

Smudge Cells (CLL) 🩸

Definition: 

Fragile lymphocytes that rupture during slide preparation, leaving behind smudged nuclear material.

Seen in: 

Chronic Lymphocytic Leukaemia (CLL).

Hallmarks:

• Appears as faint, ghost-like remnants of lymphocytes.
• Often found alongside small, mature lymphocytes in CLL.

Clinical relevance: 

Smudge cells are characteristic of CLL (as the malignant lymphocytes are abnormally fragile and break during preparation) but they can be found in other malignancies and viral illnesses. 

In CLL, the presence and number of smudge cells can be used as a prognostic indicator,  with a higher percentage of smudge cells generally indicating a more favourable prognosis. This fragility is linked to a reduced expression of vimentin, a protein that provides structural support to the cell. Smudge cell percentage is correlated with other prognostic factors in CLL, such as mutated IgVH gene status, suggesting that they may be indicative of a less aggressive form of the disease. 

Clinical presentation

Insidious onset; Often asymptomatic and found incidentally on routine FBC.

When symptoms do occur:

CLL:

• Most common adult leukaemia 
• Painless lymphadenopathy, splenomegaly
• May have B symptoms (weight loss, night sweats, fever) 
• May present with recurrent respiratory infections (due to hypogammaglobulinaemia), autoimmune cytopenias (e.g. ITP)
• Can progress to high-grade lymphoma (Richter’s transformation)

CML:

• Early: asymptomatic or vague fatigue, night sweats
• May have early satiety due to splenomegaly
• Accelerated phase can lead to blast crisis (resembles acute myeloid leukaemia)
• Diagnosis confirmed by BCR-ABL PCR

Disease Course:

CLL: many are managed with "watch and wait"; therapy indicated for symptomatic disease or progression (e.g. rising lymphocyte count, cytopenias)

CML: chronic phase may now last years with TKI therapy; blast crisis has poor prognosis without transplant

Epidemiology

Leukaemia Type	Peak Age	Key Risk Factors	Notes
ALL	Bimodal: most common in children <5 yrs and a second peak in elderly	Radiation, genetic syndromes (e.g. Down syndrome), prior chemo	Most common childhood cancer
AML	Older adults (median ~65 yrs)	Benzene exposure, myelodysplastic syndromes, chemo (alkylating agents)	APL subtype (t(15;17)) is highly treatable with ATRA
CML	Middle-aged adults (45–60 yrs)	Radiation, unknown in many	Incidence ~1–2 per 100,000/year
CLL	Elderly (median ~70 yrs)	Family history, male sex, Western populations	Most common adult leukaemia in Australia

Diagnosis and Investigations

Investigation	Key Finding
FBC + film	Anaemia, thrombocytopenia, elevated/low WCC, blasts or smudge cells
Bone marrow biopsy	essential for definitive diagnosis, especially in acute leukaemias ≥20% blasts (AML/ALL)
Flow cytometry	Immunophenotype and maturity of abnormal cells for classification
Cytogenetics	Philadelphia chromosome (CML), t(15;17) in APL, etc.
Lumbar puncture	ALL – CNS involvement
LDH, urate	Often elevated (high cell turnover)
Coags	DIC in acute leukaemias
CXR	If mediastinal involvement suspected

Therapeutic Approaches

Acute leukaemias: Induction chemotherapy, sometimes stem cell transplant. Targeted therapies are emerging (e.g. venetoclax in AML, blinatumomab in ALL).

CML: Tyrosine kinase inhibior therapy has transformed prognosis; many patients achieve deep molecular remission.

 CLL: Often monitored ('watch and wait'). Treatment includes monoclonal antibodies (e.g. rituximab), BCL2 inhibitors (venetoclax), and BTK inhibitors (ibrutinib).

Type	First-Line Therapy	Targeted/Novel Therapies	Notes
ALL	Multi-agent chemo + CNS prophylaxis	Blinatumomab (BiTE), CAR-T	CNS involvement common
AML	Induction chemo ± consolidation	Venetoclax, FLT3 inhibitors, IDH1/2 inhibitors	APL: ATRA + arsenic
CML	Imatinib (TKI)	Dasatinib, nilotinib, ponatinib	Monitor BCR-ABL PCR
CLL	Observation or anti-CD20 ± BTK inhibitors	Ibrutinib, venetoclax	Transforms to Richter’s in ~5–10%

Why Staging Doesn’t Apply (Mostly)

Unlike solid organ cancers, leukaemias are by definition disseminated at diagnosis — they're not confined to a single location. 

Instead of TNM staging, we assess cytogenetic and molecular risk scores 

Blast percentage (e.g. >20% = acute leukaemia)

• Cytogenetic risk
• Response to therapy (e.g. minimal residual disease)

CLL is the exception: it is staged by the Rai (US) or Binet (Europe) systems, based on lymphadenopathy and cytopenias.

Prognostic Markers & Risk Stratification for acute leukaemias 🩸

Cytogenetic and molecular markers play a crucial role in leukaemia prognosis, influencing treatment decisions and survival outcomes:

AML:

• Favorable: NPM1 mutation (if FLT3-wildtype), inv(16), t(8;21)
• Poor prognosis: FLT3-ITD mutation, TP53 mutations, complex karyotype

ALL:

• High risk: Philadelphia chromosome (BCR-ABL, t(9;22))—traditionally poor prognosis but targeted therapy (TKIs) has improved outcomes
• Good prognosis: Hyperdiploidy, t(12;21) (ETV6-RUNX1)

Minimal Residual Disease (MRD) Monitoring

MRD refers to the small number of cancer cells that remain in the body after treatment, even when a patient is in clinical remission (i.e. no detectable disease on routine tests). These residual malignant cells can later lead to relapse, making MRD monitoring a crucial tool for refining treatment strategies.

MRD status plays a critical role in long-term prognosis, particularly in ALL and increasingly in AML. Sensitive techniques like multiparameter flow cytometry and PCR-based assays detect lingering leukaemic cells far beyond the capabilities of standard microscopy, guiding therapy intensification or transplant decisions.

• MRD-negative status post-induction is a strong predictor of improved survival and lower relapse risk.
• Routine MRD monitoring influences treatment decisions—determining whether patients require further consolidation therapy, stem cell transplant, or maintenance treatment
• MRD is now integrated into clinical trial endpoints, with emerging therapies specifically targeting MRD positivity to deepen remissions.
• In AML, MRD techniques are increasingly used post-therapy to predict relapse risk, guiding decisions on post-remission strategies such as allogeneic stem cell transplant in high-risk cases.

Emerging Treatments 

Leukaemia therapy is rapidly evolving, with precision medicine leading the charge:

• CAR-T therapy: Transformative in relapsed/refractory ALL, now being explored in CLL

AML novel therapies:

• Magrolimab (anti-CD47) for TP53-mutated AML
• Bispecific antibodies (e.g., glofitamab) targeting dual antigens in refractory disease

CLL newer agents:

• Venetoclax + obinutuzumab (chemo-free frontline option)
• BTK inhibitors evolving (next-gen: pirtobrutinib for resistance mutations)

Treatment-Related Complications 🚨

Leukaemia therapy can lead to significant complications, both from the disease itself and from the treatments used. Key risks include:

• Tumour lysis syndrome (TLS): A medical emergency caused by the rapid breakdown of malignant cells, releasing intracellular contents (potassium, phosphate, uric acid). Can lead to acute kidney injury, metabolic acidosis, cardiac arrhythmias, and seizures. Prevention strategies include allopurinol, rasburicase, aggressive hydration, and close monitoring in high-risk cases.

• Febrile neutropenia: Profound immunosuppression increases bacterial/fungal infection risk, often requiring broad-spectrum antibiotics and granulocyte colony-stimulating factor (G-CSF).

• Graft vs host disease (GVHD) post-transplant: Allogeneic stem cell transplant recipients must be monitored for GVHD, where donor immune cells attack host tissues. Acute GVHD typically affects skin, gut, and liver.

• Therapy-related myeloid neoplasms (t-MDS/t-AML): Secondary malignancies arising after chemotherapy or radiotherapy, often associated with prior exposure to alkylating agents (e.g. cyclophosphamide) or topoisomerase inhibitors (e.g. etoposide). 
•  t-MDS: Characterized by persistent cytopenias and dysplastic marrow, often progressing to AML.
• t-AML: Typically presents with complex karyotype (e.g. TP53 mutations, chromosome 5/7 abnormalities) and carries a poorer prognosis than de novo AML.
• Treatment is challenging, often requiring intensive chemotherapy or stem cell transplant.

Clinical cases

🩸 Case 1: 

A 64-year-old man presents to the emergency department with a 2-week history of profound fatigue, easy bruising, and fevers. His family report that he has become noticeably pale and short of breath with minimal exertion. Over the past few days, he has developed nosebleeds and gum bleeding. He recently completed chemotherapy for non-Hodgkin lymphoma two years ago.

On examination:

• Pale, with scattered petechiae and ecchymoses on his limbs
• Mild gingival hypertrophy
• Febrile (38.5°C)

Investigations:

• Hb: 72 g/L
• WBC: 85 × 10⁹/L
• Platelets: 18 × 10⁹/L
• Blood film: blasts with Auer rods
• Bone marrow biopsy: >30% myeloblasts
• Cytogenetics: FLT3-ITD mutation positive

Discussion Prompts:

• What clinical features here point toward bone marrow failure?
• What is the likely cause of the high WBC, and why is it dangerous?
• Why might his prior chemotherapy be relevant?
• What are Auer rods, and what do they signify?
• What is the role of FLT3 mutation testing in AML management?

Learning Point:

Acute Myeloid Leukaemia (AML) - This is a typical presentation of AML: pancytopenia due to marrow infiltration, hyperleukocytosis with risk of leucostasis, and a possible antecedent haematological malignancy or chemo exposure. FLT3 mutations confer a poor prognosis but are now actionable targets.

🩸Case 2: 

A 72-year-old woman is referred by her GP for evaluation of persistent lymphocytosis noted on routine blood tests. She feels well but reports mild fatigue and has noticed some swelling in her neck and under her arms. She has not had any infections, night sweats, or weight loss.

On examination:

• No pallor or petechiae
• Non-tender cervical and axillary lymphadenopathy
• Mild splenomegaly

Investigations:

• Hb: 112 g/L
• WBC: 58 × 10⁹/L (with lymphocytes 48 × 10⁹/L)
• Platelets: 145 × 10⁹/L
• Blood film: numerous small mature-appearing lymphocytes, some smudge cells
• Flow cytometry: CD19+, CD5+, CD23+, kappa-restricted B cells
• Immunoglobulins: low IgG and IgA
• FISH: 13q deletion only

Discussion Prompts:

• What are the typical blood film features of CLL?
• What do the immunophenotype markers confirm?
• Why is the immunoglobulin profile clinically important?
• What would indicate the need for treatment in this patient?
• What prognostic information does the 13q deletion provide?

Learning Point:

Chronic Lymphocytic Leukaemia (CLL) - This case illustrates the classic presentation of CLL: asymptomatic lymphocytosis, discovered incidentally, with characteristic flow cytometry and film findings. Most early-stage CLL is observed without treatment, but immunosuppression and disease progression are key monitoring issues.

🩸Case 3: 

A 6-year-old boy is brought to his GP by his mother because of increasing fatigue, low-grade fevers, and several episodes of spontaneous nosebleeds over the past two weeks. He has also complained of leg pain, especially at night, and has missed school due to lethargy. His appetite has decreased and he has lost 2 kg over the last month.

On examination:

• Pale and mildly febrile (38.2°C)
• Cervical and inguinal lymphadenopathy
• Hepatosplenomegaly
• Multiple petechiae on his lower limbs

Investigations:

• Hb: 78 g/L
• WBC: 34 × 10⁹/L
• Platelets: 22 × 10⁹/L
• Blood film: lymphoblasts
• Bone marrow aspirate: 80% lymphoblasts
• Flow cytometry: CD10+, CD19+, TdT+ (B-cell lineage)
• CSF: No blast cells detected
• Cytogenetics: t(12;21) ETV6-RUNX1 fusion

Discussion Prompts:

• What features suggest ALL rather than AML in this child?
• Why is CNS evaluation important at diagnosis?
• What is the significance of the ETV6-RUNX1 fusion gene?
• What would the induction phase of treatment typically include?
• What complications should be anticipated during therapy?

Learning Point:

Acute Lymphoblastic Leukaemia (ALL) - ALL is the most common cancer in children. Bone pain, pancytopenia, and lymphadenopathy are common presenting features. CNS involvement is a key concern in ALL, requiring CSF analysis and prophylaxis. This subtype (t(12;21)) is associated with good prognosis.

🩸Case 4: 

A 48-year-old man presents for evaluation of fatigue, early satiety, and night sweats. He mentions that his trousers have become tight at the waist and he's noticed fullness in the left upper quadrant. He works as a school principal and has no significant medical history.

On examination:

• Mild pallor
• Massive splenomegaly (extends 10 cm below costal margin)
• No lymphadenopathy

Investigations:

• Hb: 110 g/L
• WBC: 160 × 10⁹/L
• Platelets: 580 × 10⁹/L
• Blood film: left shift (promyelocytes, myelocytes, basophilia, eosinophilia), few blasts
• Bone marrow: hypercellular with granulocytic hyperplasia
• Cytogenetics: t(9;22) BCR-ABL fusion gene positive
• BCR-ABL PCR: high transcript levels

Discussion Prompts:

• What features distinguish this from a reactive leukocytosis?
• What does the presence of basophils suggest?
• Why is the BCR-ABL PCR result important for diagnosis and monitoring?
• What is the first-line treatment, and how is response measured?
• What is the natural history of untreated CML?

Learning Point:

Chronic Myeloid Leukaemia (CML) - CML often presents in the chronic phase, where patients may be asymptomatic or show constitutional symptoms and splenomegaly. The hallmark is the Philadelphia chromosome (BCR-ABL fusion). Tyrosine kinase inhibitors (TKIs) are the mainstay of treatment and have transformed prognosis.

In summary

Think of leukaemia as a failure of bone marrow balance: too many abnormal cells, not enough normal ones. All forms arise from clonal proliferation of haematopoietic cells, with mutations disrupting differentiation and apoptosis.

Understand the cell of origin, speed of progression, and clinical context to distinguish between types. 

Acute and chronic leukaemias differ in tempo, cell maturity, clinical presentation, and urgency of treatment. Remember acute leukaemias are haematological emergencies; chronic leukaemias often follow a slower, more nuanced course.

Diagnostic tools like flow cytometry and cytogenetics are central to modern diagnosis and targeted therapy. 

Advances in cytogenetics and targeted therapies (e.g. TKIs, BCL2 inhibitors, CAR-T cells) are improving prognosis.

Understanding the underlying cell line, clinical trajectory, and genetic drivers is essential for diagnosis and treatment.

Final point

And THIS is why knowing the cell lines of haemopoiesis are so important. Just wait until we get to lymphoma!