After reading this note you will be able to describe the clinical approach to leukaemia, recognise key signs, interpret the essential investigations and outline immediate and definitive management – remembering to verify drug doses and local protocols against the Kenya MoH guideline and your hospital formulary.
Definition
Leukaemia is a malignant clonal proliferation of hematopoietic stem cells resulting in uncontrolled growth of immature white blood cells (blasts) in the bone marrow, peripheral blood and often extramedullary sites. It is classified by lineage (myeloid vs lymphoid) and by speed of onset (acute vs chronic).
Anatomy and physiology you need
| Structure | Relevance to leukaemia |
|---|---|
| Bone marrow | Site of hematopoiesis; blasts replace normal progenitors → cytopenias |
| Spleen & liver | Common sites of extramedullary infiltration → hepatosplenomegaly |
| Lymph nodes | Primary organ for lymphoid leukaemias; may be enlarged |
| Thymus | T‑cell development; involved in T‑ALL |
| Peripheral blood | Vehicle for circulating blasts; basis for smear diagnosis |
| CNS (meninges) | Sanctuary site; risk of leukemic meningitis, especially ALL |
Causes and risk factors
Environmental & infectious exposures common in Kenya
- HIV infection – chronic immune activation, opportunistic viruses (EBV, HHV‑8) increase risk of lymphoid leukaemias.
- Tuberculosis – prolonged immune stimulation; rare direct leukemogenic effect but co‑infection complicates management.
- Malaria (Plasmodium falciparum) – chronic hemolysis and marrow stress may predispose to myelodysplastic changes.
- Chronic inflammation (rheumatic diseases) – cytokine milieu can promote clonal evolution.
- Sickle cell disease – repeated marrow infarction and chronic hemolysis increase risk of acute leukaemia, especially AML.
- Occupational exposures – benzene (e.g., in fuel stations), pesticides, radiation (radiotherapy, diagnostic X‑rays).
- Genetic syndromes – Down syndrome (ALL), Fanconi anemia, Li‑Fraumeni.
- Family history – rare inherited predisposition genes (e.g., CEBPA, RUNX1).
Pathophysiology
- Genetic hit (chromosomal translocation, mutation) →
- Clonal expansion of a hematopoietic stem/progenitor cell →
- Block in differentiation → accumulation of blasts in marrow →
- Marrow failure → anemia, neutropenia, thrombocytopenia →
- Peripheral spill of blasts → leukocytosis or leukopenia, organ infiltration →
- Cytokine release → fever, weight loss, night sweats →
- Immune evasion (PD‑L1 up‑regulation, loss of HLA) → disease progression.
Clinical features
History – key questions
| Domain | Questions | Rationale |
|---|---|---|
| General | Fever, night sweats, weight loss, fatigue, loss of appetite | Cytokine‑mediated “B‑symptoms” and marrow failure produce constitutional complaints. |
| Bleeding / bruising | Easy bruising, petechiae, gum bleeding, menorrhagia, epistaxis, prolonged bleeding after minor cuts | Thrombocytopenia from marrow infiltration or peripheral consumption. |
| Infections | Recurrent or severe infections, recent opportunistic infections (e.g., oral thrush, TB, pneumocystis), history of HIV or immunosuppression | Neutropenia and functional defects of leukocytes predispose to infections. |
| Bone‑pain / skeletal | Deep bone pain (especially long bones, pelvis, ribs), back pain | Marrow expansion and leukemic infiltration of bone. |
| Lymphadenopathy / organomegaly | Swollen neck, axillae, groin nodes; abdominal fullness, early satiety, early fullness after meals | Extramedullary disease – common in acute lymphoblastic leukaemia (ALL) and chronic lymphocytic leukaemia (CLL). |
| Constitutional in children | Failure to thrive, irritability, pallor, recurrent infections | Paediatric leukaemias often present with nonspecific growth failure. |
| Past medical / exposures | Prior chemotherapy/radiation, known genetic syndromes (Down, Fanconi), exposure to benzene, pesticides, chronic infections (HIV, TB, malaria), sickle‑cell disease | Identifies known risk factors prevalent in Kenya. |
| Medications / supplements | Use of herbal remedies, antiretrovirals, antimalarials | Some agents can cause marrow suppression or interact with chemotherapy. |
| Family history | Relatives with haematologic malignancies or inherited bone‑marrow failure syndromes | Hereditary predisposition. |
Examination – findings and why they occur
| Finding | Pathophysiologic explanation |
|---|---|
| Pallor (conjunctival, mucosal) | Anaemia from marrow replacement or haemolysis. |
| Petechiae / purpura | Platelet count <20 × 10⁹/L or platelet dysfunction. |
| Bleeding gums, epistaxis | Thrombocytopenia + mucosal fragility. |
| Hepatosplenomegaly | Extramedullary haematopoiesis and leukemic infiltration. |
| Lymphadenopathy (non‑tender, firm) | Infiltration of nodal tissue, especially in ALL and CLL. |
| Bone tenderness / joint pain | Marrow expansion causing periosteal irritation. |
Note: In chronic myeloid leukaemia (CML) splenomegaly is often massive, whereas in acute leukaemias it may be modest.
Differential diagnosis
| Condition | Points toward it | Distinguishing features |
|---|---|---|
| Acute lymphoblastic leukaemia (ALL) | Young age, bone pain, lymphadenopathy, high lymphoblasts | Predominant lymphoblasts on smear; TdT⁺ on immunophenotyping |
| Acute myeloid leukaemia (AML) | Adult, myeloblasts, Auer rods, prior MDS | Myeloperoxidase‑positive blasts; cytogenetics (e.g., t(8;21)) |
| Chronic lymphocytic leukaemia (CLL) | Older adults, lymphocytosis, smudge cells | CD5⁺ CD20⁺ B‑cell phenotype, hypogammaglobulinaemia |
| Chronic myeloid leukaemia (CML) | Marked leukocytosis with left shift, massive splenomegaly | BCR‑ABL1 fusion (Philadelphia chromosome) |
| Myelodysplastic syndrome (MDS) | Cytopenias, dysplastic cells, older age, prior chemo | Dysplasia in ≥10 % of one or more lineages, no ≥20 % blasts |
| Severe aplastic anaemia | Pancytopenia, no blasts, hypocellular marrow | Normal peripheral smear aside from low counts, absent clonal markers |
| Infectious marrow suppression (e.g., malaria, HIV) | Recent infection, endemic exposure, reversible cytopenias | Resolution with treatment of infection, lack of clonal blasts |
| Hemophagocytic lymphohistiocytosis (HLH) | Fever, splenomegaly, cytopenias, high ferritin | Elevated triglycerides, NK‑cell dysfunction, HLH‑2004 criteria |
Investigations
| Test | What it answers | Interpretation |
|---|---|---|
| Full blood count with differential | Presence of anaemia, neutropenia, thrombocytopenia, leukocytosis or blasts | Blast % ≥20 % → acute leukaemia; marked leukocytosis with left shift → CML |
| Peripheral smear (Wright‑Giemsa) | Morphology of cells, presence of blasts, Auer rods, smudge cells | Myeloblasts with Auer rods → AML; lymphoblasts → ALL |
| Bone‑marrow aspirate & trephine | Cellular composition, blast count, dysplasia, fibrosis | ≥20 % blasts → acute leukaemia; cytogenetics & molecular studies performed on marrow |
| Flow cytometry (immunophenotyping) | Lineage (myeloid vs lymphoid) and maturation stage | CD34⁺ CD117⁺ → AML; CD19⁺ CD10⁺ TdT⁺ → B‑ALL |
| Cytogenetic analysis (karyotype) | Detect chromosomal translocations, aneuploidy | t(9;22) → CML; t(15;17) → APL (a subtype of AML) |
| Molecular PCR / FISH for BCR‑ABL1, PML‑RARA, FLT3, NPM1 | Specific fusion genes or mutations | Positive BCR‑ABL1 → CML; PML‑RARA → APL (requires urgent ATRA) |
| Serum chemistry (U&E, calcium, LDH, uric acid) | Organ function, tumour lysis risk | Elevated LDH/uric acid → high cell turnover; hyper‑kalaemia, renal impairment → tumour lysis |
| Coagulation profile (PT, aPTT, fibrinogen, D‑dimer) | Baseline before chemotherapy; detect DIC | Low fibrinogen + high D‑dimer → DIC, especially in APL |
| Infectious screen (HIV, hepatitis B/C, TB PCR) | Identify co‑existing infections that affect treatment | HIV‑positive → need prophylaxis; TB → modify chemotherapy timing |
| Imaging (Chest X‑ray, abdominal US) | Assess organomegaly, mediastinal mass | Large mediastinal mass → T‑ALL; splenomegaly → CML/CLL |
Diagnosis and severity
Diagnostic criteria (based on WHO classification)
- Acute leukaemia – ≥20 % blasts in marrow or peripheral blood, or presence of defining genetic abnormality (e.g., t(15;17) for APL).
- Chronic leukaemia – Persistent clonal proliferation with characteristic cytogenetics (BCR‑ABL1 for CML; CD5⁺ B‑cell clone for CLL).
Severity grading (used to guide urgency of therapy)
| Parameter | Low‑risk | Intermediate‑risk | High‑risk |
|---|---|---|---|
| Age (ALL) | ≤35 y | 36‑50 y | >50 y |
| White‑cell count at presentation (ALL) | ≤30 × 10⁹/L | 30‑100 × 10⁹/L | >100 × 10⁹/L |
| Cytogenetics (ALL) | Hyperdiploidy, TEL‑AML1 | Normal, other intermediate | t(9;22), MLL‑rearranged |
| Blast % (AML) | ≤30 % | 30‑50 % | >50 % |
| Cytogenetics (AML) | Favorable (t(8;21), inv16) | Intermediate (normal) | Adverse (complex, monosomal) |
| Performance status (all) | ECOG 0‑1 | ECOG 2 | ECOG ≥3 |
| Organ dysfunction (renal, hepatic, cardiac) | None or mild | Moderate | Severe |
Risk stratification informs choice of induction regimen, need for early stem‑cell transplant, and intensity of supportive care.
In the Kenyan setting, special attention is given to HIV status, concomitant TB, and malaria‑related haemolysis, as these can modify both staging and therapeutic choices.
Management
Immediate stabilisation
- Airway‑breath‑circulation – give supplemental O₂ if SpO₂ < 94 %; treat hypotension with crystalloid bolus; consider vasopressor if MAP < 65 mmHg after fluids.
- Tumour lysis syndrome (TLS) prophylaxis – start aggressive IV hydration (target urine output ≥ 80 ml/h); give allopurinol or rasburicase (if high uric acid) before chemotherapy.
- Infection control – obtain blood cultures (aerobic & anaerobic) before antibiotics; start broad‑spectrum IV antibiotics covering Gram‑negatives, Gram‑positives and anaerobes (e.g., a carbapenem plus vancomycin) because neutropenia is common.
- Bleeding risk – transfuse packed red cells if Hb < 8 g/dL (or symptomatic); give platelet concentrates if platelets < 10 × 10⁹/L (or < 20 × 10⁹/L with bleeding).
Definitive treatment
| Leukemia type | Curative intent regimen (class) | Supportive adjuncts |
|---|---|---|
| ALL (children) | Multi‑agent induction (vincristine‑type, steroids, anthracycline, asparaginase) | CNS prophylaxis (intrathecal methotrexate), TLS prophylaxis |
| ALL (adults) | Similar agents, add tyrosine‑kinase inhibitor if Ph‑positive | Same as above |
| AML | “7 + 3” (anthracycline + cytarabine) ± FLT3 inhibitor if mutation | ATRA for M3, TLS prophylaxis |
| CML (chronic) | BCR‑ABL tyrosine‑kinase inhibitor (imatinib, dasatinib) | Monitor for cytopenias |
| CLL (symptomatic) | Chemo‑immunotherapy (fludarabine‑type + anti‑CD20) or BTK inhibitor | Prophylactic antivirals (HSV, VZV) |
- Allogeneic stem‑cell transplant is offered for high‑risk AML, relapsed ALL, or poor‑risk CML after failure of TKIs.
- Targeted agents – ATRA for acute promyelocytic leukemia; arsenic trioxide for same; FLT3 inhibitors for FLT3‑mutated AML; BCR‑ABL TKIs for Ph‑positive ALL/CML.
Monitoring & safety
- Daily CBC, renal panel, uric acid, LDH; adjust hydration/uric acid‑lowering therapy.
- Cardiac monitoring when anthracyclines are used (baseline & periodic ejection fraction).
- Liver function tests for agents metabolised hepatically (e.g., azacitidine, TKIs).
- Neurologic exam for ATRA differentiation syndrome or CNS involvement.
- Infection surveillance: neutrophil count, temperature spikes, fungal markers.
- Transfusion thresholds as above; avoid unnecessary platelet transfusion to reduce allo‑immunisation.
Contra‑indications & safety
- Avoid anthracyclines in severe left‑ventricular dysfunction.
- Do not give allopurinol together with rasburicase.
- TKIs contraindicated in severe hepatic impairment; monitor for QT prolongation.
- ATRA contraindicated in severe coagulopathy without aggressive supportive care.
Complications and prognosis
- Tumour lysis syndrome – acute renal failure, electrolyte disturbances; mitigated by prophylaxis.
- Infection – bacterial, fungal, viral; major cause of early mortality, especially in neutropenic phases.
- Bleeding/DIC – especially in AML M3; treat with supportive blood products and ATRA.
- Differentiation syndrome (ATRA/arsenic) – fever, weight gain, pulmonary infiltrates; treat with steroids and temporary drug hold.
- Secondary malignancies – therapy‑related AML/MDS after alkylating agents or topoisomerase II inhibitors.
- Graft‑versus‑host disease – after allogeneic transplant.
Prognosis varies:
- Pediatric ALL > 90 % cure with modern protocols.
- Adult ALL 30‑50 % long‑term survival; poorer with high‑risk cytogenetics.
- AML 40‑60 % in younger adults; declines sharply > 60 years.
- CML now chronic‑phase survival > 80 % with TKIs; blast crisis remains poor.
High‑yield exam points
- Look‑alikes: Myelodysplastic syndrome, aplastic anemia, severe infection with leukemoid reaction.
- Common wrong first step: Starting chemotherapy before TLS prophylaxis or before ruling out active infection.
- Bedside examiner questions:
- “What explains the patient’s bruising and low platelets?” (marrow infiltration).
- “Why do we give intrathecal methotrexate in ALL?” (CNS sanctuary site).
- “How would you differentiate a leukemoid reaction from CML on peripheral smear?” (presence of basophilia, left‑shift, leukocyte alkaline phosphatase).
- “What is the rationale for using all‑trans retinoic acid in M3 AML?” (induces differentiation, reverses coagulopathy).
Clinical case
Case: A 28‑year‑old male presents with 2 weeks of fatigue, easy bruising, and night sweats. Examination shows pallor, petechiae on lower limbs, splenomegaly 3 cm below costal margin, and mild lymphadenopathy. CBC: Hb 7.8 g/dL, WBC 45 × 10⁹/L (blasts 35 %), platelets 30 × 10⁹/L. Peripheral smear shows Auer rods. Serum uric acid 9 mg/dL, creatinine 1.2 mg/dL.
Questions
- What is the most urgent complication to prevent in this patient?
- Answer: Tumour lysis syndrome – start aggressive IV hydration and uric acid‑lowering therapy before induction chemotherapy.
- Which induction regimen is appropriate for his likely diagnosis?
- Answer: “7 + 3” induction (anthracycline + cytarabine) plus ATRA because of Auer rods suggesting acute promyelocytic leukemia.
- After remission induction, what is the key factor that determines need for allogeneic stem‑cell transplant?
- Answer: High‑risk cytogenetics (e.g., FLT3‑ITD) or failure to achieve molecular remission; these guide transplant referral.
Practice questions
Question 1
A 6‑year‑old girl with newly diagnosed ALL is about to start induction. Which of the following should be given before chemotherapy?
A. Broad‑spectrum antibiotics
B. Intrathecal methotrexate
C. Allopurinol
D. Prophylactic platelet transfusion
Answer: C. Allopurinol – it reduces uric acid production and helps prevent tumour lysis syndrome prior to cytotoxic therapy.
Question 2
A 55‑year‑old man with AML presents with diffuse alveolar hemorrhage and a prolonged PT. Which agent is essential in his initial management?
A. High‑dose steroids
B. All‑trans retinoic acid
C. Platelet transfusion only
D. Immediate dialysis
Answer: B. All‑trans retinoic acid – indicated for acute promyelocytic leukemia (M3) to induce differentiation and improve coagulopathy.
Question 3
A patient with chronic‑phase CML on imatinib develops rising leukocyte counts and splenomegaly. Which next step is most appropriate?
A. Increase imatinib dose
B. Switch to a second‑generation BCR‑ABL inhibitor
C. Add hydroxyurea
D. Start induction chemotherapy
Answer: B. Switch to a second‑generation BCR‑ABL inhibitor – indicates resistance or suboptimal response to first‑line TKI.
Question 4
A 40‑year‑old woman with ALL develops fever 48 h after chemotherapy, ANC = 0.3 × 10⁹/L, no source identified. What is the best immediate action?
A. Wait 24 h for culture results
B. Start empiric broad‑spectrum IV antibiotics
C. Give oral fluoroquinolone only
D. Begin antifungal therapy alone
Answer: B. Start empiric broad‑spectrum IV antibiotics – neutropenic fever mandates prompt coverage.
Question 5
Which laboratory finding helps differentiate a leukemoid reaction from chronic myeloid leukemia?
A. Elevated leukocyte alkaline phosphatase (LAP)
B. Presence of basophilia
C. BCR‑ABL fusion gene
D. Low neutrophil count
Answer: A. Elevated leukocyte alkaline phosphatase – LAP is high in reactive leukocytosis (leukemoid) and low in CML.
Drafted with AI assistance from standard references and reviewed for structure. Check details against your lecture notes and the Kenya MoH guideline.