Leukaemias — AML, APL, ALL, CML, CLL and Hairy Cell Leukaemia with Markers and Translocations

A leukaemia is a clonal malignancy of haematopoietic cells that floods the marrow and spills into the blood. The working classification uses two axes: the lineage of the malignant cell (myeloid or lymphoid) and the pace of the disease (acute, with immature blasts that fail to mature, or chronic, with mature-looking but dysfunctional cells).

ALL accounts for up to 80% of childhood leukaemia but only about 20% of adult cases. In adults, AML is the commonest acute leukaemia, while CLL is the commonest leukaemia overall in Western populations (25–30% of leukaemias in the United States).

AML is a clonal proliferation of myeloblasts. Risk factors include prior chemotherapy (secondary AML often appears 5–7 years after exposure), progression of a myeloproliferative or myelodysplastic disorder, radiation, tobacco smoke and benzene. Patients present with pallor, bruising and hepatosplenomegaly from marrow failure; lymphadenopathy is rare.

• Auer rods — red-staining, needle-like bodies in the cytoplasm of myeloblasts — mark a myeloid blast.
• Myeloid markers: myeloperoxidase (MPO), CD13, CD33, CD117 (with CD34 and HLA-DR on immature cells). MPO is absent in pure lymphoid blasts.
• DIC is common (mucosal bleeding, purpura, oozing from IV sites), and schistocytes may appear on the smear.
• Tumour lysis at presentation or with therapy: high LDH, uric acid, potassium and phosphate.
• Leukostasis with very high counts causes visual and neurological symptoms and respiratory distress.

Treatment: fit patients up to about 70 years receive '7+3' induction — continuous cytarabine for 7 days plus an anthracycline on days 1–3 — followed by high-dose cytarabine (HiDAC) consolidation. Older or unfit patients usually receive a hypomethylating agent (azacitidine or decitabine) with the BCL-2 inhibitor venetoclax.

APL is the AML subtype defined by t(15;17), which fuses the PML gene on chromosome 15 with the retinoic acid receptor alpha (RARA) gene on chromosome 17. The PML::RARA protein blocks maturation at the promyelocyte stage. Its smear feature is abundant cytoplasmic Auer rods — clumps of azurophilic granules elongated like needles.

• ATRA pushes the arrested promyelocytes on to mature granulocytes — differentiation therapy, not cytotoxic killing.
• Differentiation syndrome can appear from 48 hours to about 3 weeks after starting ATRA.
• Standard-risk APL: ATRA plus arsenic trioxide (ATO), with no need for stem-cell transplant.
• High-risk (Sanz) APL: WBC above 10,000/μL; anthracycline is added to ATRA and ATO once the diagnosis is confirmed.

ALL is a malignancy of B or T lymphoblasts. It is the most common malignancy of childhood, with a peak at 2–10 years. Risk is higher with Down syndrome (trisomy 21), neurofibromatosis type 1, Bloom syndrome and ataxia-telangiectasia. Survival has improved dramatically, with five-year overall survival now above 85%.

• Presentation: fever, fatigue, bleeding and bone pain from marrow infiltration; hepatosplenomegaly.
• CNS involvement is common — cranial nerve palsies and meningeal signs — so every regimen includes intrathecal CNS prophylaxis.
• Other sites: testicular enlargement and a mediastinal mass (typical of T-ALL).
• Treatment runs in phases: induction, consolidation and maintenance, with CNS-directed therapy throughout.

CML is a myeloproliferative neoplasm defined by the BCR::ABL1 fusion. In 90–95% of patients it arises from the reciprocal translocation t(9;22)(q34;q11.2) that produces the shortened chromosome 22 called the Philadelphia (Ph) chromosome. ABL1 (chromosome 9) encodes a non-receptor tyrosine kinase; joined to BCR (breakpoint cluster region, chromosome 22), it becomes constitutively active. The usual fusion protein is p210.

• Presentation: anaemia and splenomegaly (early satiety, left upper quadrant fullness); basophilia can release histamine and cause peptic ulcers.
• Diagnosis: FISH or RT-PCR for BCR::ABL1 on peripheral blood — marrow biopsy is not required for diagnosis (it shows a 100% cellular marrow).
• First-line tyrosine kinase inhibitors: imatinib 400 mg daily (first generation), or second-generation dasatinib, nilotinib, bosutinib (preferred for intermediate or high-risk scores).
• Ponatinib (third generation) is for patients failing several TKIs and for the T315I resistance mutation.
• Allogeneic stem-cell transplant for TKI-resistant or advanced-phase disease.

CLL/SLL is a monoclonal proliferation of morphologically mature but immunologically dysfunctional B lymphocytes. It is the most common adult leukaemia in Western populations, with an average age at diagnosis of about 70 years, and it arises from a precursor state called monoclonal B-cell lymphocytosis.

• Smudge (basket) cells on the smear — fragile lymphocytes disrupted when the slide is spread; StatPearls calls them pathognomonic.
• Immunophenotype: co-expression of CD5, CD19 and CD23, with low (dim) surface immunoglobulin. CD5 is normally a T-cell antigen.
• Lymphadenopathy in 50–90% (cervical, supraclavicular, axillary); skin is the commonest non-lymphoid site.
• Autoimmunity: autoimmune haemolytic anaemia (Coombs-positive) and immune thrombocytopenia.
• Hypogammaglobulinaemia → recurrent infections.

Hairy cell leukaemia (HCL) is a rare mature B-cell neoplasm (about 2% of leukaemias) with a male-to-female ratio of 4:1. Most cases carry the BRAF V600E mutation, which drives the RAS-RAF-MAPK pathway. The cells have abundant pale blue cytoplasm with fine circumferential hair-like projections.

• Pancytopenia with monocytopenia and splenomegaly, usually without lymphadenopathy.
• 'Dry tap' — bone marrow aspiration frequently fails (not in the HCL variant).
• Flow cytometry: CD11c, CD25, CD103, CD123 plus B-cell markers (CD19, CD20, CD22). The variant (HCL-v) is CD25- and CD123-negative and lacks BRAF mutation and monocytopenia.
• Immunohistochemistry: annexin A1 is the most sensitive and specific marker; tartrate-resistant acid phosphatase (TRAP) is a classic routine marker; BRAF V600E can be detected by molecular testing or a mutation-specific antibody.
• Treatment: purine analogues cladribine (first-line; one 5–7-day course gives complete response in about 90%) or pentostatin; vemurafenib (BRAF inhibitor) for refractory disease.