Leukaemia

Malignant clonal proliferation of hematopoietic stem/progenitor cells, causing bone marrow infiltration and impaired normal hematopoiesis, with variable peripheral blood and extramedullary involvement.

Classified by cell lineage and acuity:

• Acute lymphoblastic leukemia (ALL): predominantly pediatric (peak 2-5 years), but occurs in adults with worse prognosis; lymphoblast proliferation

• Acute myeloid leukemia (AML): predominantly adult (median age ~65-70), myeloblast proliferation; subtyped by WHO classification (genetic/molecular abnormalities increasingly define subtype and prognosis, e.g., APL with PML-RARA translocation)

• Chronic lymphocytic leukemia (CLL): most common leukemia in Western adults, indolent, elderly predominant, mature B-lymphocyte clonal proliferation

• Chronic myeloid leukemia (CML): defined by BCR-ABL1 fusion gene (Philadelphia chromosome, t(9;22)), triphasic course (chronic → accelerated → blast crisis)

• Bone marrow failure symptoms (common to acute leukemias, from crowding out of normal hematopoiesis):

• Anemia: fatigue, pallor, dyspnea

• Thrombocytopenia: easy bruising, petechiae, mucosal bleeding (epistaxis, gum bleeding), menorrhagia

• Neutropenia: recurrent/severe infections, fever

• Bone pain (marrow expansion, especially in children with ALL)

• Lymphadenopathy, hepatosplenomegaly (more prominent in ALL, CLL, CML)

• Gum hypertrophy, skin infiltration (leukemia cutis): more characteristic of certain AML subtypes (monocytic)

• CNS involvement: headache, cranial nerve palsies (more common in ALL, especially at relapse)

• AML-specific: DIC risk especially in acute promyelocytic leukemia (APL), life-threatening bleeding, requires urgent recognition

• CLL: often asymptomatic, found incidentally on routine FBC (lymphocytosis); B-symptoms (fever, night sweats, weight loss) in more advanced disease; autoimmune hemolytic anemia/thrombocytopenia can complicate

• CML: often insidious, fatigue, splenomegaly (can be massive, causing early satiety/left upper quadrant discomfort), night sweats, weight loss; blast crisis presents like acute leukemia

• B-symptoms across chronic leukemias/lymphomas: fever, drenching night sweats, unintentional weight loss (>10% in 6 months)

• FBC: leukocytosis (or leukopenia), anemia, thrombocytopenia; blast cells on differential in acute leukemia

• Peripheral blood film: blasts (acute), Auer rods (pathognomonic for AML, especially APL), smudge cells (CLL characteristic)

• Bone marrow aspirate and trephine biopsy: definitive diagnosis, blast percentage (≥20% defines acute leukemia), morphology, cellularity

• Immunophenotyping (flow cytometry): lineage determination (myeloid vs. lymphoid markers), essential for classification and treatment planning

• Cytogenetics/molecular testing: essential for prognosis and targeted therapy selection

• AML: FLT3, NPM1, CEBPA mutations; core-binding factor abnormalities; PML-RARA (APL), urgent test given specific treatment implications

• ALL: BCR-ABL1 (Philadelphia-positive ALL, different treatment pathway), other fusion genes

• CML: BCR-ABL1 confirmatory (defines diagnosis)

• CLL: FISH panel (del17p, del11q, high-risk features), IGHV mutation status (prognostic)

• Lumbar puncture with CSF cytology: CNS involvement assessment, particularly in ALL (routine) and high-risk AML

• Coagulation studies: essential in AML, especially APL (DIC screen, PT, APTT, fibrinogen, D-dimer)

• Imaging (CT/PET): staging for lymphadenopathy/organomegaly, particularly CLL

Differentials: reactive leukocytosis (infection, especially in children with high WCC, leukemoid reaction), infectious mononucleosis (atypical lymphocytosis), other bone marrow failure syndromes (aplastic anemia, myelodysplastic syndrome), lymphoma with marrow involvement.

Acute lymphoblastic leukemia (ALL):

• Multi-agent chemotherapy in phases: induction (vincristine, corticosteroids, asparaginase, ± anthracycline) → consolidation → maintenance (often 2 years, including methotrexate/mercaptopurine)

• CNS prophylaxis: intrathecal chemotherapy (methotrexate), essential given CNS relapse risk, ± cranial irradiation in high-risk cases

• Philadelphia-positive ALL: add tyrosine kinase inhibitor (imatinib, dasatinib) to chemotherapy backbone

• Targeted immunotherapy for relapsed/refractory disease: blinatumomab (bispecific T-cell engager), CAR-T cell therapy (tisagenlecleucel), inotuzumab ozogamicin

• Allogeneic stem cell transplant: for high-risk features, poor response to induction, or relapsed disease

Acute myeloid leukemia (AML):

• Standard induction: "7+3" regimen, cytarabine (7 days continuous infusion) + anthracycline (daunorubicin, 3 days)

• Acute promyelocytic leukemia (APL): distinct urgent treatment pathway: all-trans retinoic acid (ATRA) + arsenic trioxide (± chemotherapy in high-risk), differentiation syndrome risk (fever, dyspnea, pulmonary infiltrates, requires prompt steroids); aggressive management of coagulopathy/DIC critical (high early mortality from bleeding if untreated urgently)

• Targeted therapy per molecular profile: FLT3 inhibitors (midostaurin, gilteritinib) for FLT3-mutated AML; IDH1/2 inhibitors for IDH-mutated disease; venetoclax (BCL-2 inhibitor) + hypomethylating agent for older/unfit patients

• Consolidation: high-dose cytarabine, or allogeneic stem cell transplant for intermediate/high-risk cytogenetics

Chronic lymphocytic leukemia (CLL):

• Early-stage asymptomatic: "watch and wait", no survival benefit to early treatment

• Treatment indicated for: symptomatic disease, cytopenias, bulky/progressive lymphadenopathy, B-symptoms, autoimmune complications

• Targeted therapy (preferred over chemoimmunotherapy in most): BTK inhibitors (ibrutinib, acalabrutinib), BCL-2 inhibitor (venetoclax) ± anti-CD20 monoclonal antibody (rituximab, obinutuzumab)

• High-risk cytogenetics (del17p, TP53 mutation): poor response to chemotherapy, targeted agents preferred

Chronic myeloid leukemia (CML):

• Tyrosine kinase inhibitors (TKIs): revolutionary, most patients achieve near-normal life expectancy: imatinib 400mg od first-line, or second-generation TKIs (dasatinib, nilotinib) for higher-risk disease or intolerance

• Monitor BCR-ABL1 transcript levels (PCR): molecular response milestones guide treatment adjustments

• Treatment-free remission possible in select patients with sustained deep molecular response

• Blast crisis: treated as acute leukemia (lymphoid or myeloid blast phenotype-directed) with TKI continuation

Supportive care (across all leukemias):

• Transfusion support: packed red cells, platelets (irradiated/leukodepleted products in transplant candidates)

• Infection prophylaxis/management: neutropenic sepsis protocol (empirical broad-spectrum antibiotics within 1 hour of fever in neutropenic patient, e.g., piperacillin-tazobactam), antifungal/antiviral prophylaxis during intensive chemotherapy

• Tumor lysis syndrome prevention: aggressive hydration, allopurinol or rasburicase (high tumor burden, high-risk AML/ALL) before/during induction

• Fertility preservation counseling before treatment where feasible

Referral: all suspected leukemia requires urgent hematology/oncology referral, same-day/emergency referral for suspected acute leukemia given risk of rapid deterioration (bleeding, infection, tumor lysis).