Lucan · Conditions

Chronic leukaemias

Australian guidance: eviQ (Cancer Institute NSW) CML and CLL treatment protocols + HealthPathways WA Haematology referral pathways

1. Definition and epidemiology

The two chronic leukaemias encountered in adult practice arise from entirely different cell lineages and behave very differently, and are best learned as a contrasting pair rather than as separate topics. Chronic myeloid leukaemia (CML) is a clonal myeloproliferative neoplasm of the pluripotent haematopoietic stem cell, driven by a single defining genetic lesion, the BCR-ABL1 fusion, and characterised by unchecked expansion of the granulocytic lineage across all stages of maturation. It accounts for a small minority of adult leukaemias, with an Australian incidence of roughly one to two per 100,000 per year and a median age at diagnosis in the mid-fifties, though it can occur at any adult age. Chronic lymphocytic leukaemia (CLL) is, by contrast, the most common leukaemia diagnosed in Australian and other Western adults, a clonal accumulation of mature-appearing but functionally defective B lymphocytes that is frequently discovered incidentally on a routine full blood count in an asymptomatic older adult; median age at diagnosis is around 70 years, and CLL is rare before 40. Both conditions are typically indolent at presentation, but each carries a distinct pathway to more aggressive disease, blast crisis in CML and Richter transformation in CLL, that underpins why lifelong surveillance is required even once treatment has controlled the disease.

2. Pathophysiology

CML is defined by the reciprocal translocation t(9;22)(q34;q11), which juxtaposes the ABL1 gene on chromosome 9 with the BCR gene on chromosome 22, producing the derivative chromosome 22 known as the Philadelphia chromosome and the BCR-ABL1 fusion gene. The resulting BCR-ABL1 protein is a constitutively active tyrosine kinase that drives unregulated proliferation and impaired apoptosis of myeloid progenitors, expanding the granulocytic lineage while largely sparing normal differentiation, so that in chronic phase the marrow and blood show an orderly, if excessive, spectrum of maturing myeloid cells (Robbins Ch 13). Untreated or inadequately controlled CML progresses through three phases: chronic phase, in which blasts remain below 10% and the disease is typically indolent and treatment-responsive; accelerated phase, defined by rising blast counts (10 to 19%), increasing basophilia, thrombocytopenia or thrombocytosis unresponsive to therapy, and acquisition of additional cytogenetic abnormalities on top of the Philadelphia chromosome; and blast phase (blast crisis), defined by a blast count of 20% or more, which behaves clinically like an acute leukaemia and carries a poor prognosis. Blast phase is myeloid in roughly two-thirds of cases and lymphoid in the remainder, reflecting the origin of the BCR-ABL1 lesion in a multipotent stem cell capable of differentiating down either lineage.

CLL arises from a clonal population of mature CD5-positive B lymphocytes that survive abnormally long because of defective apoptosis, most classically through overexpression of the anti-apoptotic protein BCL2, rather than through rapid proliferation; the cells accumulate progressively in blood, bone marrow, lymph nodes, and spleen. Prognosis in CLL is driven substantially by cytogenetics and molecular markers identified on fluorescence in situ hybridisation (FISH) and sequencing: deletion of 17p or a TP53 mutation confers the worst prognosis and predicts resistance to conventional chemoimmunotherapy, deletion of 11q and unmutated immunoglobulin heavy-chain variable region (IGHV) genes confer intermediate-to-poor prognosis, trisomy 12 is intermediate, and an isolated deletion of 13q, the most common single abnormality, carries the most favourable prognosis. These markers are checked before any treatment decision because they directly change which agent is used.

3. Clinical presentation and diagnostic criteria

CML is frequently asymptomatic and detected incidentally on a full blood count performed for another reason; when symptomatic, patients describe fatigue, weight loss, night sweats, and abdominal fullness or early satiety from massive splenomegaly, which is the most consistent physical finding and can be striking in extent. Rarely, a very high white cell count causes symptoms of leukostasis or hyperviscosity, including visual disturbance or priapism. The blood film is the single most useful bedside clue: CML shows marked leukocytosis with the full spectrum of granulocytic maturation visible simultaneously, myeloblasts, promyelocytes, myelocytes, metamyelocytes, band forms, and mature neutrophils, together with characteristic basophilia and often eosinophilia and thrombocytosis. Diagnosis is confirmed by demonstrating BCR-ABL1, either as the Philadelphia chromosome on conventional cytogenetics, by FISH, or by quantitative reverse-transcriptase PCR for the BCR-ABL1 transcript, the last of which also becomes the primary tool for monitoring treatment response.

CLL is likewise often asymptomatic at diagnosis, with an isolated lymphocytosis noted on a routine blood count; symptomatic patients present with painless, often widespread lymphadenopathy, splenomegaly or hepatomegaly, B symptoms (fever, drenching night sweats, or weight loss exceeding 10% of body weight over six months), or recurrent infections reflecting the immune dysfunction that accompanies the disease. The diagnostic hallmark on the blood film is the smear cell (smudge cell), a fragile, disrupted lymphocyte artefact created when the abundant but mechanically fragile CLL cells are sheared during film preparation; intact cells appear as small, mature-looking lymphocytes with dense, clumped chromatin and scant cytoplasm. A formal diagnosis requires a sustained absolute clonal B lymphocyte count of at least 5 x10^9/L for three months or more, together with a characteristic immunophenotype on flow cytometry, co-expression of CD5, CD19, and CD23 with dim CD20 and dim surface immunoglobulin, which distinguishes CLL from mantle cell lymphoma (CD5-positive but typically CD23-negative) and other B-cell lymphoproliferative disorders. A clonal B-cell population below this threshold with no lymphadenopathy, organomegaly, or cytopenia is termed monoclonal B lymphocytosis, a precursor state that is monitored rather than treated.

The two diseases are readily separated at the bedside and on the film once the contrast is understood: CML shows a full myeloid maturation spectrum with basophilia and massive splenomegaly in a patient who is often, though not always, younger than the typical CLL patient, and is confirmed by BCR-ABL1; CLL shows a monomorphic population of small mature lymphocytes with smear cells, more prominent lymphadenopathy than splenomegaly in many patients, an older median age, and a CD5/CD19/CD23 immunophenotype with no BCR-ABL1 involvement.

A classic historical exam distinguisher, still occasionally tested, is the leukocyte alkaline phosphatase (LAP) score: it is characteristically low in CML because the neoplastic granulocytic clone has reduced enzyme expression, in contrast to a reactive leukaemoid reaction (a florid but non-clonal neutrophilia driven by infection or inflammation), in which LAP is normal or elevated; the test has been largely superseded by BCR-ABL1 testing in routine practice but remains a useful conceptual anchor for separating a true myeloproliferative clone from a reactive picture that can otherwise mimic it on a blood film.

4. Investigations and AU-specific cutoffs

For suspected CML, the full blood count and film are the first step, followed by bone marrow aspirate and trephine biopsy to establish a baseline blast percentage and full karyotype, which identifies additional cytogenetic abnormalities that would signal accelerated or blast phase. Quantitative BCR-ABL1 RT-PCR, reported on the International Scale (%IS), is obtained at baseline and then repeated at defined milestones during treatment, consistent with European LeukaemiaNet response criteria as adopted into Australian haematology practice via eviQ; failure to achieve the expected molecular response at three, six, and twelve months prompts kinase-domain mutation testing (looking particularly for T315I, which confers resistance to most first- and second-generation tyrosine kinase inhibitors) and consideration of switching agents.

For suspected CLL, flow cytometry immunophenotyping of peripheral blood is the essential confirmatory test alongside the film. A FISH panel for del(17p), del(11q), trisomy 12, and del(13q), together with IGHV mutational status and TP53 mutation sequencing, is obtained before any treatment decision, since these markers determine whether chemoimmunotherapy remains a reasonable option or whether a targeted agent is required from the outset. A direct antiglobulin (Coombs) test is checked if there is unexplained anaemia, since autoimmune haemolytic anaemia is a recognised complication of CLL. Clinical staging in CLL relies on physical examination rather than routine cross-sectional imaging: the Binet system, most widely used in Australian and European practice, stages disease A to C by the number of lymphoid areas involved (cervical, axillary, and inguinal nodes, spleen, and liver each counted as one area) and by the presence of anaemia or thrombocytopenia, while the Rai system (stages 0 to IV), more traditionally used in North America, is built on the same underlying findings of lymphocytosis, lymphadenopathy, organomegaly, and cytopenia; both are prognostic and both are still taught interchangeably in Australian curricula.

5. Management

Tyrosine kinase inhibitor (TKI) therapy is first-line treatment for essentially all patients with newly diagnosed chronic-phase CML in Australian practice, whether with the first-generation agent imatinib or a second-generation agent such as dasatinib or nilotinib, all PBS-subsidised for this indication. The treatment goal is a deep and sustained molecular response, monitored by serial BCR-ABL1 RT-PCR; achieving an undetectable or very low transcript level for a sustained period (typically at least two years) allows selected patients to be considered for a supervised trial of treatment-free remission, though most patients remain on lifelong therapy. Progression to accelerated or blast phase, or resistance or intolerance to sequential TKIs, is an indication for allogeneic stem cell transplantation, the only potentially curative option for advanced disease.

CLL management begins with the single most important management concept in this topic: watch-and-wait. Most patients diagnosed with early-stage, asymptomatic disease (Binet stage A, Rai stage 0) require no treatment at diagnosis, because CLL is frequently indolent and early intervention in asymptomatic disease has not been shown to improve survival, so observation with periodic clinical review and blood counts is the correct answer even though it can feel counterintuitive to a student expecting a cancer diagnosis to prompt immediate therapy. Treatment is triggered by evidence of active, progressive disease: significant B symptoms, symptomatic or bulky lymphadenopathy or splenomegaly, progressive marrow failure with anaemia or thrombocytopenia not attributable to autoimmune cytopenia, autoimmune cytopenia poorly responsive to corticosteroids, or a rapid lymphocyte doubling time (less than six months). When treatment is indicated, the choice of agent is guided directly by the FISH and TP53 results obtained in section 4: chemoimmunotherapy such as fludarabine, cyclophosphamide, and rituximab (FCR) is now reserved mainly for younger, fit patients with mutated IGHV and no TP53 abnormality, while targeted agents, Bruton tyrosine kinase (BTK) inhibitors (acalabrutinib or zanubrutinib, both PBS-subsidised as first-line monotherapy; ibrutinib is PBS-subsidised for relapsed/refractory disease rather than as first-line monotherapy) or the BCL2 inhibitor venetoclax (typically combined with an anti-CD20 antibody such as obinutuzumab), have become first-line for most Australian patients, and are essentially mandatory in del(17p) or TP53-mutated disease, which responds poorly to chemotherapy.

6. Pharmacology and AU PBS notes

Imatinib (brand Glivec) is dosed at 400 mg orally once daily in chronic-phase CML and is PBS-subsidised on an authority basis; common adverse effects include fluid retention, periorbital oedema, muscle cramps, and gastrointestinal upset. Second-generation TKIs used first-line or after imatinib failure include dasatinib (Sprycel), associated with a distinctive risk of pleural effusion and pulmonary hypertension, and nilotinib (Tasigna), associated with QT prolongation and an increased risk of arterial vascular events, both also PBS-listed. Ponatinib and asciminib are reserved for T315I-mutated or multi-TKI-resistant disease; ponatinib carries a significant arterial thrombosis risk that limits its first-line use.

In CLL, acalabrutinib and zanubrutinib are PBS-listed for first-line (frontline) treatment, while ibrutinib is PBS-listed as monotherapy only for relapsed/refractory disease; a separate fixed-duration ibrutinib-plus-venetoclax combination regimen is PBS-listed for first-line, previously untreated CLL/SLL. ibrutinib in particular carries risks of atrial fibrillation, hypertension, and bleeding that are less pronounced with the newer agents. Venetoclax requires a mandatory graded dose ramp-up protocol over several weeks, with close biochemical monitoring (potassium, phosphate, urate, and creatinine) and often inpatient observation for the first doses in higher-risk patients, because of the risk of tumour lysis syndrome from rapid apoptosis of a large tumour burden; it is commonly combined with obinutuzumab for a fixed treatment duration rather than given indefinitely. Anti-CD20 antibodies (rituximab, obinutuzumab) carry a well-recognised risk of infusion reactions, most marked with the first dose, and pre-medication with an antihistamine, paracetamol, and corticosteroid is standard. As with any oncology PBS listing, authority criteria and streamlined codes change and should be checked against the current PBS schedule and eviQ protocol before prescribing.

7. Complications and monitoring

In CML, the principal danger is progression to accelerated or blast phase, which is why lifelong molecular monitoring continues even in patients with an excellent initial response, and why any rise in BCR-ABL1 transcript level after a deep response prompts prompt reassessment for resistance or non-adherence before it is dismissed as noise.

CLL carries several complications distinct from the leukaemia itself. Hypogammaglobulinaemia develops progressively as normal B-cell function is crowded out and is a major driver of the recurrent, sometimes severe bacterial infections seen in CLL patients, particularly encapsulated respiratory organisms; regular immunoglobulin levels are checked, and intravenous immunoglobulin replacement is used in patients with recurrent serious infection and significantly low IgG. Autoimmune cytopenias, most commonly autoimmune haemolytic anaemia and immune thrombocytopenia, occur because the dysregulated immune system in CLL loses tolerance to normal blood cells, and are managed with corticosteroids in the first instance, distinct from cytopenia caused by direct marrow infiltration. Richter transformation, the evolution of CLL into an aggressive lymphoma, most often diffuse large B-cell lymphoma, occurs in a small but clinically important minority of patients (roughly 2 to 10% over the course of the disease) and should be suspected when there is rapid, asymmetric lymph node growth, new B symptoms, a sharply rising lactate dehydrogenase, or sudden loss of response to previously effective therapy; PET-CT to identify the most metabolically active node followed by excisional or core biopsy of that node is the appropriate work-up, and Richter transformation carries a poor prognosis requiring aggressive lymphoma-directed treatment. Patients with CLL also carry an increased lifetime risk of second malignancies, particularly skin cancers, reflecting the underlying immune dysregulation, and should receive routine sun-protection counselling and skin surveillance as part of long-term follow-up.

Monitoring cadence differs between the two diseases and is worth anchoring explicitly. In CML, once a patient is established on a TKI, BCR-ABL1 RT-PCR is typically checked three-monthly until a stable major molecular response is achieved and then can be spaced to six-monthly, continuing indefinitely (or throughout a supervised treatment-free remission trial) because late loss of response still requires prompt detection. In CLL, patients on watch-and-wait are reviewed clinically with a full blood count typically every three to six months, more frequently if disease is bulkier or trending, with the interval lengthened once a period of stability is demonstrated; this contrast, indefinite molecular surveillance in a treated disease versus periodic clinical review in an untreated one, is a useful way to remember why the two conditions are monitored so differently despite both being chronic leukaemias.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.