Chronic Myeloid Leukaemia (CML)

CML typically progresses through three clinical phases

Chronic phase

• Often asymptomatic or presenting with mild constitutional symptoms, characterised by <10% blasts in the blood or bone marrow.

Accelerated phase

• Defined by increasing blast counts (10–19%), rising basophils (>20%), persistent thrombocytopenia or thrombocytosis unresponsive to therapy, or emerging cytogenetic abnormalities.

Blast phase

• Resembles acute leukaemia, with ≥20% blasts in the blood or marrow, or the presence of extramedullary blast proliferation. This phase may manifest as either acute myeloid or acute lymphoblastic leukaemia.

Primary cause

• CML is a clonal myeloproliferative disorder driven by the acquired formation of the BCR::ABL1 fusion gene.
• This results from a somatic reciprocal translocation between chromosomes 9 and 22: t(9;22)(q34;q11), producing the Philadelphia chromosome.
• The fusion gene encodes a constitutively active tyrosine kinase that promotes unchecked myeloid cell proliferation.

Radiation exposure

• Ionising radiation is the only clearly established environmental risk factor.
• Risk increases with cumulative radiation dose.

Supporting evidence for radiation risk

• Atomic bomb survivors (Hiroshima and Nagasaki):
  • Higher incidence of CML observed.
  • Latency typically 2–10 years post-exposure.
  • Greater risk noted in those exposed at a younger age.
  • Occupational exposure:
    • Elevated risk suggested in workers at nuclear facilities and radiologists.
    • Not consistently confirmed across all studies.
  • Therapeutic exposure:
    • Some cases linked to prior radiation therapy, though less common.

Lack of association with other toxins

• No conclusive links to benzene, pesticides, solvents, or other environmental chemicals.
  • Unlike some other leukaemias, CML does not appear to arise from such exposures.

No hereditary component

• CML does not show familial clustering.
• No known inherited genetic mutations associated with increased risk.
• Considered a sporadic disease with no identified germline predisposition.

Genetic Basis

• CML is characterised by the reciprocal translocation between chromosomes 9 and 22, resulting in the Philadelphia chromosome [t(9;22)(q34;q11)].
• This translocation fuses the BCR gene (chromosome 22) with the ABL1 gene (chromosome 9) to create the BCR::ABL1 fusion oncogene.
• The resulting BCR::ABL1 protein is a constitutively active tyrosine kinase that drives malignant transformation.

BCR::ABL1 Protein Isoforms

• The most common isoform in CML is p210, derived from fusions e13a2 or e14a2.
• p190 (e1a2): Rare in CML, more common in Ph-positive acute lymphoblastic leukaemia (ALL); associated with monocytosis and poorer prognosis.
• p230 (e19a2): Very rare; associated with indolent presentations; not routinely detected by standard PCR assays.
• Rare transcript variants include e1a3, b2a3, and e6a2.

Molecular Consequences of BCR::ABL1 Activity

• Promotes uncontrolled proliferation of myeloid progenitors.
• Impairs apoptosis via inhibition of mitochondrial cytochrome c release and caspase activation.
• Alters cell adhesion, reducing retention of progenitors in bone marrow and promoting their release into circulation.
• Causes discordant maturation, increasing immature progenitor expansion without significantly altering stem cell numbers.

Key Signalling Pathways Activated by BCR::ABL1

• MAPK pathway: Drives proliferation.
• JAK/STAT pathway: Enhances survival and proliferation.
• SAPK/JNK: Contributes to resistance to apoptosis.
• STAT5, MYC, cyclin D1: Support cell cycle progression and growth.

Disease Progression Mechanisms

• Progression from chronic phase (CP) to accelerated (AP) or blast phase (BP) involves additional genetic and epigenetic alterations.
• These changes disrupt normal differentiation and increase blast accumulation.

Contributing mechanisms include

Additional Cytogenetic Abnormalities (ACAs)

• Seen in >80% of AP/BP cases; includes:
  • Trisomy 8 or 19
  • Duplication of the Ph chromosome
  • Isochromosome 17q, leading to TP53 loss
• Presence at diagnosis (∼7%) predicts worse response and survival.

BCR::ABL1 Activity Escalation

• Progression correlates with increased kinase activity.
• May interact with transcription factors (e.g., C/EBPα, Ikaros) to inhibit differentiation.

Mutations in Key Regulators

• TP53: Altered in 20–30% of BP patients.
• Epigenetic regulators:
  • TET2, ASXL1, DNMT3A mutations associated with clonal expansion and TKI resistance.
• MYC amplification and deletions in RB1/CDKN2A are common in lymphoid BP.
• Chromosome 9 deletions: Present in 15–20% of CP cases; associated with poorer outcomes.

Global Overview

• CML is a rare haematological malignancy with a global annual incidence of approximately 0.87 per 100,000 population.
• Incidence increases with age, reaching 1.52 per 100,000 in individuals over 70 years old.
• A slight male predominance is observed across populations.
• CML accounts for about 15% of all leukaemia cases in the United States.

United Kingdom

• The annual incidence of CML is approximately 1.1 per 100,000, equating to around 720 new diagnoses per year (based on 2010–2019 data).
• Peak incidence occurs in the 85–89 age group, reflecting the age-related risk increase.

United States

• In 2024, it is estimated there will be 9280 new CML cases and 1280 deaths due to the disease.
• From 2016–2020, the age-adjusted incidence rate was 1.9 per 100,000 per year, while the mortality rate was 0.3 per 100,000 per year.
• Median age at diagnosis is 66 years.
• CML is more common in males, with incidence rates of 2.2 per 100,000 in men compared to 1.4 per 100,000 in women (based on 2009–2013 data).
• Male-to-female ratio in incidence: approximately 2.5:1.5.

Trends Over Time

• In both the US and UK, incidence and mortality rates have remained relatively stable over the past decade.
• The introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved survival, contributing to a growing population of patients living with CML.

Age Distribution

• While CML can occur at any age, it is primarily a disease of older adults.
• Incidence increases steadily with age, with peak diagnosis rates occurring between ages 65–89 depending on population.

Asymptomatic at Presentation

• Up to 50% of patients in the chronic phase are diagnosed incidentally.
• Detected through routine blood tests showing leukocytosis.
• Occasionally picked up due to splenomegaly on unrelated physical examination.

Constitutional and Non-specific Symptoms

Fatigue

• Most common complaint, especially in chronic phase (∼34%).

Weight loss

• Occurs in ∼20%; more common in accelerated or blast phases.

Loss of energy/decreased exercise tolerance

• Progressive, reflecting chronic disease burden.

Excessive sweating/night sweats

• Reported by ∼15%, typically in later phases.

Low-grade fever

• May reflect hypermetabolism or, in later stages, infection.

Shortness of breath

• Usually exertional, may reflect anaemia.

Abdominal Symptoms Related to Splenomegaly

Left upper quadrant discomfort or fullness

• Common due to splenic enlargement or infarction.
• Can refer pain to the left shoulder.

Early satiety and reduced food intake

• Due to splenic pressure on the stomach.

Left upper quadrant ‘gripping’ pain

• Suggestive of splenic infarction.

Bone and Joint Symptoms

Bone pain

• Especially in the sternum, due to bone marrow expansion.

Sternal tenderness

• Should be specifically elicited.

Arthralgia or acute gouty arthritis

• Caused by elevated uric acid from high cell turnover.

Haemorrhagic and Anaemic Symptoms

Bruising, petechiae, or epistaxis

• More frequent in accelerated or blast phases, due to thrombocytopenia or platelet dysfunction.

Pallor

• May be inferred historically via fatigue or shortness of breath, reflecting anaemia.

Retinal haemorrhages

• Rare but may be reported as blurred vision or visual disturbances.

Fever and Infection

Fever in CML

• Low-grade in chronic phase (linked to hypermetabolism).
• High-grade and associated with infections in accelerated/blast phase.

Recurrent infections

• Can indicate progression or marrow failure.

Risk Factor History

Age

• Peak incidence in US: 65–74 years (median 66 years).
• Peak in UK: 85–89 years.
• Younger median age in Southeast Asia.

Sex

• CML is more common in males (∼2.5:1.5 male:female incidence ratio).

Radiation exposure

• Prior therapeutic radiotherapy.
• Occupational exposure in nuclear industry.
• History of atomic bomb radiation (especially Japanese survivors).

Splenomegaly

• Most common physical finding in CML, observed in >50% of patients at diagnosis.
• The spleen often extends >5 cm below the left costal margin.
• Size correlates with WBC count; massive splenomegaly suggests a higher disease burden.
• A rapidly enlarging spleen may herald transformation into blast crisis.
• Associated features:
  • Left upper quadrant fullness or tenderness
  • Referred pain to the left shoulder due to diaphragmatic irritation
  • Early satiety from gastric compression

Hepatomegaly

• Occurs less frequently than splenomegaly.
• Usually due to extramedullary haematopoiesis.
• May contribute to weight loss and abdominal discomfort.

Sternal Tenderness

• May be elicited due to marrow expansion within the sternum.
• Suggestive of hyperproliferative marrow activity or progression.

Retinal Findings on Fundoscopy

• Seen in hyperleucocytic states or leukostasis.
• Examination may reveal:
  • Papilloedema
  • Venous congestion or obstruction
  • Retinal haemorrhages
• These findings indicate hyperviscosity syndrome, often associated with very high WBC counts (>300,000–600,000/μL).

 Signs of Hyperviscosity

• Physical signs may include:
  • Visual disturbances
  • Neurological symptoms (though these are better elicited on history)
  • Fundoscopic abnormalities
• Typically seen in patients with extreme leukocytosis.

Bleeding or Bruising

• Examination may reveal:
  • Petechiae
  • Ecchymoses
  • Mucosal bleeding (e.g. epistaxis)
• These findings are more common in the accelerated or blast phases, linked to thrombocytopenia or platelet dysfunction.

Pallor

• May be observed in patients with anaemia, due to marrow infiltration by leukaemic cells.
• Reflects disease burden or progression to accelerated/blast phase.

Soft-Tissue or Skin Infiltration

• Seen predominantly in blast phase disease.
• Physical examination may reveal:
  • Skin nodules or plaques
  • Lymphadenopathy (uncommon in chronic phase)
  • Gingival hypertrophy or organomegaly beyond spleen/liver

Lymphadenopathy

• Rare in chronic phase.
• Presence may indicate blast crisis, especially if firm, non-tender, and generalised.

Gouty Changes (Uncommon)

• Examination may detect signs of acute gout (e.g. tender, swollen joints), usually the first MTP joint.
• Related to hyperuricaemia from rapid cell turnover.

Initial Investigations at Diagnosis

Full Blood Count (FBC) and Differential

• Nearly all patients present with marked leukocytosis; >50% have WBC counts >100,000/μL.
• Anaemia is common (typically normocytic, normochromic).
• Platelet count may be elevated (thrombocytosis), normal, or occasionally low.
• Persistent cytopenias or cytoses unresponsive to therapy may indicate accelerated phase.
• FBC is also used for monitoring haematologic response during treatment.

Peripheral Blood Smear

• Shows a left shift with presence of:
  • Myeloblasts, promyelocytes, myelocytes, metamyelocytes, and band forms
  • Basophilia and eosinophilia
  • Nucleated red blood cells may also be present
• Presence of a broad spectrum of myeloid precursors distinguishes CML from acute leukaemia (which exhibits a maturation arrest).
• In accelerated phase:
  • Blasts ≥15%, basophils ≥20%, and promyelocytes ≥30%
  • Often accompanied by thrombocytopenia and poor response to therapy

Bone Marrow Aspirate and Biopsy

• Typically reveals:
  • Hypercellular marrow with marked granulocytic hyperplasia
  • Increased megakaryocytes
  • Mild fibrosis on reticulin staining
• Essential for:
  • Confirming diagnosis
  • Establishing phase (chronic, accelerated, or blast)
  • Identifying additional cytogenetic abnormalities (ACAs)
• Cytogenetic analysis detects:
  • Philadelphia chromosome t(9;22)(q34;q11)
  • ACAs such as trisomy 8, isochromosome 17q, additional Ph chromosome, and deletions (e.g., Y chromosome)

Cytogenetic Testing

• Standard karyotyping on bone marrow cells to detect the Ph chromosome
• Recommended to analyse 20–25 metaphase cells
• Important for monitoring and detecting progression via emergence of ACAs

Fluorescence In Situ Hybridisation (FISH)

• Detects BCR::ABL1 rearrangements in interphase or metaphase cells
• Can be done on peripheral blood or bone marrow
• Used when:
  • Bone marrow sample is not available
  • qRT-PCR and cytogenetics yield discordant results
• Not suitable for routine monitoring if qRT-PCR is available
• Cannot detect additional cytogenetic abnormalities

Quantitative Reverse Transcriptase PCR (qRT-PCR)

• Most sensitive method for detecting BCR::ABL1 transcripts
• Should be performed:
  • At diagnosis to establish baseline
  • Every 3 months during treatment until BCR::ABL1 ≤1% (IS)
  • Then every 3–6 months for long-term monitoring
• Can detect 1 leukaemic cell among 10⁵–10⁶ normal cells
• Used to assess molecular response, guide treatment changes, and detect minimal residual disease

Additional Investigations and Considerations

Mutational Analysis

• Indicated in:
  • Inadequate response to TKI therapy
  • Disease progression or relapse
• Involves next-generation sequencing (NGS) or BCR::ABL1 kinase domain mutation analysis
• Detects mutations conferring TKI resistance (e.g., T315I)
• May identify mutations in other genes (e.g., ASXL1, DNMT3A) with prognostic impact

Biochemical Tests (Metabolic Profile)

• May show:
  • Hyperuricaemia due to high cell turnover
  • Elevated LDH and potassium (pseudohyperkalaemia may occur)
• Useful in assessing tumour lysis risk or metabolic complications

Risk Stratification Tools

• ELTS, Sokal, or Hasford scores are calculated at diagnosis to predict prognosis and guide TKI therapy selection.
• Parameters include age, spleen size, platelet count, and peripheral blast percentage (ELTS omits eosinophils/basophils).

Imaging (Optional)

• Liver/spleen scans are rarely needed due to clear clinical findings
• Reserved for equivocal physical exams or suspected complications
• Monitor treatment response and resistance

Benign Reactive Conditions

Leukaemoid Reaction

• A transient response to acute infections, inflammation, or malignancy.
• Typically involves WBC counts below 50 × 10⁹/L.
• Toxic granulation, Döhle bodies, and absence of basophilia are classic features.
• Resolves with treatment of the underlying cause.
• BCR::ABL1 testing (FISH or qPCR) is negative.

Benign Neutrophilic Leukocytosis

• Seen in physiological stress, corticosteroid use, or pregnancy.
• Lacks immature granulocytes and does not show left shift.
• Investigations will show normal morphology and no clonal markers.

Other Myeloproliferative Neoplasms (MPNs)

Essential Thrombocythaemia (ET)

• Characterised by isolated and sustained thrombocytosis.
• Generally has a more indolent course and a lower risk of leukaemic transformation.
• JAK2, CALR, or MPL mutations are often found; BCR::ABL1 is absent.
• Bone marrow shows megakaryocyte proliferation without significant fibrosis.

Polycythaemia Vera (PV)

• Features elevated haemoglobin or haematocrit, often with leukocytosis and thrombocytosis.
• Almost always associated with the JAK2 V617F mutation.
• BCR::ABL1 testing is negative.
• Panmyelosis is seen in the bone marrow.

Primary Myelofibrosis (PMF)

• Typically presents with anaemia, splenomegaly, and a leukoerythroblastic blood film.
• Early PMF may resemble ET or PV.
• Bone marrow biopsy shows fibrosis, abnormal megakaryocytes, and absence of BCR::ABL1.
• Often associated with JAK2, CALR, or MPL mutations.

Chronic Neutrophilic Leukaemia (CNL)

• A rare MPN presenting with persistent neutrophilia, usually with segmented forms and minimal left shift.
• Unlike CML, there is no basophilia or monocytosis, and BCR::ABL1 is negative.
• CSF3R mutations are common.

Overlap Syndromes and MDS/MPN

Chronic Myelomonocytic Leukaemia (CMML)

• Defined by sustained monocytosis ≥1 × 10⁹/L and evidence of dysplasia.
• Peripheral smear reveals immature granulocytes and monocytes.
• Bone marrow typically shows multilineage dysplasia.
• Occasionally, PDGFR rearrangements may be identified.
• No BCR::ABL1 fusion gene is present.

Atypical CML (aCML)

• Falls under the MDS/MPN category.
• Lacks the BCR::ABL1 rearrangement and displays prominent dysgranulopoiesis and thrombocytopenia.
• Genetic studies may reveal SETBP1 or ETNK1 mutations.

Acute Leukaemias

Acute Myeloid Leukaemia (AML)

• Presents with rapid-onset symptoms, often with cytopenias, fever, or bleeding.
• Peripheral blood and bone marrow show ≥20% blasts with maturation arrest.
• Leukaemic hiatus—absence of mid-stage myeloid cells—distinguishes AML from CML.
• Cytogenetics are variable; BCR::ABL1 typically absent.

Philadelphia-Positive Acute Lymphoblastic Leukaemia (Ph+ ALL)

• A rapidly progressive B-cell lineage malignancy with systemic symptoms (fever, weight loss, sweats).
• Features anaemia, thrombocytopenia, and circulating lymphoid blasts.
• TdT+ immature B cells confirmed on flow cytometry.
• FISH/qPCR reveals p190 BCR::ABL1, in contrast to the p210 isoform seen in CML.

Treatment Principles

• Primary goals: Achieve and maintain haematologic, cytogenetic, and molecular remission; prevent progression to accelerated or blast phase; and preserve quality of life.
• Secondary goals: Enable treatment-free remission (TFR) in selected patients with durable deep molecular response (DMR).
• Initial approach: TKI therapy is initiated in all patients unless contraindicated. Choice of agent is influenced by disease phase, risk stratification, comorbidities, and patient preference.

Risk Stratification

• ELTS score (preferred): Developed during the TKI era to estimate disease-related mortality.
• Sokal score and Hasford (Euro) score: Older systems still in use, based on age, spleen size, platelet count, and blast percentages.

First-Line Therapy in Chronic Phase (CP)

Low- to Intermediate-Risk CP

• Imatinib (first-generation TKI):
  • Preferred for low-risk patients and older individuals with comorbidities.
  • Excellent long-term outcomes (≥80% survival at 10 years).
• Second-generation TKIs (dasatinib, nilotinib, bosutinib):
  • Achieve deeper and more rapid molecular responses than imatinib.
  • Preferred if TFR is a key treatment objective or if high response rates are desired early.

High-Risk CP

• Second-generation TKIs are recommended to reduce risk of progression.
• All second-generation TKIs have shown similar efficacy; choice is based on side effect profile, comorbidities, and logistics.

Asciminib

• A newer agent targeting the ABL1 myristoyl pocket.
• Suitable for patients intolerant to or failing prior TKIs.
• Active against most resistance mutations, including T315I.
• May be considered as initial therapy, particularly in cases of intolerance to other TKIs.

Monitoring and Response Milestones

Treatment efficacy is assessed by

• Complete haematologic response (CHR): Normal blood counts and spleen size.
• Cytogenetic response: Assessed via karyotyping or FISH for Ph+ cells.
• Molecular response: Measured by qRT-PCR on the international scale (IS).

Key milestones (BCR::ABL1 IS)

• 3 months: ≤10% (optimal), >10% (warning/failure)
• 6 months: ≤1% (optimal), >1% (warning), >10% (failure)
• 12 months: ≤0.1% (MMR, optimal)

Management of Resistance or Suboptimal Response

• Mutation testing (ABL1 kinase domain) is essential in guiding TKI switch.
• T315I mutation:
  • Resistant to imatinib, nilotinib, dasatinib, bosutinib.
  • Sensitive to asciminib and ponatinib.
• Multiple TKI failure:
  • Consider ponatinib (third-generation TKI).
  • Allogeneic haematopoietic cell transplantation (HSCT) if patient is fit and suitable donor is available.

Advanced Disease (Accelerated and Blast Phases)

• Treated with:
  • A second- or third-generation TKI (based on prior use and mutational profile).
  • Induction chemotherapy (AML/ALL protocols) in blast phase.
  • Early donor search for HSCT is critical.
• Prognosis is significantly poorer compared to CP.
• TKI therapy may be combined with cytotoxic agents.

Alternative Therapies

• Used when TKIs are contraindicated or to control symptoms
• Hydroxyurea: Temporising measure for hyperleukocytosis or massive splenomegaly.
• Interferon alfa: Considered safe in pregnancy.
• Cytotoxic chemotherapy (e.g., cytarabine, busulfan): Historically used, rarely first-line now.

TKI Discontinuation and Treatment-Free Remission (TFR)

• Considered in patients with:
  • ≥3 years on TKI
  • Sustained DMR (MR4 or deeper) for ≥2 years
  • No prior resistance to 2G TKIs
  • Access to reliable qPCR monitoring
• Around 40–60% of patients maintain TFR; >80% if DMR sustained >5 years.
• Most patients regain DMR if relapse occurs and TKI is reintroduced.

Allogeneic HSCT

• Reserved for:
  • TKI-refractory disease
  • Advanced phase CML
  • Multiple TKI intolerance or resistance
• Outcomes depend on:
  • Phase at transplant (better in CP)
  • Age and comorbidity profile
  • Donor availability
  • Post-transplant TKI maintenance may improve outcomes and reduce relapse risk.

Survival Outcomes

Historical context

• Prior to the introduction of TKIs, median survival ranged from 3 to 5 years.
• The 5-year survival rate in the early 1990s was approximately 31%.

Modern era

• SEER data (2000–2020):
  • 2-year survival: 77.9%
  • 5-year survival: 66.8%
  • 10-year survival: 58%
• Age-adjusted 5-year survival:
  • <50 years: 87.5%
  • 50–64 years: 78.2%
  • ≥65 years: 44.7%
• IRIS trial (imatinib):
  • 89% estimated 5-year overall survival
  • Only 7% progressed to accelerated or blast phase
• Second- and third-generation TKIs (e.g., dasatinib, nilotinib, bosutinib, ponatinib, asciminib) have demonstrated superior molecular responses and lower progression rates compared to imatinib.

Impact of Disease Phase

Chronic phase

• Excellent prognosis with appropriate TKI therapy.
• Long-term disease control and treatment-free remission possible in selected patients.

Accelerated phase

• Prognosis variable and depends on response to TKI therapy.
• With favourable response, survival can approximate that of chronic phase patients.

Blast phase

• Remains challenging with a poor prognosis.
• Median survival is typically 3–6 months.
• Use of TKIs combined with chemotherapy and/or haematopoietic stem cell transplantation (HSCT) may improve outcomes.
• One retrospective study reported:
  • 5-year survival of 34% in patients treated with TKI and intensive therapy
  • 58% in those proceeding to HSCT

Role of Comorbidities

• Comorbid conditions have become increasingly relevant due to prolonged survival.
• Charlson Comorbidity Index (CCI) has prognostic significance.
• 8-year overall survival by CCI score:
  • CCI 2: 94%
  • CCI 3–4: 89%
  • CCI 5–6: 78%
  • CCI ≥7: 46%

Prognostic Scoring Systems

Sokal Score

• Developed in the pre-TKI era.
• Uses age, spleen size, platelet count, and percentage of blood blasts.
• Categories:
  • Low risk: <0.8
  • Intermediate risk: 0.8–1.2
  • High risk: >1.2

Hasford (Euro) Score

• Incorporates eosinophil and basophil counts in addition to Sokal parameters.
• Stratifies patients into low-, intermediate-, and high-risk groups.
• May better predict molecular response to TKI therapy.

EUTOS Score

• Simpler tool differentiating only between low- and high-risk groups.
• Based on spleen size and peripheral blood basophil count.

ELTS (EUTOS Long-Term Survival) Score

• Specifically predicts CML-related mortality in the TKI era.
• Utilises age, spleen size, platelet count, and blast percentage.
• Risk categories:
  • Low risk: <1.5680
  • Intermediate risk: 1.5680–2.2185
  • High risk: >2.2185
• The ELTS score is now preferred for its superior prediction of CML-specific mortality.

Additional Cytogenetic Risk Factors

• Additional chromosomal abnormalities (ACAs) may emerge at diagnosis or during disease course and influence prognosis.

More favourable prognosis

• Trisomy 8
• -Y (loss of Y chromosome)
• Additional copy of Philadelphia chromosome (+Ph), if occurring in isolation

Poor prognosis (regardless of phase)

• Isochromosome 17q [i(17q)]
• Monosomy 7 or deletion 7q [-7/del(7q)]
• 3q26.2 rearrangements

High-risk combinations

• Multiple ACAs including +17, +19, +21, 11q23, or combination of +Ph with other abnormalities
• Trisomy 8 accompanied by other ACAs confers worse outcomes than trisomy 8 alone

Disease-Related Complications

Organomegaly

• Splenomegaly is common and may result in abdominal discomfort, early satiety, and in rare cases, splenic infarction.
• Hepatomegaly may occur due to extramedullary hematopoiesis.

Anaemia

• Can develop due to marrow infiltration by leukaemic cells or treatment-related myelosuppression.

Platelet Dysfunction

• Both thrombocytosis and thrombocytopenia may occur.
• Patients are at risk for bleeding and, less commonly, thrombosis.

Infections

• Increased susceptibility to bacterial and viral infections, particularly in advanced phases or during treatment with TKIs and after HSCT.
• Latent virus reactivation (e.g., varicella zoster, hepatitis B) is a concern.
• Higher severity and poor vaccination response seen in COVID-19 infections.

Constitutional Symptoms

• Bone pain and fever are more common during disease progression.
• Persistent fever may also suggest transformation to blast phase or infection.

Tyrosine Kinase Inhibitor–Associated Complications

Common Adverse Effects Across TKIs

• Myelosuppression:
  • Grade 3/4 anaemia, neutropenia, or thrombocytopenia.
  • Management includes dose interruption, dose reduction (~30%), and possible use of growth factors.
• Muscle Cramps and Fatigue:
  • Often seen with imatinib; electrolyte replacement may be beneficial.
• Skin Reactions:
  • Rash can occur with various TKIs; typically treated with corticosteroids and dose adjustment.
• QT Prolongation:
  • Most concerning with nilotinib, which carries a black box warning.
  • Requires ECG monitoring, avoidance of QT-prolonging drugs, and correction of electrolyte disturbances.

Agent-Specific Complications

• Dasatinib:
  • Pleural Effusion: Occurs in up to 20%; may be immune-mediated. Presents with dyspnoea. Management includes TKI interruption, diuretics, corticosteroids, or switching to an alternative TKI.
  • Pulmonary Arterial Hypertension: Rare (0.5–3%), presents similarly but in the absence of effusion; requires referral to pulmonary hypertension specialists.
• Ponatinib:
  • Cardiovascular Events: High risk of arterial occlusion, venous thromboembolism, and heart failure. Cardiovascular assessment and dose reduction strategies are essential.
  • Pancreatitis and Hepatotoxicity: Require immediate interruption and specialist input; dose reinitiation is based on risk-benefit re-evaluation.
  • Posterior Reversible Encephalopathy Syndrome (PRES): Rare but serious neurological complication; symptoms include altered mental state, seizures, and vision loss.
• Nilotinib:
  • Associated with vascular events and QT prolongation. Fasting administration is necessary with most formulations (unless otherwise approved). Monitoring and avoidance of interacting drugs is advised.
• Asciminib:
  • Generally well tolerated but may cause pancreatitis and upper respiratory tract symptoms. Long-term safety data continue to evolve.

Haematopoietic Stem Cell Transplant–Related Complications

Infectious Risks

• Post-transplant immunosuppression increases susceptibility to opportunistic infections.
• Prophylactic antimicrobials and regular surveillance are recommended.

Graft-versus-Host Disease (GVHD)

• May occur post-transplant and contributes to long-term morbidity and mortality.

Long-Term Toxicities

• Secondary malignancies and organ dysfunction can emerge years after transplant.

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