EBL: Specialist and TDM and SACT Toxicities

How does mechanism of toxicity differ between immunotherapy, chemotherapy, and targeted therapy?

Immunotherapy: Overactivation of immune system, leading to immune-related adverse events

Chemotherapy: Direct damage to rapidly dividing cells (both cancerous and healthy)

Targeted therapy: Off-target effects on molecular pathways affecting normal cells

How do common toxicities differ between immunotherapy, chemotherapy, and targeted therapy?

Immunotherapy: Fatigue, immune-related adverse events (e.g. colitis, pneumonitis, endocrinopathies)

Chemotherapy: Nausea, vomiting, hair loss, bone marrow suppression, neutropenia, bleeding risk, mouth ulceration, diarrhoea

Targeted therapy: Skin rash, diarrhoea, liver toxicity, cardiotoxicity (more specific side effects)

How does severity differ between immunotherapy, chemotherapy, and targeted therapy?

Immunotherapy: Can be severe if immune system attacks healthy organs

Chemotherapy: Often severe due to effects on normal cells

Targeted therapy: Moderate, dependent on drug target

How does onset of toxicity differ between immunotherapy, chemotherapy, and targeted therapy?

Immunotherapy: Delayed (weeks to months)

Chemotherapy: Immediate (within days)

Targeted therapy: Gradual (weeks)

How do long-term effects differ between immunotherapy, chemotherapy, and targeted therapy?

Immunotherapy: Potential for chronic autoimmune conditions

Chemotherapy: Secondary malignancies, infertility

Targeted therapy: Long-term organ damage (e.g. heart, liver)

How does management differ between immunotherapy, chemotherapy, and targeted therapy?

Immunotherapy: Corticosteroids, immunosuppressants

Chemotherapy: Supportive care (antiemetics, growth factors). Focus on boosting the function of affected cells

Targeted therapy: Dose modifications, symptomatic management. Pause treatment until symptoms resolve

How is hyperuricaemia defined?

Urate ≥ 476 µmol/L or 25% increase from baseline

What are the signs/symptoms of hyperuricaemia?

• Nausea

• Vomiting

• Lethargy

• Anorexia

• Haematuria

• Olig-/anuria

How is hyperuricaemia treated?

• Give rasburicase unless contraindicated

  • Dose as per local preference

• Use febuxostat if both rasburicase and allopurinol contraindicated

• Aggressive hydration: 3L/m²

• If hyperuricaemia persists or rasburicase is contraindicated, contact renal team urgently to discuss need for dialysis

How is hyperphosphataemia defined?

Phosphate ≥ 1.45 mmol/L or 25% increase from baseline

How is hyperphosphataemia treated?

• Control with hydration and maintenance of high urine output

• Uncontrolled hyperphosphataemia is an indication for dialysis

• High phosphate levels are difficult to control other than by dialysis: oral phosphate binders (e.g. aluminium hydroxide) are slow to act and poorly tolerated by ill patients. They should be seldom used except if patient is considered unfit for dialysis or as a temporary measure where immediate access to renal dialysis is not available

How is hypocalcaemia defined?

Adjusted calcium ≤ 1.75 mmol/L or 25% decrease from baseline

What are the signs/symptoms of hypocalcaemia?

• Lengthening of QT interval on ECG (ventricular arrhythmias)

• Muscle cramps

• Tetany

• Seizures

How is hypocalcaemia treated?

• Continuous cardiac monitoring

• No treatment unless symptomatic

• If symptomatic give calcium gluconate 1g (10ml of 10% solution) by slow IV injection over 10 minutes under continuous ECG monitoring

How is hyperkalaemia defined?

Moderate: Potassium 6.0-6.9 mmol/L or 25% increase from baseline

Severe: Potassium ≥ 7.0 mmol/L

What are the signs/symptoms of hyperkalaemia?

Cardiac arrhythmias

How is moderate hyperkalaemia treated?

• Continuous cardiac monitoring

• Management as per local guidelines: Emergency Management of Hyperkalaemia in Adults

How is severe hyperkalaemia treated?

Haemodialysis

What is the treatment for oliguria and fluid retention?

Furosemide (IV) 0.5mg/kg or mannitol

Describe what the BCR-ABL fusion gene is.

• An abnormal gene that results from the Philadelphia chromosome (Ph) translocation, specifically t(9;22)(q34;q11)

• This translocation fuses the BCR (Breakpoint Cluster Region) gene on chromosome 22 with the ABL1 (Abelson proto-oncogene) gene on chromosome 9

• The fusion leads to the production of the BCR-ABL oncoprotein, a constitutively active tyrosine kinase, which drives uncontrolled cell proliferation and survival

How does the BCR-ABL fusion gene promote the hallmarks of cancer?

Sustaining Proliferative Signalling

• Continuously activates key signalling pathways, including RAS/MAPK, PI3K/AKT, and JAK/STAT, leading to constant stimulation of cell cycle progression and proliferation

Evading Growth Suppressors

• Inhibits tumour suppressor pathways, such as p53 and RB, allowing cells to bypass normal growth-inhibitory signals

Apoptosis Evasion

• Enhances the expression of anti-apoptotic proteins like Bcl-2 and Bcl-xL, protecting leukaemic cells from programmed cell death

Enabling Replicative Immortality

• Indirectly supports telomerase activation, preventing telomere shortening and allowing unlimited replication

Inducing Angiogenesis

• Increases the expression of VEGF, promoting the formation of new blood vessels to supply the growing tumour

Activating Invasion and Metastasis

• Advanced phases (blast crisis) show increased invasion potential due to changes in adhesion and migration signalling

Describe how Imatinib specifically targets the BCR-ABL fusion gene.

• Imatinib is a TKI that specifically targets the BCR-ABL fusion protein in CML and Philadelphia chromosome-positive (Ph+) ALL

• The BCR-ABL fusion protein has constitutively active tyrosine kinase activity, which continuously phosphorylates downstream signalling molecules, leading to uncontrolled proliferation and survival of leukaemic cells

• Imatinib binds to the ATP-binding site of the ABL1 kinase domain, stabilising the kinase in an inactive conformation and blocking ATP binding

• Without ATP, BCR-ABL cannot phosphorylate its substrates, leading to disruption of oncogenic signalling pathways

What are the cell signalling pathways involved when imatinib targets the BCR-ABL fusion gene?

RAS/MAPK (Mitogen-Activated Protein Kinase) Pathway

• Normal function: Promotes cell proliferation through ERK1/2 activation

• Imatinib inhibits BCR-ABL-induced RAS activation, leading to cell cycle arrest and decreased proliferation

PI3K/AKT/mTOR Pathway

• Normal function: Enhances cell survival and growth via AKT phosphorylation

• Imatinib suppresses AKT activation, reducing survival signals and increasing apoptosis

JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) Pathway

• Normal function: Stimulates proliferation and anti-apoptotic gene expression

• Imatinib reduces phosphorylation of STAT5, reducing expression of Bcl-XL and Mcl-1, promoting apoptosis

c-Myc and Cell Cycle Regulation

• BCR-ABL enhances c-Myc expression, driving rapid cell cycle progression

• Imatinib downregulates c-Myc, leading to G1 cell cycle arrest and inhibition of leukaemic cell expansion

What are the functional consequences of imatinib on cancer cells?

• Leukaemic cells undergo apoptosis

• Halts uncontrolled proliferation → leads to G1-phase arrest and prevents clonal expansion

• Normal bone marrow function is re-established, allowing normal blood cell production

• Reduces progression to blast crisis, a deadly phase of CML

What are the common adverse effects of imatinib?

• GI issues

  • Nausea and vomiting

  • Diarrhoea

  • Abdominal pain

• Oedema and fluid retention

  • Periorbital swelling

  • Ankle swelling

• Fatigue and weakness

  • Mild lethargy

  • Muscle cramps

• Skin reactions

  • Rash

  • Dry skin

  • Pruritus

What counselling would you provide to a patient about self-care and monitoring at home for imatinib?

• Take with food and a full glass of water to reduce nausea

• Stay hydrated to prevent diarrhoea

• Elevate legs if experiencing ankle swelling

• Reduce salt intake to minimise fluid retention

• Report sudden weight gain (≥2 kg in a week) to your doctor

• Watch for signs of infection (fever, sore throat) - report immediately

• If bruising or bleeding occurs, consult a doctor

• Gentle stretching exercises for muscle cramps

• Apply moisturisers for dry skin

• Avoid excess sun exposure; use sunscreen

• Watch for jaundice or dark urine (possible liver issue)

What are the pre-screening requirements before starting treatment with 6-MP, and why are they needed?

Required

Baseline

• Full blood count

  • Can cause myelosuppression, leading to neutropenia, anemia, and thrombocytopenia

• Liver function tests

  • Metabolised in the liver and can cause hepatotoxicity (elevated ALT, AST, bilirubin)

• Urea and electrolytes

• TPMT assay

  • TPMT is an enzyme that metabolises 6-MP

  • TPMT deficiency can lead to excessive drug accumulation and severe toxicity, particularly myelosuppression

• Serum creatinine (for creatinine clearance) or eGFR

  • Ensures normal kidney function as impaired renal clearance may increase drug toxicity

Consider

Baseline

• Epstein Barr Virus - consider antivirals in acute infection

• Hep B and C

  • Suppresses the immune system, increasing the risk of viral reactivation

• HIV

  • Immunosuppression from chemotherapy increases infection risk

• NUDT15 genotype

  • NUDT15 deficiency (common in East Asian and Hispanic populations) increases sensitivity to 6-MP, leading to severe bone marrow suppression

• Varicella Zoster Virus Immunity - if no history of infection; vaccinate if low

During treatment with 6-MP, clinical monitoring is conducted by the hospital team. What specific clinical monitoring would you expect to see and at what frequency do you recommend it occurs?

After started or dose changed

• At week 2, 4, 8 and 12

  • Full blood count

  • Liver function tests

  • Serum creatinine (for CrCl) or eGFR

    Urea and electrolytes

Ongoing once stable

• Every 3 months

  • Full blood count

  • Liver function tests

  • Serum creatinine (for creatinine clearance) or eGFR

  • Urea and electrolytes