Side effects of systemic cancer therapy - bone marrow suppression
Lineages and timing
- Suppression of the rapidly dividing haematopoietic compartment - the dose-limiting toxicity of most cytotoxic chemotherapy
- Three lineages, three different problems and three different timelines
| Lineage | Consequence | Nadir | Recovery |
|---|---|---|---|
| Neutrophils | Infection - the one that kills | Days 7-14 | Days 21-28 |
| Platelets | Bleeding | Days 7-14 | Days 21-28 |
| Red cells | Fatigue, dyspnoea | Later (120-day RBC lifespan) | Slow, cumulative |
- *Neutropenic fever is the emergency; anaemia and thrombocytopenia rarely are*
Epidemiology and risk factors
- Febrile neutropenia in ~10-50% of cytotoxic regimens depending on intensity
- Anaemia in up to 90% of patients receiving chemotherapy
- Risk factors for severe/prolonged myelosuppression: age >65, poor performance status, prior chemotherapy or radiotherapy to marrow-bearing bone, marrow infiltration, renal or hepatic impairment, low baseline counts, malnutrition, comorbidity
- Regimen-specific: anthracycline/cyclophosphamide, platinum-taxane, ifosfamide, topotecan, and all induction regimens for acute leukaemia carry the highest risk
Mechanisms
- Cytotoxics kill dividing haematopoietic progenitors
- Cell-cycle-specific agents (antimetabolites, taxanes) -> earlier, shorter nadir
- Alkylating agents and nitrosoureas -> later (weeks 4-6), prolonged, sometimes cumulative and permanent stem cell damage
- Additional mechanisms
- Marrow infiltration by tumour (leukaemia, lymphoma, myeloma, small cell, breast, prostate)
- Radiotherapy to marrow-bearing bone - pelvis, spine, sternum; up to 50% of active marrow is in the pelvis
- Nutritional - B12, folate, iron deficiency (often coexisting and correctable)
- Renal impairment -> reduced erythropoietin
- Chronic inflammation -> functional iron deficiency (hepcidin-mediated)
- Drug-specific: CDK4/6 inhibitors cause cell-cycle arrest of neutrophil precursors rather than cytotoxic death - hence neutropenia is common but *febrile neutropenia is NOT increased*, and it reverses within days of interruption
- Immune-mediated cytopenias (checkpoint inhibitors), TTP/HUS (gemcitabine, mitomycin)
- Late: therapy-related MDS/AML from alkylators (5-7 yr latency, chromosome 5/7 deletions) and topoisomerase-II inhibitors (1-3 yr, 11q23/MLL)
Definitions
| Threshold | |
|---|---|
| Neutropenia | ANC <1.5 x10^9/L |
| Severe neutropenia | ANC <0.5 (or <1.0 and predicted to fall below 0.5) |
| Febrile neutropenia | ANC <0.5 (or expected to fall) + single temperature >=38.3 degC, or >=38.0 degC sustained over 1 hour |
| Thrombocytopenia | Plt <100; spontaneous bleeding risk rises below 10-20 |
| Anaemia | Hb <130 (M) / <120 (F) |
Assessment of febrile neutropenia
- *A fever in a neutropenic patient is sepsis until proven otherwise - antibiotics within 60 minutes, before imaging or results*
- Examine: mouth, skin, line sites, perineum (never do a PR - risk of bacteraemia), chest, abdomen
- FBE and film, UEC, LFT, CRP, lactate, blood cultures (peripheral AND each lumen of any central line), urine, CXR
- MASCC score stratifies low vs high risk; low-risk patients may be suitable for oral outpatient therapy in a supported setting
- Signs of inflammation are blunted - there may be no consolidation on CXR, no pus, no peritonism
Anaemia workup - do not just transfuse
- Iron studies, B12, folate, reticulocytes, haemolysis screen (LDH, haptoglobin, bilirubin, DAT), renal function
- Blood film - blasts, leucoerythroblastic picture (marrow infiltration), schistocytes (TTP/HUS)
- Bone marrow if unexplained or persisting after recovery expected
Febrile neutropenia - the emergency
A. Febrile neutropenia - the emergency
- Empirical IV antibiotics within 60 minutes: piperacillin-tazobactam 4.5 g IV (or cefepime); add gentamicin if shocked; vancomycin only for line infection, skin/soft tissue infection, MRSA colonisation or haemodynamic instability
- Fluid resuscitation, sepsis pathway
- Reassess at 48-72 h; consider antifungal cover if fever persists beyond 4-7 days (esp. haematology patients)
- Antimicrobial adjustment by culture; de-escalate once afebrile and recovering
- G-CSF is not routine treatment for established febrile neutropenia; consider in high-risk, prolonged, or profoundly neutropenic patients
Prevention of neutropenia
B. Prevention of neutropenia
- G-CSF primary prophylaxis (filgrastim, pegfilgrastim) when the regimen's febrile neutropenia risk is >=20%, or 10-20% with patient risk factors
- Also permits dose-dense scheduling
- Bone pain is common - loratadine or simple analgesia
- Secondary prophylaxis after an episode of febrile neutropenia, where dose reduction would compromise cure
- Dose reduction or delay where the intent is palliative
- Antimicrobial prophylaxis (fluoroquinolone, aciclovir, PJP, azole) in specified high-risk groups - haematology and transplant, not solid tumours generally
- Vaccination (inactivated only; avoid live vaccines), hand hygiene, dental review
Thrombocytopenia
C. Thrombocytopenia
- Prophylactic platelet transfusion if Plt <10 (<20 if febrile/sepsis; <50 for procedures; <100 for neurosurgery or ocular surgery)
- Avoid NSAIDs, aspirin and anticoagulation where possible; tranexamic acid for mucosal bleeding
- Delay or reduce the next cycle
- Consider drug-induced immune thrombocytopenia, TTP/HUS (gemcitabine, mitomycin), heparin-induced thrombocytopenia and DIC
Anaemia
D. Anaemia
- Correct what is correctable first - iron (IV if functional deficiency), B12, folate
- Transfuse for symptoms, not a number - restrictive threshold Hb <70 g/L (or <80 with cardiac disease or symptoms)
- Erythropoiesis-stimulating agents: only in chemotherapy-induced anaemia with palliative intent
- *Avoid where the intent is cure - inc thrombosis, and evidence of worse tumour outcomes in some cancers*
- Ensure iron replete before starting
Growth factor and dose-modification principles
D. Growth factor and dose-modification principles
- Do not reduce the dose of a curative regimen for uncomplicated neutropenia - add G-CSF instead
- Do reduce the dose in palliative regimens - quality of life is the endpoint
- CDK4/6 inhibitor neutropenia is managed by dose interruption and reduction, not G-CSF
Culprit agents
- Alkylating agents, anthracyclines, antimetabolites, platinums, taxanes, topoisomerase inhibitors
- CDK4/6 inhibitors (palbociclib, ribociclib) - neutropenia without increased febrile neutropenia
- PARP inhibitors - anaemia predominantly; rarely MDS/AML
- Antibody-drug conjugates (sacituzumab govitecan, T-DM1 - thrombocytopenia)
- Radiotherapy to pelvis, spine, sternum; radiopharmaceuticals (Lu-177, Ra-223)
- Marrow infiltration - leukaemia, lymphoma, myeloma, small cell lung, breast, prostate
- Nutritional deficiency, renal impairment, hypersplenism
- Concurrent drugs - co-trimoxazole, linezolid, valganciclovir, allopurinol, azathioprine
- Therapy-related MDS/AML - the late consequence
- Immune cytopenias from checkpoint inhibitors; CAR-T-associated prolonged cytopenias
Nadir and recovery
- Nadir at days 7-14, recovery by days 21-28 for most 3-weekly regimens - the reason cycles are 21 days long
- Nitrosoureas and mitomycin have a delayed nadir at 4-6 weeks and cumulative marrow damage
- Cumulative toxicity: counts recover more slowly with each successive cycle
- Febrile neutropenia mortality ~5-10%, higher with shock, prolonged neutropenia, or haematological malignancy
- Prolonged neutropenia (>7 days) -> invasive fungal infection (Aspergillus, Candida)
- Most cytopenias resolve fully; prolonged or irreversible marrow failure after heavy alkylator exposure, extensive radiotherapy, or CAR-T
- Therapy-related MDS/AML - latency 1-3 yr (topoisomerase-II) or 5-7 yr (alkylators); poor prognosis
- A single episode of febrile neutropenia usually changes the whole subsequent treatment plan - G-CSF support, dose reduction, or a different regimen
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