Complications
An oncological emergency requiring immediate management.
TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment (including chemotherapy and targeted agents e.g., venetoclax). Spontaneous TLS is rare; elevated white blood cell count (tumour burden) is a risk factor.
TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.
Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS.
TLS associated with venetoclax may occur as early as 6-8 hours following the first dose in patients with AML.[96] TLS risk assessment should be carried out before administering venetoclax, and guidance on TLS prophylaxis, laboratory monitoring, dose titration, and drug interactions should be strictly adhered to during treatment with venetoclax.[45][96]
A life-threatening complication that may occur if white blood cell (WBC) count is extremely elevated (>100 × 10⁹/L [>100,000/microlitre]).
Symptoms of leukostasis include respiratory distress and altered mental status, caused by leukaemia cells impairing microvascular perfusion in pulmonary and central nervous system tissue, respectively.
In AML patients with hyperleukocytosis, hydroxycarbamide is recommended for leukoreduction.[27][45] Lower WBC count to <25 × 10⁹/L (<25,000/microlitre) before initiating treatment (particularly if hypomethylating agents and venetoclax are to be used).[27][45]
In acute promyelocytic leukaemia (APL) patients with low-risk disease, hydroxycarbamide should be considered to manage high WBC count during treatment with all-trans-retinoic acid (ATRA; also known as tretinoin) and arsenic trioxide (particularly if differentiation syndrome occurs).[45][107]
Urgent leukapheresis may be considered in a symptomatic patient with AML and a very high WBC count; however, this approach is not recommended in patients with APL because leukapheresis may worsen coagulopathy.[27][45][70][107]
Consequence of bone marrow infiltration by leukaemic cells. May also occur as an adverse effect of treatment.
Packed red blood cell transfusion is recommended to keep haematocrit >25%.
Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45] Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in patients with acute promyelocytic leukaemia (APL) or those with significant bleeding.[45][107][117]
Activated partial thromboplastin time and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in patients with APL or those with significant bleeding.[45][107]
Neutropenia may lead to severe infections by endogenous aerobic gram-positive and gram-negative bacteria, and Candida and Aspergillus species.[47]
During acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118] Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118] Increasing neutrophil counts is a useful predictor of treatment response in acute myeloid leukaemia.
Other measures to reduce the risk of febrile neutropenia such as body hygiene, germ-reduced food, and reverse isolation or high-efficiency particulate air filtration are indicated.
Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents.
DIC is frequently present at diagnosis or occurs soon after acute promyelocytic leukaemia patients commence chemotherapy.[62] It is potentially life-threatening.
DIC is less common in patients with acute myeloid leukaemia.[62]
DIC requires emergency management. Refer to the International Society on Thrombosis and Haemostasis (ISTH) scoring system for DIC.[58]
The induction of tumour cell differentiation with all-trans-retinoic acid (also known as tretinoin) and supportive therapy with appropriate blood products can lead to a rapid reversal of the coagulopathy.
AML rarely involves the CNS in adult patients, but may be more common in paediatric AML patients.
Incidence of CNS leukaemia has decreased since the incorporation of cytarabine.[136]
Patients at high-risk for CNS disease include those with extramedullary disease, monocytic differentiation, biphenotypic leukaemia, white blood cell (WBC) count >40 × 10⁹/L (>40,000/microlitre) at diagnosis, FLT3 mutations, or high-risk acute promyelocytic leukaemia.[45]
Morphological and flow cytometric examination of the cerebrospinal fluid confirms the diagnosis.
Treated with intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs).[45]
Drugs used in the management of acute myeloid leukaemia (e.g., ivosidenib, enasidenib, olutasidenib, gilteritinib) and acute promyelocytic leukaemia (e.g., all-trans-retinoic acid [ATRA; also known as tretinoin], arsenic trioxide) can cause differentiation syndrome.[97][98][99][114][115][100]
Differentiation syndrome has been reported as early as 10 days, and up to 5 months, after starting enasidenib.
Differentiation syndrome can be life-threatening if not treated promptly.
Differentiation syndrome is characterised by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated white blood cell (WBC) count (>10 × 10⁹/L [>10,000/microlitre]).
Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion.
Patients with differentiation syndrome should be promptly treated with dexamethasone.[107]
In severe cases, the drug causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[107]
Long-term complications of chemotherapy include myelodysplasia, secondary malignancies, endocrine dysfunction (mainly hypothyroidism), and cardiomyopathy. Investigations are instigated on suspicion.
Infertility may be an issue for younger patients treated for AML, and they should be referred to specialised fertility/assisted conception units.
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