Complications
Pancytopenia is initially caused by bone marrow infiltration by lymphoblasts and later by the myelosuppressive effects of the treatment.
Platelets should be prophylactically transfused once the platelet count is less than 10 × 10⁹/L (10,000/microlitre). Packed red blood cell transfusion is recommended to keep haematocrit above 25%. Growth factors have been shown to shorten the duration of neutropenia.[1][98]
Patients receiving treatment, or those with neutropenia, CD4 lymphopenia, antibody deficiency, and/or multiple immunosuppressions due to transplants, are at greater risk of infection.
Prophylactic antimicrobial agents that cover all possible infections should be given. Selection of agents varies based on individual unit protocols and individual patient needs.
Prevention of herpes virus reactivation can be accomplished with aciclovir. During periods of severe neutropenia, prophylaxis with a fluoroquinolone antibiotic is often used.[163] Patients should receive trimethoprim/sulfamethoxazole prophylaxis (or an alternative) to prevent Pneumocystis jirovecii pneumonia infection.[163][189] Fungal prophylaxis (e.g., using fluconazole, itraconazole, or posaconazole) should be considered, though mould infections in ALL are generally less common than with acute myeloid leukaemia.[162]
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Fluoroquinolones are associated with disabling and potentially permanent nervous system and musculoskeletal adverse effects and should be used with caution, particularly in patients with renal impairment, patients who are older, those who have a history of solid organ transplantation, or those who are receiving corticosteroids.[190]
Azole antifungals can interfere with metabolism and clearance of vincristine, so either the dose of vincristine should be reduced or the azole substituted with an alternative agent (e.g., an echinocandin, liposomal amphotericin B).[191]
Long-term phenoxymethylpenicillin is advised for patients who are being treated for chronic graft-versus-host disease due to the increased risk of encapsulated bacterial infection. Re-vaccination is also required.
An oncological emergency.
Careful history collection, thorough physical examination, and early extensive diagnostic procedures are warranted in the evaluation of febrile neutropenia. Pancultures are mandatory.
Risk of infection is greatest following induction chemotherapy when neutropenia is profound and prolonged. Use antibiotics, antifungals, and antivirals to prevent or treat infections and febrile neutropenia.[62][161][162][163][164]
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Risk of febrile neutropenia can be reduced with use of antimicrobial prophylaxis and granulocyte colony-stimulating factors (G-CSFs; e.g., filgrastim, pegfilgrastim), and by maintaining good body hygiene, and reverse isolation or high-efficiency particulate air filtration.
Mortality rate associated with febrile neutropenia in hospitalised patients with leukaemia is reported to be approximately 14%.[165] Use of G-CSFs to prevent febrile neutropenia is recommended during myelosuppressive therapy or as directed by the treatment protocol.[60][166]
An oncological emergency.
Use vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) to prevent or treat TLS. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following chemotherapy (or spontaneously in rare cases), particularly if WBC count (tumour burden) is high. Close monitoring is essential.
TLS can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated.
Nausea, mucositis, diarrhoea, constipation, and abdominal pain may result from treatment and will vary in degree between patients.
Anti-emetics should be given as needed before and after chemotherapy.[60] An H2 antagonist or proton-pump inhibitor should be considered if patients are receiving high doses of corticosteroids.[60]
Most patients will develop absolute alopecia due to the cytotoxic regimen, or due to radiotherapy. Hair will regrow at the end of chemotherapy treatment, although may be thinner after total body irradiation or cranial irradiation.
Central nervous system (CNS) involvement is a major complication of ALL. CNS involvement occurs in 5% to 7% of patients at diagnosis; incidence is highest in patients with T-ALL (8%) and mature B-ALL (Burkitt's lymphoma/leukaemia, 13%).[9][55][56][57][58]
CNS involvement can lead to severe neurological morbidity (e.g., cranial nerve palsies), and is a major obstacle to cure, accounting for up to 40% of initial relapses in clinical trials.[90][91][92] Studies have shown that use of intensive regimens in patients with CNS involvement at diagnosis results in similar outcomes (e.g., complete remission, disease-free survival, and overall survival) to patients without CNS involvement at diagnosis, particularly among adults.[55][56][93][94][95][96] However, outcomes are often poor in patients with CNS relapse (median overall survival <1 year).[97] Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for post-remission allogeneic SCT.[74][82]
Pegylated formulations of Escherichia coli-derived asparaginase (e.g., pegaspargase and calaspargase pegol), are associated with hepatotoxicity, central nervous system toxicity, pancreatitis, hyperglycaemia, allergic reactions/anaphylaxis, and thrombosis due to AT3 and fibrinogen depletion.[182][183][184][185]
Crisantaspase (asparaginase Erwinia chrysanthemi recombinant) should be used in patients who develop sensitivity to pegaspargase or calaspargase pegol.[60]
There is a suggestion that targeted replacement of clotting factors can reduce the risk of thrombotic events and is justified in high-risk patients, but this is not routine clinical practice.[186][187][188]
Occurs with WBC of more than 100 × 10⁹/L (100,000/microlitre), thereby impairing circulation and resulting in organ dysfunction: e.g., pulmonary infiltrates, coma, seizures, and retinal haemorrhages.
Leukapheresis may be considered in patients with symptomatic leukostasis (hyperleukocytosis) prior to initiation of induction therapy. Systemic therapy (e.g., cytarabine, hydroxycarbamide, and/or corticosteroids) can also achieve urgent cytoreduction in this situation.
High-dose methotrexate and intrathecal methotrexate is associated with methotrexate encephalopathy and may reflect differences in intracranial folate homeostasis.[195][196][197]
Crisantaspase (L-asparaginase Erwinia chrysanthemi) is associated with the development of sagittal sinus venous thromboses.[198]
Semen cryopreservation should be offered to male patients post-puberty.
Options for female patients are limited and merit discussion with the fertility centre. There will typically be insufficient time to stimulate oocyte production to allow oocyte or embryo (if a partner is available) cryopreservation. Furthermore, cryopreserved ovarian tissue from female patients with ALL can harbour malignant cells, which may cause disease recurrence when re-implanted.[170]
Avascular necrosis typically affects the heads of the femora and humeri and is associated with high corticosteroid intensity regimens in adolescents. The cumulative incidence in those aged under 20 years is 17%, and 3% in those aged over 20 years.[192]
MRI is the diagnostic investigation of choice; treatment is joint replacement.[193]
Anthracycline (e.g., doxorubicin) use increases the long-term risk of cardiotoxicity, especially if the total dose exceeds a doxorubicin isotoxic dose of 450 mg/m² or is combined with cardiac irradiation.
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Dexrazoxane can be used to protect against anthracycline-related cardiotoxicity (e.g., when cumulative dose of doxorubicin is ≥300 mg/m²), though experience with this agent in adults is limited.[169] Dexrazoxane does not appear to compromise overall survival in adults or children receiving an anthracycline.[199][200]
Some studies suggest a protective role for carvedilol in preventing doxorubicin-induced cardiotoxicity.[201][202] Further research is required.
Ponatinib is associated with serious adverse events (e.g., severe cardiovascular events, hepatotoxicity).
Ponatinib should be interrupted immediately if serious adverse events occur, and a decision to re-start should be guided by a benefit-risk assessment.
Vincristine is associated with a painless sensory neuropathy as well as slowed gastrointestinal motility (constipation) and jaw pain. Toxicity is increased in predisposed individuals or if used in conjunction with azole antifungals.[191][194] In the latter scenario, the dose of vincristine should be reduced or the azole substituted with an alternative agent (e.g., an echinocandin, liposomal amphotericin B).[191]
Some recovery is expected but may not be complete and may be slow.
Blinatumomab is associated with cytokine release syndrome and neurological toxicity.[147]
Inotuzumab ozogamicin is associated with severe hepatotoxicity (including sinusoidal obstruction syndrome).[156]
Tisagenlecleucel (a CD19-targeted chimeric antigen receptor [CAR] T-cell immunotherapy) is associated with cytokine release syndrome.[152][157][158] Brexucabtagene autoleucel and obecabtagene autoleucel (CD19-targeted CAR T-cell immunotherapies) are associated with cytokine release syndrome and neurological toxicity.[79][153] T-cell malignancies may also occur following treatment with CD19-targeted CAR T-cell immunotherapies.[160] Some cases have occurred weeks after treatment, and some have been fatal.
Tocilizumab is recommended for the management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome.[159]
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported with ponatinib.[203] Presenting signs and symptoms may include seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.
Treatment should be interrupted if PRES is confirmed; a decision to re-start should be guided by a benefit-risk assessment.
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