Complications
Pancytopenia is initially caused by bone marrow infiltration by lymphoblasts and later by the myelosuppressive effect of the treatment.
Platelets should be prophylactically transfused once the platelet count is less than 10,000/microliter (10 × 10⁹/L). Packed red blood cell transfusion is recommended to keep hematocrit above 25%. Growth factors have been shown to shorten the duration of neutropenia.[1][90]
Patients receiving induction chemotherapy, 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 acyclovir. During periods of severe neutropenia, prophylaxis with a fluoroquinolone antibiotic is often used.[157] Patients should receive trimethoprim/sulfamethoxazole prophylaxis (or an alternative) to prevent Pneumocystis jirovecii pneumonia infection.[157][192] Fungal prophylaxis (e.g., using fluconazole, itraconazole, or posaconazole) should be considered, though mold infections in ALL are generally less common than with acute myeloid leukemia.[156]
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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.[193]
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).[194]
Long-term penicillin V is advised for patients who are being treated for chronic graft-versus-host disease due to the increased risk of encapsulated bacterial infection. Revaccination is also required.
An oncologic 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.[56][155][156][157][158]
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Risk of febrile neutropenia can be reduced with use of antimicrobial prophylaxis and granulocyte colony-stimulating factors, and by maintaining good body hygiene, and reverse isolation or high-efficiency particulate air filtration.
Mortality rate associated with febrile neutropenia in hospitalized patients with leukemia is reported to be approximately 14%.[159] Use of granulocyte colony-stimulating factors (G-CSFs; e.g., filgrastim, pegfilgrastim) to prevent febrile neutropenia is recommended during myelosuppressive therapy or as directed by the treatment protocol.[57][160]
An oncologic emergency.
Use vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricemic agents (e.g., allopurinol or rasburicase) to prevent or treat TLS. TLS is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and/or elevated serum lactate dehydrogenase, which can occur following chemotherapy (or spontaneously in rare cases), particularly if WBC count (tumor burden) is high. Close monitoring is essential.
TLS can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated.
Nausea, mucositis, diarrhea, constipation, and abdominal pain may result from treatment and will vary in degree between patients.
Antiemetics should be given as needed before and after chemotherapy.[57] An H2 antagonist or proton-pump inhibitor should be considered if patients are receiving high doses of corticosteroids.[57]
Most patients will develop absolute alopecia due to the cytotoxic regimen, or due to radiation therapy. 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 lymphoma/leukemia, 13%).[50][51][52][53][54]
CNS involvement can lead to severe neurologic morbidity (e.g., cranial nerve palsies), and is a major obstacle to cure, accounting for up to 40% of initial relapses in clinical trials.[82][83][84] 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.[50][51][85][86][87][88] However, outcomes are often poor in patients with CNS relapse (median overall survival <1 year).[89] Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic SCT.[59][69]
Asparaginase, and pegylated formulations of Escherichia coli-derived asparaginase, such as pegaspargase, are associated with hepatotoxicity, central nervous system toxicity, pancreatitis, hyperglycemia, allergic reactions/anaphylaxis, and thrombosis due to AT3 and fibrinogen depletion.[185][186][187][188]
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.[189][190][191]
Occurs with white blood cell count of more than 100,000/microliter, thereby impairing circulation and resulting in organ dysfunction: e.g., pulmonary infiltrates, coma, seizures, and retinal hemorrhages.
Leukapheresis may be considered in patients with symptomatic leukostasis (hyperleukocytosis) prior to initiation of induction therapy. Systemic therapy (e.g., cytarabine, hydroxyurea, and/or corticosteroids) can also achieve urgent cytoreduction in this situation.
Semen cryopreservation should be offered to male patients postpuberty.
Options for female patients are limited and merit discussion with the fertility center. 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 harbor malignant cells, which may cause disease recurrence when reimplanted.[164]
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 ages under 20 years is 17%, and 3% in those ages over 20 years.[195]
MRI is the diagnostic investigation of choice; treatment is joint replacement.[196]
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.[163] Dexrazoxane does not appear to compromise overall survival in adults or children receiving an anthracycline.[202][203]
Some studies suggest a protective role for carvedilol in preventing doxorubicin-induced cardiotoxicity. Further research is required.[204][205] 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 restart 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.[194][197] 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).[194]
Some recovery is expected but may not be complete and may be slow.
Blinatumomab is associated with cytokine release syndrome and neurologic toxicity.[143]
Inotuzumab ozogamicin is associated with severe hepatotoxicity (including veno-occlusive liver disease).[150]
Tisagenlecleucel (a CD19-targeted chimeric antigen receptor [CAR] T-cell immunotherapy) is associated with cytokine release syndrome.[147][151][152] Brexucabtagene autoleucel (a CD19-targeted CAR T-cell immunotherapy) is associated with cytokine release syndrome and neurologic toxicity.[148] T-cell malignancies may also occur following treatment with CD19-targeted CAR T-cell immunotherapies.[154] Some cases have occured 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.[153]
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported with ponatinib.[206] Presenting signs and symptoms may include seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurologic disturbances.
Treatment should be interrupted if PRES is confirmed; a decision to restart should be guided by a benefit-risk assessment.
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