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Acute myeloid leukemia (AML) accounts for ~20% of acute leukemia cases in children and adolescents, with higher overall survival rates improving in recent years.1 This improvement is attributable to intense standard chemotherapy and advances in supportive care. However, there is lack of consensus among various international groups regarding best practice.1
In planning for a new trial protocol (CHIP-AML 2022) in pediatric patients with AML, the Nordic-Dutch-Belgian-Spain-Hong-Kong-Israel-Portugal (NOPHO-DB-SHIP) consortium formed a group spanning 14 countries to address issues around supportive care in pediatric AML.1 The NOPHO-DB-SHIP supportive care group met to discuss the topics at three meetings in 2021–2022 and achieved a consensus level of 75–100%.1 Here, we summarize their recommendations published in Expert Review of Anticancer Therapy by Arad-Cohen, et al.1 They include general management of children and adolescent patients with AML, with a specific focus on hyperleukocytosis, tumor lysis syndrome (TLS), coagulation abnormalities and bleeding, infection, typhlitis, malnutrition, cardiotoxicity, and fertility preservation.
Pediatric patients with AML are at risk of complications, such as bleeding, respiratory distress, upper airway obstruction, pulmonary infiltration, and renal and metabolic disturbances; therefore, several general recommendations should be considered (Figure 1).
Figure 1. General supportive care recommendations*
*Data from Arad-Cohen, et al.1
Hyperleukocytosis is defined as a white blood cell count >100 x 109/L and is associated with a higher risk of leukostasis, which can lead to complications, such as bleeding, thrombosis, seizures, stroke, and lung involvement with respiratory distress. There is also an increased risk of renal dysfunction and metabolic disturbances exacerbating TLS due to hyperleukocytosis.
The use of exchange transfusion and leukapheresis for the treatment of hyperleukocytosis is not recommended by the consortium due to the risks and lack of benefit; however, full-dose chemotherapy should be commenced immediately (Figure 2).
Figure 2. Management of hyperleukocytosis*
AML, acute myeloid leukemia; DIC, disseminated intravascular coagulation; ET, exchange transfusion; FAB, French-American-British; FISH, fluorescence in situ hybridization; FFP, fresh frozen plasma; ICU, intensive care unit; LP, leukapheresis; PCR, polymerase chain reaction; PLC, platelet count; M3, acute promyelocytic; M4, myelomonocytic; M5, monocytic; TLS, tumor lysis syndrome.
*Adapted from Arad-Cohen, et al.1
Although TLS is less common in patients with AML compared with those with acute lymphoblastic leukemia, it can still occur. Patients with a white blood cell count >50–100 x 109/L, organomegaly, pre-existing hyperuricemia, lactate dehydrogenase ≥2-times the upper normal limit, increased creatinine, renal and/or urinary tract disorders, severe dehydration, and FAB-M5 (a French-American-British classification of acute monocytic leukemia) have an increased risk of TLS.
Pediatric patients with AML have high incidences of coagulation disorders, such as disseminated intravascular coagulation (DIC). Recommendations for the diagnosis and management of DIC are shown in Figure 3, and include the following:
Thromboprophylaxis and the use of heparin are not recommended. In patients with thromboembolism, treatment should be given on an individual basis due to lack of evidence-based guidelines.
Figure 3. Recommendations for the diagnosis and management of disseminated intravascular coagulation*
aPPT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; PLC, platelet count; PPT, partial thromboplastin time; PT, prothrombin; ULN, upper limit normal.
*Adapted from Arad-Cohen, et al.1
Pediatric patients with AML are at an increased risk of bacterial, fungal, and viral infections, exposing them to fatal complications.
The risk of invasive fungal disease is increased in pediatric patients with AML due to age, prolonged neutropenia, and intensive chemotherapy.
Due to the risk of sepsis, neutropenic fever in pediatric patients with AML is considered a medical emergency, requiring evaluation and empirical treatment of all patients immediately.
amphotericin B should be considered, based on the local policy, imaging, and laboratory findings.
This is a severe abdominal complication that occurs in ~14–38% of neutropenic patients and can lead to mucosal damage.
The consortium does not recommend a neutropenic diet for pediatric patients with AML, as these diets have significant restriction on the types of food an individual is able to consume and there is lack of evidence to justify their use in this population.
Acute, early-onset, and late cardiotoxicity may occur in pediatric patients with AML leading to poor survival outcomes. Pediatric patients are at a higher risk of anthracycline-induced cardiotoxicity even at lower threshold doses.
Figure 4. Recommended cardiac monitoring during and after AML treatment*
AML, acute myeloid leukemia; ECG, electrocardiogram; FS fractional shortening.
*Adapted from Arad-Cohen, et al.1
Most fertility guidelines consider the risk of permanent gonadotoxicity secondary to conventional AML therapy to be <20%, although if myeloablative conditioning is undergone then this risk increases to >80%. Therefore, children undergoing hematopoietic stem cell transplantation may be offered gonadal biopsy cryopreservation, with the following considerations:
The recommendations by the NOPHO-DB-SHIP consortium will facilitate further improved cure rates in a highly susceptible pediatric population with AML. These recommendations are also essential for the implementation of the new CHIP-AML 2022 protocol across 14 countries. Further research is needed to improve the initial management of hyperleukocytosis, define the role of prophylactic antibiotics, and improve cardioprotection, including investigating the beneficial effect of dexrazoxane. As novel agents advance, unique toxicities will emerge, defining new supportive care guidelines in the future.
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