Abstract
The CACA Guidelines was summarized by Hematology Oncology Committee of China Anti- Cancer Association. This portion of the CACA Guidelines for adult acute myeloid leukemia (AML) not only focuses on diagnosis, the treatment options for younger (age < 60 years) and older (age ≥ 60 years) patients (including non-APL, APL, R/R AML), but also pay attention to the treatment of AML complications, including central nervous system leukemia (CNSL), cardiotoxicity, agranulocytosis and fever, hepatitis B virus reactivation, uric acid nephropathy, bleeding and coagulation disorders, and nursing for patients with AML from the perspective of holistic integrative medicine to enhance the quality of life and treatment effects.
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1 Diagnosis of adult acute myeloid leukemia
1.1 Diagnosis of adult acute myeloid leukemia
The diagnostic criteria for acute myeloid leukemia (AML) are based on the World Health Organization (WHO) 2016 classification criteria for tumors of hematopoietic and lymphoid tissues. Blast cells ≥ 20% in peripheral blood or bone marrow are the necessary for the diagnosis of AML. If patients are confirmed to have recurrent cytogenetic abnormalities including t (8; 21) (q22; q22), inv (16) (p13; q22) or t (16; 16) (p13; q22) and t (15; 17) (q22; q12), they should be diagnosed with AML even when blast cells are < 20% [1].
During clinical reception, history-taking should include age, the past medical history and treatment situation (especially the history of blood diseases or history of tumors), vital organs insufficiency, extramedullary infiltration, and the family history (especially the history of blood diseases or history of tumors), as well as the history of inherited metabolic diseases. For patients suspected of having leukemia, medical examinations should be carried out, while in the diagnosis process, bone marrow cell morphology (cell morphology, cytochemistry and histopathology), immunophenotyping and cytogenetics (karyotypes) should be assessed. When necessary, fluorescence in situ hybridization (FISH) and molecular tests for fusion genes and gene mutations related to leukemia should be conducted. Human leukocyte antigen (HLA) matching may be performed for patients undergoing allogeneic hematopoietic stem cell transplantation.
1.2 Prognosis and stratification factors of AML
1.2.1 Poor prognosis factors for AML
Age ≥ 60 years old and a history of myelodysplastic syndromes (MDS) or myeloproliferative neoplasm (MPN), treatment-related/secondary AML, hyperleukocytosis (≥ 100 × 109/L), central nervous system leukemia (CNSL), or extramedullary infiltration (except for liver, spleen and lymph node involvement), among other factors, are factors indicating a poor prognosis of AML.
1.2.2 Risk rating of cytogenetic/molecular genetic indexes
Genetic prognostic grouping for AML is carried out according to the cytogenetic and molecular genetic abnormalities of AML during diagnosis, as shown in Table 1 [2,3,4,5,6,7,8].
1.3 Diagnosis of relapsed or refractory acute myeloid leukemia (R/R AML)
1.3.1 Diagnostic criteria for relapsed AML
Leukemia blast cells ≥ 0.05 in bone marrow or peripheral blood reoccur after complete remission (CR) (except for other reasons including bone marrow regeneration after consolidation chemotherapy), or the occurrence of extramedullary infiltration of leukemia cells are factors for the diagnosis of relapsed AML.
1.3.2 Diagnostic criteria for refractory leukemia
Patients who do not achieve CR after 2 courses of standard treatment regimens, patients who relapse within 12 months following CR; patients who relapse more than 12 months after CR but not CR after re-induction treatment; patients who relapse for 2 or more times, and patients with persistent AML are diagnosed with refractory leukemia.
2 Treatment and nursing of adult acute myeloid leukemia and its complications
For patients with AML (not APL), participation in clinical studies is first recommended. If patients are not able to participate in a clinical study, they should be treated according to the following suggestions.
2.1 Treatment of preliminarily diagnosed AML (not APL)
2.1.1 Treatment for patients with AML < 60 years old
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(1)
Induction treatment (Table 2)
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(2)
Monitoring after induction treatment
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(3)
Treatment options after CR of AML (Table 6)
The treatment options after the remission of AML should be not only based on the above genetic risk grouping but also dynamically adjusted according to the measurable residual disease (MRD). For patients who are persistently positive for MRD or for whom MRD becomes positive after being negative, especially those who are positive for MRD after consolidation treatment, hematopoietic stem cell transplantation is recommended even if the patients are in the good or intermediate prognosis group. Multiparameter flow cytometry and PCR can be used for the detection of MRD.
2.1.2 Treatment for patients ≥ 60 years old
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(1)
Induction treatment for patients ≥ 60 years old (Table 7)
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(2)
Bone marrow monitoring after intensive induction chemotherapy for patients ≥ 60 years old with AML (Table 8)
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(3)
Treatment options for patients ≥ 60 years old after CR of AML
Treatment options after CR through standard-dose induction chemotherapy:
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① A standard dose of Ara-C (75-100 mg/m2/d for 5–7 days) is used as the consolidation and intensification regimen, which can be combined with anthracyclines or anthraquinones (IDA, DNR or Mitox, etc.), HHT, podophyllotoxin analogues. The total cycle of chemotherapy after remission is 4–6 courses.
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② 4–6 doses of Ara-C (0.5-2 g/m2/q12h) for 1–2 courses of treatment for fit patients < 70 years old with normal renal functions (creatinine clearance rate ≥ 70 mL/min) and good prognostic karyotypes or normal karyotypes accompanied by good molecular genetic abnormalities, followed by standard-dose treatment. The total cycle of treatment after remission is 4–6 courses.
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③ Allogeneic hematopoietic stem cell transplantation with nonmyeloablative condition for fit patients < 70 years old with normal organ functions, poor prognostic factors and suitable donors [34, 35].
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④ Treatment with demethylation drugs (such as azacitidine or decitabine) until the disease progresses.
Treatment options after CR with low-intensity induction chemotherapy: For some patients who can tolerate standard-dose chemotherapy after CR with a good prognosis, the treatment regimen can be changed to intensive chemotherapy. Alternatively, low-intensity treatment regimen may be continued as well.
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(4)
Maintenance treatment
Demethylation drugs (azacitidine or decitabine) can be used for maintenance treatment after induction and consolidation treatment until the disease progresses [36, 37].
2.2 Treatment of acute promyelocytic leukemia
In recent years, all trans retinoic acid (ATRA) and arsenious oxide have been used for the treatment of acute promyelocytic leukemia (APL) so that APL can be cured without hematopoietic stem cell transplantation (Table 9).
2.3 Treatment of relapsed or refractory AML
Examinations of chromosomes and molecular abberations (such as next-generation sequencing, RNA sequencing) should be carried out for relapsed or refractory AML(R/R AML) to assess the disease status and choose the appropriate regimens or clinical trials Early relapse refers to relapse within 12 months after remission, while late relapse refers to the relapse more than 12 months after remission (Tables 10 and 11).
2.4 Treatment of complications in patients with AML
2.4.1 Treatment of CNSL
The incidence of CNSL in AML is usually less than 3%. It is recommended by the National Comprehensive Cancer Network (NCCN) that lumbar puncture shouldn’t be routinely performed for patients without CNS symptoms at initial diagnosis. Lumbar puncture and intrathecal injection (Ara-C 40-50 mg and/or MTX 5-15 mg + dexamethasone5-10 mg) for patients with CR in CNSL screening (Table 12). Four times of intrathecal injection are recommended in case of no CNSL. Intrathecal injection of chemotherapeutic drugs twice a week until the CSF is normal, and subsequently once a week for 4–6 weeks.
2.4.2 Treatment of cardiotoxicity in AML
Clinical observations and studies have shown that cardiotoxicity caused by anthracyclines is generally progressive as well as irreversible and the heart may suffer damage after the first use of anthracyclines. Thus, early monitoring and prevention in advance are particularly important.
Classification of cardiotoxicity caused by anthracyclines
The cardiotoxicity caused by anthracyclines can be divided into acute, chronic and delayed according to the time of onset [51, 52] (Table 13).
Diagnosis
Drug cardiotoxicity refers to one or more of the following, but does not include subclinical cardiovascular injury occurring early in the use of chemotherapeutic drugs [53](Table 14).
Treatment
Symptomatic treatment for routine heart failure due to cardiotoxicity involves a combination of three drug types: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and β-receptor blockers.
Cardioprotective agents include coenzyme Q10, levocarnitine, N-acetylcysteine, antioxidants (vitamin C and vitamin E) and other iron chelating agents (such as desferrioxamine and EDTA).
2.4.3 Treatment of agranulocytosis and fever in AML
Diagnosis of agranulocytosis and fever in AML
Agranulocytosis refers to an absolute neutrophil count (ANC) < 0.5 × 109/L in peripheral blood while serious agranulocytosis refers to an ANC < 0.1 × 109/L. Fever refers to a single oral temperature ≥ 38.3℃ (axillary temperature ≥ 38.0℃), or oral temperature ≥ 38.0℃ (axillary temperature ≥ 37.7℃) for more than 1 h.
Treatment of agranulocytosis and fever in AML
Initial empiric treatment with antibiotics should be administered as soon as possible, the principle of which is to cover the most common and virulent pathogens that can quickly lead to serious complications or threats to life. The epidemiology of infection in the region, the hospital and the department must be taken into account to cover drug-resistance bacteria until accurate etiological results are obtained. Gram-negative bacteria are the main cause of infection in agranulocytosis.
In patients with an ANC ≥ 0.5 × 109/L with stable defervescence for 48 h after empiric treatment with antibiotics for agranulocytosis with fever of unknown origin, antibiotics can be discontinued; if the ANC continues to be < 0.5 × 109/L, antibiotics can be discontinued after 7 days of defervescence. In patients in whom the ANC is still < 0.5 × 109/L and empiric antibiotics are discontinued, fluoroquinolones can be adopted for preventive treatment [54].
2.4.4 Prevention of AML hepatitis B virus reactivation
Hepatitis B virus (HBV) reactivation is fairly common in patients with solid tumors and hematological malignancies undergoing conventional chemotherapy and may cause serious complications.
High-risk factors for AML HBV reactivation
High-risk factors for AML HBV reactivation include treatment with anthracyclines; hormonotherapy with prednisone at a dosage greater than or equivalent to 10-20 mg daily for more than 4 weeks; monoclonal antibody treatment, such as rituximab, obinutuzumab and alemtuzumab; and a history of breast cancer or lymphoma.
Examination
Examinations following HBV reactivation should look for improvements in routine blood and biochemical parameters as well as HBsAg, anti-HBc, anti-HBs and HBV-DNA. It is recommended to monitor HBV DNA and ALT every 3 months, and monthly monitor after the withdrawal of antiviral treatment [55].
Treatment
For patients with a history of hepatitis B, lamivudine, entecavir or nucleotide analogs should be used in antiviral treatment while they are receiving immunosuppressant treatment [55, 56]. Antiviral treatment can be discontinued after one year of immunosuppressant withdrawal [55]. Moreover, regular examinations of HBV-DNA and ALT are required.
2.4.5 Prevention and treatment of uric acid nephropathy
Chemotherapy-induced destruction of leukemia cells (especially in patients with hyperleukocytosis) will easily lead to uric acid nephropathy. Notably, for hydration and alkalization, allopurinol may be used to inhibit the formation of uric acid.
2.4.6 Correction of bleeding and coagulation disorders
The bleeding time and coagulation time should be closely monitored in patients with leukemia, and coagulation factor supplementation should be provided when necessary to correct any bleeding or coagulation disorders.
2.5 Nursing for patients with AML
Before chemotherapy, patients should be educated regarding their treatment regimens and any adverse events and common complications. During agranulocytosis, patients are required to stay in laminar air-flow wards that are regularly and periodically disinfected and kept clean with reduced visitation. Patients are advised to wear medical masks, eat clean food, and prevent oral and perianal infection. The importance of recurrence prevention should be explained during the period of remission. Regular follow-up by phone to ask about patient’s psychological states after hospital discharge is necessary. Patients should be advised repeatedly to have more meals a day but less food at each meal, with a light diet consisting of digestible food, ensuring the intake of protein, vitamins and energy, and to eat plenty of fresh vegetables and fruits. Eating greasy, raw, cold, spicy or stimulating food is forbidden. Moreover, it is important to prevent getting cold and to maintain a good mood as well as mental health.
3 Follow-up of adult AML
Monitoring MRD through real-time PCR (RT-PCR) and flow cytometry can provide an early warning of relapse so that effective measures can be taken as soon as possible. Patients with persistently negative MRD are expected to reach disease-free survival for a long period of time and even be cured. Thus, MRD must be regularly monitored. It is recommended to examine MRD during and after consolidation treatment. MRD should be monitored once every 3 months within 2 years after consolidation treatment [57, 58].
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Funding for this research was provided by the National Key Research and Development Program of China (2021YFC2500300), and CAMS Innovation Fund for Medical Sciences (2021-I2M-1–041).
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Professor Hui Wei conceived the manuscript under the valuable advice and guidance of Professor Jianxiang Wang. Members of Hematology Oncology Committee of China Anti- Cancer Association. drafted and approved the manuscript for publication. The author(s) read and approved the final manuscript.
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Wei, H., Mi, Y., Wang, Y. et al. CACA guidelines for holistic integrative management of adult acute myeloid leukemia. Holist Integ Oncol 3, 12 (2024). https://doi.org/10.1007/s44178-024-00078-9
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DOI: https://doi.org/10.1007/s44178-024-00078-9