Diagnosis of adult acute myeloid leukemia
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.
Prognosis and stratification factors of AML
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.
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 [2–8].
Table 1. Genetic prognostic grouping for AML
Level of prognosis | Cytogenetics | Molecular genetics |
|---|---|---|
Good prognosis | inv (16) (p13; q22) or t (16; 16) (p13; q22) t (8; 21) (q22; q22) | NPM1 mutation without FLT3-ITD mutation or with FLT3-ITD mutationa of a low allelic ratio Biallelic mutated CEBPA |
Moderate prognosis | Normal karyotypes t (9; 11) (p22; q23) Other abnormalities | inv (16) (p13; q22) or t (16; 16) (p13; q22) with C-kit mutationb t (8; 21) (q22; q22) with C-kit mutationb NPM1 mutation with FLT3-ITD mutationa of a high allelic ratio |
Poor prognosis | Monomeric karyotypes Complex karyotypes (≥ 3 chromosome aberrations), without t (8; 21) (q22; q22), inv (16) (p13; q22) or t (16;16) (p13; q22) or t (15; 17) (q22; q12) -5 -7 5q- -17 or abn (17p) 11q23 chromosome translocation, except for t (9; 11) inv (3) (q21; q26.2) or t (3; 3) (q21q26.2) t (6; 9) (p23; q34) t (9; 22) (q34.1; q11.2) t (7; 11) (p15; p15) | TP53 mutation RUNX1 (AML1) mutationc ASXL1 mutationc FLT3-ITD mutationa and c of a high allelic ratio |
Monomeric karyotypes: two or more autosomal monomers, or one autosomal monomer complicated with at least one chromosomal structural abnormality
Modifying gene mutations of DNMT3a and RNA splicing chromatins (SF3B1, U2AF1, SRSF2, ZRSR2, EZH2, BCOR and STAG2) will lead to a poor prognosis if they are not accompanied by t (8; 21) (q22; q22), inv (16) (p13q22) or t (16; 16) (p13; q22) or t (15; 17) (q22; q12) [9, 10]. However, the level of their evidence-based medical evidence cannot be equal to those of TP53, ASXL1, RUNX1 and other mutations. Therefore, they are not used as the basis for risk stratification
aThe low allelic ratio is < 0.5 while the high allelic ratio is ≥ 0.5. If no FLT3 testing for allelic ratio is performed, positive FLT3-ITD should be treated as a high allele ratio
bC-kit D816 has prognostic effects on t (8; 21) (q22; q22), inv (16) (p13; q22) and t (16; 16) (p13; q22), while the other mutation sites have no prognostic effect and are still classified into the good prognosis group
c Such abnormalities should not be stratefied as poor markers if they occur with good markers
Diagnosis of relapsed or refractory acute myeloid leukemia (R/R AML)
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.
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.
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.
Treatment of preliminarily diagnosed AML (not APL)
Treatment for patients with AML < 60 years old
Induction treatment (Table 2)
Table 2. Induction treatment regimens for patients with AML < 60 years old
Classification of chemotherapy regimens
Conventional induction treatment regimen
A standard dose of Ara-C (100-200 mg/m2/d) for 7 days, accompanied by IDA of 12 mg/m2/d for 3 days or DNR of 60-90 mg/m2/d for 3 days [11–13]
Induction treatment regimen with an intermediate dose of Ara-C
HHT of 2 mg/m2/d for 7 days, DNR of 40 mg/m2/d for 3 days, Ara-C of 100 mg/m2/d for days 1–4 and of 1 g/m2/q12h for days 5–7 [6, 14]
Other induction treatment regimens
A regimen composed of IA, DA, MA and HA + anthracyclines, such as HAA (HA + aclacinomycin), HAD (HA + DNR)4
Refer to the low-dose regimen for aged patients when patients have severe complications
Monitoring after induction treatment
① Treatment monitoring after induction with a standard dose of Ara-C (Tables 3 and 4):
Table 3. Bone marrow examination from day 7 to day 14 after chemotherapy
Residual leukemia cells
Treatment regimen
Residual leukemia cells ≥ 10%
Consider double-induction treatmenta or watch and wait
Residual leukemia cells < 10%, but without hypoplasia
Perform double-induction treatmenta or wait for recovery
Residual leukemia cells < 10%, with hypoplasia
Wait for recovery
aA standard dose of Ara-C + anthracyclines or anthraquinones (IDA or DNR, Mitox, etc.); a preexcitation regimen with G-CSF (such as GAG regimen: G-CSF + Ara-C + Acla)
Table 4. Bone marrow and hemogram examination from day 21 to day 28 (recovery of bone marrow) after chemotherapy
Remission of bone marrow
Treatment regimen
Complete remission
Begin treatment after remission
Proportion of leukemia cells decreased < 60%
Treat according to induction failure
Incomplete remission, but with a proportion of leukemia cells decreased > 60%
Repeat the original regimen for one course of treatment; or chang to a second-line regimen
Residual leukemia cells < 10%, with hypoplasia
Wait for recovery
Residual leukemia cells ≥ 10%, with hypoplasia
Consider further treatment (refer to the double-induction treatment regimen or the treatment regimens chosen for patients with failed induction treatment)
② Monitoring after induction with a intermediate or high dose of Ara-C (Table 5):
Table 5. Bone marrow and hemogram reexamination from day 21 to day 28 (recovery of bone marrow) after termination of chemotherapy
Remission of bone marrow
Treatment regimen
Complete remission
Begin treatment after remission
Not achieved complete remission with bone marrow recovery
Treat according to induction failure
Residual leukemia cells < 10%, with hypoplasia
Wait for recovery
Residual leukemia cells ≥ 10%, with hypoplasia
Treat according to treatment failure
Treatment options after CR of AML (Table 6)
Table 6. Treatment options for different risk groups after CR of AML
Level of prognosis
Treatment regimen after complete remission
Good prognosis group
Multiple courses of treatment with a high dose of Ara-Ca
Othersb
Intermediate prognosis group
Allogeneic hematopoietic stem cell transplantationc
Multiple courses of treatment with a high dose of Ara-Ca
Autologous hematopoietic stem cell transplantationd
Othersb
Poor prognosis group
Allogeneic hematopoietic stem cell transplantationc
Multiple courses of treatment with a high dose of Ara-Ca
Othersb
Patients not stratified
Refer to the treatment for patients in the intermediate prognosis group
Treat as for the poor prognosis group if the white blood cell count ≥ 100 × 109/L during diagnosis
aA high dose of Ara-C (3 g/m2/q12h for 6 doses) for 3–4 courses of treatment [15, 16]
bA intermediate or high dose of Ara-C (1-2 g/m2/q12h for 6 doses); an intermediate or high dose of Ara-C for 2–3 courses of treatment as consolidation therapy, followed by autologous hematopoietic stem cell transplantation [16–19]; standard-dose chemotherapy (Ara-C plus anthracyclines/anthraquinones, HHT, podophyllotoxin analogues, etc.) for ≥ 6 courses cycle of chemotherapy after remission, or consolidation of standard-dose chemotherapy for 3–4 courses, followed by autologous hematopoietic stem cell transplantation [20]
cAn intermediate or high dose of Ara-C for 1–2 courses during the search for donors during chemotherapy [21]. Depending on the risk of relapse and the hematopoietic recovery after allogeneic hematopoietic stem cell transplantation, FLT3-ITD positive patients can receive FLT3 inhibitors for maintenance treatment, while demethylation drugs can be chosen for the maintenance treatment of FLT3-ITD negative patients
dAn intermediate or high dose of Ara-C for 2–3 courses, followed by autologous hematopoietic stem cell transplantation [17–19]
eAn intermediate or high dose of Ara-C for 2–3 courses, or consolidation therapy of standard-dose chemotherapy, followed by autologous hematopoietic stem cell transplantation [17–19]
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.
Treatment for patients ≥ 60 years old
Induction treatment for patients ≥ 60 years old (Table 7)
Table 7. Induction treatment options for patients ≥ 60 years old
Age
Patients aged 60 to 75 (fit for intensive chemotherapy)
Without poor prognosis factors
Standard-dose chemotherapya
Low-intensity chemotherapyb
With poor prognosis factors
Low-intensity chemotherapyb
Standard-dose chemotherapya
Patients ≥ 75 years old or < 75 years old, with severe nonhematologic complications or who are unfit for intensive chemotherapy
Low-intensity chemotherapy
Supportive treatment
aStandard-dose chemotherapy: Ara-C (100 mg/m2/d for 7 days) plus IDA (10-12 mg/m2/d for 3 days) or DNR (45-60 mg/m2/d for 3 days) [22–25]
bLow-intensity chemotherapy: venetoclax (100 mg, d1, 200 mg, d2, 400 mg, d3-28) plus azacitidine (75 mg/m2/d for 7 days) or decitabine (20 mg/m2/d for 5 days) [26–28]. For patients with IDH1 mutations, azacitidine (75 mg/m2/d for 7 days) plus ivosidenib (500 mg, oral, once daily) can be used. Azacitidine (75 mg/m2/d for 7 days) or decitabine (20 mg/m2/d for 5 days). Low-dose chemotherapy ± G-CSF (e.g. a low dose of Ara-C as the basic regimen—CAG, CHG, CMG, C-cytarabine, A-aclacinomycin, H-homoharringtonine and M-mitoxantrone); azacitidine or decitabine plus low-dose chemotherapy, etc [29–33]
Bone marrow monitoring after intensive induction chemotherapy for patients ≥ 60 years old with AML (Table 8)
Table 8. Bone marrow examination from day 21 to day 28 after intensive induction chemotherapy for patients with AML ≥ 60 years old
Remission of bone marrow
Treatment regimen
Complete remission
Begin treatment after remission
Proportion of leukemia cells decreased < 60%
Treat according to induction failure
Proportion of leukemia cells decreased > 60%, but with incomplete remission
Repeat the original regimen for one course of treatment or chang to a second-line regimen
Residual leukemia cells < 10%, with hypoplasia
Wait for recovery
Residual leukemia cells ≥ 10%, with hypoplasia
Treat according to treatment failure
Treatment options for patients ≥ 60 years old after CR of AML
Treatment options after CR through standard-dose induction chemotherapy:
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.
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.
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].
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.
Maintenance treatment
Demethylation drugs (azacitidine or decitabine) can be used for maintenance treatment after induction and consolidation treatment until the disease progresses [36, 37].
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).
Table 9. Treatment options for APL
Preliminarily diagnosed WBC ≤ 10 × 109/L | ||
Treatment regimen with ATRA + arsenic-trioxide [38–40] | Induction treatment | ATRA plus arsenic-trioxide or compound realgar natural indigo tablets until complete remission (CR)a |
Consolidation treatment | ATRA for 7 courses. Arsenic-trioxide or compound realgar natural indigo tablets for 4 coursesb | |
Maintenance treatment | Every 3 months for a cycle. Month 1: ATRA for 2 weeks with an interval for 2 weeks; Month 2 and Month 3: arsenic-trioxide or compound realgar natural indigo tablets for 2 weeks with an interval for 2 weeksa, repeating for 3 cycles | |
ATRA + arsenic-trioxide + other chemotherapy regimens [41] | Induction treatment | Same as the induction treatmenta in the treatment regimen with ATRA + arsenic-trioxide; anthracyclines or anthraquinones used for the control of leucocytosis |
Consolidation treatment | HA regimen, MA regimen, DA regimen and IA regimenc | |
Maintenance treatment | Same as the maintenance treatment in the treatment regimen with ATRA + arsenic-trioxide, repeating for 8 cycles | |
ATRA + other chemotherapy regimens (arsenic-trioxide intolerance or arsenic-trioxide-free drugs) | Induction treatment | ATRA until CR and ATRA plus DNR or IDA for Days 2, 4, 6 and 8a |
Consolidation treatment | ATRA for 14d plus DNR or IDA for 3d with an interval for 28d as a course of treatment with a total of 2 coursesa | |
Maintenance treatment | Every 3 months for a cycle: Days 1–14: ATRA; Days 15–90: 6-MP; MTX once a week for a total of 11 times, with 8 cyclesa | |
Newly diagnosed WBC > 10 × 109/L | ||
ATRA + arsenic-trioxide + induction chemotherapy, consolidation chemotherapy and maintenance treatment alternatively combined with ATRA/arsenicals [38] | Induction treatment | ATRA plus arsenic-trioxide or compound realgar natural indigo tablets until CR; ATRA plus DNR or IDA for Days 1-3a |
Consolidation treatment | HA regimen, MA regimen, DA regimen and IA regimenc | |
Maintenance treatment | Same as the maintenance treatment in the treatment regimen with ATRA + arsenic-trioxide for newly diagnosed WBC ≤ 10 × 109/L, repeating for 8 cycles | |
ATRA + arsenicals + induction chemotherapy, consolidation with ATRA + arsenic-trioxide and maintenance treatment with ATRA/6-MP/MTX [42] | Induction treatment | ATRA (Days 1–36) + arsenic-trioxide (Days 9–36) + IDA (Days 2, 4, 6 and 8)a |
Consolidation treatment | ① ATRA (Days 1–28) + arsenic-trioxide (Days 1–2); ② ATRA (Days 1–7, 15–21 and 29–35) + arsenolite (Days 1–5, 8–12, 15–19, 22–26 and 29–33) | |
Maintenance treatment | Same as the maintenance treatment in the treatment regimen with ATRA + arsenic-trioxide for newly diagnosed WBC ≤ 10 × 109/L | |
aDrug dose: ATRA of 25 mg/m2/d; arsenic trioxide of 0.16 mg/m2/d; compound realgar natural indigo tablets of 60 mg/m2/d; DNR of 45 mg/m2/d; IDA of 8 mg/m2/d; 6-MP of 50-90 mg/m2/d;MTX of 5-15 mg/m2/d
bATRA of 25 mg/m2/d for 2 weeks with an interval for 2 weeks as a course of treatment. Arsenic-trioxide of 0.16 mg/m2/d or compound realgar natural indigo tablets of 60 mg/m2/d for 4 weeks with an interval for 4 weeks as a course of treatment
cHA regimen: HHT of 2 mg/m2/d for Days 1–7; Ara-C of 100 mg/m2/d for Days 1–5. MA regimen: MIT of 6-8 mg/m2/d for Days 1–3; Ara-C of 100 mg/m2/d for Days 1–5. DA regimen: DNR of 40 mg/m2/d for Days 1–3; Ara-C of 100 mg/m2/d for Days 1–5. IA regimen: IDA of 8 mg/m2/d for Days 1–3; Ara-C of 100 mg/m2/d for Days 1–5
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).
Table 10. Treatment principles of R/R AML
Age | Treatment recommendations | |
|---|---|---|
Patients < 60 years old | Those with early relapse | Clinical trials (highly recommended) |
Targeted drug treatment | ||
Salvage chemotherapy, followed by HSCT with identical sibling or unrelated donors after CR | ||
Direct allogeneic hematopoietic stem cell transplantation | ||
Those with late relapse | Repeating the initially effective induction chemotherapy regimen and considering allo-HSCT after remission | |
Clinical trials | ||
Targeted drug treatment | ||
Salvage chemotherapy, followed by HSCT with identical sibling or unrelated donors after CR | ||
Those with refractory AML | Same as those with early relapse | |
Patients ≥ 60 years old | Those with early relapse | Clinical trials(highly recommended) |
Treatment with new drugs (including targeted and untargeted drugs) | ||
Optimal supportive treatment | ||
Salvage chemotherapy and allo-HSCT for fit patients after CR | ||
Those with late relapse | Clinical trials (highly recommended) | |
Repeating the initially effective induction chemotherapy regimen | ||
Treatment with new drugs (including targeted and untargeted drugs) | ||
Salvage chemotherapy and allo-HSCT for fit patients after CR | ||
Optimal supportive treatment (for patients untolerate or unwilling to treatment) | ||
Those with refractory AML | Same as those with early relapse | |
Table 11. Treatment regimens of relapsed or refractory AML
Treatment regimens | ||
|---|---|---|
Targeted treatment ± demethylation drugs | FLT3-ITD mutation | Gilteritiniba |
Sorafenib + demethylation drugs (azacitidine or decitabine)b | ||
FLT3-TKD mutation | Gilteritiniba | |
IDH1 mutation | Ivosidenib, plus demethylation drugsc | |
IDH2 mutation | Enasidenib, plus demethylation drugsd | |
Combination chemotherapy | Intensive chemotherapy regimen (for fit patients) | CLAG ± IDA/Mitox regimene |
A high dose of cytarabine ± anthracyclinesf | ||
FLAG ± IDA regimeng | ||
HAA (HAD) regimenh | ||
EA ± Mitox regimeni | ||
CAG regimenj | ||
Non-intensive chemotherapy regimen (for unfit patients) | Demethylation drugs (azacitidine and decitabine)k | |
A low-dose of Ara-Cl | ||
Venetoclax + demethylation drugs/ a low-dose of Ara-Cm | ||
Allogeneic hematopoietic stem cell transplantation | Allogeneic hematopoietic stem cell transplantation should be carried out as soon as possible if permitted | |
Immunotherapy | CAR-T immunotherapy, etc | |
Venetoclax plus demethylation drugs: venetoclax: 100 mg for Day 1, 200 mg for Day 2 and 400 mg from Day 3 to Day 28; demethylation drugs: azacitidine of 75 mg/m2 for Days 1–7; decitabine of 25 mg/m2 for Days 1–5. Venetoclax plus a low dose of Ara-C: venetoclax: 100 mg for Day 1, 200 mg for Day 2, 400 mg for Day 3 and 600 mg from Day 4 to Day 28; Ara-C: 10 mg/m [2], subcutaneous, q12h, d1-10 [43–45]
aGilteritinib: a therapeutic dose of 120 mg/day [46, 47]. Clinical tirals of gilteritinib have shown that patients who didn’t reach CR after one course of standard-dose induction treatment benefited from gilteritinib monotherapy as well. Thus, treatment with gilteritinib is recommended for patients without CR after one course of standard-dose induction treatment
bSorafenib + demethylation drugs (azacitidine or decitabine): sorafenib of 200 mg, Bid; azacitidine of 75 mg/m2 for Days 1–7 or decitabine of 20 mg/m2 for Days 1–5
cIvosidenib of 500 mg qd, plus demethylation drugs as appropriate. Same as above for doses of demethylation drugs [48, 49]
dEnasidenib of 100 mg qd, plus demethylation drugs as appropriate. Same as above for doses of demethylation drugs [50]
eCLAG ± IDA/Mitox regimen: Cladribine (Cla), Ara-C and G-CSF with or without IDA/Mitox; Cla of 5 mg/m2, d1-5; Ara-C of 1-2 g/m2, 4 h after Cla, d1-5, intravenous infusion for 3 h; G-CSF of 300 μg/m2, d0-5 (stopping when WBC > 20 × 109/L); IDA of 10-12 mg/m2, d1-3, or Mitox of 10-12 mg/m2, d1-3
fA high dose of cytarabine ± anthracyclines: Ara-C of 1-3 g/m2, q12h, d1, 3 and 5; plus DNR of 45 mg/m2 or IDA of 10 mg/m2, d2, 4 and 6, or Ara-C (not exposed to high dose of ARA-C) of 3 g/m2, q12h, d1-3
gFLAG ± IDA regimen: Flu, Ara-C, G-CSF ± IDA; Flu of 30 mg/m2, d1-5; Ara-C 1-2 g/m2, 4 h after Flu, d1-5, intravenous infusion for 3 h; G-CSF of 300 μg/m2, d0-5; IDA of 10-12 mg/m2, d1-3
hHAA (HAD) regimen: HHT, Ara-C, Acla or DNR: HHT of 2 mg/m2, d1-7 (or HHT of 4 mg/m2, administration in two separate doses, d1-3); Ara-C of 100-200 mg/m2, d1-7; Acla of 20 mg/d, d1-7 (or DNR of 45 mg/m2/d, d1-3)
iEA ± Mitox regimen: VP16, Ara-C ± Mitox: VP16 of 100 mg/m2, d1-5; Ara-C of 100-150 mg/m2, d1-7; ± Mitox of 10 mg/m2, d1-5
jCAG regimen: Acla, Ara-C + G-CSF regimen: G-CSF of 150U/m2, q12h, d0-14; Acla of 20 mg/d, d1-4; Ara-C of 10 mg/m2, subcutaneous, q12h, d1-4
kDemethylation drugs: azacitidine of 75 mg/m2, d1-7, 28 days for a course of treatment, until there is disease deterioration or serious adverse events; decitabine of 20 mg/m2, d1-5, 28 days for a course of treatment, until there is disease deterioration or serious adverse events
lA low dose of Ara-C: Ara-C of 10 mg/m2, subcutaneous, q12h, d1-14
mVenetoclax + demethylation drugs/ a low-dose of Ara-C
Treatment of complications in patients with AML
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.
Table 12. Treatment of CNSL
CT/MRI for patients with nervous system symptoms | Lumbar puncture without intracranial/ spinal tumor | Normal CSF | Observation |
Leukemia cells found in CSF | Intrathecal injection of chemotherapeutic drugs (twice a week) until the CSF is normal, and subsequently once a week for 4–6 weeks | ||
Patients with intracranial/ spinal tumors or increased intracranial pressure | Radiotherapy, followed by intrathecal injection of drugs (twice a week) until the CSF is normal, and subsequently once a week for 4–6 weeks | ||
Patients without nervous system symptoms | Leukemia cells in CSF when lumbar puncture isperformed after CR1 | Intrathecal injection of chemotherapeutic drugs twice a week until the CSF is normal, and subsequently once a week for 4–6 weeks. CSF reexamination after treatment if HD-Ara-C treatment is received | |
Normal findings of lumbar puncture after CR1 | Lumbar puncture and intrathecal injection for patients with CR in CNSL screening. Four times of intrathecal injection are recommended in case of no CNSL | ||
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).
Table 13. Classification of cardiotoxicity caused by anthracyclines
Acute | Occurring within hours or days after administration and commonly presenting as an intracardiac conduction disturbance and arrhythmia, rarely presenting as pericarditis and acute left heart failure |
Chronic | Occurring within one year of chemotherapy and presenting as left ventricular dysfunction, which may eventually lead to heart failure |
Delayed | Occurring years after chemotherapy and presenting as heart failure, cardiomyopathy and arrhythmia |
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).
Table 14. Cardiotoxic manifestations caused by anthracyclines
Cardiomyopathy with decreased LVEF, manifesting as overall functions degradation or significant reduction in ventricular septal motion |
Congestive heart failure (CHF) -related symptoms |
CHF-related signs, such as the third heart sound gallop, tachycardia or both |
LVEF decreased by at least 5% from the baseline to the absolute value < 55%, accompanied by symptoms or signs of CHF; or LVEF decreased by at least 10% to the absolute value < 55%, not accompanied by symptoms or signs |
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).
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].
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.
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.
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.
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.
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].
Authors’ contributions
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.
Funding
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).
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Consent for publication bas been obtained from all authors of this manuscript.
Competing interests
The authors have no conflicts of interest to declare.
Publisher’s Note
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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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Details
1 Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Hematology & Blood Diseases Hospital, Tianjin, PR China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839)
2 Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fujian Provincial Key Laboratory of Hematology, Fuzhou, PR China (GRID:grid.411176.4) (ISNI:0000 0004 1758 0478)
3 The First Affiliated Hospital of China Medical University, Shenyang, PR China (GRID:grid.412636.4)
4 The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, PR China (GRID:grid.413375.7) (ISNI:0000 0004 1757 7666)
5 The First Affiliated Hospital of Guangxi Medical University, Guilin, PR China (GRID:grid.412594.f)
6 Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223)
7 The First Hospital of Jilin University, Changchun, PR China (GRID:grid.430605.4) (ISNI:0000 0004 1758 4110)
8 Chinese PLA General Hospital, Medical College of Chinese PLA, Beijing, PR China (GRID:grid.414252.4) (ISNI:0000 0004 1761 8894)
9 The First Affiliated Hospital of Xiamen University, Xiamen, PR China (GRID:grid.412625.6)
10 The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China (GRID:grid.452661.2) (ISNI:0000 0004 1803 6319)
11 Southwest Hospital, Third Military Medical University, Chongqing, PR China (GRID:grid.416208.9) (ISNI:0000 0004 1757 2259)
12 The First Affiliated Hospital of Soochow University, Suzhou, PR China (GRID:grid.429222.d) (ISNI:0000 0004 1798 0228)
13 Harbin First Hospital, Institute of Hematology and Oncology, Harbin, PR China (GRID:grid.429222.d)
14 The Second Hospital of Shanxi Medical University, Taiyuan, PR China (GRID:grid.452845.a)
15 Changhai Hospital of Shanghai, Shanghai, PR China (GRID:grid.411525.6) (ISNI:0000 0004 0369 1599)
16 Shenzhen Second People’s Hospital, Shenzhen, PR China (GRID:grid.452847.8) (ISNI:0000 0004 6068 028X)
17 The First Affiliated Hospital of Nanchang University, Nanchang, PR China (GRID:grid.412604.5) (ISNI:0000 0004 1758 4073)
18 Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, PR China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839)
19 Rui-Jin Hospital, Shanghai Second Medical University, Institute of Hematology, Institutes of Clinical Research, Shanghai, PR China (GRID:grid.412277.5) (ISNI:0000 0004 1760 6738)
20 Army Medical University, Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, PR China (GRID:grid.410570.7) (ISNI:0000 0004 1760 6682)
21 The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China (GRID:grid.452438.c) (ISNI:0000 0004 1760 8119)
22 Nanfang Hospital, Southern Medical University, Guangzhou, PR China (GRID:grid.416466.7) (ISNI:0000 0004 1757 959X)
23 The Second Xiangya Hospital, Central South University, Changsha, PR China (GRID:grid.452708.c) (ISNI:0000 0004 1803 0208)
24 Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, PR China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)
25 The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China (GRID:grid.412633.1)
26 Peking University People’s Hospital, Beijing, PR China (GRID:grid.411634.5) (ISNI:0000 0004 0632 4559)
27 Beijing Boren Hospital, Beijing, PR China (GRID:grid.411634.5)
28 West China Hospital, Sichuan University, Chengdu, PR China (GRID:grid.412901.f) (ISNI:0000 0004 1770 1022)
29 Shengjing Hospital of China Medical University, Shenyang, PR China (GRID:grid.412467.2) (ISNI:0000 0004 1806 3501)
30 Tianjin Medical University General Hospital, Tianjin, PR China (GRID:grid.412645.0) (ISNI:0000 0004 1757 9434)
31 Anhui Provincial Hospital, Hefei, PR China (GRID:grid.411395.b) (ISNI:0000 0004 1757 0085)
32 Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, PR China (GRID:grid.410587.f)
33 The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China (GRID:grid.452244.1)
34 The Affiliated ZhongShan Hospital of Dalian Medical University, Dalian, PR China (GRID:grid.411971.b) (ISNI:0000 0000 9558 1426)
35 Harbin First Hospital, Institute of Hematology and Oncology, Harbin, PR China (GRID:grid.452708.c)
36 The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, PR China (GRID:grid.429222.d) (ISNI:0000 0004 1798 0228)
37 Beijing Boren Hospital, Beijing, PR China (GRID:grid.429222.d)
38 Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (GRID:grid.412793.a) (ISNI:0000 0004 1799 5032)
39 Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
40 Jiangsu Province Hospital, First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China (GRID:grid.412676.0) (ISNI:0000 0004 1799 0784)
41 Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Hematology & Blood Diseases Hospital, Tianjin, PR China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839); Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin, China (GRID:grid.461843.c)