The levels of evidence (I–IV) and strength of recommendations (A–C) are defined at the end of the "Major Recommendations" field.
Diagnosis
- Bone marrow aspirate and trephine biopsy unless the peripheral blast count is high.
- Immunophenotyping (CD3, CD7, CD13, CD14, CD33, CD34, CD64, CD117, cytoplasmic myeloperoxidase (MPO)
- Cytochemistry (MPO or Sudan Black, combined esterase). Can be omitted if 4 colour flow cytometry is available.
- Cytogenetics (with reverse transcription-polymerase chain reaction [RT-PCR] for AML1-ETO and CBFB-MYH11 in non-acute promyelocytic leukemia (APL) and PML-RARA in suspected APL; fluorescent in situ hybridization [FISH] in selected cases).
Treatment of Acute Myeloid Leukemia (AML)
General Measures and Supportive Care
Prevention of Tumour Lysis Syndrome
- Rasburicase should be used with chemotherapy in patients with a white cell count >100x109/L at risk of acute tumour lysis syndrome (Recommendation Grade B; Evidence level IIb)
Bacterial Infection
- There is no firm evidence of a survival advantage to support the routine use of prophylactic antibiotics in patients with AML and they are currently not recommended. Further large controlled trials are warranted. (Recommendation grade B; evidence level IIb)
Growth Factors
- There is no survival benefit from the use of growth factors following AML chemotherapy but growth factor use does reduce the duration of neutropenia, of antibiotic use and of hospital stay. The cost benefit advantages of routine growth factor use are uncertain. The routine use of growth factor therapy in AML is not recommended. (Recommendation Grade A; Evidence level IIa)
Treatment of Younger Adult Patients
- All eligible patients up to age 60 (or greater than 60 but able to receive intensive treatment) with de novo or secondary AML should be asked to participate in the current UK National Cancer Research Institute (NCRI) study, at present AML 15 (www.aml15.bham.ac.uk/trial/index.htm).
- Patients over 60 able to tolerate remission induction chemotherapy should be asked to participate in the current NCRI study, at present Leukemia Research Foundation (LRF) AML 14 (http://www.aml14.bham.ac.uk) or HOVON/SAKK AML43.
- Patients not eligible or unwilling to participate in the NCRI studies should be offered standard daunorubicin and cytarabine 3+10 or 3+7 induction chemotherapy (Level 1b)
- Patients opting for non-intensive chemotherapy who are not entered into clinical trials should be offered treatment with low-dose cytarabine (Recommendation grade A; Evidence level Ib). Patients not able to tolerate chemotherapy should be given best supportive care: transfusion support and hydroxycarbamide to control the white count (Recommendation grade A; Evidence level Ib).
Management of AML in Patients who are Pregnant
- AML in pregnancy should be managed jointly between the haematologist and the obstetrician with full involvement of the mother. (Recommendation grade B; Evidence level III)
- Chemotherapy in the first trimester is associated with a high risk of fetal malformation and should be avoided if possible. The opportunity to terminate the pregnancy should be discussed with the mother. If termination is refused and the mother's life is at risk, chemotherapy should be started. (Recommendation grade B; Evidence level III).
- Chemotherapy in the second and third trimesters is associated with an increased risk of abortion and premature delivery as well as small-for-dates babies. Consideration should be given to early induced labour between cycles of chemotherapy. (Recommendation grade B; Evidence level III).
- All trans retinoic acid (ATRA) can be used in pregnancy in the second and third trimesters (Recommendation grade B; Evidence level III).
Management of Extra-Medullary Disease
- Patients presenting with extramedullary leukaemia should receive systemic antileukaemic chemotherapy. (Recommendation grade C; Evidence level IV).
Acute Promyelocytic Leukemia (APL)
- ATRA should be started as soon as the diagnosis is suspected (Recommendation grade A; Evidence level Ib).
- Leucopheresis should be avoided in high count patients. (Recommendation grade B; Evidence level III).
- The coagulopathy should be treated to keep the platelets >50x109/L, together with fresh frozen plasma (FFP) and cryoprecipitate to normalise the activated partial thromboplastin time and fibrinogen levels (Recommendation grade B; Evidence level IIb).
- ATRA syndrome should be treated promptly with dexamethasone 10mg twice daily intravenously, until the symptoms resolve. (Recommendation grade C; Evidence level IV).
- Diagnostic work-up should include documentation of underlying PML-RARA fusion. (Recommendation grade B; Evidence level IIa).
- Patients with PML-RARA positive APL, deemed suitable for intensive therapy, should be treated with concurrent ATRA and anthracycline-based chemotherapy for induction, followed by anthracycline-based consolidation therapy and should be offered entry into the NCRI AML trial (currently AML15) (Recommendation grade A; Evidence level Ib)
- Patients should undergo molecular monitoring after treatment to guide further therapy. (Recommendation grade B; Evidence level IIa)
- For relapsed disease, ATRA should not be used as single agent therapy due to significant possibility of acquired secondary resistance and arsenic trioxide (ATO) should only be used in patients with confirmed PML-RARA positive APL (Recommendation grade B; Evidence level IIa).
Transplantation in AML
- Patients should be fully informed of both the advantages and disadvantages of the available treatments, and of the strategies that can be used to treat long-term side effects, particularly in the area of sexual function and infertility.
- Intensive consolidation chemotherapy treatment during first complete remission (CR) should be offered as the preferred treatment to patients with favourable cytogenetics and to those unwilling to accept the risk of permanent damage to their sexual health and fertility, with bone marrow transplantation (BMT) remaining as the choice for salvage treatment in the event of relapse.
- All patients of childbearing years undergoing BMT should be offered the opportunity of preserving their fertility (where possible) prior to treatment.
- Allogeneic transplantation should be offered to patients with high risk AML (risk groups are defined in Table 2 of the original guideline document) in first remission who have an HLA identical donor, although it is accepted that only a minority of patients will benefit. (Recommendation grade B; Evidence level III). Standard risk patients may be offered allo-transplantation as part of a clinical trial (Recommendation grade B; Evidence level III).
- Allogeneic transplantation may be the treatment of choice for younger patients who are in second remission. (Recommendation grade B; Evidence level III).
- Older patients with high-risk disease or beyond first remission may be offered a reduced intensity transplant but this should be in the context of a clinical trial. (Recommendation grade C; Evidence level IV).
- Younger high-risk patients or those beyond first remission may be considered for a haploidentical transplant but this should be in the context of a clinical trial. (Recommendation grade C; Evidence level IV).
- The role of autografting in the management of AML is contentious. Autografting should only be carried out in a clinical trial. (Recommendation grade A; Evidence level Ib).
Acute Myeloid Leukemia in the Elderly
- For patients in whom intensive chemotherapy is deemed justified (e.g. age <70 years, good performance status, white blood cell (WBC) <100 x 109/L, no adverse cytogenetic abnormalities or multidrug resistance (MDR) expression), standard induction chemotherapy with daunorubicin (or an equivalent anthracycline) for 3 days plus cytarabine for 7-10 days is recommended (Recommendation grade A, Evidence level Ib). Where possible patients should be entered into clinical trials.
- There is no firm evidence to date to support the use of MDR-blocking agents as an adjunct to induction chemotherapy (Recommendation grade A recommendation; Evidence level Ib).
- Similarly there is insufficient evidence to support routine use of G-colony stimulating factor (CSF) or granulocyte macrophage (GM)-CSF with induction chemotherapy in patients over 60 years of age, although this may be appropriate if it is desirable to reduce hospitalisation or antibiotic usage (Recommendation grade A, Evidence level Ib).
- The optimal post-remission chemotherapy for older adult patients with AML remains unclear. There does not seem to be a role for extended consolidation chemotherapy or maintenance treatment (Recommendation grade A, Evidence level Ib).
- Gemtuzumab ozogamicin shows promise as a salvage agent in patients with relapsed disease, and may be preferable to further intensive chemotherapy in this setting (Recommendation grade B, Evidence level IIb).
Non-intensive Palliative Chemotherapy
- Unless patients opting for palliative chemotherapy are entered into clinical trials, treatment should be offered with low-dose cytarabine (Recommendation grade A; Evidence level Ib).
Definitions:
Classification of Evidence Levels
Ia Evidence obtained from meta-analysis of randomized controlled trials.
1b Evidence obtained from at least one randomized controlled trial.
IIa Evidence obtained from at least one well-designed controlled study without randomization.
IIb Evidence obtained from at least one other type of well-designed quasi-experimental study
III Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies.
IV Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.
Classification of Grades of Recommendation
- Requires at least one randomised controlled trial as part of a body of literature overall good quality and consistency addressing specific recommendation. (Evidence levels Ia, Ib).
- Requires the availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendation. (Evidence levels IIa, IIb, III).
- Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV).