Acute Myeloid Leukemia (excluding acute promyelocytic leukemia)

Title: Acute Myeloid Leukemia
Leads: Lee Mozessohn and Shannon Goddard
Date of last revision: June 28, 2020

Terms of use

These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

1. Diagnosis and pathologic classification

   Acute myeloid leukemia (AML) is a relatively uncommon cancer with a rate of new cases of 4.3 per 100,000/year.¹ It is most frequently diagnosed in older adults aged 65-74 years with a slight male preponderance.¹ A diagnosis of AML requires a marrow or blood blast count > 20%, except for AML with the following recurrent genetic abnormalities: t(15;17) [reviewed in separate guideline], t(8;21), inv(16) or t(16;16) and some cases of acute erythroid leukemia.² The 2016 WHO classification of myeloid neoplasms and acute leukemia have a number of distinct categories for classification of AML²:
   
   

   AML with recurrent genetic abnormalities
   AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1
   AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11
   APL with PML-RARA
   AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A
   AML with t(6;9)(p23;q34.1);DEK-NUP214
   AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
   AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1
   Provisional entity: AML with BCR-ABL1
   AML with mutated NPM1
   AML with biallelic mutations of CEBPA
   Provisional entity: AML with mutated RUNX1
   AML with myelodysplasia-related changes*
   Therapy-related myeloid neoplasms†
   AML, NOS
   AML with minimal differentiation
   AML without maturation
   AML with myelomonocytic leukemia
   Acute monoblastic/monocytic leukemia
   Pure erythroid leukemia
   Acute megakaryoblastic leukemia
   Acute basophilic leukemia
   Acute panmyelosis with myelofibrosis
   Myeloid sarcoma
   Myeloid proliferations related to Down syndrome
   Transient abnormal myelopoiesis (TAM)
   Myeloid leukemia associated with Down syndrome

   *Requires: previous history of MDS, dysplasia in at least 2 cell lines (> 50% dysplasia) or presence of MDS-related cytogenetic abnormality (see Arber et al., 20162);
   Note: presence of > 50% dysplasia in at least 2 cell lines will not classify as AML with myelodysplasia-
   related changes when mutation of NPM1 or biallelic mutation of CEBPA is present
   †Refers to patients developing AML following cytotoxic therapy including radiation

2. Baseline investigations:

   • Full history and physical including assessment of functional status
   • CBC, group and screen, blood film, reticulocyte count, electrolytes, calcium profile, magnesium, random glucose, creatinine, LFTs including AST and GGT, uric acid, LDH, ferritin, INR, PTT, fibrinogen
   • Hepatitis B surface antigen, Hepatitis B surface antibody, hepatitis B core antibody, hepatitis C, HIV serology, CMV serology (prior to transfusion, if possible),
   • Strongyloides serology (and stool for ova + parasite) is recommended in patients who were born, resided, or traveled long-term (i.e. 6 months cumulative exposure to rural or beach areas, or contact with skin with sand/soil) in the following regions: Southeast Asia, Oceania, Sub-Saharan Africa, South America, Caribbean, Mediterranean countries, Middle East, North Africa, Indian sub-continent, Asia
   • ß-HCG (females of childbearing potential)
   • HLA typing, PRA typing, family contact information and donor search initiation forms (if stem cell transplant eligible)
   • Peripheral blood for: flow cytometry, cytogenetics, molecular studies
   • Bone marrow biopsy and aspirate (5 tubes: morphology, flow cytometry, cytogenetics, molecular/NGS x 2 tubes); note that the collection of peripheral blood for flow cytometry, cytogenetics and molecular (x 2 tubes) is essential when the bone marrow aspirate is considered poor/dry. If the bone marrow aspirate is dry +/- hemodilute with a low number of circulating blasts, obtain 2 biopsy samples
   • Baseline ECG
   • MUGA scan (if induction therapy candidate)
   • Baseline CT chest
   • TB skin test
   • Discuss sperm banking/fertility preservation
   • Lumbar puncture +/- CNS imaging for the following:
     • Myelomonocytic or monocytic subtype
     • Extramedullary involvement
     • CD56+ blasts
     • WBC > 40 x 10⁹/L at presentation
     • CNS signs/symptoms
       
       

3. Prognostic factors

   A number of clinically relevant classification by cytogenetic/molecular abnormalities exist. We utilize the European Leukemia Network classification as follows³:

   Risk category	Genetic abnormality
   Favorable	t(8;21)(q22;q22.1); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow† Biallelic mutated CEBPA
   Intermediate	Mutated NPM1 and FLT3-ITDhigh† Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse-risk genetic lesions) t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡ Cytogenetic abnormalities not classified as favorable or adverse
   Adverse	t(6;9)(p23;q34.1); DEK-NUP214 t(v;11q23.3); KMT2A rearranged t(9;22)(q34.1;q11.2); BCR-ABL1 inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) −5 or del(5q); −7; −17/abn(17p) Complex karyotype,§ monosomal karyotype|| Wild-type NPM1 and FLT3-ITDhigh† Mutated RUNX1¶ Mutated ASXL1¶ Mutated TP53

   †Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5); note that our FLT3 assay is RNA-based (ELN is DNA-based) and that these assays may not always be concordant
   ‡The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations
   §Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1
   ||Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional monosomy or structural chromosome abnormality (excluding core-binding factor AML)
   ¶These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk subtypes

4. Treatment

   Induction chemotherapy will generally be offered to patients < 65 years of age. For patients between 65 to 75 years old, careful assessment of functional status including frailty, comorbidities, disease risk, calculation of treatment related mortality,⁴ and patient preference will inform the decision to proceed with induction chemotherapy versus a non-curative treatment approach. Patients > 75 years old will typically be managed with non-curative intent. For patients that will proceed with induction chemotherapy, a double-lumen Hickman line will be inserted. Selection of induction chemotherapy will be primarily guided by disease risk (as per ELN³), if available at induction.

   First-line induction-eligible patients (see appendix for regimen details):
   
   

   	Induction regimen	Consolidation regimen
   Favorable risk core-binding factor (CBF) [t(8;21)(q22;q22.1) or inv(16)(p13.1q22) or t(16;16)(p13.1;q22)]	“3+7” plus Gemtuzumab ozogamicin†	Daunorubicin + high-dose cytarabine plus gemtuzumab ozogamicin (cycle 1) High-dose cytarabine plus gemtuzumab ozogamicin (cycle 2) High-dose cytarabine alone (cycle 3)
   Favorable risk non-CBF‡	“3+7” plus either: Midostaurin (FLT3+) Or Gemtuzumab ozogamicin (FLT3-)†	Daunorubicin + high-dose cytarabine (cycle 1 and 2) +/- gemtuzumab ozogamicin Or High-dose cytarabine plus midostaurin (cycles 1 to 4) for FLT3+
   Intermediate risk‡	“3+7” plus either: Midostaurin (FLT3+) Or Gemtuzumab ozogamicin (FLT3-)†	Daunorubicin + high-dose cytarabine for cycle 1 and 2 +/- gemtuzumab ozogamicin Or High-dose cytarabine plus midostaurin (cycles 1 to 4) for FLT3+
   Adverse risk [without mutated TP53, complex cytogenetics, monosomal karyotype, AML with myelodysplasia-related changes or therapy-related AML] ‡	FLAG-IDA Or “3+7” plus midostaurin (FLT3+)	FLAG-IDA (cycle 1 and 2) Or High-dose cytarabine plus midostaurin (cycles 1 to 4) for FLT3+
   Adverse risk [with complex cytogenetics, monosomal karyotype, AML with myelodysplasia-related changes/arising from previous MPN or therapy-related AML and fit (generally < 60 yo)] ‡	FLAG-IDA	FLAG-IDA (cycle 1 and 2)
   Adverse risk [with complex cytogenetics, monosomal karyotype, AML with myelodysplasia-related changes or therapy-related AML and less fit but suitable for allogeneic stem cell transplant (generally 60 - 75 yo)] ‡	Daunorubicin/cytarabine liposome (Vyxeos)	Daunorubicin/cytarabine liposome (Vyxeos) (cycle 1 and 2)

   ^†Need not wait for cytogenetics studies to start gemtuzumab but discontinue if adverse risk. For stable patients, preference to wait for confirmation of FLT3 negative status prior to induction with gemtuzumab.

   ^‡Fit patients with intermediate/adverse risk AML achieving CR will be referred for allogeneic stem cell transplant consultation if suitable donor identified (and consistent with patient preference). Also, patients with presence of FLT3-ITD (with or without presence of NPM1) will also be referred for allogeneic stem cell transplant.

   First-line for non-induction-eligible patients (see appendix for regimen details):

   • Patients with known TP53 mutation:
     
     • Clinical trial
       OR
     • Hypomethylating agent (e.g. azacitidine) +/- venetoclax
       OR
     • Best supportive care (based on functional status and patient preference)
   • Patients not eligible for induction chemotherapy:
     • Clinical trial
       OR
     • Hypomethylating agent (e.g. azacitidine) +/- venetoclax
       OR
     • Low-dose cytarabine (consider for patients with normal cytogenetics or favorable risk)
       OR
     • Best supportive care (based on functional status and patient preference)
       
       

   Response assessment (first-line induction patients):
   

   Upon count recovery (approximately day 28 to 35 post-start of induction), a bone marrow aspirate +/- biopsy will be performed to assess remission status. Recommend following order of aspirate samples (ensure first aspirate sample be labelled for flow cytometry).

   1. Flow cytometry (heparin)
   2. Morphology (EDTA)
   3. Molecular (EDTA)
   4. Cytogenetics (heparin)
      
      
   Please record the date since start of induction on the bone marrow requisition.
   
   

   Minimal or measurable residual disease (MRD) status will be determined by molecular for the following 4 AML subtypes:

   AML Molecular MRD Available (UHN) AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11 AML with BCR-ABL1 (provisional entity) APL with PML-RARA†

   †See separate APL guidelines for details
   
   

   Upon completion of consolidation chemotherapy (i.e. in complete remission), patients to be followed every 3 months with molecular testing for CBF AML (on peripheral blood) x 2 years⁵
   

   Response assessment (first-line non-induction patients):
   

   • Hypomethylating agent alone: assess remission status with bone marrow aspirate +/- biopsy following 6 cycles and/or at the time of suspected progression.
   • Hypomethylating agent plus venetoclax: assess remission status with bone marrow aspirate +/- biopsy following cycle 1 or 2 and/or at the time of suspected progression. If remission achieved and patient remains neutropenic (neutrophils < 0.5), consider holding hypomethylating agent and venetoclax for up to 14 days⁶ and consider reduction in venetoclax for subsequent cycles (e.g. 200 mg daily for days 1-14 of each 28-day cycle). GCSF dosed every 2-3 days can also be used during that 14-day period off of therapy with a neutrophil goal of >5.
   • Bone marrow aspirate +/- biopsy may not be necessary for patients on low-dose cytarabine if hematologic response but may be indicated if suspected progression and/or will alter management.
     
     
   Relapsed/refractory disease:
   
   

   Treatment will be individualized and will depend upon performance/functional status, patient preference, age, suitability for allogeneic stem cell transplant and prior regimen. Potential options include re-induction with FLAG-IDA, hypomethylating agent +/- venetoclax, targeted agent (e.g., enasidenib, gilteritinib), low-dose cytarabine, clinical trial and best supportive care. At the time of relapse, recommend discussion with hematopathology about reassessing FLT3 status (gilteritinib eligibility) and additional molecular/cytogenetic studies if there is a suggestion of a phenotypic change.

   Supportive care: For antimicrobial prophylaxis, please refer to the complete guidelines.

   “3+7”/daunorubicin+cytarabine liposome (Vyxeos):
   

   	Induction	Consolidation
   Antibiotic Prophylaxis	None	Ciprofloxacin 500 mg PO BID starting day 8, until recovery (ANC > 0.5)
   Antifungal Prophylaxis	Voriconazole 200 mg PO BID starting day 4, until recovery (ANC > 0.5)	Voriconazole (or fluconazole if cost prohibitive) starting day 8, until recovery (ANC > 0.5)
   Antiviral Prophylaxis	Valacyclovir 500 mg PO daily stating day 1 and continued until completion of all chemotherapy

   
   “3+7”/Midostaurin:
   

   	Induction	Consolidation
   Antibiotic Prophylaxis	None	Ciprofloxacin 500 mg PO BID starting day 8, until recovery (ANC > 0.5) Alternative: TMP/SMX i DS PO BID starting day 8, until recovery (ANC > 0.5)
   Antifungal Prophylaxis	Caspofungin 50 mg IV daily starting day 4, until recovery (ANC > 0.5)	None
   Antiviral Prophylaxis	Valacyclovir 500 mg PO daily starting day 1 and continued throughout

   
   AML (FLAG-IDA):
   

   	Induction	Consolidation
   Antibiotic Prophylaxis	None.	Ciprofloxacin 500 mg PO BID starting day 8, until recovery (ANC > 0.5)
   Header textHeader text	Voriconazole 200 mg PO BID starting day 4, until recovery (ANC > 0.5)	Voriconazole (or fluconazole if cost prohibitive) starting day 8, until recovery (ANC > 0.5)
   	AND: TMP/SMX i DS PO qMWF starting day 1 and continued for 6 months after completion of chemotherapy
   Antiviral Prophylaxis	Valacyclovir 500 mg PO daily and continued until 2 months after stopping chemotherapy (including corticosteroids)

   
   AML (non-induction regimens):

   Antibiotic Prophylaxis	None
   Antifungal Prophylaxis	For azacitidine plus venetoclax, voriconazole 200 mg PO BID if neutrophils < 0.5. For others, consider on case-by-case basis at discretion of prescriber.
   Antiviral Prophylaxis	For azacitidine-based regimens, valacyclovir 500 mg PO daily and continued until end of chemotherapy. Do not recommend for low-dose cytarabine

   
   Suppression of Menstruation
   

   For menstruating women, consider use of either an oral contraceptive (taken continuously) or a gonadotropin-releasing hormone agonist (e.g. leuprolide) given as a depot injection.

   Bleeding Prophylaxis
   

   For patients with platelets below 20, consider use of tranexamic acid prophylaxis to reduce bleeding risk. For patients requiring tranexamic acid post discharge, EAP approval is required.

   Thromboprophylaxis
   

   For patients in hospital and platelets over 30 (without transfusion support) with no clinical evidence of bleeding, consider use of low molecular weight heparin for thromboprophylaxis (e.g. enoxaparin 40 mg SC qhs. If weight less than 40 kg or CrCl < 30mL/min, give enox 30 mg SC qhs).

   Appendix: Suggested Chemotherapy dosing:

   “3+7” Induction Consolidation	Daunorubicin 60 mg/m2 IV days 1 to 3 plus Cytarabine 200 mg/m2 IV days 1 to 7† Daunorubicin 45 mg/m2 IV days 1, 2 plus Cytarabine 3 g/m2 IV days 1, 3, 5 for cycle 1‡ Cytarabine 3 g/m2 IV days 1, 3, 5 for cycle 2 and 3‡§ OR Daunorubicin 45 mg/m2 IV days 1, 2 plus Cytarabine 3 g/m2 IV days 1, 3, 5 for cycle 1 and 2‡
   FLAG-IDA Induction Consolidation	Fludarabine 30 mg/m2 IV days 1 to 5 plus Cytarabine 2 g/m2 IV days 1 to 5 plus Idarubicin 10 mg/m2 IV days 1 to 3 plus G-CSF 300 mcg SC days 0 to 5 Fludarabine 30 mg/m2 IV days 1 to 4 plus Cytarabine 2 g/m2 IV days 1 to 4 plus Idarubicin 10 mg/m2 IV days 1 to 2 plus G-CSF 300 mcg SC days 1 to 4 for cycle 1 and 2
   Daunorubicin/cytarabine liposome (Vyxeos) Induction Consolidation	Vyxeos 44 mg/m2 IV days 1, 3,5 Vyxeos 44 mg/m2 IV days 1, 3 for cycle 1 and 2
   Midostaurin7 Induction Consolidation	Midostaurin 50 mg PO BID days 8-21 (with “3+7”) Midostaurin 50 mg PO BID days 8-21 (cytarabine 3 g/m2 cycles 1 to 4)‡
   Gemtuzumab Ozogamicin8 Induction Consolidation	Gemtuzumab ozogamicin 3 mg/m2 IV (max. 4.5 mg/dose) days 1, 4, 7 Gemtuzumab ozogamicin 3 mg/m2 IV (max. 4.5 mg/dose) day 1 (cycle 1 and 2)
   Azacitidine	Azacitidine 75 mg/m2 SC days 1-5, 8-9 of 28-day cycle (‘5-2-2’ schedule) for at least 6 cycles
   Venetoclax	Venetoclax 200 - 400 mg PO daily to be added to azacitidine (dose adjusted if concomitant antifungal prophylaxis) Suggested ramp-up for cycle 1: Venetoclax 50 mg on day 1 Venetoclax 100 mg on day 2 Venetoclax 200 mg daily day 3 Venetoclax 400 mg daily starting day 4 (if no concomitant anti-fungal prophylaxis)
   Low-dose cytarabine	Low-dose cytarabine 20 mg/m2 SC daily x 10 days of 28-day cycle

   †Consider cytarabine dose reduction to 100 mg/m2 for patients age > 60 years
   ‡Consider cytarabine dose reduction to 1.5 g/m2 for patients age > 60 years; §For CBF leukemia

Key references

1. SEER Cancer Stat Facts: Acute Myeloid Leukemia. National Cancer Institute. Accessed May 4, 2020.
2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405.
3. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
4. Walter RB, Othus M, Borthakur G, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29(33):4417-4423.
5. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275-1291.
6. Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia. 2019;33(12):2795-2804.
7. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454-464.
8. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.