What are the diagnosis and management options for acute myeloid leukemia (AML)?

Acute Myeloid Leukemia: Diagnosis and Management

Diagnosis

The diagnosis of AML requires ≥20% myeloblasts in bone marrow or peripheral blood (except for AML with specific recurrent genetic abnormalities like t(15;17), t(8;21), or inv(16) where any blast percentage suffices), confirmed through a comprehensive workup including morphology, immunophenotyping, cytogenetics, and molecular testing. 1

Essential Diagnostic Components

Peripheral Blood and Bone Marrow Examination:

• Obtain complete blood count with differential showing myeloblasts, monoblasts, or megakaryoblasts, typically accompanied by anemia and thrombocytopenia 2
• Perform bone marrow aspirate (mandatory) with examination of ≥500 nucleated cells on marrow smears containing spicules 1
• Count ≥200 leukocytes on peripheral blood smears using May-Grünwald-Giemsa or Wright-Giemsa stain 1, 2
• Include myeloblasts, monoblasts, and megakaryoblasts in blast count; for monocytic differentiation, count monoblasts and promonocytes but not mature monocytes 1, 3
• Perform bone marrow trephine biopsy if dry tap (punctio sicca) occurs 1

Immunophenotyping (Mandatory):

• Use multiparameter flow cytometry (≥3-4 color) to determine lineage involvement 1, 2
• Test for precursor markers: CD34, CD38, CD117, CD133, HLA-DR 1, 2
• Test for granulocytic markers: CD13, CD15, CD16, CD33, CD65, cytoplasmic myeloperoxidase 1, 2
• Test for monocytic markers: NSE, CD11c, CD14, CD64, lysozyme 1
• Test for megakaryocytic markers: CD41, CD61, CD42 1

Cytogenetic Analysis (Mandatory):

• Perform conventional cytogenetics on bone marrow with analysis of minimum 20 metaphase cells to establish normal karyotype 1, 2
• Identify recurrent abnormalities: t(8;21), inv(16)/t(16;16), t(15;17), t(9;11), t(6;9), inv(3)/t(3;3), t(1;22) 1
• Use FISH if cytogenetic analysis fails to detect RUNX1-RUNX1T1, CBFB-MYH11, MLL rearrangements, EVI1 fusions, or loss of 5q/7q 1

Molecular Genetic Testing (Mandatory for CN-AML):

• Test for NPM1, CEBPA, and FLT3 mutations in all cytogenetically normal AML patients receiving intensive therapy 1, 2
• Extract both DNA and RNA from marrow/blood specimens; prioritize RNA extraction if cell numbers limited 1
• Use RT-PCR for fusion genes: RUNX1-RUNX1T1, CBFB-MYH11, MLLT3-MLL, DEK-NUP214 1
• Store viable cells for future molecular analysis 1

Risk Stratification

Favorable Risk (treat with intensive chemotherapy):

• t(8;21)(q22;q22.1); RUNX1-RUNX1T1 1
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 1
• t(15;17)(q22;q12); PML-RARA (acute promyelocytic leukemia) 1
• Mutated NPM1 without FLT3-ITD or with low FLT3-ITD allelic ratio 1
• Biallelic mutated CEBPA 1

Adverse Risk (consider allogeneic transplant in first remission):

• Complex karyotype (≥3 chromosomal abnormalities) 1
• Monosomal karyotype 1
• inv(3)/t(3;3); GATA2, MECOM(EVI1) 1
• t(6;9)(p23;q34); DEK-NUP214 1
• Mutated TP53 1
• -5, del(5q), -7, del(7q) 1
• Antecedent myelodysplastic syndrome or therapy-related AML 1

Age and Comorbidity Assessment:

• Patients >60 years have adverse prognosis, particularly with MDR-positivity or unfavorable genetics 1
• Perform cardiac examination including echocardiography for patients with risk factors or heart disease history 1
• Assess performance status and comorbidities to determine intensive therapy eligibility 1

Management

Patients eligible for intensive therapy should receive induction chemotherapy with curative intent, while those with poor performance status or significant comorbidities should receive lower-intensity therapy or supportive care. 1, 4

Pre-Treatment Considerations

Emergency Management:

• Perform emergency leukapheresis or administer hydroxyurea for hyperleukocytosis (WBC >100,000/μL) prior to induction 3
• Postpone chemotherapy until adequate diagnostic material obtained 1
• Perform HLA typing on transplant candidates and family members early during induction 1
• Obtain coagulation screening before central venous line insertion 1

Imaging and Infection Workup:

• Perform thoracic CT and abdominal ultrasound/CT if fungal infection suspected to assess liver, spleen, lymph nodes, kidneys 1

Treatment Approach by Patient Category

Fit Patients (Age <60, Good Performance Status):

• Administer intensive induction chemotherapy (anthracycline + cytarabine "7+3" regimen remains standard) 1, 4
• Follow with consolidation chemotherapy 1
• Consider allogeneic stem cell transplantation for intermediate and adverse-risk patients in first complete remission 1

Older/Unfit Patients:

• Use hypomethylating agents (azacitidine or decitabine) combined with venetoclax (BCL-2 inhibitor) as this has revolutionized therapy and extends survival over monotherapy 5, 4
• Consider lower-intensity chemotherapy regimens 1
• Provide supportive care for those not eligible for curative treatment 1

Molecularly-Targeted Therapy:

• Add midostaurin to induction/consolidation for FLT3-mutated AML 4
• Use gilteritinib for relapsed/refractory FLT3-mutated AML 5, 4
• Use quizartinib for FLT3-ITD positive AML 4
• Use ivosidenib or olutasidenib for IDH1-mutated AML 4
• Use enasidenib for IDH2-mutated AML 4
• Use CPX-351 (liposomal cytarabine/daunorubicin) for therapy-related AML or AML with myelodysplasia-related changes 5

Acute Promyelocytic Leukemia (APL) with t(15;17):

• Treat with all-trans retinoic acid (ATRA) and arsenic trioxide; this is a distinct entity requiring specialized management 1

Treatment Setting

Treatment should occur in centers offering:

• Full hematology and medical oncology services 1
• Close collaboration with bone marrow transplant unit 1
• Adequate infectious disease services 1
• Transfusion services 1
• Enrollment in clinical trials whenever possible 1

Supportive Care Throughout Treatment

• Provide blood product transfusions as needed 6
• Administer antimicrobial prophylaxis and treatment 6
• Monitor frequently for chemotherapy-related complications 6

Common Pitfalls

• Recent growth factor therapy, transfusions, or certain medications can obscure or mimic acute leukemia features 2
• Failure to obtain adequate diagnostic material before starting chemotherapy compromises classification and risk stratification 1
• Not identifying transplant candidates early during induction delays optimal consolidation therapy 1
• Treating elderly patients with intensive chemotherapy without considering MDR-positivity and genetic changes increases treatment-related mortality 1