What is the recommended diagnostic work‑up and initial therapy for a newly diagnosed acute myelogenous leukemia (AML) patient, including induction, consolidation, and options for those unsuitable for intensive chemotherapy?

Acute Myelogenous Leukemia: Diagnostic Work-up and Initial Therapy

Diagnostic Work-up

All patients with suspected AML require immediate bone marrow aspirate with comprehensive ancillary testing before initiating chemotherapy. 1

Initial Assessment

• Obtain complete blood count with differential and review peripheral blood smear for blast morphology 1, 2
• Document history of antecedent hematologic disorders (myelodysplastic syndrome, myeloproliferative neoplasm), prior chemotherapy exposure, and family history of hematologic malignancies 2
• Perform physical examination specifically assessing for mediastinal masses, cutaneous lesions, organomegaly (liver, spleen), and lymphadenopathy 1, 2
• Obtain coagulation studies prior to central line insertion 1
• Perform cardiac evaluation including echocardiography, particularly in patients with cardiac risk factors or history of heart disease 1

Bone Marrow Examination

• Obtain fresh bone marrow aspirate for morphologic evaluation with adequate aspirate smears 1, 2
• Evaluate bone marrow trephine core biopsy with touch preparations 1, 2
• If aspirate is inadequate ("dry tap"), use peripheral blood for diagnosis if sufficient blasts are present, or submit additional core biopsy unfixed in tissue culture medium for disaggregation 1

Essential Ancillary Studies

The following studies must be performed on all patients and cannot be substituted for one another: 1

• Conventional cytogenetic analysis (karyotype) - this is mandatory and cannot be replaced by FISH or molecular testing alone 1, 2
• Flow cytometry immunophenotyping with panel sufficient to distinguish AML from acute promyelocytic leukemia (APL), T-ALL, B-ALL, and acute leukemia of ambiguous lineage 1, 2
• Molecular genetic testing for FLT3-ITD in all patients 2
• FISH testing as appropriate based on morphology and immunophenotype 1, 2

Risk-Stratification Molecular Testing

• For core-binding factor AML (CBF-AML) with t(8;21) or inv(16)/t(16;16): perform KIT mutation analysis 2
• For suspected APL: obtain rapid PML-RARA testing 2
• For non-CBF, non-APL cases: perform mutational analysis for NPM1, CEBPA, and RUNX1 2

Special Circumstances

• If APL is suspected clinically: initiate all-trans retinoic acid (ATRA) immediately before confirmatory testing returns 1
• For white blood cell count >100 × 10⁹/L with leukostasis: administer hydroxycarbamide 50-60 mg/kg/day for cytoreduction; avoid leukapheresis in APL due to coagulopathy risk 1
• For CNS symptoms: obtain cerebrospinal fluid with cell count and cytocentrifuge preparation reviewed by pathologist 1
• For extramedullary disease: perform PET/CT and process tissue biopsy with same studies as bone marrow 2

HLA Typing

• Perform HLA typing on all patients who are potential allogeneic transplant candidates, including family members, early during diagnostic work-up 1

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Initial Therapy

Treatment Assignment Algorithm

First, determine if the patient is fit for intensive chemotherapy based on: 1

• Age and performance status
• Comorbidities (cardiac, hepatic, renal function)
• Patient preference

For Patients Fit for Intensive Chemotherapy

Acute Promyelocytic Leukemia (APL)

Induction: ATRA plus anthracycline (daunorubicin or idarubicin) 1

Consolidation: 1-2 cycles of chemotherapy including ATRA 1

Maintenance: ATRA plus chemotherapy is beneficial 1

Critical caveat: Delay intrathecal therapy until coagulopathy resolves 1

Core-Binding Factor AML (CBF-AML)

Induction: 7 days cytarabine + 3 days daunorubicin + 1-3 days gemtuzumab ozogamicin (7+3+GO) 1

Consolidation: High-dose cytarabine-based chemotherapy without allogeneic transplant in first remission 1

Expected outcome: 10-year survival rates ≥75% with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin 3

Non-CBF, Non-APL AML - Favorable/Intermediate Risk

Induction: 7+3 (7 days cytarabine + 3 days anthracycline) 1

Consolidation: 1-2 cycles of high-dose cytarabine-based chemotherapy 1

Allogeneic transplant: Not recommended in first remission for favorable-risk patients 1

Non-CBF, Non-APL AML - Adverse Risk

Induction options (prioritized): 1

1. CPX-351 (liposomal daunorubicin/cytarabine) for therapy-related AML or AML with myelodysplasia-related changes 1, 4
2. 7+3 with targeted agents if specific mutations present (FLT3 inhibitors for FLT3-ITD, IDH inhibitors for IDH1/IDH2 mutations) 1
3. Standard 7+3 if no specific indication for alternatives 1

Consolidation: Allogeneic hematopoietic cell transplantation in first remission with HLA-identical sibling or matched unrelated donor 1

For Patients Unsuitable for Intensive Chemotherapy

Standard of care: Hypomethylating agent (azacitidine or decitabine) plus venetoclax 3

Alternative options: 1

• Hypomethylating agents alone
• Low-dose cytarabine plus venetoclax
• Targeted agents as monotherapy if specific mutations present (gilteritinib for FLT3-mutated, ivosidenib for IDH1-mutated, enasidenib for IDH2-mutated)

Supportive care only: For patients with very poor performance status and extensive comorbidities 1

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Response Assessment

During Induction

• Obtain bone marrow aspirate during induction-induced aplasia to assess early marrow response or blast persistence 1, 5
• Monitor with serial complete blood counts and clinical examination 1, 5

Remission Criteria

Complete remission requires: 1, 5

• Normal bone marrow cellularity
• Morphologically normal hematopoiesis
• Blast levels <5% on bone marrow smears

Measurable Residual Disease (MRD)

• Assess MRD at diagnosis to establish aberrant marker profile 1
• Reassess after 2 cycles of chemotherapy and after end of treatment 1
• Monitor every 3 months from bone marrow (flow cytometry) or every 4-6 weeks from peripheral blood (molecular) for 24 months in patients with molecular markers 1

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Critical Pitfalls to Avoid

• Never delay diagnostic testing to start chemotherapy (except ATRA in suspected APL) - obtain all necessary material first 1, 2
• Never use leukapheresis alone for hyperleukocytosis - it does not reduce early mortality and must be accompanied by cytoreductive chemotherapy if used 1
• Never omit conventional cytogenetics - FISH and molecular testing cannot replace karyotype analysis 1, 2
• Never treat patients with refractory disease after 1-2 induction cycles with the same regimen - these patients require alternative approaches or clinical trial enrollment 1