Acute Myeloid Leukemia: Symptoms and Clinical Presentation
Initial Clinical Manifestations
AML typically presents with symptoms related to bone marrow failure, including fatigue, bleeding, and recurrent infections, often preceded by these symptoms for 1 month or greater in some cases. 1
Hematologic Symptoms
- Anemia-related symptoms: Fatigue, weakness, and shortness of breath due to inadequate red blood cell production 2
- Thrombocytopenia-related symptoms: Bleeding manifestations including petechiae, bruising, and mucosal bleeding (menorrhagia in females) 1, 2
- Neutropenia-related symptoms: Recurrent or severe infections due to impaired white blood cell function 2, 3
Hyperleukocytosis Complications
- Leukostasis symptoms occur when white blood cell counts exceed 100 × 10⁹/L, manifesting as neurological symptoms (confusion, headache, visual changes), respiratory distress, or hypoxia 1, 4
- Tumor lysis syndrome risk increases with extreme leukocytosis, requiring monitoring of uric acid, potassium, phosphorus, calcium, and renal function 4
Coagulopathy
- Disseminated intravascular coagulation (DIC) is particularly common in acute promyelocytic leukemia (APL), presenting with both bleeding and thrombotic complications 1
- Coagulation status must be assessed before central line insertion 1
Extramedullary Disease
- Central nervous system involvement can occur, presenting with headache, cranial nerve palsies, or altered mental status 1
- Organomegaly: Splenomegaly, hepatomegaly, and lymphadenopathy may be present 2
Treatment Approach for Acute Myeloid Leukemia
Immediate Management Decisions
APL-Specific Emergency Treatment
If APL is suspected based on morphology, immediately initiate all-trans retinoic acid (ATRA) before confirmatory molecular/cytogenetic results are available. 1
- Do not perform leukapheresis in APL patients as it exacerbates coagulopathy 1, 4
- Delay intrathecal treatment until coagulopathy resolves 1
Hyperleukocytosis Management (WBC >100 × 10⁹/L)
Cytoreduction with hydroxycarbamide 50-60 mg/kg/day orally, or intravenous/subcutaneous cytarabine, or intravenous daunorubicin is recommended for patients with signs of leukostasis. 1, 4
- Leukapheresis is not generally recommended as it does not reduce early mortality in non-APL AML 1
- If leukapheresis is performed, it must be accompanied by chemotherapy 1
- Aggressive intravenous hydration (2.5-3 liters/m²/day) is essential 4
- Consider rasburicase to prevent hyperuricemia and renal failure, though data are insufficient for firm recommendation 1, 4
CNS Involvement
Treat with intrathecal cytarabine twice weekly, continuing for two injections beyond blast clearance from cerebrospinal fluid. 1
Risk Stratification and Treatment Selection
Pre-Treatment Assessment
Perform complete diagnostic workup including peripheral blood and bone marrow examination with morphology, cytochemistry, immunophenotyping, cytogenetic and molecular analysis before initiating therapy. 5, 6
- Cardiac evaluation: Echocardiography is mandatory for patients with cardiac risk factors before anthracycline therapy 1, 5
- Infection screening: CT scans of chest and abdomen, plus radiological imaging of teeth and jaws to identify infectious foci 1
- HLA typing: Perform at diagnosis for patients potentially eligible for allogeneic stem cell transplantation, including first-degree family members 1, 5
- Coagulation studies: Essential before central line insertion, particularly in APL 1
Treatment Eligibility Determination
Patients are assigned to either intensive chemotherapy or non-intensive treatment based on age (typically <60-65 years for intensive), performance status, and comorbidities 1
Intensive Treatment Regimen
Induction Chemotherapy
For core-binding factor AML, the recommended regimen is 7 days of cytarabine plus 3 days of daunorubicin (7+3) plus 1-3 days of gemtuzumab ozogamicin (GO) for CD33-positive disease. 1
For non-APL AML, standard induction consists of 7 days of cytarabine with 3 days of an anthracycline (7+3 regimen). 1, 7
- Daunorubicin combined with cytarabine produces complete remission rates of 53-65% 8
- Treatment initiation can be safely delayed several days until all diagnostic material is collected and molecular typing results are available 1, 4
- Central intravenous line insertion is required, performed under platelet transfusion if necessary 1
Dose modifications for organ dysfunction:
- Bilirubin 1.2-3 mg/dL: Give 75% of usual daunorubicin dose 8
- Bilirubin >3 mg/dL: Give 50% of usual daunorubicin dose 8
- Creatinine >3 mg/dL: Give 50% of usual daunorubicin dose 8
Response Assessment
Evaluate bone marrow after hematological recovery or between days 28-35 if recovery is lacking. 1
- Repeat bone marrow aspirations until clear assessment of complete remission is obtained 1
- If second induction cycle is applied, assess bone marrow after hematological recovery or days 28-35 1
Consolidation Therapy
For favorable-risk patients (core-binding factor AML, NPM1-mutated without FLT3-ITD, biallelic CEBPA): Administer high-dose cytarabine-based chemotherapy without allogeneic stem cell transplantation. 1, 7, 9
For intermediate and adverse-risk patients with HLA-identical sibling: Proceed to allogeneic stem cell transplantation in first remission. 1, 7
- Allogeneic transplantation is not justified in favorable-risk patients in first remission as transplant-related mortality exceeds benefit 1
- Matched unrelated donor transplantation may be considered for intermediate and poor-risk groups 1
- Assess bone marrow morphology before each consolidation cycle and before allogeneic transplantation 1
Non-Intensive Treatment
For patients ineligible for intensive chemotherapy, assess response after at minimum 4 cycles to diagnose refractory disease, then every 3 months thereafter. 1
- Hypomethylating agents combined with venetoclax have revolutionized therapy for older adults, extending survival over monotherapy 9
Molecular Targeted Therapies
For FLT3-mutated AML: Add midostaurin to standard 7+3 induction and continue through consolidation. 9, 6
For IDH1-mutated AML: Consider ivosidenib or olutasidenib. 9
For IDH2-mutated AML: Consider enasidenib. 9
Supportive Care Requirements
Essential Supportive Measures
All patients require prophylaxis and management of tumor lysis syndrome, infection, hyperfibrinolysis, bleeding, and thrombosis. 1
- Blood product transfusions as needed for anemia and thrombocytopenia 2
- Antimicrobial prophylaxis and treatment 2
- GnRH agonist may be used in females to prevent menorrhagia, though data are limited 1
Monitoring for Chemotherapy Complications
- Cytarabine syndrome: Fever, myalgia, bone pain, chest pain, maculopapular rash, conjunctivitis, malaise occurring 6-12 hours post-administration; treat with corticosteroids 10
- Cardiotoxicity: More frequent in elderly and pediatric patients, may occur at lower cumulative anthracycline doses 8
- Infectious complications: Viral, bacterial, fungal, parasitic infections can be severe and fatal 10
Post-Treatment Surveillance
Monitoring Schedule
Perform bone marrow morphology every 3 months for 24 months after completing intensive treatment. 1
Obtain differential blood counts every 3 months for 5 years after treatment completion. 1
Measurable Residual Disease (MRD) Assessment
Assess MRD at diagnosis to establish aberrant marker profile, after 2 cycles of chemotherapy, and after treatment completion. 1
- Molecular MRD: Every 3 months from bone marrow or every 4-6 weeks from peripheral blood for 24 months in patients with molecular marker 1, 5
- Flow cytometric MRD: Assess from bone marrow 1
Management of Relapsed/Refractory Disease
Options include clinical trials, intensive re-induction chemotherapy, allogeneic stem cell transplantation, or best supportive care. 5, 7
- Allogeneic transplantation should be considered for patients achieving second remission 5, 7
- For relapsed APL, arsenic trioxide induces remission even in ATRA-refractory disease 7
- Patients failing 1-2 induction cycles are considered refractory and may benefit from allogeneic transplantation with HLA-matched donor 5
Critical Pitfalls to Avoid
- Never delay ATRA in suspected APL while awaiting confirmatory testing 1
- Never perform leukapheresis in APL due to exacerbation of coagulopathy 1, 4
- Never use diluents containing benzyl alcohol for experimental high-dose cytarabine therapy 10
- Never assume all extreme leukocytosis is malignant—consider leukemoid reaction from severe infection 4
- Never proceed with allogeneic transplantation in favorable-risk AML in first remission—transplant mortality exceeds benefit 1