Leukemia Mieloid Akut (AML)

01Pathophysiology

AML arises from the accumulation of acquired somatic mutations in hematopoietic stem or progenitor cells committed to the myeloid lineage. These mutations fall into two broad functional categories, and understanding this "two-hit" model is essential for connecting the biology to the clinical picture.

Class I mutations activate proliferative and survival signaling pathways. The most commonly tested is the FLT3 internal tandem duplication (FLT3-ITD), which constitutively activates a receptor tyrosine kinase, driving uncontrolled cell division. This mutation confers a poor prognosis and is now a targetable lesion with midostaurin. Other class I mutations include RAS and KIT.

Class II mutations impair normal myeloid differentiation. The hallmark example is the t(15;17)(q24;q21) translocation in APL, which fuses the PML gene to the retinoic acid receptor alpha (RARA) gene. The resulting PML-RARA fusion protein acts as a dominant-negative transcriptional repressor, blocking the normal differentiation of promyelocytes into mature granulocytes. This is why ATRA works: it forces the fusion protein into a conformation that releases transcriptional repression, allowing the arrested promyelocytes to terminally differentiate.

The net result of these two hit categories is a bone marrow packed with immature blasts that cannot differentiate into functional blood cells but continue to proliferate. This directly explains every symptom the patient develops:

• Anemia (decreased red cell production) causes fatigue and pallor.

• Thrombocytopenia (decreased platelet production) causes bleeding, petechiae, and bruising.

• Neutropenia (decreased functional white cells despite a high total white count) causes recurrent and often severe infections.

• Marrow expansion causes bone pain.

• Extramedullary infiltration of leukemic blasts into the gums, skin, and organs causes gingival hyperplasia, leukemia cutis, and hepatosplenomegaly.

A particularly high-yield pathophysiologic concept involves APL (formerly classified as FAB M3). The abnormal promyelocytes in APL contain dense azurophilic granules loaded with procoagulant tissue factor and other substances. When these cells lyse, either spontaneously or during initial chemotherapy, they release these granule contents into the bloodstream, triggering DIC. This is why APL is a medical emergency: untreated DIC leads to simultaneous thrombosis and hemorrhage, and the mortality is front-loaded in the first hours to days. Recognizing this pattern (young patient + pancytopenia + DIC) and initiating ATRA immediately, even before cytogenetic confirmation, is the single most testable management concept in APL.

02Classification and Clinical Manifestation

FAB Classification (Morphology-Based)

WHO Classification (Genetics-Based)

The WHO system categorizes AML by recurrent genetic abnormalities, which carry prognostic and therapeutic significance.

Clinical Manifestation by Organ System

03Diagnostic Workup

The best initial test when AML is suspected based on the clinical picture (pancytopenia, bleeding, infections in an adult) is a CBC with differential and a peripheral blood smear. The smear may reveal circulating blasts. The presence of Auer rods, which are crystallized aggregates of myeloperoxidase within the cytoplasm of myeloblasts, is pathognomonic for a myeloid neoplasm and should never be seen in ALL. In APL, multiple Auer rods bundled together in a single cell form what are called "faggot cells", a nearly diagnostic finding.

However, the peripheral smear alone is insufficient for a definitive diagnosis. The most accurate (confirmatory) test is the bone marrow biopsy and aspirate. According to WHO criteria, a diagnosis of AML requires > 20% myeloblasts in the bone marrow (or in peripheral blood). The exception is when a defining recurrent genetic abnormality, such as t(8;21), inv(16), or t(15;17), is present; in these cases, AML is diagnosed regardless of blast percentage.

Once blasts are identified, flow cytometry is performed to confirm myeloid lineage. The key myeloid markers are CD13, CD33, CD117, and cytoplasmic MPO. This step is critical because it distinguishes AML from ALL, which expresses lymphoid markers (CD10, CD19, CD20 for B-ALL; CD2, CD3, CD5, CD7 for T-ALL). Some AML subtypes co-express lymphoid markers (mixed phenotype acute leukemia), so flow cytometry interpretation requires the full panel.

Cytogenetics and molecular studies must be sent on every new AML diagnosis because they determine both the prognosis and the treatment plan. The three most testable cytogenetic findings are:

• t(15;17): PML-RARA fusion, defines APL, treated with ATRA + ATO rather than standard chemotherapy.

• t(8;21): RUNX1-RUNX1T1, favorable prognosis, good response to high-dose cytarabine consolidation.

• inv(16) or t(16;16): CBFB-MYH11, favorable prognosis, also responds well to consolidation cytarabine.

In clinical practice, when APL is suspected (pancytopenia + DIC + hypergranular promyelocytes on smear), FISH for t(15;17) or PCR for PML-RARA should be sent urgently, and ATRA should be started immediately without waiting for results, because the mortality risk from DIC is highest in the first 24 to 48 hours.

A coagulation panel is essential at presentation, particularly to identify DIC. Look for the classic laboratory pattern: prolonged PT and aPTT, markedly decreased fibrinogen, and elevated D-dimer and fibrin degradation products. This pattern in the context of acute leukemia should immediately raise suspicion for APL.

04Management and Treatment

Acute Stabilization

Before initiating definitive therapy, several urgent issues may need attention:

1. DIC (APL): Start ATRA immediately if APL is clinically suspected. Do not wait for cytogenetic confirmation. Aggressively replace fibrinogen with cryoprecipitate (target fibrinogen > 150 mg/dL) and transfuse platelets to maintain counts above 30,000 to 50,000/microL during the acute DIC phase.

2. Leukostasis: When the WBC exceeds approximately 100,000/microL and the patient develops respiratory distress or neurologic symptoms, this constitutes a hematologic emergency. Management includes urgent leukapheresis and initiation of induction chemotherapy. Avoid red blood cell transfusion before cytoreduction, as this increases blood viscosity and can worsen symptoms.

3. Tumor lysis syndrome (TLS) prophylaxis: Begin IV hydration and allopurinol (300 mg/day orally) before starting chemotherapy. For patients at very high risk (elevated uric acid, high WBC, large tumor burden), use rasburicase (0.2 mg/kg IV once), which is a recombinant urate oxidase that rapidly converts uric acid to the more soluble allantoin. A contraindication to rasburicase is G6PD deficiency, as it can trigger hemolytic anemia.

Induction Chemotherapy (Non-APL AML)

The standard induction regimen is the "7+3" protocol: 7 days of continuous infusion cytarabine combined with 3 days of an anthracycline (daunorubicin or idarubicin). The goal is to achieve complete remission (CR), defined as less than 5% blasts in the bone marrow with recovery of peripheral blood counts. A bone marrow biopsy is performed approximately 14 days after induction to assess response. If residual disease is present, a second cycle of induction (re-induction) may be given.

For patients with FLT3-ITD positive AML, the tyrosine kinase inhibitor midostaurin is added to the 7+3 induction and subsequent consolidation cycles. This is based on the RATIFY trial, which demonstrated improved overall survival.

Induction for APL

APL is treated with a fundamentally different regimen. Low-to-intermediate risk APL (WBC < 10,000/microL) is treated with ATRA + ATO alone, without conventional chemotherapy. ATRA induces the differentiation of the arrested promyelocytes into mature granulocytes, while ATO induces apoptosis and degradation of the PML-RARA oncoprotein. High-risk APL (WBC > 10,000/microL) adds idarubicin to the ATRA + ATO backbone.

A critical complication of ATRA therapy is differentiation syndrome (formerly called retinoic acid syndrome), characterized by fever, dyspnea, weight gain, pulmonary infiltrates, pleural and pericardial effusions, and hypotension. It occurs because the differentiating leukemic cells release cytokines and infiltrate tissues. Treatment is dexamethasone 10 mg IV every 12 hours, and ATRA may be temporarily held in severe cases.

Consolidation Therapy

After achieving CR, consolidation is necessary to eliminate residual disease and prevent relapse. The consolidation strategy depends on the cytogenetic risk group:

• Favorable risk [t(8;21), inv(16), NPM1-mutated/FLT3-wild type]: 3 to 4 cycles of high-dose cytarabine (HiDAC) without transplant. A side effect to watch for with high-dose cytarabine is cerebellar toxicity (ataxia, dysarthria, nystagmus), particularly in patients over 60 years old.

• Intermediate risk: Allo-HSCT in first CR is preferred if a matched donor is available. HiDAC is an alternative for patients without a donor.

• Adverse risk [complex karyotype, TP53 mutation, FLT3-ITD with high allelic ratio]: Allo-HSCT in first CR is strongly recommended, as chemotherapy alone has a very high relapse rate.

Elderly or Unfit Patients

Patients who cannot tolerate intensive induction (generally older adults with significant comorbidities) are treated with hypomethylating agents (azacitidine or decitabine) combined with venetoclax, a BCL-2 inhibitor. This lower-intensity regimen has shown response rates comparable to 7+3 in older adults with significantly less toxicity. A notable side effect of venetoclax is prolonged cytopenias, requiring dose adjustments and careful monitoring.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on AML questions is by failing to recognize APL as a distinct entity that requires immediate, different treatment. A vignette describing a young adult with pancytopenia, bleeding, and laboratory evidence of DIC should trigger the response: "Start ATRA now." The trap is selecting standard 7+3 chemotherapy as the first step, or waiting for cytogenetic results before initiating therapy. Standard chemotherapy given to an APL patient without ATRA can worsen DIC by lysing the granule-laden promyelocytes, leading to fatal hemorrhage.

A second common trap involves the blast percentage. Students sometimes diagnose AML when blasts are between 10 and 20%. Remember: the WHO threshold is > 20% blasts. Below that number, the diagnosis is MDS (unless a defining cytogenetic abnormality is present, which overrides the blast percentage rule). Conversely, if the question stem provides a recurrent cytogenetic abnormality like t(8;21), the blast count does not need to reach 20% for the diagnosis to be AML.

Another tested concept is differentiating the cause of gingival hyperplasia. When a vignette describes swollen, bleeding gums in the context of pancytopenia and blasts, the answer is leukemic infiltration (M4 or M5 subtype AML). When it describes gingival hyperplasia in a patient on an antiepileptic, the answer is phenytoin. When it describes it in a transplant patient, the answer is cyclosporine. The context makes the diagnosis.

The distinction between AML and ALL on a peripheral smear is another favorite testing point. If the question mentions Auer rods, the answer is always AML. If it mentions TdT positivity, the answer is ALL (though TdT can rarely be positive in M0/M1 AML, this nuance is not tested at the licensing exam level). MPO positivity confirms myeloid lineage; PAS positivity (periodic acid-Schiff, coarse granular staining in blasts) suggests ALL.

Finally, be alert for the complication questions. If a patient on ATRA develops fever, dyspnea, and pulmonary infiltrates with weight gain, the answer is differentiation syndrome, treated with dexamethasone. If a patient starting chemotherapy for high-burden AML develops hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, the answer is tumor lysis syndrome, and the question will likely test whether you choose allopurinol (prevention) versus rasburicase (treatment of established TLS with elevated uric acid). Remember the G6PD contraindication to rasburicase.

The core competency being tested across AML questions is your ability to: (1) recognize the acute leukemia presentation, (2) correctly identify the lineage (myeloid vs. lymphoid), (3) distinguish APL from non-APL AML, and (4) select the appropriate next step in management based on the subtype and clinical urgency.