Acute Promyelocytic Leukemia

Etiology

The RARA gene, located on the long arm of chromosome 17, encodes retinoic acid receptor alpha, a nuclear receptor transcription factor. After binding to retinoic acid, this receptor regulates the expression of multiple genes. The RARA gene is involved in nearly all cases of acute promyelocytic leukemia (APL). In 90% to 95% of cases, APL results from the t(15;17)(q24;q21) translocation, which fuses the promyelocytic leukemia (PML) gene with RARA, generating the PML::RARA fusion gene. A reciprocal RARA::PML fusion gene is also present in approximately 80% of cases. The resulting fusion protein functions as an aberrant retinoid receptor.

Less common cytogenetic abnormalities include t(5;17)(q35;q21), t(11;17)(q23;q21), t(11;17)(q13;q21), and t(17;17)(q11;q21), which generate the NPM1::RARA, ZBTB16::RARA, NUMA1::RARA, and STAT5B::RARA fusion genes, respectively. ZBTB16 was previously referred to as promyelocytic leukemia zinc finger, and NUMA1 was previously referred to as nuclear mitotic apparatus protein 1. These variant translocations have clinical significance because they differ in their responsiveness to retinoids. The NPM1::RARA and NUMA1::RARA fusion genes are generally associated with responsiveness to all-trans retinoic acid, whereas ZBTB16::RARA and STAT5B::RARA may be associated with partial or complete resistance.[4][5]

The mechanisms underlying these chromosomal rearrangements and the development of leukemia remain incompletely understood. Therapy-related APL may develop after prior cytotoxic chemotherapy, particularly treatment with topoisomerase II inhibitors, or exposure to ionizing radiation. Exposure to industrial solvents and other toxic agents has also been proposed as a risk factor.

Epidemiology

Acute promyelocytic leukemia is relatively rare and accounts for approximately 7% to 8% of adult acute myeloid leukemia (AML) cases. The condition most commonly occurs in middle-aged adults, with a median age at diagnosis of 47 years. Acute promyelocytic leukemia is rare in individuals younger than 20 years. The incidence is slightly higher in men than in women.

Pathophysiology

The PML::RARA fusion protein heterodimerizes with the retinoid X receptor (RXR). The resulting PML::RARA–RXR complex binds to retinoic acid response elements in target genes and disrupts transcriptional regulation, leading to arrest of myeloid differentiation at the promyelocytic stage. The excessive accumulation of abnormal promyelocytes contributes to coagulopathy. These cells express tissue factor, which forms a complex with factor VII and activates factors X and IX, promoting a procoagulant state. The accumulation of immature promyelocytes also impairs normal hematopoiesis, increasing the risk of infection.[6][7] Certain variant fusion genes are associated with reduced sensitivity or resistance to all-trans retinoic acid and may also influence responsiveness to conventional therapy.

Histopathology

Acute promyelocytic leukemia is characterized by abnormal promyelocytes in the peripheral blood and bone marrow. The bone marrow is typically hypercellular with a predominance of atypical promyelocytes. In the classic hypergranular variant, the promyelocytes have folded, bilobed, kidney-shaped, or dumbbell-shaped nuclei; a high nuclear-to-cytoplasmic ratio; fine chromatin; and prominent nucleoli. The cytoplasm contains numerous violet granules. Auer rods may be present singly or in bundles and may form characteristic faggot cells. The abnormal promyelocytes also demonstrate strong myeloperoxidase activity.

The microgranular variant accounts for approximately 15% to 25% of cases in adults. In this variant, cytoplasmic granules may be sparse or difficult to visualize by light microscopy, and Auer rods may be less prominent. The nuclei often have a characteristic bilobed or folded appearance. Less common morphologic variants, including the hyperbasophilic variant and acute promyelocytic leukemia associated with the ZBTB16::RARA fusion gene, have also been described.

On immunophenotyping, the abnormal promyelocytes typically express strong cytoplasmic myeloperoxidase, CD13, CD33, and CD117. They generally lack expression of human leukocyte antigen DR, CD11b, and CD34. However, immunophenotypic variability can occur. Expression of CD2 and CD34 is more common in the microgranular variant.

History and Physical

Patients commonly present with generalized weakness, fatigue, gingival bleeding, petechiae, ecchymoses, epistaxis, menorrhagia, or infections. Visual changes may occur secondary to retinal hemorrhage. Patients may also present with thrombotic complications, including deep vein thrombosis, pulmonary embolism, or cerebrovascular accident. Some patients with advanced disease develop overt disseminated intravascular coagulation with severe bleeding.

Pancytopenia is common at presentation. A key distinction between acute promyelocytic leukemia and other forms of acute myeloid leukemia is the high risk of disseminated intravascular coagulation and associated hyperfibrinolysis in APL. This coagulopathy requires emergency treatment because it may lead to life-threatening central nervous system or pulmonary hemorrhage.

Evaluation

When acute promyelocytic leukemia is suspected, evaluation of the peripheral blood smear and rapid genetic testing for the PML::RARA fusion gene should be expedited because this condition is a medical emergency. Fluorescence in situ hybridization can provide rapid confirmation of the PML::RARA rearrangement. A prompt coagulopathy evaluation should include a platelet count, prothrombin time, activated partial thromboplastin time, D-dimer level or fibrin degradation products, and fibrinogen level. Bone marrow aspiration and biopsy with immunophenotyping should also be performed. Conventional karyotyping is recommended as part of the initial evaluation because it can identify the characteristic t(15;17) translocation, additional cytogenetic abnormalities, and some variant rearrangements. Reverse transcription polymerase chain reaction testing for the PML::RARA fusion transcript can confirm the diagnosis and provide a baseline for subsequent monitoring of measurable residual disease.

Acute promyelocytic leukemia is classified as low risk, intermediate risk, or high risk to guide treatment. Low-risk disease is defined by a white blood cell count of 10,000/µL or less and a platelet count greater than 40,000/μL. Intermediate-risk disease is defined by a white blood cell count of 10,000/µL or less and a platelet count of 40,000/µL or less. High-risk disease is defined by a white blood cell count greater than 10,000/µL.[8][9][10][11] Lumbar puncture is done in high-risk patients with an elevated white blood cell count if intrathecal therapy is contemplated. Further, a cardiac evaluation is necessary before administering anthracyclines.

Treatment / Management

Chemotherapy

Acute promyelocytic leukemia is a medical emergency associated with high mortality before treatment. All-trans retinoic acid (ATRA) is a cornerstone of modern treatment regimens. ATRA should be initiated immediately when APL is suspected, even before cytogenetic or molecular confirmation is available. Before the introduction of ATRA in the 1980s, outcomes were poor with chemotherapy alone. Combining ATRA with anthracycline-based chemotherapy substantially improved survival and cure rates.

Arsenic trioxide (ATO) also targets the PML::RARA fusion protein, promoting differentiation and apoptosis of malignant promyelocytes. ATO acts synergistically with ATRA. For patients with non–high-risk disease, defined by a white blood cell count of 10,000/µL or less, ATRA plus ATO is the preferred regimen for induction and consolidation. This regimen is associated with less toxicity than ATRA plus conventional chemotherapy.Patients with high-risk disease, defined by a white blood cell count greater than 10,000/µL, require additional cytoreductive therapy. Treatment options include ATRA plus ATO with an anthracycline or gemtuzumab ozogamicin and ATRA plus anthracycline-based chemotherapy. The selection of a treatment regimen should account for disease risk, cardiac function, comorbidities, and functional status. An ATRA- and ATO-based regimen with appropriate cytoreductive therapy may be considered for older adults and patients who cannot tolerate anthracycline-based chemotherapy.

The need for maintenance therapy depends on the induction and consolidation regimens used. Maintenance therapy is generally not required for patients who receive ATRA plus ATO for non-high-risk disease. Reverse transcription polymerase chain reaction testing for the PML::RARA fusion transcript should be used to assess molecular response after consolidation and monitor for measurable residual disease according to the patient’s risk category and treatment protocol. Treatment of relapsed APL is beyond the scope of this article.

Supportive Therapy 

Supportive therapy plays a critical role in the survival of patients with APL. Coagulopathy may cause life-threatening hemorrhage, particularly during the early treatment period. Transfusions of fibrinogen concentrate or cryoprecipitate, platelets, and fresh frozen plasma should be initiated promptly when APL is suspected and continued as needed during induction therapy. The platelet count should be maintained between 30 and 50 × 10⁹/L, the fibrinogen level between 100 and 150 mg/dL, and the international normalized ratio below 1.5. Invasive procedures, including lumbar puncture and central venous catheter placement, should be avoided when possible until the coagulopathy has resolved.

Patients should also be monitored closely for infection. Patients with fever and neutropenia require prompt empiric broad-spectrum antibiotic therapy active against gram-positive and gram-negative organisms, including Pseudomonas aeruginosa. Vancomycin should not be included routinely but may be added when a catheter-related infection, skin or soft tissue infection, pneumonia, hemodynamic instability, or resistant gram-positive infection is suspected. Persistent fever after 4 to 7 days of broad-spectrum antibiotic therapy should prompt reassessment and consideration of empiric or preemptive antifungal therapy in patients at high risk of invasive fungal infection.

Because cure rates for APL are high, hematopoietic stem cell transplant is not used as first-line treatment. Transplant may be considered for selected patients with relapsed or treatment-resistant disease. Central nervous system prophylaxis is not routinely administered. Intrathecal therapy may be considered for selected patients with high-risk disease or hyperleukocytosis after complete remission has been achieved.

Differential Diagnosis

The differential diagnosis includes:

• Acute lymphoblastic leukemia 
• Acute myeloid leukemia 
• Aplastic anemia
• Folic acid deficiency
• Myelodysplastic syndrome

Toxicity and Adverse Effect Management

Arsenic trioxide may cause QT interval prolongation and hepatotoxicity. Chemotherapy-containing regimens may cause cytopenias, an increased risk of infection, and mucositis. Intracranial hypertension, also known as pseudotumor cerebri, is a recognized complication of retinoic acid derivatives, including all-trans retinoic acid. This complication occurs more commonly in pediatric patients and may present with headache, papilledema, nausea, vomiting, or visual disturbances. Patients with suspected intracranial hypertension should undergo neurological evaluation. Interruption, dose reduction, or discontinuation of all-trans retinoic acid may be necessary. Acetazolamide and analgesics may be considered for persistent symptoms.

Medical Oncology

Guidelines:

1. Immediately admit the patient, initiate ATRA, and manage the coagulopathy
2. Confirm the diagnosis
3. Monitor coagulation parameters
4. Start transfusions until coagulation parameters are normalized
5. Start therapy with ATRA
6. Perform a bone marrow assessment to determine the response
7. Continue ATRA therapy until there is clinical benefit
8. Combine ATRA with chemotherapy in patients who relapse

Prognosis

The prognosis of acute promyelocytic leukemia is poor without treatment, with a median survival of approximately 1 month. However, outcomes have improved substantially with modern treatment. Most patients achieve complete remission, and many experience durable disease-free survival. Results from the Lo-Coco et al study showed that the 2-year disease-free survival rate was 97% (95% CI, 94%–100%) in the all-trans retinoic acid (ATRA) plus arsenic trioxide group and 90% (95% confidence interval, 84%–97%) in the ATRA plus chemotherapy group (P = .11).[12]

Untreated APL is rapidly fatal, primarily because of hemorrhage and infection. Differentiation syndrome may develop after initiation of treatment with ATRA or arsenic trioxide and can also cause serious complications. The white blood cell count at presentation is an important prognostic indicator, with higher counts associated with increased risk. Additional factors associated with early mortality include older age, male sex, elevated serum creatinine levels, low platelet counts, and low fibrinogen levels.

Complications

Differentiation syndrome is a potentially life-threatening inflammatory complication that may occur after initiation of differentiating agents, including all-trans retinoic acid and arsenic trioxide. Clinical manifestations may include unexplained fever, weight gain, peripheral edema, dyspnea, pulmonary infiltrates, pleural or pericardial effusions, hypotension, acute kidney injury, and multiorgan dysfunction. Prompt recognition is essential because severe cases can be fatal. Intravenous dexamethasone should be initiated immediately when differentiation syndrome is suspected. Temporary interruption of differentiation therapy may be necessary in severe cases. Hyperleukocytosis may also develop during treatment with differentiating agents due to rapid differentiation and proliferation of abnormal promyelocytes. Clinicians should monitor the white blood cell count closely during induction therapy.