What is Acute Promyelocytic Leukemia (APL)?

From the Guidelines

Acute Promyelocytic Leukemia (APML) is a distinct subtype of acute myeloid leukemia that requires immediate treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) or anthracycline-based chemotherapy upon clinical suspicion, due to the high risk of early mortality from hemorrhage. APML is characterized by the t(15;17) translocation that creates the PML-RARA fusion gene, and typically presents with pancytopenia, coagulopathy, and a high risk of life-threatening hemorrhage 1. The standard treatment involves ATRA at 45 mg/m² daily divided into two doses, combined with ATO for low-to-intermediate risk disease or anthracycline-based chemotherapy for high-risk disease.

Key Considerations in APML Treatment

• Treatment should begin immediately upon clinical suspicion, even before genetic confirmation, due to the high risk of early mortality from hemorrhage 1.
• ATRA works by inducing differentiation of leukemic promyelocytes, while ATO promotes apoptosis of leukemic cells.
• Patients require close monitoring for differentiation syndrome, characterized by fever, weight gain, respiratory distress, and pleural/pericardial effusions, which is treated with dexamethasone 10 mg twice daily.
• Coagulopathy management with fibrinogen replacement and platelet transfusions is essential during initial treatment.

Monitoring and Follow-up

• The therapeutic end point in APL is achievement of a molecular remission as defined by the absence of the PML-RAR fusion transcript using RT-PCR methods with a sensitivity threshold of 10^3 or 10^4 2.
• RT-PCR for the fusion transcript should be performed every 3 months for the first 2 years of complete remission (CR), then every 3 to 6 months for the following 2 to 3 years 2.
• With current therapies, APML has become highly curable with complete remission rates exceeding 90%.

From the Research

Acute Myeloid Leukemia (AML) Treatment

• The standard treatment for AML is induction chemotherapy based on anthracyclines and cytarabine (Ara-C) combination, with daunorubicin (DNR) and Ara-C being a common regimen 3, 4.
• This regimen has been the standard of care for AML patients for over four decades, with the "3 + 7" schedule being the most commonly used 4, 5.
• However, the toxicity of this regimen is high, and clinical outcomes are disappointing among poor-prognosis AML subsets, including those with adverse cytogenetic risk, secondary AML, and relapse/refractory AML 3.

Resistance Mechanisms

• Resistance to daunorubicin and cytarabine is a major issue in AML treatment, with various mechanisms contributing to chemoresistance 5.
• Somatic mutations in AML, such as FLT3-ITD, can also contribute to chemoresistance to the "3 + 7" regimen 4.

Alternative Treatments

• Alternative treatments, such as clofarabine, cytarabine, and mitoxantrone, have shown high response rates and effective bridge to allogeneic hematopoietic stem cell transplantation in refractory/relapsed AML patients 6.
• New drugs and targeted therapies are being developed for AML treatment, including maintenance therapy following allogeneic stem cell transplantation to mitigate relapse risk 7.

Clinical Trials and Outcomes

• Clinical trials have shown improved outcomes with novel therapies, such as CPX-351, compared to standard "3 + 7" combination in older patients with secondary AML or high-risk cytogenetics 3.
• Multivariate analyses have shown that superior overall survival is associated with complete remission after treatment and allogeneic hematopoietic stem cell transplantation 6.