Topic Editor: Becky Box, MBBS
Review Date: 8/24/2012
Definition 
Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia (AML). APL has distinct cytogenetic, clinical and prognostic features, and is characterized by a translocation between chromosomes 15 & 17. This highly curable condition often presents with bleeding complications with coagulopathy and pancytopenia.
Description
- APL is a distinct clinic-pathologic disorder that accounts for 10–15% cases of AML
- APL is characterized by a balanced reciprocal translocation between chromosomes 15 & 17. This leads to the fusion of 2 genes, promyelocytic leukemia (PML) gene and retinoic acid receptor alpha (RARalpha) gene
Epidemiology
Incidence/Prevalence
- Among the ~13,400 adults diagnosed with AML in United States each year, only 10–15% are APL
- In children and adolescents, only 5-8% of AML cases are APL. This equates to 600–800 cases (U.S.) in this age group, being diagnosed with APL
- Incidence of APL varies widely among nations, with an increased incidence of APL among children in Italy, and Central and South America
Age
- The incidence of APL is rare in the first decade of life, peaks and reaches a plateau in the second and third decades and then remains constant until after age 60, when it rapidly declines
- This age distribution varies from other forms of AML and this is thought to be related to a single, rate limiting genetic event resulting in disease, as opposed to the multi-step process of multiple somatic mutations, that is believed to be required for the development of the majority of other malignant neoplasms
Gender
- Slightly more common in females than males
Race
- Some reports indicate a higher incidence of APL in Hispanics and a lower incidence in blacks
Genetics
- More than 95% of cases of APL are due to a translocation mutation involving two genes: the PML gene on chromosome 15, and the RARA gene on chromosome 17
- The remaining 5% of mutations involve chromosome 17 with other gene partners on alternate chromosomes
- Translocation between chromosomes 15 and 17 results in gene fusion known as PML-RARa gene. This is a somatic mutation that occurs during the patient's lifetime and is therefore not inherited
- The RAR alpha gene is part of the retinoic acid nuclear receptor family that is expressed primarily on hematopoeitic stem cells and is important regulation of gene expression, playing a large role in cell differentiation of the myeloid lineage
- The mutated gene in affected cells, results in both loss of ability of promyelocytic cells to differentiate and/or the inability perform programmed cell death if abnormal
Risk factors
- Prior therapy for an unrelated malignancy, specifically associated with therapy for Breast cancer and also following therapy for Non-Hodgkin's Lymphoma
[Outline]
History
- The clinical presentation of APL is similar to AML, in that they present with signs and symptoms related to pancytopenia, due to lack of differentiation of the myeloid cell lineage.
- These symptoms include:
- Symptoms related to thrombocytopenia; bleeding gums, easy bruising, petechiae or coagulopathy. One study reports 79% of presentations were related to an acute bleeding episode
- Symptoms related to anemia; fatigue, shortness of breath and weakness
- Symptoms related to leukopenia; increased incidence of infections/sepsis
- APL is distinct from other forms of AML in that it appears to independently induce a disseminated intravascular coagulopathy (DIC). This may be present at time of diagnosis or occur after the initiation of induction treatment. In such cases, there is a 10–20% incidence of early death due to hemorrhage. The mechanism for DIC is unclear, but APL has been associated with low levels of plasminogen, alpha2-plasmin inhibitor, and plasminogen activator inhibitor 1 found in fibrinolytic states. There is increased expression of annexin II (a receptor for plasminogen and plasminogen-activating factor) on the surface of leukemic promyelocytes
- It is important to treat coagulopathy as a medical emergency in patients with APL: Pulmonary and cerebral hemorrhages occur in ~40% of untreated patients
- Most cases of APL manifest as pancytopenia; However, approximately 10-30% of cases present with leukocytosis
- Leukocytosis at diagnosis is more common in children and is an independent poor prognostic factor for greater risk of relapse
Physical findings on examination
- Physical examination may reveal pallor, petechiae, and areas of ecchymoses
- Patient may manifest bleeding from the gums or elsewhere (e.g. gastrointestinal)
- A flow murmur may be heard in patients with severe anemia
- While CNS involvement in APL is rare, patients can present with neurologic deficits or headaches if CNS involvement is present
[Outline]
Blood test findings
Initial laboratory tests should include the following:
- Complete blood count: Usual findings are pancytopenia (Anemia, Leukopenia and thrombocytopenia)
- Peripheral blood smear
- Comprehensive metabolic profile for baseline electrolytes, and renal and liver function tests
- Coaugulation profile including:
- Prothrombin time (PT) or INR
- Activated partial thromboplastin time (aPTT)
- Fibrinogen
Other laboratory test findings
- Blood Film:
- Promyelocytes on blood film are morphologically different in mutated cells, being larger with nuclei that are creased, bilobed, kidney shaped or folded with heavy azurophilic granules. The presence of faggot cells is a pathognomic finding. These cells have clumps of granular material, that align themselves in rod shapes and contain lysosymes, peroxidases, lysosomal enzymes and crystalline inclusions
- The main morphological variants on blood film include:
- Hypergranular or typical form: 75% of cases. The cytoplasm 'contains densely packed, bright-pink, reddish-blue or dark purple granules' as well as Auer rods, which if aligned in bundles are called faggot cells.
- Microgranular: 25% of cases. They contain bilobed nuclei, usually without Auer rods & fine, dusky granules in the cytoplasm. This form is more common in pediatric cases
- Hyperbasophilic/microgranular subtype: This subtype has a strongly basophilic cytoplasm, mimicking micromegakarocytes with cytoplasmic budding. They have increased nucleocytoplasmic ratio, with few granules, and a lack of Auer rods
- PLZF-RAR alpha (M3r): These variants are due to a translocation involving alternate chromosomes (11;17) and therefore have nuclei with more regular outlines and condensed chromatin in the nucleus. Granules are fewer & Auer rods are rarer than in the hypergranular form
Other diagnostic test findings
- Bone marrow biopsy with aspirate: All patients should have a marrow aspirate and the sample should be sent for flow cytometry and cytogenetics
- Flow cytometry typically shows phenotyping consistent with normal pro-myelocytes including the presence of CD13;19;33;34;117 to varying levels, and are negative for HLA-DR. The most useful pattern is a negative HLA-DR, presence of CD13 and CD34 with abnormally low CD15 expression
- Molecular/genetic diagnosis can be performed at any level, from DNA, RNA, protein or chromosomal testing, using a broad spectrum of tests including: karyotyping; fluorescent in situ hybridization (FISH); RT-PCR and anti-PML monoclonal antibody testing
- Karyotyping is expensive and time-consuming, but allows for the identification of rare molecular subtypes which is important for molecular monitoring of residual disease. FISH can be performed within 24hrs and is highly specific but it cannot detect molecular subtypes. RT-PCR is considered gold-standard, but has a long turn around in approximately 2 days and has high false positive and negative rates
- Lumbar puncture: Indicated in patients presenting with a very high WBC count. In such cases, CNS can serve as a sanctuary site warranting intrathecal therapy. Prior to performing this procedure, coagulopathy must be corrected
- CSF should be cytospun and examined by a pathologist trained in examination of cytospins
- Flow cytometry of CSF should be obtained to look for abnormal cells
- Echocardiography should be performed before starting a patient on anthracyclines (idarubicin, daunorubicin) to assess cardiac function in order to monitor for changes in cardiac function which may occur due to cardiotoxicy of these agents
[Outline]
General treatment items
- Treatment of APL involves institution of:
- Supportive care measures
- Induction therapy
- Consolidation therapy
- Maintenance therapy
Supportive Care measures- Supportive care measures, including prevention of tumor lysis syndrome, the use of antibiotics and hemopoetic growth factors, are in-line with management of all patients with AML
- FFP, cryoprecipitate, and/or platelet transfusions to maintain platelet count >20, 000-50,000/mm3 and fibrinogen above 100- 150mg/dL are recommended in the induction phase of treatment, when bleeding risk is highest
- If the initial clinical presentation and the specific morphology on blood film of the promyelocyte is suggestive of APL, treatment should be commenced immediately, even without genetic test confirmation. The rationale, is that this is a typically a rapidly progressive and aggressive disease, with a high risk of fatal hemorrhage if treatment is delayed
- Intracerebral & pulmonary hemorrhage are not uncommon complications of induction therapy, and may also occur prior to the diagnosis being confirmed
- The rapid initiation of tretinoin (also known as all-trans retinoic acid or ATRA) has been shown to reduce APL coagulopathy rapidly and is therefore presumed to significantly reduce bleeding risk
- Additional supportive care includes checking coagulation profile and CBC; typically 3-4 times daily, with initiation of treatment. It is generally recommended to avoid invasive procedures such as lumbar puncture and insertion of central venous lines until coagulopathy has resolved or been treated
- Administration of dexamethasone is advised for patients with high-risk of Retinoic Acid syndrome (RAS) (hyperleukocytosis more thanWCC > 30,000-50,000)
Induction Therapy- The standard approach in treating patients with APL is with tretinoin (ATRA), in combination with an anthracycline (idarubicin or daunorubicin) administered with or without cytarabine
- The type of anthracycline (idarubicin or daunorubicin), and also the combination of additional chemotherapeutic drugs, such as cytarabine remains controversial, and is up to the treating oncologist
- In patients unable to tolerate anthracyclines, tretinoin plus arsenic trioxide is an alternative
- Induction therapy with anthracycline should only be commenced immediately [i.e., prior to genetic confirmation] in patients with hyper-leukocytosis, due to increased risk of Retinoic Acid Syndrome (RAS) if tretinoin is administered as a sole agent. Otherwise, tretinoin is commenced as a sole agent awaiting results of tests confirming the diagnosis
- Assessing 'response to induction therapy in the first month of treatment using morphologic and molecular criteria' is not advised, as this often gives misleading results due to delayed persistence of differentiating leukemia cells despite ultimately achieving complete remission
Consolidation Therapy- Consolidation therapy consists of 2 or 3 courses of anthracycline based chemotherapy in combination with tretinoin
- Addition of cytarabine has been advised for high risk patients with leukocytosis >10,000 cells/mm^3
- RT-PCR should be performed on bone marrow aspirate to confirm molecular remission at the cessation of consolidation therapy
Maintenance Therapy- Maintenance therapy consists of tretinoin plus 6-mercaptopurine and methotrexate which showed an advantage over tretinoin alone in randomized trials in adults with APL
- Maintenance therapy is controversial as some experts have substantial support for their position that it is unnecessary with close monitoring after consolidation therapy
- Studies in adults have 'reported that maintenance therapy does not improve event-free survival (EFS) for patients with APL who achieve a complete molecular remission at the end of consolidation.' Utilization of maintenance therapy may be dependent on multiple factors (eg, risk group, the anthracycline used during induction, the intensity of induction and consolidation therapy, etc)
- Maintenance therapy has been advised for all children with APL regardless of remission. The current recommended schedule is tretinoin for 15 days, with intervals of 3 months, for a period of 3 years
- Monitoring of Bone Marrow for residual disease is recommended every 3 months for up to 3 years after completing consolidation therapy, as treatment with evidence of residual disease after complete remission shows better outcome than in disease with full relapse
Resistant or Relapsed disease- Consider APL cases to be resistant if patients do not achieve complete molecular remission at the end of consolidation therapy, and relapsed disease if individuals achieve molecular remission, but monitoring of the RT-PCR assay shows positivity on consecutive samples
- Arsenic Trioxide (ATO) based regimens: Showing promising results at achieving remission at induction and also with consolidation therapy in combination with ATRA therapy
- A recent study including 129 patients from 27 Australian cancer centers have showed significant benefit for disease-free survival and lack of relapse with the combined use of ATO, ATRA (tretinoin), and chemotherapy for induction and consolidation
- Until further studies are conducted, ATO-based regimens are advised as second line in those patients that show resistance to treatment or for those whom anthracycline chemotherapy is contraindicated
- ATO-based regimens are being adopted as a more fiscal alternative in developing countries and have been adopted as ‘standard of care'
- Approximately 10-20% of patients relapse. Arsenic trioxide (ATO) is recommended in relapsed or refractory cases: ~85% of patients achieve remission following treatment
- Data on the use of ATO in children is limited, though published reports suggest the response is similar to that of adults
- ATO causes QT interval prolongation which can lead to life-threatening arrhythmias, hence it is essential to monitor electrolytes closely, and to maintain potassium and magnesium values at mid-normal ranges
- Hematopoietic Stem Cell Transplantation (HSCT) should be considered for all patients with molecular persistence at this stage
- Patients who have CNS involvement or who are at higher risk for CNS relapse are usually given 5 doses of intrathecal chemotherapy consisting of a combination of cytarabine (50 mg), methotrexate (15 mg), and hydrocortisone (30 mg), administered weekly for 5 weeks. For prophylaxis, a dose is given during induction, and 4 doses given during consolidation
Medications indicated with specific doses
- Arsenic trioxide
- Idarubicin
- Tretinoin
- Cytarabine
- Daunorubicin
Dietary or Activity restrictions
- Neutropenic diet should be advised in patients with leukopenic or neutropenic patients
- Do not allow fresh fruits or flowers in patient's room
[Outline]
