Acute promyelocytic leukemia (APL) is a rare hematologic disorder with approximately 600 to 800 new patients diagnosed per year in the United States.1,2 In contrast to other forms of leukemia, the incidence of APL is uncommon in children aged 1 APL is more common in people from Mexico, Central and South America, Italy, and Spain. Between 22% and 37% of all cases of acute myeloid leukemia (AML) are classified as APL in these countries.3 Risk factors for APL are thought to include prior exposure to chemotherapy agents and radiation therapy. An increase in reported cases of APL has been noted in survivors with a history of breast cancer, Hodgkin lymphoma, and non-Hodgkin lymphoma, particularly those who were treated with topoisomerase II inhibitors.1
APL was first distinguished from other types of acute leukemia in 1957 by the Norwegian hematologist L.K. Hillestad.4 He recognized APL as a distinct clinical entity whose most outstanding features were its very rapidly downhill course of few weeks’ duration, a white blood cell (WBC) picture dominated by promyelocytes, and severe bleeding caused mainly by fibrinolysis. In 1959, a more detailed description of APL was given by J. Bernard, who reported a series of 20 patients with the full definition of the disease, its association with promyelocytic proliferation, acute onset, and catastrophic hemorrhagic events.4 APL is characterized by the French–American–British classification system as an M3 subtype of AML, with a key characteristic being the presence of atypical promyelocytes in the bone marrow and peripheral blood.5 Cytogenetically, APL is characterized by a chromosomal abnormality with the translocation between the long arm of chromosomes 15 and 17. This exchange occurs without loss of chromosomal material and causes abnormal fusion of the promyelocyte leukemia (PML) gene and the retinoid acid receptor-alpha (RARA) gene. The fusion prevents cells from differentiating past the promyelocyte differentiation stage, which leads to the accumulation of abnormal promyelocytes in the bone marrow and peripheral blood. The leukemic promyelocytes then lead to the signs and symptoms associated with the coagulopathy that is seen in APL. The PML-RARA translocation can be detected by karyotyping with or without fluorescence in situ hybridization, and it should be analyzed with reverse transcription–polymerase chain reaction (RT-PCR) studies to assess prognosis.6,7
Given the rarity and acuteness of the disease, it is very important for oncology nurse navigators to be familiar with APL.
APL was once the most malignant form of leukemia, with the worst prognosis. However, due to advancements made during the past few decades, APL has become the most curable form of adult AML,8 with a 90% to 95% cure rate.4,6 Achieving a cure in APL has been made possible through treatment with a retinoid in combination with anthracycline-based chemotherapy for induction and consolidation, and a retinoid-based maintenance treatment.1,7 For patients who are unable to tolerate an anthracycline, arsenic trioxide is an effective treatment.1,7
Given the rarity and acuteness of the disease, it is very important for oncology nurse navigators (ONNs) to be familiar with APL. In particular, it is imperative that they be familiar with the signs and symptoms, diagnostic tests, and management strategies associated with the disease, especially during the first 30 days of treatment when the patient is at the highest risk for coagulopathy issues. Resources for patients with APL are limited, including patient assistance programs for medications; therefore, ONNs play a vital role in connecting patients with resources that can enable them to continue treatment. This article provides an overview of APL, including diagnostic testing, treatment considerations, complications related to the disease and/or its management, and survivorship issues.
Diagnostic Testing for APL
The National Comprehensive Cancer Network (NCCN) has developed guidelines for the diagnostic workup of a patient who is suspected to have APL.7 Common clinical presentations for patients with the disease include anemia, fatigue, shortness of breath, neutropenia, fever, excessive sweating, thrombocytopenia, bruising, epistaxis, bleeding gums, petechiae, and menstrual irregularity. Patients may often present with hemorrhagic bleeding with an acute onset. If a patient is presumed to have leukemia and also has signs of bleeding and thrombosis, they should be quickly evaluated for APL.
In addition to the diagnostic workup that is specific to leukemia and APL, the patient needs preparation for chemotherapy, including cardiac function testing.
Given the urgency in beginning treatment, it is imperative to perform a thorough history and physical examination and to order the appropriate tests. Laboratory tests that should be done include a complete blood cell (CBC) count, a complete metabolic panel (CMP), uric acid, lactate dehydrogenase, and a disseminated intravascular coagulation (DIC) panel. The DIC panel should include a prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and domain dimer. The bone marrow aspirate and biopsy should include cytogenetic and molecular studies for the PML-RARA mutation.7
During the diagnostic workup for APL, it is particularly important to pay attention to the WBC and platelet counts. Based on the level of these counts, the patient will be assigned to 1 of 3 prognostic categories that correlate with the likelihood of relapse: low, intermediate, and high risk (Table).1,2 Patients in the low-risk category are not very likely to relapse, and are typically treated less aggressively, whereas patients in the high-risk category should be considered for more aggressive treatment, as they are more prone to relapse after therapy is completed.1
The roles of the ONN during the diagnostic process are to ensure that the patient is emergently admitted to the care of a hematologist in a hospital setting, and to educate the patient and his or her family members on what to expect. In addition to the diagnostic workup that is specific to leukemia and APL, the patient needs preparation for chemotherapy, including cardiac function testing. Central line placement and other invasive procedures should be limited because of the risk for bleeding. Given the acute onset of the disease, patients are often emotionally and psychologically in need of additional support. The ONN can be effective in connecting patients with resources such as a chaplain, social worker, or psychologist. Nursing interventions for the symptoms of APL include monitoring laboratory results, administering blood products, monitoring closely for fever, administering antibiotics and antivirals, and monitoring for DIC.8,9
Treatment Considerations in APL
Since APL is considered a medical emergency, treatment should begin as quickly as possible. Therapy is divided into 3 phases: (1) induction to reduce the burden of leukemia; (2) consolidation to destroy any remaining leukemia cells that survived induction; and (3) maintenance to prolong the remission. Combination therapy using multiple agents is used in all of these phases, and treatment can last 1 to 2 years. Guidelines for the treatment of APL are provided by the NCCN7 and the European LeukemiaNet.1
To decrease the risk for mortality precipitated by severe hemorrhage, it is recommended that patients initiate treatment with a retinoid agent immediately upon suspicion of APL, even if the diagnostic workup has not been completed.9 Retinoid agents are related to vitamin A and reverse the coagulopathy process in patients with APL.7 Once the diagnosis is confirmed, the patient can continue on the treatment, or if it is determined that the patient has a different form of AML, their treatment can be changed to the appropriate regimen.
During induction therapy, the standard treatment is combination therapy using a retinoid and an anthracycline. This combination leads to complete remission in 90% to 95% of patients.1 For patients who are unable to tolerate an anthracycline, arsenic trioxide in combination with a retinoid agent is an option for treatment, according to NCCN guidelines.7 Upon count recovery, if the patient is in bone marrow remission, he or she proceeds to consolidation therapy. If he or she is not in remission, further induction regimens should be considered.
Consolidation therapy is used to destroy any leukemia cells that survived induction therapy. NCCN guidelines recommend maintaining consistency throughout all phases of treatment and continuing with the same regimens that were initiated.7 Upon completion of consolidation therapy, molecular response and bone marrow response should be evaluated and documented. If the patient has achieved a complete remission, he or she should proceed to the maintenance phase of therapy.
Maintenance therapy consists of treatment for 1 to 2 years with a retinoid agent, which may be combined with 6-mercaptopurine and methotrexate.7 This treatment may cause myelosuppression and an increase in liver enzymes. Therefore, the patient should be monitored closely with a CBC count and CMP during the first few weeks of treatment and monthly afterwards. NCCN guidelines recommend that, during this time, the PML-RARA mutation be monitored every 3 months for 2 years with a peripheral blood or bone marrow RT-PCR test.7
The responsibilities of the ONN during treatment are to provide support to the patient and family members, and to be the main point of contact for communication between members of the healthcare team and the patient. It is important for nurse navigators to have a solid knowledge base about APL and its treatment, so they can educate patients as well as recognize side effects and complications related to therapy.8
During the induction phase of treatment, the ONN may be most effective by reiterating education about the disease, treatment, and long-term goals of therapy. Since APL has such an acute presentation, the patient may need support with practical issues such as employment disability, financial resources, transportation, and child care. If the patient does not reside close to a medical academic institution or similar facility that is capable of effectively treating the disease, temporary housing accommodations will need to be arranged. Communication between ONNs and other members of the multidisciplinary team, such as the pharmacist and social worker, will enhance education and support for the patient.8,9
During the consolidation phase of treatment, the ONN can play an effective role in educating the patient on the importance of timely administration of chemotherapy, and coordinating care between the pharmacist, chemotherapy infusion department, laboratory, and physician. Patients may also continue to need assistance with financial resources and transportation to a treatment facility.8,9
During the maintenance phase of treatment, the patient must be educated on disease monitoring and response, and be encouraged to adhere to treatment, especially orally administered agents. The patient may need assistance with locating a specialty pharmacy for administration of medications, as well as financial resources, since patient assistance programs for these particular classes of medications are limited. During the induction and consolidation phases, the patient will require a central line, and the nurse navigator must ensure that he or she is provided with education on proper care for this line or coordinate home healthcare to provide support.8,9
Complications Related to APL and Its Management
There are several life-threatening complications related to APL and its treatment that the nurse navigator should be well aware of. These include coagulopathy issues, differentiation syndrome, and medication-related side effects.
Severe DIC, common in patients with APL, is a complex microvascular disorder involving activation of the coagulation pathways, which may lead to thrombotic events and bleeding. The pathway begins when the underlying malignant disorder causes the intrinsic and extrinsic pathways of the clotting cascade to be activated, resulting in excess thrombin. The thrombin causes multiple fibrin clots, and the clots trap platelets, which leads to multiple micro- and macrovascular thrombosis. The thrombosis causes ischemia and consumption of coagulation factors that the body is not able to keep up with, followed by the bleeding that is seen with DIC (Figure).10
Patients may bleed from multiple sites at one time, including petechiae, ecchymosis, mucosal bleeding, and oozing around the catheter site. Laboratory values that predict DIC include a decreased platelet count, decreased hemoglobin and hematocrit, prolonged PT/PTT, decreased fibrinogen level, elevated D-dimer, and prolonged international normalized ratio. Treatment should be focused on the underlying cause of the DIC, but hemodynamically, the patient may be stabilized through the infusion of blood products, fresh frozen plasma, and cryoprecipitate. The goal when treating patients for DIC is to keep the fibrinogen level >150 mg/dL and the platelet count between 30 × 109/L and 50 × 109/L. Because of the risk for bleeding, invasive procedures such as lumbar punctures, central line placement, esophagogastroduodenoscopy, and injections should be avoided. The patient should be advised to use a sponge or soft toothbrush for oral care to prevent trauma and bleeding.11
Patients who develop neutropenic fever should seek immediate medical attention and not attempt to treat the fever with antipyretics.
Differentiation syndrome is a complex syndrome that is seen in patients with APL after the initiation of treatment with a retinoid or arsenic trioxide, as single agents or in combination. Studies have reported this syndrome in 15% to 25% of patients with APL. Differentiation syndrome is caused by a release of cytokines that leads to leukocytosis, weight gain, fever, pulmonary edema, renal impairment, pleural and pericardial effusions, hypotension, congestive heart failure, and respiratory failure. Treatment should be initiated quickly once differentiation syndrome is suspected. It consists of twice-daily intravenous injections of a corticosteroid for 3 to 5 days, then tapering of the dose over a 2-week period.7
Another treatment-related side effect of arsenic trioxide is QT interval prolongation on electrocardiography, which can lead to a fatal ventricular arrhythmia called torsade de pointes if not appropriately monitored. Other risk factors may contribute to QT interval prolongation, such as cardiac abnormalities or congestive heart failure. An electrocardiogram should be performed prior to the start of treatment, and, in elderly patients, weekly for the duration of therapy. Concurrent close monitoring of electrolyte levels such as potassium, magnesium, calcium, and creatinine should also occur. The patient may need to be placed on an oral electrolyte supplement to maintain appropriate levels of potassium >4 mEq/dL and magnesium >1.8 mg/dL.7
General complications that are not unique to APL but that may occur with the diagnosis and treatment of leukemia include fever, infection, tumor lysis syndrome, and bleeding.8 The ONN should educate patients and their family members on basic hygiene to prevent infection, and what to do in the case of neutropenic fever. Patients who develop neutropenic fever should seek immediate medical attention and not attempt to treat the fever with antipyretics.8
Survivorship Issues in APL
Patients with APL should be monitored for long-term survivorship issues. Those who stay in remission for >3 years experience a low incidence of relapse.12 However, long-term medical issues may include cardiac complications from treatment with anthracyclines and fertility issues related to chemotherapy treatment. Psychosocial issues from a past diagnosis of cancer may also be present, such as lingering financial obligations, or strain on a marriage or partner relationship. Specific information on medical issues of survivors was reported in a study of 185 patients with APL who achieved complete remission that lasted ≥3 years after their initial treatment between 1991 and 2010; 60% of these patients were treated without chemotherapy and 40% with chemotherapy.12 At the 3-year mark, the new medical conditions that the non–chemotherapy-treated patients developed were hypertension (39%); cardiac disease (including coronary artery disease, myocardial infarctions, and arrhythmias in 11%), renal insufficiency (3%), diabetes mellitus (25%), hematologic disorders (8%), pulmonary disorders (5%), and neurologic disorders (9%). The new medical problems that were present at the 3-year mark in the chemotherapy-treated patients included hypertension (19%), cardiac disease (7%), diabetes mellitus (7%), and neurologic disorders (7%). At the 3-year mark, the patients who were treated without chemotherapy were on a median of 3 medications; those treated with chemotherapy were on a median of 0 medications.
In some cases, patients and practitioners may need to engage in a conversation about referral to a hospice program if the patient’s medical situation suggests that it is necessary.
Conclusion
APL is a variant of AML with specific morphology and abnormality on chromosomes 15 and 17. If a patient is not immediately and appropriately diagnosed and treated, the disease can be fatal because of the risk for hemorrhage and bleeding complications. APL was once a very deadly form of leukemia because it was not well understood. However, in recent decades, much research has been done to understand the pathology and treatment of the disease, which has led to its being one of the most curable forms of leukemia. The ONN plays a vital role in decreasing time to diagnosis and treatment, as well as supporting patients throughout the 3 phases of treatment and onto long-term survivorship. It is imperative that the nurse navigator be familiar with the pathology of APL, risk factors, treatment options, and complications associated with the disease itself, as well as the side effects of treatment. A strong knowledge base will promote understanding of the need for close monitoring, collaboration between specialty providers, and education of the patient.
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