Acute promyelocytic leukemia is a unique subtype of acute myeloid leukemia that exhibits significant treatment outcomes by the fusion gene transcript PML-RAR-alpha. The late 1950s witnessed the first description of APL as a deadly acute sickness that was associated with a hemorrhagic condition in Norway and France. The association of APL with a severe hemorrhagic diathesis was discovered in 1959 and it was the cause of hyperfibrinolysis and disseminated intravascular coagulation (DIC). The complete remissions from the condition were reported by 1973 when daunorubicin was used as a therapy. 

Leo Sachs was the first person to perform in-vivo leukemic cell differentiation studies in 1974. Dr. Zhen Yi Wang, a hematologist from China, came to France in 1985 and gave information about the effectiveness of trans-retinoic acid (ATRA) in treating his patients with APL. There were several articles in 1990 which linked APL disease to a chromosome translocation of the chromosomes 15 and 17. 

Among 5 to 15% of adult leukemias in the US, acute promyelocytic leukemias (APLs) are the most common. In the United States, an average of 30,800 people with acute leukemia are diagnosed annually, out of which about 1000 are APL cases. In Italy the yearly incidence of APL is at 0. 6 per million individuals. 

According to Douer, people who frequently have APL and are originally from Latin America also have a different type of PML/RARA gene rearrangement that is unique to APL compared to non-Latinos. As per Matasar et al., the long-term incidence rates of APL in US Hispanics were not higher than those of Whites; on the contrary, the age distribution of Hispanics was different from that of non-Hispanic Whites, with higher incidence rates for adults aged 20 to 44 and children aged 1 to 19. 

The PML/RARa protein forms a complex with the retinoid X receptor (RXR), and this complex then binds to the retinoic acid-responsive elements in the genes which are the specific target of the protein at the promyelocytic stage of myeloid differentiation. The interruption leads to a hyper leukocytosis with a high level of promyelocytes that are expressing tissue factor (TF) that in turn binds with factor VII, thus activating factors X and IX, which finally cause a pro-coagulant condition. Besides, immature promyelocytes are not capable of defending against infections leading to the patients to be immunocompromised. Moreover, some fusion events can make this leukemia resistant to both retinoic acid and chemotherapy treatments. 

The RAR-alpha gene, which is responsible for producing nuclear hormone receptor transcription factors, is found on the long arm of chromosome 17 and is always involved in acute promyelocytic leukemia (APL). When retinoic acid binds to the receptor it helps in the activation of many genes. The vast majority (90% to 95%) of the APL cases are due to the specific translocation (t (15;17) (q22;q21)) which results in the fusion of the promyelocytic leukemia (PML) gene with RAR-alpha. This fusion generates two hybrid genes, PML-RARalpha and a reciprocal RAR-alpha-PML (80%), which results in a protein that functions as an abnormal retinoid receptor. The rearrangements have clinical significance since they are sensitive to therapy (NPM/RAR-alpha, NuMA/RAR-alpha) or they are resistant to retinoids (STAT5B/RAR-alpha, PLZF/RAR-alpha). 

The exact mechanisms that cause these chromosomal rearrangements and the beginning of leukemia are yet to be discovered. On the other hand, risk factors for cancer have been identified as chemotherapy, ionizing radiation, exposure to industrial solvents, and other toxic substances. 

Acute promyelocytic leukemia (APL) is a form of leukemia that is not treated and carries a very bad prognosis, with a median survival of one month. On the other hand, the current treatment has greatly improved the results and caused the survival rates to be much higher and most of the patients to be cured completely, which is also maintained. In a study done by Lo-coco et al., the 2-year disease-free survival rate was remarkably high, with 97% in the ATRA–arsenic trioxide group compared to 90% in the ATRA–chemotherapy group 11. 

Mortality becomes unavoidable under the circumstance of no intervention which results to complications such as infection and hemorrhagic differentiation syndrome. The researchers have established that prognostic indicators such as the WBC count, which is higher in stages of a certain disease, are the proof of greater risk. Moreover, things like advanced age, male gender, high serum creatinine and fibrinogen levels also influence the prognosis. 

In young people, the APL may show up with nonspecific symptoms such as tiredness, weakness, easy bruising, and recurrent infections. Nonetheless, in children and adolescents, APL can occasionally simulate the symptoms of other pediatric diseases, thus the diagnosis is not as easy. 

The APL presentation in older adults, especially those with existing comorbidities like cardiovascular disease or diabetes, is usually more complicated. Thus, it may cause the signs of short breath, chest pain, or neurological deficits due to intracranial hemorrhage. 

The clarity of the presentation in APL can differ remarkably. Some patients may have acute symptoms like severe bleeding, disseminated intravascular coagulation (DIC) or acute respiratory distress syndrome (ARDS) that need emergency treatment. Some people may have a lazy way of life, the symptoms of which could develop gradually over time. 

Skin: Look for the signs of ecchymoses (bruises) and mucosal bleeding which are usually the indications of thrombocytopenia and coagulopathy in APL. Besides, patients might show pale skin or yellow color of the eyes and skin due to anemia. 

Lymph Nodes: Check lymph nodes for enlargement, which can be a sign of the disease extracardial involvement or lymphoproliferative disorders. 

Splenomegaly: An enlarged spleen may be the indication of leukemic cells infiltrating the spleen, which is a common finding in APL. Nevertheless, splenomegaly is not all the time, and it can be of different degrees. 

Liver: Check for hepatomegaly due to hepatic infiltration by leukemic cells or as a result of chemotherapy-induced hepatotoxicity. 

Diet and Exercise: A neutropenic diet is suggested for patients who are suffering from leukopenia or neutropenia. It is recommended to limit the fresh fruits and flowers in the patient’s room to reduce the risk of infection. In cases of severe thrombocytopenia (platelet count < 10,000/μL), the patient’s activity should be limited. These people are more likely to have spontaneous bleeding, so it is necessary to minimize the chances of falls and injuries. 

Induction Therapy: 

• All-trans retinoic acid (ATRA): Promotes differentiation of leukemic promyelocytes into mature granulocytes. 
• Arsenic trioxide (ATO): Induces apoptosis of leukemic cells and promotes degradation of PML-RARα fusion protein. 

• Chemotherapy: Anthracyclines used in combination with ATRA and ATO to reduce leukemic cell burden. 

Consolidation Therapy: Administered after achieving remission to eradicate residual leukemic cells. Involves additional cycles of chemotherapy. ATO may also be used as consolidation therapy. 

Maintenance Therapy: ATRA alone or in combination with low-dose chemotherapy may be used as maintenance therapy. 

Supportive Care: Transfusions of blood products, antibiotics for infection prophylaxis, and supportive care for coagulopathies. 

Oncology, Other

Nutritional Support: Proper nutrition is the key to the proper immune function, energy levels and overall health. Nutritionists or dietitians can design the meal plans which are personalized. 

Psychosocial Support: Services such as counseling, support groups, and psychotherapy can assist patients in managing stress, anxiety, and depression. Social workers and mental health specialists are the ones who can give emotional assistance. 

Physical Activity: Physical activity on a regular basis can be the source of the improvement of the mood, the reduction of fatigue, and the better quality of life. The exercise programs are unique for each individual and the healthcare providers create them for the patients. 

Mind-Body Therapies: Mind-body therapies such as mindfulness meditation, yoga, and tai chi can be used to either manage stress or to relax yourself. 

Education and Empowerment: Patient education programs, informational resources and peer support networks can furnish the information and support. 

Oncology, Other

All-Trans Retinoic Acid (ATRA) is the main treatment for the acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML) which is characterized by the presence of a chromosomal translocation that involves the retinoic acid receptor alpha (RARα) gene on chromosome 17. This translocation leads to the combination of the RARα gene with the promyelocytic leukemia (PML) gene on chromosome 15, which causes the generation of the PML-RARα fusion gene. 

The application of ATRA in the treatment of APL is due to its capability of making the leukemic promyelocytes transform into the mature granulocytes which results in the cure of the disease. ATRADO works by attaching itself to the PML-RARα fusion protein, which results in a change in the protein complex and the release of the transcriptional repression of the genes involved in the differentiation of the myeloid cells. Thus, this results in the transformation of leukemic cells into normal granulocytes, which in turn restores the normal hematopoiesis. 

The association of ATRA with the anthracycline-based chemotherapy has completely transformed the treatment of APL, thus, the survival rate of patients has been significantly increased. This type of treatment which is a combination therapy has now become the norm for APL. ATRA is usually given orally, most of the time in combination with ATO, which is another agent that triggers differentiation and apoptosis of APL cells. This hybrid treatment has boosted expulsions rates and the survival of patients with APL even in the low-to-intermediate risk cases, thus, making a major progress to remission and long-term survival among patients with APL. 

Oncology, Other

Cytarabine: It is also known as cytosine arabinoside, is a chemotherapy drug that stops the growth of cancer cells by blocking the process of DNA synthesis. In this regime, cytarabine is administered at a dose of 50 mg. 

Methotrexate: It is a chemotherapy drug that obstructs the formation of DNA, RNA, and proteins that are necessary for cell replication. It is widely used in the treatment of many cancers, among which is leukaemia. The regimen, in this case, methotrexate is given at a dose of 15 mg. 

Hydrocortisone: It is a corticosteroid drug that has both the anti-inflammatory and the immunosuppressive properties. This regimen contains hydrocortisone which is used at a dose of 30 mg. It is used to decrease inflammation and the risk of adverse reactions to the other chemotherapy agents that are intrathecally administered. 

Oncology, Other

The National Comprehensive Cancer Network (NCCN) comes up with the consolidation therapy for acute promyelocytic leukemia (APL) according to the agents used during induction therapy. Patients treated with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) usually continue this treatment, while the ones who are managed with ATRA and chemotherapy usually persist with this combination.  

In certain situations, mitoxantrone may be used as an additional agent. The second consolidation way is a two-year program with 6-mercaptopurine (6-MP), methotrexate, and ATRA. The retrospective analyses carried out by the independent groups, GINEMA and PETHEMA, showed that the outcomes were significantly enhanced with the addition of ATRA to chemotherapy for a 15-day period.  

PETHEMA had three consolidation cycles that included idarubicin, which was then replaced by mitoxantrone and then it was replaced by idarubicin again with higher idarubicin doses for intermediate- to high-risk patients. The APL 2000 group used different doses of daunorubicin and cytarabine during the two consolidation cycles. Montesinos et al. discovered that 17 patients were diagnosed with therapy-related myeloid neoplasms (t-MN) or secondary acute myelogenous leukemia among the 918 patients who attained complete remission after induction and consolidation therapy with ATRA and anthracycline-based chemotherapy. 

Oncology, Other

The maintenance therapy is the key for patients with low-risk acute promyelocytic leukemia (APL) who reached the molecular remission after the consolidation treatment. Most of the studies that proved the advantages of the therapy maintenance were conducted before the appearance of the agents like all-trans-retinoic acid (ATRA), arsenic trioxide (ATO), or cytarabine for the consolidation. A randomized trial comparing the intermittent ATRA alone, ATRA combined with 6-MP, methotrexate, or observation showed that the overall survival was improved in patients who received ATRA or ATRA combined with chemotherapy. 

 A three-drug regimen is currently being given for 1 to 2 years and is being closely monitored for abnormal liver function and myelosuppression. Disease surveillance in APL most of the time is done by reverse transcription polymerase chain reaction (RT-PCR) assays for the PML-RARA fusion transcript. The treatment objective is total molecular remission demonstrated by the lack of the fusion transcript as shown by the RT-PCR with a sensitivity threshold of 10 to 4.  

Oncology, Other

Differentiation Therapy: 

The specialty of APL therapy lies in the fact that differentiation-inducing agents, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are used to make immature promyelocytes mature into normal granulocytes. 

These medications are usually given orally or intravenously as part of induction and consolidation therapy for the purpose of remission induction and disease relapse prevention. 

Chemotherapy: 

Besides differentiation therapy peasants get chemotherapy involved in the treatment protocols of APL typically depending on the patient’s risk level, either in the initial phase of disease or relapse. 

Supportive Care: 

These supportive care measures play a key role in handling problems derived from APL and its treatment (that are sometimes complicated), such as coagulopathy, infections, bleeding, and organ failure. 

Blood product transfusions (e. g. , red blood cell packs, platelet concentrates, and the fresh frozen plasma) is the type of transfusion that may be used to treat a cytopenia or blood losses. 

Oncology, Other

Induction Phase: The main purpose of the induction phase is to quickly decrease the number of leukemic promyelocytes in the bone marrow and peripheral blood and hence attain remission. This phase usually consists of the administration of induction chemotherapy that includes agents such as all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy. ATRA stimulates the differentiation of malignant promyelocytes into mature granulocytes, while chemotherapy concentrates on the rapidly dividing leukemia cells. 

Consolidation Phase: After the induction phase and the acquisition of remission, the consolidation phase is the period that eradicates the residual leukemia cells and prevents the relapse. Consolidation therapy usually consists of giving more cycles of chemotherapy, which often includes the use of agents like ATRA and arsenic trioxide (ATO). The aim is to further diminish the risk of the disease recurrence and to enhance the long-term results. Hematopoietic stem cell transplantation (HSCT) might be an option for high-risk or relapsed cases during this phase. 

Maintenance Phase: In some instances a maintenance phase may be introduced for patients at high risk of relapse. Maintenance therapy is the treatment which is given to the patient to extend the remission period and to prevent the disease from coming back in the future. The maintenance regimens may be the follow-up of a low-dose chemotherapy, immunotherapy, or targeted therapy agent such as ATRA. The duration and the way of maintenance therapy are different for every patient and the protocol of treatment can also be different. 

Monitoring Phase: The treatment course is accompanied by the regular monitoring of the disease response, molecular markers (for example, the PML-RARA fusion transcript), and possible side effects even after the completion of the treatment. Monitoring is a process that evaluates the treatment output, identifies the early signs of relapse and thus guides the next treatment decisions. The monitoring may be done through the blood tests, marrow examinations, imaging studies, and molecular testing.