Patients who are affected by promyelocytic leukemia exhibit decreased numbers of all three types of blood cells: erythrocytes, leukocytes and platelets. Therefore, patients affected by the condition are expected to present with fatigue and pallor caused by anemia, frequent infections and fever due to the leukocytopenia and hematuria or a general hemorrhagic tendency due to the low platelet count.

Thrombocytopenia is a potentially fatal complication, as it can follow disseminated intravascular coagulation (DIC) and threaten the life of the patient, leading to a mortality rate of up to 20% of sudden deaths [16]. The pathophysiologic process that induced DIC in patients with promyelocytic leukemia is not fully clarified yet; it is believed, however, that an augmented rate of multifactorial fibrinolytic activity is responsible for the phenomenon [17].

The central nervous system can also be affected by promyelocytic leukemia, but this is more commonly observed during a relapse rather than at the time of the initial episode [18] [19].

• Easy Bruising

  A 56-year-old man presented to the ED of an outside hospital with 2 days of bleeding gums and easy bruising. He denied episodes of melena, hematemesis, or hematuria and had no epistaxis. [ncbi.nlm.nih.gov]

  Repeated exposure to benzene, a chemical found in cigarette smoke, gasoline and other petroleum products Genetic disorders including Down syndrome and Shwachman-Diamond syndrome Exposure to high levels of radiation Acute promyelocytic leukemia symptoms Easy [rush.edu]

  Easy bruising or hemorrhagic diathesis (epistaxis, gums bleeding, hematuria, petechiae, metroragia) are frequently observed. [orpha.net]

  If your child has APL, the following symptoms may be present: Bleeding that is hard to stop, even from a small cut Blood in the urine Heavy nosebleeds Bleeding gums and easy bruising Fever and infections Low red blood cell count Paleness Tiring easily [stjude.org]

• Fever

  RAS is characterized by unexplained fever, dyspnea, pulmonary infiltrate, leukocytosis and nephropathy. [ncbi.nlm.nih.gov]

• Fatigue

  CASE REPORT A 9-year-old male child was admitted to the Oncology Service of the hospital complaining of fever, progressive fatigue, oral petechiae with severe bleeding in the oral cavity. Bone marrow examination showed some promyelocytes. [ncbi.nlm.nih.gov]

  Symptoms include anemia, fatigue, weight loss, easy bruising, thrombocytopenia, and granulocytopenia that leads to persistent bacterial infections. [medical-dictionary.thefreedictionary.com]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 12, 2019 [patientslikeme.com]

  The signs and symptoms of APL are nonspecific and include fatigue, minor infections, or hemorrhagic diathesis. There is usually pancytopenia with anemia, low levels of the granulocytes and monocytes, and low levels of platelets. [blog.cellavision.com]

• Weakness

  He presented with progressive back pain and bilateral leg weakness, and was unable to walk. [go.gale.com]

  Despite chemotherapy and ATRA, the patient presented deterioration in the weakness of his legs and lost bladder sphincter control. [scielo.br]

  And you should be aware of it when the patient presents with weakness, bleeding, bruises, and things like that. When you see their blood count, it’s generally abnormal, and, in particular, they often have coagulation abnormalities. [onclive.com]

  Possible side effects The possible side effects of ATRA include: Fever Headache Feeling tired and weak Bone pain Skin rash Dry skin, dry mouth, or cracking at the corners of the mouth Nausea and vomiting Sores in the mouth and throat Eye irritation The [urmc.rochester.edu]

• Anemia

  An 84-year-old man presented with leukopenia (2.2 10(9)/L) and anemia (Hb 12.5 g/dL). Five months later, the bone marrow (BM) was hypoplastic with a normal proportion of blasts and promyelocytes (5.2%), although the latter cells were hypergranular. [ncbi.nlm.nih.gov]

  It is accompanied by a reduced number of erythrocytes and blood platelets, resulting in anemia and increased susceptibility to infection and hemorrhage. [medical-dictionary.thefreedictionary.com]

  There is usually pancytopenia with anemia, low levels of the granulocytes and monocytes, and low levels of platelets. [blog.cellavision.com]

  The complete blood count with differential revealed atypical promyelocytic cells with Auer rods and granulation, anemia, and thrombocytopenia with a platelet count of 30 x10 3 µL.The WBC count also indicated leukocytosis. [mlo-online.com]

  The patient was placed on arsenic trioxide (ATO) 0.15 mg/m2 for 2 cycles, 5 weeks each, with no apparent toxicities and only moderate anemia. [gotoper.com]

• Weight Loss

  Clinical description APL onset usually occurs in middle-aged adults where it manifests by fever, fatigue, dizziness, mild cough with expectoration, exercise-induced dyspnea, weight loss or loss of appetite. [orpha.net]

  This leads to the symptoms of APL such as bruising and bleeding, infections and weight loss. APL is a rare form of acute myeloid leukaemia (AML) - around 200 people in the UK find out they have APL every year. [bloodwise.org.uk]

• Dyspnea

  RAS is characterized by unexplained fever, dyspnea, pulmonary infiltrate, leukocytosis and nephropathy. [ncbi.nlm.nih.gov]

  Clinical description APL onset usually occurs in middle-aged adults where it manifests by fever, fatigue, dizziness, mild cough with expectoration, exercise-induced dyspnea, weight loss or loss of appetite. [orpha.net]

  […] cytokine release à capillary leak Treatment: dexamethasone (without treatment, mortality 30%) Role of prophylactic steroids prior to ATRA induction unclear Hyperleukocytosis/leukostasis: from maturation of promyelocytes into neutrophils igns and symptoms: dyspnea [errolozdalga.com]

• Abdominal Pain

  A 43-year-old female with no past medical history presented complaining of mild abdominal pain, fever, and chills for the past day. [ncbi.nlm.nih.gov]

  pain from a swollen spleen or liver Some people with APL may also develop small lumps on their skin, called chloromas, but this is very uncommon. [lundbeck.com]

  She denied photophobia, had no further nausea, and denied abdominal pain. She reported that the headache worsened with standing and improved with lying down. Review of systems was significant only for pallor. [hindawi.com]

  pain The following symptoms require medical attention, but are not emergency situations. [chemocare.com]

  We watch closely for toxicities, including prolongation of the QT interval on electrocardiogram, liver function test abnormalities, GI symptoms (nausea, vomiting, or abdominal pain), and neuropathy. [ascopubs.org]

• Loss of Appetite

  Clinical description APL onset usually occurs in middle-aged adults where it manifests by fever, fatigue, dizziness, mild cough with expectoration, exercise-induced dyspnea, weight loss or loss of appetite. [orpha.net]

  In addition to a patient facing an increased risk to bleeding and forming blood clots, persons with APL often cope with pain in the affected area, exhaustion, loss of appetite and weight loss. [oncbiomune.com]

  Other general signs and symptoms may occur as well, such as fever, loss of appetite, and weight loss. Acute promyelocytic leukemia is most often diagnosed around age 40, although it can be diagnosed at any age. [ghr.nlm.nih.gov]

• Bleeding Gums

  A 56-year-old man presented to the ED of an outside hospital with 2 days of bleeding gums and easy bruising. He denied episodes of melena, hematemesis, or hematuria and had no epistaxis. [ncbi.nlm.nih.gov]

  If your child has APL, the following symptoms may be present: Bleeding that is hard to stop, even from a small cut Blood in the urine Heavy nosebleeds Bleeding gums and easy bruising Fever and infections Low red blood cell count Paleness Tiring easily [stjude.org]

  A 6-year-old boy was brought to our hospital with the chief complaint of bleeding gums twice and intermittent fever for 3 days in January 2013. [journals.lww.com]

  A hemorrhaging tendency is also noticed with its main manifestations being hematuria, epistaxis and bleeding gums. [symptoma.com]

• Petechiae

  CASE REPORT A 9-year-old male child was admitted to the Oncology Service of the hospital complaining of fever, progressive fatigue, oral petechiae with severe bleeding in the oral cavity. Bone marrow examination showed some promyelocytes. [ncbi.nlm.nih.gov]

  Easy bruising or hemorrhagic diathesis (epistaxis, gums bleeding, hematuria, petechiae, metroragia) are frequently observed. [orpha.net]

  The skin examinations revealed a small purpuric lesion on the tip of the tongue and diffuse petechiae predominantly on the lower extremities, but also on the torso and upper extremities. [mlo-online.com]

  The bleeding can manifest itself as petechiae (little bleeding spots in the skin or elsewhere), small ecchymosis ( bruises ), epistaxis (nose bleeds), bleeding in the mouth, hematuria (blood in the urine), bleeding from venipuncture and bone marrow sites [medicinenet.com]

• Nail Deformity

  Double nail beds were short with anti-nail deformity. She was diagnosed with APL according to the 2016 WHO classification after a MICM analysis (bone marrow morphology [M], immunophenotype [I], cytogenetics [C], and molecular biology [M]). [ncbi.nlm.nih.gov]

• Bone Pain

  Transcript: Ehab Atallah, MD: Patients with APL usually present with bleeding or sometimes they present with feeling tired and having bone pain. Sometimes, if they’ve had a major CNS bleed, they present with change in mental status. [onclive.com]

  Possible side effects The possible side effects of ATRA include: Fever Headache Feeling tired and weak Bone pain Skin rash Dry skin, dry mouth, or cracking at the corners of the mouth Nausea and vomiting Sores in the mouth and throat Eye irritation The [urmc.rochester.edu]

  Common symptoms can be: 1 Unusual bruising and bleeding Paleness Breathlessness and tiredness Frequent and persistent infections There are some less common symptoms: 1 Bone pain from a build up of cancer cells in the bone marrow Swollen glands from a [lundbeck.com]

  Symptoms include anemia, fatigue, weight loss, easy bruising, thrombocytopenia, granulocytopenia with bacterial infections, bone pain, lymphadenopathy, hepatosplenomegaly, and sometimes spread to the central nervous system ( meningism ) or to other organs [medical-dictionary.thefreedictionary.com]

• Musculoskeletal Pain

  Adverse effects were relatively mild and included rash, lightheadedness, fatigue, and musculoskeletal pain. [ncbi.nlm.nih.gov]

• Epistaxis

  He denied episodes of melena, hematemesis, or hematuria and had no epistaxis. Routine blood work showed pancytopenia and evidence of diffuse intravascular coagulation. A bone marrow biopsy confirmed the diagnosis of acute promyelocytic leukemia. [ncbi.nlm.nih.gov]

  Easy bruising or hemorrhagic diathesis (epistaxis, gums bleeding, hematuria, petechiae, metroragia) are frequently observed. [orpha.net]

  The bleeding can manifest itself as petechiae (little bleeding spots in the skin or elsewhere), small ecchymosis ( bruises ), epistaxis (nose bleeds), bleeding in the mouth, hematuria (blood in the urine), bleeding from venipuncture and bone marrow sites [medicinenet.com]

• Hematuria

  He denied episodes of melena, hematemesis, or hematuria and had no epistaxis. Routine blood work showed pancytopenia and evidence of diffuse intravascular coagulation. A bone marrow biopsy confirmed the diagnosis of acute promyelocytic leukemia. [ncbi.nlm.nih.gov]

  Easy bruising or hemorrhagic diathesis (epistaxis, gums bleeding, hematuria, petechiae, metroragia) are frequently observed. [orpha.net]

  The bleeding can manifest itself as petechiae (little bleeding spots in the skin or elsewhere), small ecchymosis ( bruises ), epistaxis (nose bleeds), bleeding in the mouth, hematuria (blood in the urine), bleeding from venipuncture and bone marrow sites [medicinenet.com]

• Scrotal Ulcer

  We report a novel case of ATRA-induced scrotal ulcers in a black man with APL. The differential diagnosis of scrotal ulcerations in immunocompromised patients is lengthy, and misdiagnosis can lead to substantial morbidity and mortality. [ncbi.nlm.nih.gov]

• Testicular Mass

  In this report, we describe an APL patient who had received standard induction/maintenance therapy resulting in durable remission for 4.5 years, when he presented with a unilateral testicular mass confirmed as myeloid sarcoma; this was followed by systemic [ncbi.nlm.nih.gov]

• Headache

  The patient received ibuprofen and oral rehydration and her headache further improved. A presumptive diagnosis of migraine headache was made and was discharged with primary care follow-up the following day. [hindawi.com]

  Review of systems was positive for fever, tachycardia, odynophagia, productive cough with wheezing, and marked peripheral edema in upper extremities and negative for headache, nausea, vomiting, dysacusis, meningismus, or skin changes. [jamanetwork.com]

  Possible side effects The possible side effects of ATRA include: Fever Headache Feeling tired and weak Bone pain Skin rash Dry skin, dry mouth, or cracking at the corners of the mouth Nausea and vomiting Sores in the mouth and throat Eye irritation The [urmc.rochester.edu]

  […] persistent CNS deficits In APL, leukapheresis should not be performed, given that this can worsen the coagulopathy from DIC Supportive: if possible, hold PRBC transfusions, as this increases viscosity Idiopathic intracranial hypertension: Signs and symptoms: headache [errolozdalga.com]

  PTC is mostly observed in children and adolescents, and is characterized by headache as the main presenting symptom with clinical signs of papilledema, provided the exclusion by cerebral imaging of intracranial space-occupying lesions and alteration of [academic.oup.com]

The first step towards a successful diagnosis involves laboratory blood testing. Patients with promyelocytic leukemia exhibit low counts of all lines of blood cells. The pancytopenia also causes abnormal results in other tests, such as a prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), high levels of fibrin D-dimer and hypofibrinogenemia.

Another test that is essential for the characterization of a condition as PL is a bone marrow biopsy. The aspirate tests positive to Sudan black and myeloperoxidase. The bone marrow itself can be either hypogranular or hypergranular, with the latter amounting to approximately 75% of the cases [20]. Histologically, promyelocytes are irregular, with azurophilic granulation. The Auer rods are the most typical histologic finding and constitute structures shaped like needles, which are found in the cytoplasm of the promyelocytes.

The hypergranular PL type, which is the most common disease type diagnosed, exhibits increased auto-fluorescence blasts during an immunophenotyping study. Genetic evaluation is also mandatory in order for a decisive diagnosis to be established: fluorescence in situ hybridization (FISH) and standard cytogenetic techniques are amongst the methods that are able to detect the translocation or the fused RARA-PML gene [21]. The polymerase chain reaction by reverse transcriptase (RT-PCR) is a popular method as well.

• Thrombocytosis

  The peripheral smear showed normochromic, normocytic anemia (Hgb 8.6 g/dL, mean corpuscular hemoglobin concentration [MCHC] 35.2%, MCV 90 fL), mild thrombocytosis (platelets 455,000/mL), and no circulating promyelocytes. [gotoper.com]

  Thrombocytosis is not a unique feature of the inv(3) karyotype but can also be present in other patients with AML at the time of diagnosis, particularly those in whom normal numbers of megakaryocytes are present. 124 The gene at the chromosome 3q21 breakpoint [ncbi.nlm.nih.gov]

Promyelocytic leukemia treatment is based on a protocol which calls for an initial induction therapy, followed by consolidation therapy and then maintenance therapy. A specific treatment scheme has been established for relapses of the disease as well. The induction therapy includes the administration of all-trans retinoic acid (ATRA), chemotherapy which contains anthracycline and possibly arsenic trioxide (ATO).

Consolidation therapy also consists of ATO and ATRA, so that the potential risk of relapse can be calculated. Patients who display relapses are either treated with ATO or with a stem cell transplantation; both autologous and allogeneic stem cell transplantation can be performed with none having a therapeutic advantage over the other [21].

PL is a hematopoietic malignancy accompanied by a poor prognosis in patients that have been newly diagnosed. The actual mortality rate and general prognosis vary considerably, depending on the type of proteins expressed by the cells; it has been observed that CD56+, CD3+ and CD2+ immunophenotypes constitute poor prognostic factors. Such patients are faced with a higher mortality and a greater risk of relapses [12] [13] [14] [15].

Almost every single occurrence of promyelocytic leukemia is a result of a genetic mutation, that leads to the fusion of two distinct genes: the PML gene (promyelocytic leukemia gene) with the RARA gene, which stands for retinoic acid receptor alpha gene [2]. Both genes are involved in the hematopoietic procedure under normal circumstances; the PML protein, encoded for by the PML gene, functions as a tumor suppressor and partakes in the regulation of apoptosis, whereas RARA regulates the function of retinoic acid (RA), which, in turn, influences the differentiation process of promyelocytes into neutrophils. The specific mutation that leads to these two genes being conjoined is the t(15;17)(q22;q21) translocation, but various other translocations may lead to the same leukocytic phenotype, although they are very rarely observed.

In a considerable number of cases, promyelocytic leukemia is accompanied by other congenital defects, with trisomy 8 being the most commonly diagnosed one. A minority of PL cases may be induced by prior chemotherapy or radiotherapy.

Promyelocytic leukemia is a condition primarily diagnosed in adults between the ages of 20 to 60 years old; it evinces no sex predilection [3]. Radiation therapy or chemotherapy can occasionally lead to PL. It has been calculated that out of all cases of acute myeloid leukemia, approximately 15% of the cases fall into the sub-group of promyelocytic leukemia, amongst the target group of adult people; in some regions, the percentage may be even higher, such as in Brazil (28%), Mexico (20%) and other locations [4] [5] [6] [7] [8] [9].

Promyelocytic leukemia is a malignancy caused by a genetic mutation. In the greatest majority of the cases, this mutation encompasses a translocation between the PML and RARA genes and is described as t(15;17)(q22;q21). The mutation occurs following conception, and therefore cannot be inherited.

The PML gene, or promyelocytic gene, is located on chromosome 15. Its function has not been thoroughly investigated but it is believed to play a significant role in the process of cellular death and in tumor suppression. On the other hand, the RARA gene, located on chromosome 17, functions based on the concentrations of retinoic acid: in its presence, RARA is activated and mediates the differentiation of promyelocytes. If retinoic acid is unavailable, the nuclear corepressor factor attaches itself onto the gene and transcription is hindered.

The translocation that occurs between the two aforementioned genes gives rise to a new, abnormal PML-RARA protein that leads to the need for higher concentrations of retinoic acid, in order for the gene to be activated.

In a minority of PL cases, the translocation does not involve the PML gene, but the translocation occurs between RARA and other genes, such as PZLF, nucleophosmin, STAT5b, NuMa, ORF2BP2 [10]. The type of genes involved in the mutation that leads to PL is indeed significant because it alters the therapeutic interventions that will prove effective against the disease [11]. Additional genetic abnormalities that may accompany PL are not believed to contribute to the prognosis either positively or negatively.

There are no established guidelines concerning the prevention of promyelocytic leukemia, due to the fact that its causes remain undefined. However, the avoidance of various risk factors that have been linked to the condition is advised, such as ionizing radiation, smoking, benzene, obesity and electromagnetic fields.

Promyelocytic leukemia (PL) is a hematopoietic malignancy, caused by a genetic mutation in the myeloid cells. It constitutes 5 to 10% of adult leukemias and is frequently a type of cancer with a rapid progression [1]. The mutation involves a translocation that leads to the fusion of two genes, mostly the retinoic acid receptor alpha gene (RARA) and promyelocytic leukemia gene (PML). Both genes partake in the hematopoietic process and regulate various functions such as apoptosis, differentiation and tumor suppression.

Promyelocytic leukemia primarily affects the adult population and is diagnosed in the ages of 20 to 60 years old. It is a rather uncommon type of malignancy, which has been calculated to affect approximately 1 out of 1,000,000 individuals in the European region.

Due to the fact that the condition leads to pancytopenia, the symptoms are caused due to the inadequacy of all three lines of cells. Fatigue, weakness, pallor, weight loss, dyspnea, and fever are the initial, nonspecific symptoms that patients usually present with. A hemorrhaging tendency is also noticed with its main manifestations being hematuria, epistaxis and bleeding gums.

Diagnosis is achieved via laboratory blood testing which reveals pancytopenia, in combination with a bone marrow biopsy that is expected to yield results including a hyper- or hypogranular bone marrow with increased numbers of promyelocytes. Genetic confirmation is also required and can be achieved through various techniques.

Treatment includes the administration of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy or ATRA and arsenic trioxide. Consolidation therapy is also employed, as a means of eliminating the residual malignant cells. As a last resort, after a drug-refractory relapse, autologous or allogeneic stem cell transplantation can be opted for, although this is rarely required.

Promyelocytic leukemia (PL) is a type of cancer that affects the bone marrow, and, subsequently, the blood. It can occur at any age, but adults between the ages of 20 and 60 are most commonly affected by it.

The bone marrow is a vital organ, that is responsible for the production and maturation of all of the cellular components of the blood: red blood cells, white blood cells and platelets. In cases of PL, the white blood cells do not develop properly and experience a very early arrest in their maturation process. As a result, they are released into the circulation at an earlier developmental stage and are too immature to fight infections and diseases. Moreover, these immature cells, called lymphoblasts, progressively replace the material that the bone marrow is made of and lead to a decreased production of red blood cells and platelets as well.

Patients with PL present with a variety of symptoms. Decreased concentrations of red blood cells lead to anemia, fatigue and weakness; fewer platelets imply a tendency towards hemorrhaging and the presence of immature white blood cells leads to the inability of the organism to protect itself against infections.

Promyelocytic leukemia is diagnosed with a complete blood count and a bone marrow biopsy. Radiologic evaluation is necessary to find out whether the malignant cells have infiltrated the brain or spinal cord. The condition is treated with chemotherapy.

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