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Promyelocytic Leukemia

APL

Promyelocytic leukemia (PL) is a hematopoietic malignancy and more specifically a type of acute myelogenous leukemia (AML), which is characterized by the increased levels of promyelocytes. Promyelocytes are partly differentiated granulocytes, which develop from a myeloblast into the final, completely differentiated myelocyte.

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Presentation

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
  • Abstract 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]
  • Symptoms include anemia, fatigue, weight loss, easy bruising, thrombocytopenia, and granulocytopenia that leads to persistent bacterial infections.[medical-dictionary.thefreedictionary.com]
Fever
  • 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]
  • The full-blown syndrome consists of unexplained fever, weight gain, dyspnea with pulmonary infiltrates, pleuropericardial effusion, hypotension, and renal failure.[ncbi.nlm.nih.gov]
  • PATIENT CONCERNS: An 18-year-old girl was referred to the Hematology Department because of a lasting history (10 days) of repeated fever and bleeding on skin. The girl was of short stature for age and with short fingers.[ncbi.nlm.nih.gov]
  • CASE REPORT: 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]
  • […] molecular biology, cytogenetic, and fluorescence in situ hybridization (FISH) analyses were performed at initial diagnosis and during the treatment.A 6-year-old boy was brought to our hospital with the chief complaint of bleeding gums twice and intermittent fever[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]
  • Adverse effects were relatively mild and included rash, lightheadedness, fatigue, and musculoskeletal pain.[ncbi.nlm.nih.gov]
  • 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.[symptoma.com]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 12, 2019[patientslikeme.com]
  • Symptoms include anemia, fatigue, weight loss, easy bruising, thrombocytopenia, and granulocytopenia that leads to persistent bacterial infections.[medical-dictionary.thefreedictionary.com]
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]
  • 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.[symptoma.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]
Weakness
  • 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.[symptoma.com]
  • 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]
  • HLA-DR, and CD34 are also further evidence of the atypical population. 13 Expression of CD33 gradually decreases as granulocytic cells mature, and is present at all stages. 5,13 Weak expression of other mature cellular markers is also possible.[mlo-online.com]
  • Motor weakness: Motor weakness was the initial sign in 25% to 33% of patients. At the time of diagnosis, hemiparesis or hemiplegia was present in nearly all patients.[mdedge.com]
  • During the repeat blood draw in the clinic lab, the patient began to feel weak and was taken to the emergency department via ambulance.[jmvh.org]
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
  • The full-blown syndrome consists of unexplained fever, weight gain, dyspnea with pulmonary infiltrates, pleuropericardial effusion, hypotension, and renal failure.[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]
  • Pulmonary infiltrates were documented in 14/15 patients and in 3 of them without dyspnea. Fever was present in 12 patients, weight gain in all, renal failure in 2, pleural/pericardial effusions were present in 3 patients.[doi.org]
  • 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.[symptoma.com]
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
  • Abstract 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]
  • gums twice and intermittent fever for 3 days in January 2013.[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 hemorrhaging tendency is also noticed with its main manifestations being hematuria, epistaxis and bleeding gums.[symptoma.com]
  • 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]
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]
  • 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]
  • Patient history showed no previous fever, bone pain, or malaise, but did indicate easy fatigability after physical activity. Approximately six to eight random donor platelet units were administered before referral.[mlo-online.com]
  • pain and/or an enlarged spleen Excessive bleeding, bruising, or inappropriate blood clotting Early in APL, a person may have few or no symptoms.[labtestsonline.org]
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]
  • A bone marrow examination in a 19-year-old woman who presented with ecchymoses and epistaxis showed morphologic and immunophenotypic features consistent with APL. PML oncogenic domain antibody was positive.[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]
Headache
  • […] 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]
  • . • Diagnosis of IIH is suspected in patients with headache, papilledema, and/or vision loss. • Evaluation includes a physical examination including lumbar puncture, cerebral imaging studies (computed tomography or magnetic resonance) and fundus oculi[slideshare.net]
  • Acute leukemia is characterized by fatigue, headache, sore throat, and dyspnea, followed by symptoms of acute tonsillitis, stomatitis, bleeding from the mucous membranes of the mouth, alimentary canal, and rectum, and pain in the bones and joints.[medical-dictionary.thefreedictionary.com]
  • Neurologic deficits or headaches may be present if central nervous system (CNS) involvement has occurred. Bernard J. History of promyelocytic leukaemia. Leukemia. 1994. 8 suppl 2:S1-5. [Medline]. Lo-Coco F, Cicconi L, Voso MT.[emedicine.medscape.com]
  • At initial evaluation, the patient complained of headache in recent weeks but lacked other abnormal symptoms. Hepatosplenomegaly and lymphadenopathy were absent.[mlo-online.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]
  • A hemorrhaging tendency is also noticed with its main manifestations being hematuria, epistaxis and bleeding gums.[symptoma.com]
  • 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]

Workup

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]

Treatment

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].

Prognosis

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].

Etiology

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.

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

  1. Ribeiro RC, Rego E. Management of APL in developing countries: epidemiology, challenges and opportunities for international collaboration. Hematology Am Soc Hematol Educ Program. 2006;162-8.
  2. Lo-Coco F, Hasan SK. Understanding the molecular pathogenesis of acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 2014;27:3–9. doi: 10.1016/j.beha.2014.04.006.
  3. Douer D. The epidemiology of acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 2003; 16(3): 357-67
  4. Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood. 2009; 114(25): 5126-35
  5. Tallman MS, Altman JK. Curative strategies in acute promyelocytic leukemia. Hematology Am Soc Hematol Educ Program. 2008: 391-9
  6. Rego EM, Jácomo RH. Epidemiology and treatment of acute promyelocytic leukemia in Latin America. Mediterr J Hematol Infect Dis. 2011; 3(1): e2011049.
  7. Ruiz-Arguelles GJ. Promyelocytic leukemia in Mexican Mestizos. Blood. 1997; 89(1): 348-9 Comment on: Blood. 1996;87(1):308-13
  8. De Salvo L, Weir Medina J, Gómez Sánchez O, et al. [Acute promyelocytic leukemia in the west of Venezuela]. Sangre (Barc). 1989; 34(5): 329-31
  9. Otero JC, Santillana S, Fereyros G. High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia. Blood. 1996; 88(1): 377 Comment on: Blood. 1996;87(1):308-13
  10. Yin CC, Jain N, Mehrotra M, et al. Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia. J Natl Compr Canc Netw. 2015 Jan. 13(1):19-22.
  11. Jurcic JG, Soignet SL, Maslak AP. Diagnosis and treatment of acute promyelocytic leukemia. Curr Oncol Rep. 2007; Sep. 9(5):337-44.
  12. Ahmad EI, Akl H, Hashem ME, et al.The biological characteristics of adult CD34+ acute promyelocytic leukemia. Medical Oncology. 2012; 29(2):1119–1126
  13. Albano F, Mestice A, Pannunzio A, et al.The biological characteristics of CD34+ CD2+ adult acute promyelocytic leukemia and the CD34- CD2- hypergranular (M3) and microgranular (M3v) phenotypes. Haematologica. 2006; 91(3):311–316.
  14. Kaito K, Katayama T, Masuoka H, et al. CD2+ acute promyelocytic leukemia is associated with leukocytosis, variant morphology and poorer prognosis. Clinical and Laboratory Haematology. 2005; 27 (5):307–311.
  15. Montesinos P, Rayón C, Vellenga E, et al. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens. Blood. 2011; 117(6):1799–1805.
  16. Barbui T, Finazzi G, Falenga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood. 1998;91:3093–3102.
  17. Menell JS, Cesarman GM, Jacovina AT. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med. 1999;340:994–1004.
  18. Evans GD, Grimwade DJ. Extramedullary disease in acute promyelocytic leukemia. Leuk Lymphoma. 1999;33:219–229.
  19. de Botton S, Sanz MA, Chevret S, et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia. 2006;20:35–41.
  20. Arber DA. Acute promyelocytic leukamia with t(15,17)(q22;q12); PML-RARA In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of tumors of Haematopoietic and Lymphoid Tissues. Geneva: WHO; 2008.
  21. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009; 113(9): 1875-91.

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Last updated: 2018-06-22 00:47