Erythroleukemia
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahda Alihashemi M.D. [2] [3] [4] Synonyms and keywords:Pure erythroid leukemia, FAB ( French-American-British) M6, acute erythroid leukemia, Di Guglielmo’s disease
Overview
Erythroleukemia was first discovered by M. Copelli, in 1912. In 1917, Di Guglielmo, Italian hematologist, described leukemic nature of the erythroleukemia. Erythroleukemia accounts for < 5 % of acute myeloid leukemia (AML). Erythroleukemia may be classified into 2 groups: De novo cases of erythroleukemia and secondary erythroleukemia. Erythroleukemia may be classified according to previous version WHO into 2 sub-types : The erythroid/myeloid type and the pure type. Erythroleukemia is the neoplastic proliferation of myeloid and erythroid precursors of bone marrow hematopoietic stem cells. A pure erythroid proliferation may also occur. The erythroblasts do not stain with myeloperoxidase (MPO). Markers of myeloid lineage can not be expressed on the erythroblasts. Leukemic cells are positive for myeloid markers such as CD117, CD13, CD33, andmyeloperoxidase (MPO). Megakaryocytes antigens can be positive in some cases of erythroleukemia, such as CD41 and CD61. Erythroleukemia may be caused by translocation t(1;16) generating the fusion gene NFIA/CBFA2T3. Erythroleukemia must be differentiated from MDS with erythroid predominance, other types of AML with increased erythroid precursors, AML with myelodysplasia-related changes. Non-neoplastic disorders that can cause erythroid predominance in the bone marrow such as megaloblastic anemia due to vitamin B12 or folate deficiency, heavy metal intoxication such as arsenic, drug effects (such as antineoplastic agents or chloramphenicol) are other differential diagnoses. The incidence of erythroleukemia is approximately 0.077 per 100,000 individuals worldwide. Erythroleukemia commonly affects individuals older than 50 years of age with a median age of 65. There is no racial predilection to erythroleukemia. Men are more commonly affected by erythroleukemia than women. The male to female ratio is approximately 2 to 1. There are no established risk factors for de novo cases of erythroleukemia. The most potent risk factor in the development of secondary erythroleukemia is previous myelodysplastic syndrome (MDS). There is insufficient evidence to recommend routine screening for erythroleukemia. If left untreated, patients with erythroleukemia may progress to develop bleeding due to disseminated intravascular coagulation (DIC). Common complications of erythroleukemia include infection and bleeding. Therapy related complications are rash, cardiomyopathy and cerebellar toxicity. Prognosis is generally poor. Median survival ranges from 3 - 9 months after the initial diagnosis. A high proerythroblast/myeloblast ratio correlates with worse outcome. The diagnosis of erythroleukemia is based on the 2016 version of WHO classification for AML. History and symptoms include fatigue, Malaise, bone pain, abdominal pain, weight loss, Easy bruising, Fever, and Dyspnea. Patients with erythroleukemia usually appear anemic. Physical examination of patients with erythroleukemia may include Ecchymoses or petechiae, Hepatomegaly, Splenomegaly, Lymphadenopathy, and headache. Laboratory findings include Pancytopenia, few peripheral blood blasts, Dysplasia in bone marrow and peripheral blood, dysplastic PAS positive erythroblasts with overexpression of the multidrug resistance (MDR) gene product P-glycoprotein, and high frequency of mutations, especially of TP53. Electrocardiogram is useful for the assessment of QT interval prior to starting chemotherapy. An x-ray may be helpful in the diagnosis of complications of erythroleukemia management which include infection, volume overload. Chest x-ray is also useful for venous catheter placement for chemotherapy. An echocardiogram is helpful for assessing cardiac function (ejection fraction) in patients with acute myeloid leukemia before and after receiving anthracycline chemotherapy. An ultrasound is useful for the diagnosis of lower extremity thrombosis, which commonly occurs in patients with acute myeloid leukemia. Abdominal and chest CT scan may be helpful in the diagnosis of acute myeloid leukemia. Findings on CT scan suggestive of acute myeloid leukemia include lymphadenopathy, hepatomegaly, splenomegaly and pulmonary embolism because of deep venous thrombosis. Brain MRI is helpful in the diagnosis of CNS bleeding in acute myeloid leukemia (AML). There are no other imaging findings associated with erythroleukemia. Other diagnostic studies include cytogenetics and flow cytometry. Pharmacologic medical therapy is recommended for patients with erythroleukemia who are not candidates for intensive chemotherapy or allogenic hematopoietic stem cell transplantation. Pharmacologic medical therapies for erythroleukemia include hypomethylating agents (HMA) such as azacitidine and Decitabine. Surgical interventions include allogenic hematopoietic stem cell transplantation (Allo-SCT). There are no established measures for the primary prevention of erythroleukemia. Effective measures for the secondary prevention of erythroleukemia include maintenance of remission treatment post-transplant.
Historical Perspective
- Erythroleukemia was first discovered by M. Copelli, in 1912.[1]
- In 1917, Di Guglielmo, Italian hematologist, described leukemic nature of the erythroleukemia. Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).
Classification
- Erythroleukemia accounts for < 5 % of acute myeloid leukemia (AML).
- Erythroleukemia may be classified into 2 groups: De novo cases of erythroleukemia and secondary erythroleukemia.
- Erythroleukemia may be classified according to previous version WHO into 2 sub-types : The erythroid/myeloid type and the pure type.[2]
2016 version of WHO classification for AML (erythroid/myeloid type) :
- Erythroblasts (at the stage of pronormoblast > 80% of the marrow cells in patients without exposure to cytotoxic agent and without AML genetic abnormalities). Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).
Pathophysiology
- Erythroleukemia is the neoplastic proliferation of myeloid and erythroid precursors of bone marrow hematopoietic stem cells.
- Erythroleukemia accounts for 3 - 5% of all AML cases.[3]
- A pure erythroid proliferation may also occur.
- The erythroblasts do not stain with myeloperoxidase (MPO).
- Markers of myeloid lineage can not be expressed on the erythroblasts.
Microscopic Examanination:
- Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).
Immunohistochemistry
Leukemic cells are positive for myeloid markers such as:[4]
Megakaryocytes antigens can be positive in some cases of erythroleukemia, such as:
- CD41
- CD61
Causes
Erythroleukemia may be caused by translocation t(1;16) generating the fusion gene NFIA/CBFA2T3.[5]
Differentiating Erythroleukemia from Other Diseases
- Erythroleukemia must be differentiated from MDS with erythroid predominance, other types of AML with increased erythroid precursors, AML with myelodysplasia-related changes.
- Non-neoplastic disorders that can cause erythroid predominance in the bone marrow such as megaloblastic anemia due to vitamin B12 or folate deficiency, heavy metal intoxication such as arsenic, drug effects (such as antineoplastic agents or chloramphenicol) are other differential diagnoses.[6]
Epidemiology and Demographics
- There is no racial predilection to erythroleukemia.
- Men are more commonly affected by erythroleukemia than women. The male to female ratio is approximately 2 to 1.
Risk Factors
- There are no established risk factors for de novo cases of erythroleukemia.
- The most potent risk factor in the development of secondary erythroleukemia is previous myelodysplastic syndrome (MDS).[9]
- Other risk factors include:
- Ionizing radiation such as Thorium dioxide suspension (Thorotrast)
- Previous use of chemotherapy drugs such as alkylating agents
- Familial erythroleukemia, autosomal dominant disorder
Screening
There is insufficient evidence to recommend routine screening for erythroleukemia.
Natural History, Complications, and Prognosis
- If left untreated, patients with erythroleukemia may progress to develop bleeding due to disseminated intravascular coagulation (DIC).
- Common complications of erythroleukemia include infection and bleeding. Therapy related complications are rash, cardiomyopathy and cerebellar toxicity.
- Prognosis is generally poor.
- Median survival ranges from 3 - 9 months after the initial diagnosis.[10]
- A high proerythroblast/myeloblast ratio correlates with worse outcome.[11]
Diagnosis
Diagnostic Study of Choice
Bone Marrow Biopsy
The diagnosis of erythroleukemia is based on the 2016 version of WHO classification for AML:
- AML (erythroid/myeloid type): 20% or more blasts in the bone marrow irrespective of the number of erythroid precursors
- Pure erythroid leukemia: Erythroblasts, at the stage of pronormoblast, more than 80% of the marrow cells in patients without exposure to cytotoxic agent and without AML genetic abnormalities. Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).
History and Symptoms
Less common symptoms of erythroleukemia include diffuse joint pain.
Physical Examination
Patients with erythroleukemia usually appear anemic. Physical examination of patients with erythroleukemia may include:[12]
Laboratory Findings
- Pancytopenia[13]
- Few peripheral blood blasts[14]
- Dysplasia in bone marrow and peripheral blood
- Dysplastic PAS positive erythroblasts with overexpression of the multidrug resistance (MDR) gene product P-glycoprotein
- High frequency of mutations, especially of TP53[15]
Electrocardiogram
- Electrocardiogram is useful for the assessment of QT interval prior to starting chemotherapy.
- It is also useful for assessing arrhythmias induced by anthracycline chemotherapy.[16]
- For more information, click here.
X-ray
- An x-ray may be helpful in the diagnosis of complications of erythroleukemia management which include infection, volume overload.
- Chest x-ray is also useful for venous catheter placement for chemotherapy.
Echocardiography or Ultrasound
- An echocardiogram is helpful for assessing cardiac function (ejection fraction) in patients with acute myeloid leukemia before and after receiving anthracycline chemotherapy. [17]
- An ultrasound is useful for the diagnosis of lower extremity thrombosis, which commonly occurs in patients with acute myeloid leukemia.[18]
CT scan
- Abdominal and chest CT scan may be helpful in the diagnosis of acute myeloid leukemia.
- Findings on CT scan suggestive of acute myeloid leukemia include lymphadenopathy, hepatomegaly, splenomegaly and pulmonary embolism because of deep venous thrombosis.[19]
MRI
Brain MRI is helpful in the diagnosis of CNS bleeding in acute myeloid leukemia (AML).[21]
Other Imaging Findings
There are no other imaging findings associated with erythroleukemia.
Other Diagnostic Studies
Flow Cytometry:
- The erythroblasts lack myeloid antigens. They are postive for glycophorin A.
Cytogenetics:
- Loss of all or part of the long arm (q) of chromosomes 5 and/or 7. [23]
Treatment
Medical Therapy
- Pharmacologic medical therapy is recommended for patients with erythroleukemia who are not candidates for intensive chemotherapy or allogenic hematopoietic stem cell transplantation.[24]
- Pharmacologic medical therapies for erythroleukemia include hypomethylating agents (HMA) such as:[25]
For more information about acute myeloid leukemia (AML) medical therapy, click here.
Surgery
- Allo-SCT (Allogenic hematopoietic stem cell transplantation)[24]
Primary Prevention
There are no established measures for the primary prevention of erythroleukemia.
Secondary Prevention
Effective measures for the secondary prevention of erythroleukemia include maintenance of remission treatment post-transplant.[26]
References
- ↑ Santos FP, Bueso-Ramos CE, Ravandi F (December 2010). "Acute erythroleukemia: diagnosis and management". Expert Rev Hematol. 3 (6): 705–18. doi:10.1586/ehm.10.62. PMID 21091147.
- ↑ Forestier E, Heim S, Blennow E, Borgström G, Holmgren G, Heinonen K, Johannsson J, Kerndrup G, Andersen MK, Lundin C, Nordgren A, Rosenquist R, Swolin B, Johansson B (May 2003). "Cytogenetic abnormalities in childhood acute myeloid leukaemia: a Nordic series comprising all children enrolled in the NOPHO-93-AML trial between 1993 and 2001". Br. J. Haematol. 121 (4): 566–77. PMID 12752097.
- ↑ Santos FP, Bueso-Ramos CE, Ravandi F (December 2010). "Acute erythroleukemia: diagnosis and management". Expert Rev Hematol. 3 (6): 705–18. doi:10.1586/ehm.10.62. PMID 21091147.
- ↑ Cuneo A, Van Orshoven A, Michaux JL, Boogaerts M, Louwagie A, Doyen C, Dal Cin P, Fagioli F, Castoldi G, Van den Berghe H (July 1990). "Morphologic, immunologic and cytogenetic studies in erythroleukaemia: evidence for multilineage involvement and identification of two distinct cytogenetic-clinicopathological types". Br. J. Haematol. 75 (3): 346–54. PMID 2386768.
- ↑ Micci F, Thorsen J, Panagopoulos I, Nyquist KB, Zeller B, Tierens A, Heim S (April 2013). "High-throughput sequencing identifies an NFIA/CBFA2T3 fusion gene in acute erythroid leukemia with t(1;16)(p31;q24)". Leukemia. 27 (4): 980–2. doi:10.1038/leu.2012.266. PMC 3626019. PMID 23032695.
- ↑ Zuo Z, Polski JM, Kasyan A, Medeiros LJ (September 2010). "Acute erythroid leukemia". Arch. Pathol. Lab. Med. 134 (9): 1261–70. doi:10.1043/2009-0350-RA.1. PMID 20807044.
- ↑ Wells AW, Bown N, Reid MM, Hamilton PJ, Jackson GH, Taylor PR (August 2001). "Erythroleukaemia in the north of England: a population based study". J. Clin. Pathol. 54 (8): 608–12. PMC 1731487. PMID 11477115.
- ↑ Santos FP, Bueso-Ramos CE, Ravandi F (December 2010). "Acute erythroleukemia: diagnosis and management". Expert Rev Hematol. 3 (6): 705–18. doi:10.1586/ehm.10.62. PMID 21091147.
- ↑ Atkinson J, Hrisinko MA, Weil SC (December 1992). "Erythroleukemia: a review of 15 cases meeting 1985 FAB criteria and survey of the literature". Blood Rev. 6 (4): 204–14. PMID 1486289.
- ↑ Almeida AM, Prebet T, Itzykson R, Ramos F, Al-Ali H, Shammo J, Pinto R, Maurillo L, Wetzel J, Musto P, Van De Loosdrecht AA, Costa MJ, Esteves S, Burgstaller S, Stauder R, Autzinger EM, Lang A, Krippl P, Geissler D, Falantes JF, Pedro C, Bargay J, Deben G, Garrido A, Bonanad S, Diez-Campelo M, Thepot S, Ades L, Sperr WR, Valent P, Fenaux P, Sekeres MA, Greil R, Pleyer L (April 2017). "Clinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study". Int J Mol Sci. 18 (4). doi:10.3390/ijms18040837. PMC 5412421. PMID 28420120.
- ↑ Srinivas U, Kumar R, Pati H, Saxena R, Tyagi S (October 2007). "Sub classification and clinico-hematological correlation of 40 cases of acute erythroleukemia - can proerythroblast/myeloblast and proerythroblast/total erythroid cell ratios help subclassify?". Hematology. 12 (5): 381–5. doi:10.1080/10245330701393816. PMID 17852448.
- ↑ Zuo Z, Polski JM, Kasyan A, Medeiros LJ (September 2010). "Acute erythroid leukemia". Arch. Pathol. Lab. Med. 134 (9): 1261–70. doi:10.1043/2009-0350-RA.1. PMID 20807044.
- ↑ Peng J, Hasserjian RP, Tang G, Patel KP, Goswami M, Jabbour EJ, Garcia-Manero G, Medeiros LJ, Wang SA (2016). "Myelodysplastic syndromes following therapy with hypomethylating agents (HMAs): development of acute erythroleukemia may not influence assessment of treatment response". Leuk. Lymphoma. 57 (4): 812–9. doi:10.3109/10428194.2015.1079318. PMID 26293512.
- ↑ Lessard M, Struski S, Leymarie V, Flandrin G, Lafage-Pochitaloff M, Mozziconacci MJ, Talmant P, Bastard C, Charrin C, Baranger L, Hélias C, Cornillet-Lefebvre P, Mugneret F, Cabrol C, Pagès MP, Fert-Ferret D, Nguyen-Khac F, Quilichini B, Barin C, Berger R (December 2005). "Cytogenetic study of 75 erythroleukemias". Cancer Genet. Cytogenet. 163 (2): 113–22. doi:10.1016/j.cancergencyto.2005.05.006. PMID 16337853.
- ↑ Grossmann V, Bacher U, Haferlach C, Schnittger S, Pötzinger F, Weissmann S, Roller A, Eder C, Fasan A, Zenger M, Staller M, Kern W, Kohlmann A, Haferlach T (September 2013). "Acute erythroid leukemia (AEL) can be separated into distinct prognostic subsets based on cytogenetic and molecular genetic characteristics". Leukemia. 27 (9): 1940–3. doi:10.1038/leu.2013.144. PMID 23648669.
- ↑ Hefti E, Blanco JG (2016). "Anthracycline-Related Cardiotoxicity in Patients with Acute Myeloid Leukemia and Down Syndrome: A Literature Review". Cardiovasc Toxicol. 16 (1): 5–13. doi:10.1007/s12012-015-9307-1. PMC 4514565. PMID 25616318.
- ↑ Armenian SH, Gelehrter SK, Vase T, Venkatramani R, Landier W, Wilson KD, Herrera C, Reichman L, Menteer JD, Mascarenhas L, Freyer DR, Venkataraman K, Bhatia S (December 2014). "Screening for cardiac dysfunction in anthracycline-exposed childhood cancer survivors". Clin. Cancer Res. 20 (24): 6314–23. doi:10.1158/1078-0432.CCR-13-3490. PMC 4268342. PMID 24947931.
- ↑ Oehadian A, Iqbal M, Sumantri R (October 2009). "Deep vein thrombosis in acute myelogenous leukemia". Acta Med Indones. 41 (4): 200–4. PMID 20124617.
- ↑ Vallipuram J, Dhalla S, Bell CM, Dresser L, Han H, Husain S, Minden MD, Paul NS, So M, Steinberg M, Vallipuram M, Wong G, Morris AM (April 2017). "Chest CT scans are frequently abnormal in asymptomatic patients with newly diagnosed acute myeloid leukemia". Leuk. Lymphoma. 58 (4): 834–841. doi:10.1080/10428194.2016.1213825. PMID 27642861.
- ↑ Chen CY, Tai CH, Cheng A, Wu HC, Tsay W, Liu JH, Chen PY, Huang SY, Yao M, Tang JL, Tien HF (August 2012). "Intracranial hemorrhage in adult patients with hematological malignancies". BMC Med. 10: 97. doi:10.1186/1741-7015-10-97. PMC 3482556. PMID 22931433.
- ↑ Cervantes GM, Cayci Z (May 2015). "Intracranial CNS Manifestations of Myeloid Sarcoma in Patients with Acute Myeloid Leukemia: Review of the Literature and Three Case Reports from the Author's Institution". J Clin Med. 4 (5): 1102–12. doi:10.3390/jcm4051102. PMC 4470219. PMID 26239467.
- ↑ Sharma A, Buxi G, Walia R, Yadav RB, Sharma S (2011). "Childhood acute erythroleukemia diagnosis by flow cytometry". Indian J Pathol Microbiol. 54 (1): 173–5. doi:10.4103/0377-4929.77395. PMID 21393910.
- ↑ Atkinson J, Hrisinko MA, Weil SC (December 1992). "Erythroleukemia: a review of 15 cases meeting 1985 FAB criteria and survey of the literature". Blood Rev. 6 (4): 204–14. PMID 1486289.
- ↑ 24.0 24.1 Almeida AM, Prebet T, Itzykson R, Ramos F, Al-Ali H, Shammo J, Pinto R, Maurillo L, Wetzel J, Musto P, Van De Loosdrecht AA, Costa MJ, Esteves S, Burgstaller S, Stauder R, Autzinger EM, Lang A, Krippl P, Geissler D, Falantes JF, Pedro C, Bargay J, Deben G, Garrido A, Bonanad S, Diez-Campelo M, Thepot S, Ades L, Sperr WR, Valent P, Fenaux P, Sekeres MA, Greil R, Pleyer L (April 2017). "Clinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study". Int J Mol Sci. 18 (4). doi:10.3390/ijms18040837. PMC 5412421. PMID 28420120.
- ↑ Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR (February 2010). "Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia". J. Clin. Oncol. 28 (4): 562–9. doi:10.1200/JCO.2009.23.8329. PMID 20026804.
- ↑ Oran B, de Lima M (November 2011). "Prevention and treatment of acute myeloid leukemia relapse after allogeneic stem cell transplantation". Curr. Opin. Hematol. 18 (6): 388–94. doi:10.1097/MOH.0b013e32834b6158. PMID 21897227.