Acute myeloid leukemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]; Grammar Reviewer: Natalie Harpenau, B.S.[3]

In the 17th and 18th centuries, scientists first discovered and described blood cells, which are the malignant cells in acute myeloid leukemia. In the 19th century, the first case of acute leukemia was described. In the 20th century, chemotherapy was introduced for the treatment of acute leukemia. The 21st century witnessed advancements in the understanding of disease biology, and targeted therapies for acute myeloid leukemia were introduced to the market.

• In 130-200 AD, Galen first used the term cancer. This included hematologic and solid malignancies.
• In 1674, Van Leeuwenhoek was the first scientist to discover red blood cells.^[1]
• In 1749, Joseph Lieutaud, a French anatomist, described what he called the globuli albicantes, which later came to be known as white blood cells.
• In 1749, after De Sanc described globules blancs du pus, it became known that pus and inflammation were related to blood.
• In 1774, William Hewson gave a detailed description of the lymphatic system and lymphocytes.
• In 1846, Dr. Henry Fuller, a physician at St George’s Hospital in London, published the first case report of chronic granulocytic leukemia. This was the first recorded use of the microscope to diagnose leukemia in a patient. He noted that the time from the onset of ill health to death was 8 months. He labeled his diagnosis as “leucocythaemia”.
• In 1857, Nikolaus Friedreich documented the first case of acute leukemia.^[2]
• In 1877, Paul Ehrlich performed polychromatophilic stains to classify leukemia into myeloid or lymphoid.^[2]
• In 1878, Ernst Neumann described the bone marrow as the origin of leukemia.^[2]
• In 1882, A.C. Doyle reported on the efficacy of arsenic in acute promyelocytic leukemia.^[3]
• In 1889, Willhelm Ebstein described leukemia as a fast and fatal disease.^[2]
• In 1900, Otto Naegeli described the differences between blasts (blood cancer cells) of myeloid versus lymphoid origin.^[2]
• In 1914, Theodor Boveri described the role of chromosomal aberrations in the development of cancer. This later became very important to the classification of acute myeloid leukemia, which is largely based on chromosomal abnormalities.^[2]
• In 1973, cytarabine and anthracyclines were introduced as induction therapy for acute myeloid leukemia.
• In 2000, gemtuzumab ozogamycin was approved by the Food and Drug Administration and was introduced to the market after phase II data showed a 26% response rate.^[4]
• In 2010, gemtuzumab ozogamycin was taken off the market after data showed concerns about the safety and efficacy of this medication in acute myeloid leukemia.^[4]
• In 2017, the European LeukemiaNet (ELN) classification system was devised to help risk stratify patients with acute myeloid leukemia.^[5]
• In 2017, there were multiple new drugs approved for acute myeloid leukemia after a 40-year period of stagnation. These medications included midostaurin, enasidenib, CPX-351, and gemtuzumab ozogamycin (re-approved in 2017 after its discontinuation in 2010).
• In 2018, ivosidenib was approved by the Food and Drug Administration after a phase 1 dose-escalation and dose-expansion study showed an overall response rate of 40%.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2], Carlos A Lopez, M.D. [3], Shyam Patel [4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

There are three classification systems for acute myeloid leukemia. These classifications include French-American-British (FAB) , the World Health Organization (WHO), and the European LeukemiaNet (ELN) . The original classification was the French-American-British (FAB) classification, and the most recent classification was the 2017 European LeukemiaNet (ELN) classification. There are several broad classification schemes for acute promyelocytic leukemia. The most well-accepted classification scheme is risk-based classification, which categories patients into low-risk, intermediate-risk, or high-risk based on the white blood cell count and platelet count. Another classification scheme is based on the origin of the leukemia, which categorized patients as having de novo or therapy-related disease. A final classification scheme is cytogenetic-based, in which case specific chromosomal abnormalities are used to stratify patients.

The French-American-British (FAB) classification system divided acute myeloid leukemia into 8 sub-types, M0 through to M7, based on the type of cell from which the leukemia developed and its degree of maturity. This was done by examining the appearance of the malignant cells under light microscopy and/or by using cytogenetics to characterize any underlying chromosomal abnormalities. The sub-types have varying prognoses and responses to therapy. Although the World Health Organization (WHO) classification (see below) may be more useful, the FAB system is still widely used as of mid-2006.

The eight FAB sub-types are:^[1]

Type	Name	Cytogenetics
M0	Minimally differentiated AML
M1	Acute myeloblastic leukemia, without maturation
M2	Acute myeloblastic leukemia, with granulocytic maturation	t(8;21)(q22;q22), t(6;9)
M3	Promyelocytic, or Acute promyelocytic leukemia (APL)	t(15;17)
M4	Acute myelomonocytic leukemia	inv(16)(p13q22), del(16q)
M4eo	Myelomonocytic together with bone marrow eosinophilia	inv(16), t(16;16)
M5	Acute monoblastic leukemia (M5a) or Acute monocytic leukemia (M5b)	del (11q), t(9;11), t(11;19)
M6	Acute erythroid leukemias, including erythroleukemia (M6a) and very rare pure erythroid leukemia (M6b)
M7	Acute megakaryoblastic leukemia	t(1;22)

The World Health Organization (WHO) classification of acute myeloid leukemia attempts to be more clinically useful and to produce more meaningful prognostic information than the FAB criteria. Each of the WHO categories contains numerous descriptive sub-categories of interest to hematopathologists and oncologists; however, most of the clinically significant information in the WHO schema is communicated via categorization into one of the five sub-types listed below. The 2016 revision of the WHO classification was recently developed.

The sub-types of acute myeloid leukemia are shown below:^[2]

Name	Description	ICD-O
Acute myeloid leukemia with characteristic genetic abnormalities	This category includes: AML with translocations between chromosome 8 and 21; RUNX1/RUNX1T1[3] AML with inversions in chromosome 16; CBFB/MYH11[4] APL with translocations between chromosome 15 and 17; RARA;PML[5] Patients with acute myeloid leukemia in this category generally have a high rate of remission and a better prognosis compared to other types of acute myeloid leukemia.	Multiple
Acute myeloid leukemia with multilineage dysplasia	This category includes patients who have had a prior myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD) that transforms into acute myeloid leukemia. This category of acute myeloid leukemia occurs most often in elderly patients and often has a worse prognosis.	Template:ICDO
Acute myeloid leukemia and MDS, therapy-related	This category includes patients who have had prior chemotherapy and/or radiation and subsequently develop acute myeloid leukemia or MDS. These leukemias may be characterized by specific chromosomal abnormalities, and often carry a worse prognosis.	Template:ICDO
Acute myeloid leukemia not otherwise categorized	This category includes sub-types of acute myeloid leukemia that do not fall into the above categories.	Template:ICDO

The European LeukemiaNet classification is a risk-based classification system that was recently revised in 2017.^[6]

Name	Description
Favorable risk	Includes: AML with translocations between chromosome 8 and chromosome 21; t(8;21); RUNX1/RUNX1T1 AML with inversions in chromosome 16; inv(16); CBFB/MYH11 AML with mutant NPM1 and wild-type FLT3 AML with biallelic CEBPalpha mutation
Intermediate risk	Includes: AML with mutant NPM1 and mutant FLT3 (FLT3-ITD) AML with wild-type NPM1 and wild-type FLT3 (no FLT3-ITD) AML with translocations between chromosome 9 and chromosome 21 (MLLT3-KMT2A) AML with cytogenetic abnormalities not classified as favorable or adverse
Adverse risk	Includes: AML with translocations between chromosome 6 and chromosome 9 AML with inversion of chromosome 3 AML with translocations involving chromosome 11q23 AML with translocations between chromosome 6 and chromosome 9 AML with monosomy 5 or 7 AML with complex karyotype (2 or more cytogenetic abnormalities) AML with mutant RUNX1, mutant ASXL1, or mutant TP53

Acute promyelocytic leukemia is further classified in to the following several classification schemes.

• Low-risk disease:
  • Low-risk disease is defined as the presence of less than 10000 white blood cells per microliter and greater than 40000 platelets per microliter in the peripheral blood.
  • Treatment of low-risk disease involves non-chemotherapy-based regimens, such as the combination of all trance retinoic acid and arsenic trioxide.^[7]
• Intermediate-risk disease:
  • Intermediate-risk disease is defined as the presence of less than 10000 white blood cells per microliter and less than 40000 platelets per microliter in peripheral blood.^[8]
• High-risk disease:
  • High-risk disease is defined as the presence of greater than 10000 white blood cells per microliter in peripheral blood, regardless of the platelet count.
  • Platelet count is typically less than 40,000 cells per microliter, though platelet count is not a formal criterion in the classification of acute promyelocytic leukemia.^[7]

• De novo disease:
  • De novo acute promyelocytic leukemia is the most common sub-type.
  • This refers to development of the disease in the absence of prior cytotoxic therapy or prior precursor conditions.
  • De novo acute promyelocytic leukemia is due to a sporadic events in cells, without prior DNA damaging insults. This is in contrast to therapy-related disease.

• Therapy-related disease:
  • Therapy-related disease refers to the development of acute promyelocytic leukemia in-patients who were previously treated with DNA-damaging or genotoxic agents for other conditions, such as other cancers.
  • The most common DNA-damaging agents that cause therapy-associated acute promyelocytic leukemia are topoisomerase inhibitors and alkylating agents.
  • Therapy-related acute promyelocytic leukemia is typically seen in patients with a history of breast cancer who received cyclophosphamide or patients with a history of a germ cell tumor who have received etoposide.
  • The prognosis of therapy-related disease is worse than that of de novo disease, with a 5-year survival of less than 10 years. The 4-year overall survival for therapy-related disease is 24.5%, compared to 39.5% for de novo disease.^[9]

Chemotherapeutic agents
Topoisomerase II inhibitors:	This class of chemotherapeutics causes early-onset leukemia, with a typical latency of 2-3 years from the receipt of the topoisomerase inhibitor. Cytogenetics from the leukemia diagnosis typically shows the MLL rearrangement (chromosome 11q23). There is usually no preceding myelodysplastic phase; the onset of leukemia is relatively sudden.[10]
Alkylating agents:	This class of chemotherapeutics causes late-onset leukemia, with a typical latency of greater than 7 years from the receipt of the alkylating agent. Cytogenetics from the leukemia diagnosis typically shows monosomy 5 or monosomy 7. Mutational analyses can show a TP53 mutation. There is usually a preceding myelodysplastic phase.[10]
Other chemotherapeutic agents:	Although other chemotherapy medications are not classically associated with therapy-related apromyelocytleukemiamiaiamia, there have been cases of such associations. In a patient with gastric cancer treated with oxaliplatin and capecitabine, acute promyleukemia leukemia developed after a latency period of 4 years. The leukemic cells had chromosomal abnormalities, suggesting that the secondary neoplasm was chemotherapy-induced rather than de novo.[9]

• The karyotype of most cases of acute promyelocytic leukemia involves the t(15;17) translocation between the PML and RARA genes. However, complex karyotypes may co-exist in some cases of acute promyelocytic leukemia.^[11]

Cytogenetics
Complex karyotype	Complex karyotype is defined as the presence of two or more chromosomal abnormities. Complex karyotype acute promyelocytic leukemia is associated with worse prognosis and lower rates of complete remission, similar to complex karyotype acute myeloid leukemia[11]. Patients with complex karyotype are more likely to have a TP53 mutation and are more likely to be resistant to chemotherapy.[11]
Trisomy 8	Trisomy 8 is characterized by three copies of chromosome 8 in cells. This chromosomal abnormality is commonly found in patients with myelodysplastic syndrome, which is a precursor condition for acute myeloid leukemia. Aside from t(15;17), trisomy 8 is the most frequent chromosomal abnormality in acute promyelocytic leukemia.[11]
Tetraploidy	Tetraploidy is defined as the presence of four sets of chromosomes in a cell. Tetraploidy is generally rare in acute promyelocytic leukemia and accounts for approximately 0.75% of cases. The karyotype of most cases of acute promyelocytic leukemia involves the t(15;17) translocation between the PML and RARA genes. However, complex karyotypes may co-exist in some cases of acute promyelocytic leukemia. Tetraploidy in acute promyelocytic leukemia is more commonly associated with CD2 expression in the malignant cells. Tetraploid acute promyelocytic leukemia is mostly sensitive to all-trans retinoic acid.[11]
t(8;21)	The t(8;21) translocation sometimes co-exists with the t(15;17) translocation. The t(8;21) translocation is more commonly found in acute myeloid leukemia and involves the juxtaposition of the ETO (RUNX1T1) gene on chromosome 8 with AML1 (RUNX1) gene on chromosome 21. A total of six cases of coexisting t(8;21) and t(15;17) have thus far been described.[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2], Raviteja Guddeti, M.B.B.S. [3], Carlos A Lopez, M.D. [4], Shyam Patel [5]; Grammar Reviewer: Natalie Harpenau, B.S.[6]

Normal hematopoiesis involves the production of blood cells, and this normal physiologic process is dysregulated in acute myeloid leukemia. The pathophysiology of acute myeloid leukemia involves multiple mechanisms, including altered signal transduction and autonomous proliferation, differentiation blockade, evasion of apoptosis, and self-renewal. The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene production causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.

In order to understand the pathophysiology of acute myeloid leukemia, it is important to understand normal physiology of hematopoiesis or blood cell production.

• Hematopoiesis is defined as the production of blood cells.
• This process is typically tightly-regulated under physiological conditions via a number of lineage-specific growth factors and lineage-specific growth signaling pathways.
• The differentiation of myeloid stem cells into mature myelocytes is controlled by lineage-specific transcription factors that regulate the expression of lineage-specific genes.
• In normal hematopoiesis, the myeloblast is an immature precursor of myeloid white blood cells.
• A normal myeloblast will gradually mature into a mature white blood cell.
• Normal hematopoiesis is dependent upon specific growth factor receptors.
• The two key growth factor receptors involved are as following:
  • Growth factor receptors with intrinsic tyrosine kinase activity:
    • These are expressed on CD34+ hematopoietic progenitor cells.
    • Examples include receptors for the platelet-derived growth factors (PDGFs), PDGFR A and B, the receptor for macrophage colony stimulating factor (M-CSF), FMS-like tyrosine kinase receptor (FLT3R), and the receptors for Kit ligand (stem cell factor)^[1]
  • Growth factor receptors without intrinsic tyrosine kinase activity:
    • These depend upon intracellular kinases of the Src and Janus kinase (JAK) families. Examples include the JAK-STAT pathway.^[2]

• The malignant cell in acute myeloid leukemia is the myeloblast. However, in acute myeloid leukemia a single myeloblast accumulates genetic changes, which “freeze” the cell in its immature state and prevent differentiation.^[3]
• This type of mutation alone does not cause leukemia. However, when such a differentiation arrest is combined with other mutations, which disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of acute myeloid leukemia.^[4]
• Much of the diversity and heterogeneity of acute myeloid leukemia stems from the fact that leukemic transformation can occur at a number of different steps along the differentiation pathway.^[5]
• Human acute myeloid leukemia is organized as a hierarchy, and the cancer stem cell hypothesis best models the pathophysiology of acute myeloid leukemia.
• Modern classification schemes for acute myeloid leukemia recognize that the characteristics and behavior of the leukemic cell (and the leukemia) may depend on the stage at which differentiation was halted.

• Activation of tyrosine kinase receptors is followed by signal transduction via intracellular signal cascades leading to alteration of transcription within the cell nucleus.^[6]
• An important pathway that leads to cellular proliferation is the Ras-MAP Kinase pathway, where Ras is activated by binding of guanosine triphosphate (GTP). Ras-bound GTP in turn triggers a cascade of events that finally lead to activation of serine/threonine kinases.
• Consequently, there is an activation of MAP kinases, which phosphorylate important transcriptional regulators of cell cycle.^{[7][8][9][10]}
• As a consequence of these, there is autonomous increased proliferation of cells.

• Altered gene expression leads to autonomous cellular proliferation with defects in regulatory pathways involved in cellular proliferation.
• Chromosomal translocations and point mutations both play a pivotal role in generating a differentiation blockade on myeloid cells.
• This results in a disruption in transcription factors.
• Transcription factors affected by chromosomal rearrangement (translocations) include:
  • Core binding factor complex [t(8;21), ETO-AML1 fusion]
  • Core binding factor complex [inv(16), CBFβ-MYH11 fusion]
  • Chromosome 3 translocation [t(3;21), RUNX1-EVI1 fusion]^[11][12][13]
  • Retinoic acid receptor (RAR) fusion [t(15;17), PML-RARα fusion]^[14][15]
  • MLL rearrangement [Activator protein of Hox gene promoters; Hox gene promoters in turn promote self-renewal of immature myeloid cells]^[16]
  • Hox proteins^[17][18]
• Point mutations in myeloid transcription factors include:
  • C/EBPα^[13][19]
  • PU.1^[20]

• The increased expression of Bcl-2 pro-survival molecule plays a key role in evasion of programmed cell death in AML.^[21]
• PI 3-kinase activates the AKT serine/threonine kinase, and this kinase in turn phosphorylates BAD and releases the BCL-2 anti-apoptotic molecule.^[22][23]
• The RUNX1-MTG8 fusion protein of AML represses the expression of p14ARF and promotes destabilization of p53 (a tumor suppressor gene).^[24][25][26]

• The myeloid cells in acute myeolid leukemia have an ability to self-renew without being committed to a specific cell lineage.^[27]
• The self-renewing capacity of myeloid cells in AMLs is thought to be mediated by the following:
  • Fusion of ALK tyrosine kinase with nucleophosmin protein (NPM)^[28]
  • Mutation of FLT3-ITD^[29][30]
  • RUNX1-MTG8, PML-RARα, and PLZF-RARα fusions can all induce the expression of β-catenin and γ-catenin (plako-globin) proteins^[31][32]
  • The Wnt signalling pathway has also been shown to be involved in self-renewal of myeloid cells^[33]

• The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells.
• The chromosomal translocation involves the juxtaposition of the retinoic acid receptor-alpha gene (RARA) on the long arm of chromosome 17 with another gene (most commonly the promyelocytic leukemia gene (PML) on the long arm of chromosome 15).^[34]
• The translocation is designated as t(15;17)(q22;q12). The PML-RARA fusion product is a transcriptional regulator and binds to retinoic acid response elements in the promoter regions of the genome. The PML-RARA fusion product serves to recruit co-repressors of gene transcription, preventing myeloid differentiation.^[35]
• This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells.
• The cells remain primitive and stem-like, which is the basis for the malignancy.
• The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.^[34]
• In 95% of cases of acute promyelocytic leukemia, the translocation involved PML and RARA. However, it is important to note that RARA has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.

Translocation Partner	Chromosomal Location	Function	Response to Therapy	Other Features
PML	15q24.1	A member of the tripartite motif (TRIM) family Localizes to nucleolar bodies and functions as a transcription factor and tumor suppressor Regulate p53 response to oncogenic growth signals Influenced by the cell cycle	Sensitive to all-trans retinoic acid[36]	Most common translocation Found in 70-90% of cases[37]
PLZF (ZBTB16)[34][37]	11q23.2	Encodes a zinc finger transcription factor Involved in cell cycle regulation Interacts with histone deacetylases	Resistant to all-trans retinoic acid[36]	Second most common translocation (after PML-RARA)
NPM1	5q35.1	Encodes nucleophosmin 1 (a nucleolar shuttle protein) Involved in centromere duplication Serves a protein chaperone Regulates the cell cycle Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation	Sensitive to all-trans retinoic acid[36]	NPM1 mutation carries a favorable prognosis in acute myeloid leukemia Rare translocation
NUMA[36]	11q13.4	Contributes to a structural component of the nuclear matrix Interacts with microtubules Contributes to mitotic spindle formation during cell division	Sensitive to all-trans retinoic acid[36]	Rare translocation
STAT5B[37]	17q21.2	Encodes a signal transducer and activator of transcription (STAT) Serves an intracellular transduction molecule for cytokine signaling Translocates to the nucleus and functions as a transcription factor Involved in T cell receptor signaling Involved in apoptosis Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation	Resistant to all-trans retinoic acid[36]	Rare translocation

Description of pictures (shown below) according the classification of Acute myeloid leukemia system.

• Acute myeloid leukemia M0 with lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts
• Morphologically, blasts are small to large with no granules or Auer rods

• Presence of more than 90% myeloblasts in blood
• Peroxidase

• Presence of granules can be noted
• Large myeloblasts with prominent nucleoli

• Also known as promyelocytic leukemia
• Hypergranular morphology with most cells containing abundant large granules
• Ruptured cells are releasing their granules free onto the slide
• Presence of Auer rods can be noticed

• M5a: >80% monoblasts in the marrow
• M5a: large monoblasts with fine nuclear chromatin and prominent nucleoli (note the absence of Auer rods)
• M5b: <80% monoblasts in the marrow

• Irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present
  • Megakaryoblasts are usually medium-sized to large cells with a high nuclear-cytoplasmic ratio
  • Nuclear chromatin is dense and homogeneous
  • Variable basophilic cytoplasm which may be vacuolated
  • An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present
  • Megakaryoblasts lack myeloperoxidase (MPO) activity and stain negatively with Sudan black B
  • Clumps or granules in the cytoplasm
  • PAS staining varies from negative to focal or granular positivity, to strongly positive staining
  • More precise identification is by immunophenotyping or with electron microscopy (EM)
  • Immunophenotyping using MoAb to megakaryocytic restricted antigen (CD41 and CD61) may be diagnostic

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Carlos A Lopez, M.D. [2], Shyam Patel [3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

The causes of acute myeloid leukemia are broad and include benzene, radiation, alkylating agents, topoisomerase II inhibitors, and specific gene mutations. Each of these risk factors carries a defined probability of progression into acute myeloid leukemia. Acute promyelocytic leukemia is caused by a reciprocal translocation between chromosomes 15 and 17, which creates a novel protein known as PML-RARA, leading to a differentiation block. Overall, most cases of acute myeloid leukemia are sporadic rather than inherited.

• Benzene: Benzene is a chemical liquid chemical with a sweet odor and is used in a variety of products, including heaters and other appliances. This chemical is a known cause of acute myeloid leukemia.^[1] In general, benzene exposure accounts for a very small fraction of acute promyelocytic leukemia, since most cases are sporadic.
• Radiation: Ionizing radiation is known cause of acute leukemia of myeloid origin. Radiation-inducing DNA damage can create double-stranded breaks, which can result in leukemia.^[1] In general, ionizing radiation accounts for a very small fraction of acute promyelocytic leukemia, since most cases are sporadic. If the double-stranded breaks are not properly repaired, cellular transformation can result.
• Alkylating agents: Chemotherapy agents that function via DNA alkylation are known to contribute to acute myeloid leukemia. Alkylating agents include nitrogen mustards (such as carmustine (BCNU) and lomustine (CCNU)) and cyclophosphamide. Alkylating agents typically cause late-onset leukemia: the latency between the exposure to the alkylating agent and the diagnosis of leukemia is usually 5-7 years. There is frequently an antecedent myelodysplastic phase (a precursor state of acute leukemia).
• Topoisomerase II inhibitors: Chemotherapy agents that function via inhibition of topoisomerase II are known to contribute to acute myeloid leukemia. Topoisomerase II inhibitors include anthracyclines, etoposide (VP-16), and topotecan. Topoisomerase II inhibitors typically cause early-onset leukemia: the latency between the exposure to the topoisomerase II inhibitor and the diagnosis of leukemia is usually 2-3 years. These are usually associated with the MLL rearrangement on chromosome 11q23.
• Specific gene mutations: In rare cases, acute leukemia can arise in the setting of mutations. Most of these mutations are located in genes involved in epigenetic regulation. Such genes include TET2, DNMT3A, ASXL1, and EZH2. In addition to these, mutations in metabolic enzymes, such as IDH2 can contribute. These mutations are more common in acute myeloid leukemia compared to acute promyelocytic leukemia. Mutations can also occur in RNA splicing genes.
  • TET2: Ten eleven translocation 2 (TET2) is a gene that encodes an enzyme that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The function of the TET2 protein is to effectively demethylate DNA. Mutations in this gene result confer a worse prognosis for acute myeloid leukemia.^[1] In general, TET2 mutations occur early during leukemogenesis.
  • DNMT3A: DNA methyltransferase 3a (DNMT3A) is a gene that encodes an enzyme that methylates DNA. In general, DNMT3A mutations occur early during leukemogenesis.^[1]
  • ASXL1: Additional sex combs like 1 (ASXL1) is a transcription regulator and a modulator of histone methylation. Mutations in this gene are associated with a very poor prognosis in acute myeloid leukemia.
  • EZH2: Enhancer of zeste (EZH2) is a gene involved in the maintenance of transcription repression. It encodes a subunit of a histone methyltransferase.^[1]
  • SRSF2: Serine and arginine rich splicing factor 2 (SRSF2) is a gene that encodes a splicosome component. Mutations in this gene are also involved in myelodysplastic syndrome.
  • SF3B1: Splicing factor 3b subunit 1 (SF3B1) is a gene that encodes for a splicosome component. Mutations in this gene are also involved in myelodysplastic syndrome and presence of ringed sideroblasts.
  • IDH2: Isocitrate dehydrogenase 2 (IDH2) is a gene that encodes for an enzyme that results in the production of 2-hydroxyglutarate, which is an oncometabolite that results in a differentiation block.^[2] The differentiation block that arises from IDH2 mutations is similar pathophysiologically to the differentiation block that occurs with the PML-RARA translocation.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2], Zahir Ali Shaikh, MD[3], Raviteja Guddeti, M.B.B.S. [4], Carlos A Lopez, M.D. [5], Shyam Patel [6]; Grammar Reviewer: Natalie Harpenau, B.S.[7]

The differential diagnosis of acute myeloid leukemia includes a variety of other hematologic malignancies, specifically acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). Each of these conditions has distinct causes and therapies. There is some overlap between the causes and laboratory abnormalities amongst these diseases.

ABBREVIATIONS

N/A: Not available, NL: Normal, FISH: Fluorescence in situ hybridization, PCR: Polymerase chain reaction, LDH: Lactate dehydrogenase, PUD: Peptic ulcer disease, EPO: Erythropoietin, LFTs: Liver function tests, RFTs: Renal function tests, LAP: Leukocyte alkaline phosphatase, LAD: Leukocyte alkaline dehydrgenase, WBCs: White blood cells.

Myeloproliferative neoplasms (MPN)		Clinical manifestations		Diagnosis											Other features
		Symptoms	Physical examination	CBC & Peripheral smear									Bone marrow biopsy	Other investigations
				WBCs							Hb	Plat- elets
				Leuko-cytes	Blasts	Left shift	Baso- phils	Eosino- phils	Mono- cytes	Others
Chronic myeloid leukemia (CML), BCR-ABL1+[1][2]		Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<2%	+	↑	↑	↑	N/A	↓	NL	Hypercellurarity with ↑ granuloscytosis and ↓ erythrocytosis Fibrosis	FISH for t(9;22)(q34;q11.2) Reverse transcriptase quantitative PCR (RQ-PCR) for BCR-ABL	Granulocytic dysplasia is minimal/absent May present with blast crisis Absolute leukocytosis (median of 100,000/µL) Classic myelocyte bulge thrombocytopenia indicates advanced stage
Chronic neutrophilic leukemia (CNL)[3][4][5]		Asymptomatic Constitutional symptoms Bleeding Infection	Splenomegaly Heptomegaly Purpura Anemia related	↑	Minimal	+	NL	NL	NL	↑ LDH ↑ B12 levels	↓	↓	Uniforme and intense hypercellularity with minimal to none fibrosis Neutrophil toxic granulations and Dohle bodies	FISH Imaging for hepatosplenomegaly	Associationed with polycythemia vera and plasma cell disorders Leukocytosis with chronic neutrophilia
Polycythemia vera (PV)[6][7][8][9]		Constitutional Thromboembolism and bleeding Pruritus after a warm bath PUD related	Facial ruddiness Related to underlying cause Splenomegaly Renal bruit	NL or ↑	None	–	↑ or ↓	NL or ↑	NL	↓ Serum ferritin ↓ Folate levels ↑↑ B12 levels	↑↑	NL	Hypercellularity for age with tri-lineage growth Myelofibrosis (in up to 20% of patients)	Radioisotope studies Serum EPO levels LFTs RFTs Imaging studies	May transform into myelofibrosis or leukemia
Primary myelofibrosis (PMF)[10][11][12][13]		Constitutional Anemia related Bleeding Infection Abdominal Pain	Hepatosplenomegaly Petechiae & ecchymoses Abdominal distension Lymphadenopathy	↓	Erythroblasts	–	Absent	NL	NL	↑ LAP ↑ LAD ↑ Uric acid ↑ B12 levels	↓	↓	Variable with fibrosis or hypercellularity	JAK2 mutation CALR mutation MPL mutation	Bone marrow aspiration shows a dry tap Variable with leukocytosis or leukopenia
Essential thrombocythemia (ET)[14][15][16]		Headache Dizziness Visual disturbances Priapism Acute chest pain	Splenomegaly Skin bruises	NL or ↑	None	–	↓ or absent	NL	NL	N/A	↓	↑↑	Normal/Hypercellular	JAK2 mutation CALR mutation MPL mutation	Thrombosis Hemorrhage Pregnancy loss
Chronic eosinophilic leukemia, not otherwise specified (NOS)[17][18][19][20]		Constitutional Rash Rhinitis Gastritis Thromboembolism related	Hypertension Eczema, mucosal ulcers, erythema Angioedema Ataxia Anemia Lymphadenopathy Hepatosplenomegaly	↑	Present	+	↑	↑↑	↑	↑ B12 levels ↑ LDH	↓	↓	Hypercelluar with ↑ eosinophilic precursors, ↑ eosinophils, and atypical mononuclear cells	FISH Cytogenetic analysis of purified eosinophils and X-chromosome inactivation analysis	Heart failure Lung fibrosis Encephalopathy Erythema annulare centrifugam
MPN, unclassifiable		Similar to other myeloproliferative neoplasms	Similar to other myeloproliferative neoplasms	↑	Variable	±	↑ or ↓	↑ or ↓	↑ or ↓	May resemble other myeloproliferative neoplasms	↓	↑	↑ megakaryocyte proliferation with variable hypercellularity in granulocytic or erythrocytic cell lines	N/A	Similar to other myeloprolifeartive neoplasms but do not fulfil the criteria to be classified to a specific type
Mastocytosis[21][22][23][24]		Constitutional Pruritus & Flushing Urticaria & Blisters Hypotension & PUD Bleeding Bronchoconstriction	Mastocytosis exanthema Blistering Swelling Lymphadenopathy Bleeding Fibrosis	↑	None	–	NL	↑	NL	↑ Alkaline phosphatase ↑ LDH	↓	↓ or ↑	Multifocal dense infiltrates of mast cells with atypical morphology in >25 %	Cytogenetic analysis for c-KIT receptor mutations Serum tryptase levels 24-hour urine test for N-methyl histamine and 11-beta-prostaglandine	Skin most commonly involved Susceptibility to anaphylaxix Osteoporosis
Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1–JAK2[25][26][27][28]		Asymptomatic Constitutional Rash Cough & breathlessness Peripheral neuropathy/ encephalopathy	Fever Lymphadenopathy	↑	NL	–	NL	↑	↑	None	NL	↓	Myeloid expansion with eosinophilia	FISH shows t(8;13) and t(8;22)	May present or evolve into acute myeloid or lymphoblastic leukemia Leukocytosis (30 – 59 × 109/L
B-lymphoblastic leukemia/lymphoma[29][30]		Constitutional Anemia related Bleeding Infection Bone pain	Pallor Petechiae Organomegaly Lymphadenopathy	NL or ↑	>25%	N/A	↑ or ↓	↑ or ↓	↑ or ↓	Auer bodies	↓	↓	Hypercellular with blast infilterationwith or without myelodysplasia	Cytogenetic analysis Flow cytometry FISH	May present as extramedullary disease (Myeloid sarcoma)
Myelodysplastic syndromes (MDS)[31][32]		Constitutional Anemia related Bleeding Infection	Pallor Petechiae Organomegaly	↓	Variable	–	↓	↓	↓	Macro-ovalocytes Basophilic stippling Howell-Jolly body	↓	↓	Hypercellular/ normocellular bone marrow with dysplastic changes	Cytogenetic analysis Flow cytometry	Leukemia transformation Acquired pseudo-Pelger-Huët anomaly
Acute myeloid leukemia (AML) and related neoplasms[33][34]		Constitutional Anemia related Bleeding Bone pain Joint pain Infections	Infection related Pallor Leukemia cutis Bruising & petechiae Lymphadenopathy Hepatosplenomegaly	NL or ↑	↑	N/A	↑ or ↓	↑ or ↓	↑ or ↓	↑ Potassium ↑ Uric acid ↑ Phosphorus ↓ Calcium ↑ LDH	↓	↓	Increased immaturemyeloid cells with dysplasia	Cytogenetic analysis Flow cytometry FISH	Common in Down syndrome
Blastic plasmacytoid dendritic cell neoplasm[35][36][37][38]		Cutaneous symptoms (brown/purple nodular lesions) on face, scalp, lower limb & trunk	Brown/violaceous bruise like lesions Lymphadenopathy Splenomegaly	NL	↑		NL	NL	NL	Neutropenia	↓	↓	Malignant cells	Immunohistochemistry or flow cytometry for CD4 & CD56	TdT expression positive May develop chronic myelomonocytic leukemia (CMML)
Myelodysplastic /myeloproliferative neoplasms (MDS/MPN)	Chronic myelomonocytic leukemia (CMML)[39] [40][41]	Constitutional Anemia related Bleeding Infections Bone pain Leukemia Cutis	Organomegaly Bruising	↑	< 20%		NL	↑	↑↑	↑ LDH	↓	↓	Myelodysplastic and myeloproliferative feature	Cytogenetic analysis Flow cytometry	Overlapping of both, MDS and MPN Absolute monocytosis > 1 × 109/L (defining feature) MD-CMML:WBC ≤ 13 × 109/L (FAB)  MP-CMML:WBC > 13 × 109/L (FAB)
	Atypical chronic myeloid leukemia (aCML), BCR-ABL1-[42][43]	Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<20%	+	<2% of WBCs	N/A	N/A	N/A	↓	↓	Granulocytic hyperplasia with prominent dysplasia	Cytogenetic analysis Flow cytometry	Granulocytic dysplasia is prominent Absence of BCR-ABL or PDGFRA, PDGFRB, or FGFR1 rearrangements WBC > 13 × 109/L
	Juvenile myelomonocytic leukemia (JMML)[44][45]	Infections Anemia related	Hepatosplenomegaly Lymphadenopathy Rash	↑	↑	N/A	N/A	N/A	↑	↓ Serum Iron ↑ B12 levels	↓	↓	Hypercelluar with ↑ myeloid cells in stages of maturation	Cytogenetic analysis Flow cytometry	Polyclonal hypergammaglobulinemia
	MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)[46][47][48]	Constitutional Anemia related Thrombosis	Variable	NL or ↑	NL	–	NL	N/A	N/A	↑ Serum Iron	↓	↑	Hypercellularity with dyserythropoiesis and increased megakaryocytes	Cytogenetic analysis Flow cytometry	Large atypical megakaryocytes Ringed sideroblasts SF3B1 mutation
T-lymphoblastic leukemia/ lymphoma	T-lymphoblastic leukemia/ lymphoma[49][50][51]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	>25% blasts (Leukemia) <25% blasts (Lymphoma)	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH Positive for TdT	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysisFlow cytometry FISH	May involve brain, skin, and testes.
	Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymph[52]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH	↓	↓	N/A	Cytogenetic analysis FISH Flow cytometry	Similar to T-cell lymphoblastic leukemia but may have more aggressive clinical course. Diagnosis is usually based on presence of CD56 expression, and T-cell-associated markers such as CD2 and CD7. B-cell markers are absent.
	Provisional entity: Early T-cell precursor lymphoblastic leukemia[53][54]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysis FISH Flow cytometry	Similar to T-cell lymphoblastic leukemia but is more aggressive clinically and cell are characterized by cytometry as CD1a−, CD8−, CD5− (dim), and positivity for 1 or more stem cell or myeloid antigens. Gene expression indicates more immature cells as compared to other subtypes of T-cell neoplasms.

References

1. ↑ Savage DG, Szydlo RM, Goldman JM (January 1997). “Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period”. Br. J. Haematol. 96 (1): 111–6. PMID 9012696.
2. ↑ Thompson PA, Kantarjian HM, Cortes JE (October 2015). “Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015”. Mayo Clin. Proc. 90 (10): 1440–54. doi:10.1016/j.mayocp.2015.08.010. PMC 5656269. PMID 26434969.
3. ↑ Szuber N, Tefferi A (February 2018). “Chronic neutrophilic leukemia: new science and new diagnostic criteria”. Blood Cancer J. 8 (2): 19. doi:10.1038/s41408-018-0049-8. PMC 5811432. PMID 29440636.
4. ↑ Maxson JE, Tyner JW (February 2017). “Genomics of chronic neutrophilic leukemia”. Blood. 129 (6): 715–722. doi:10.1182/blood-2016-10-695981. PMC 5301820. PMID 28028025.
5. ↑ Menezes J, Cigudosa JC (2015). “Chronic neutrophilic leukemia: a clinical perspective”. Onco Targets Ther. 8: 2383–90. doi:10.2147/OTT.S49688. PMC 4562747. PMID 26366092.
6. ↑ Vannucchi AM, Guglielmelli P, Tefferi A (March 2018). “Polycythemia vera and essential thrombocythemia: algorithmic approach”. Curr. Opin. Hematol. 25 (2): 112–119. doi:10.1097/MOH.0000000000000402. PMID 29194068.
7. ↑ Pillai AA, Babiker HM. PMID 30252337. Missing or empty |title= (help)
8. ↑ Tefferi A, Barbui T (January 2019). “Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management”. Am. J. Hematol. 94 (1): 133–143. doi:10.1002/ajh.25303. PMID 30281843.
9. ↑ Rumi E, Cazzola M (February 2017). “Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms”. Blood. 129 (6): 680–692. doi:10.1182/blood-2016-10-695957. PMC 5335805. PMID 28028026.
10. ↑ Cervantes F, Correa JG, Hernandez-Boluda JC (May 2016). “Alleviating anemia and thrombocytopenia in myelofibrosis patients”. Expert Rev Hematol. 9 (5): 489–96. doi:10.1586/17474086.2016.1154452. PMID 26891375.
11. ↑ Hoffman, Ronald (2018). Hematology : basic principles and practice. Philadelphia, PA: Elsevier. ISBN 9780323357623.
12. ↑ Michiels JJ, Bernema Z, Van Bockstaele D, De Raeve H, Schroyens W (March 2007). “Current diagnostic criteria for the chronic myeloproliferative disorders (MPD) essential thrombocythemia (ET), polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF)”. Pathol. Biol. 55 (2): 92–104. doi:10.1016/j.patbio.2006.06.002. PMID 16919893.
13. ↑ Hoffman, Ronald (2018). Hematology : basic principles and practice. Philadelphia, PA: Elsevier. ISBN 9780323357623.
14. ↑ Schmoldt A, Benthe HF, Haberland G (1975). “Digitoxin metabolism by rat liver microsomes”. Biochem Pharmacol. 24 (17): 1639–41. PMID http://dx.doi.org/10.1182/blood-2007-04-083501 Check |pmid= value (help).CS1 maint: Multiple names: authors list (link)
15. ↑ Daniel A. Arber, Attilio Orazi, Robert Hasserjian, Jurgen Thiele, Michael J. Borowitz, Michelle M. Le Beau, Clara D. Bloomfield, Mario Cazzola & James W. Vardiman (2016). “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia”. Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. PMID 27069254. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
16. ↑ A. Tefferi, R. Fonseca, D. L. Pereira & H. C. Hoagland (2001). “A long-term retrospective study of young women with essential thrombocythemia”. Mayo Clinic proceedings. 76 (1): 22–28. doi:10.4065/76.1.22. PMID 11155408. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
17. ↑ Vidyadharan S, Joseph B, Nair SP (2016). “Chronic Eosinophilic Leukemia Presenting Predominantly with Cutaneous Manifestations”. Indian J Dermatol. 61 (4): 437–9. doi:10.4103/0019-5154.185716. PMC 4966405. PMID 27512192.
18. ↑ Hofmans M, Delie A, Vandepoele K, Van Roy N, Van der Meulen J, Philippé J, Moors I (2018). “A case of chronic eosinophilic leukemia with secondary transformation to acute myeloid leukemia”. Leuk Res Rep. 9: 45–47. doi:10.1016/j.lrr.2018.04.001. PMC 5993353. PMID 29892549.
19. ↑ Yamada Y, Rothenberg ME, Cancelas JA (2006). “Current concepts on the pathogenesis of the hypereosinophilic syndrome/chronic eosinophilic leukemia”. Transl Oncogenomics. 1: 53–63. PMC 3642145. PMID 23662039.
20. ↑ Kim TH, Gu HJ, Lee WI, Lee J, Yoon HJ, Park TS (September 2016). “Chronic eosinophilic leukemia with FIP1L1-PDGFRA rearrangement”. Blood Res. 51 (3): 204–206. doi:10.5045/br.2016.51.3.204. PMID 27722133.
21. ↑ Carter MC, Metcalfe DD, Komarow HD (February 2014). “Mastocytosis”. Immunol Allergy Clin North Am. 34 (1): 181–96. doi:10.1016/j.iac.2013.09.001. PMC 3863935. PMID 24262698.
22. ↑ Macri A, Cook C. PMID 29494109. Missing or empty |title= (help)
23. ↑ Lladó AC, Mihon CE, Silva M, Galzerano A (2014). “Systemic mastocytosis – a diagnostic challenge”. Rev Bras Hematol Hemoter. 36 (3): 226–9. doi:10.1016/j.bjhh.2014.03.003. PMC 4109736. PMID 25031064.
24. ↑ Valent P, Akin C, Metcalfe DD (March 2017). “Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts”. Blood. 129 (11): 1420–1427. doi:10.1182/blood-2016-09-731893. PMC 5356454. PMID 28031180.
25. ↑ Kumar, Kirthi R.; Chen, Weina; Koduru, Prasad R.; Luu, Hung S. (2015). “Myeloid and Lymphoid Neoplasm With Abnormalities of FGFR1 Presenting With Trilineage Blasts and RUNX1 Rearrangement”. American Journal of Clinical Pathology. 143 (5): 738–748. doi:10.1309/AJCPUD6W1JLQQMNA. ISSN 1943-7722.
26. ↑ Paolo Strati, Guilin Tang, Dzifa Y. Duose, Saradhi Mallampati, Rajyalakshmi Luthra, Keyur P. Patel, Mohammad Hussaini, Abu-Sayeef Mirza, Rami S. Komrokji, Stephen Oh, John Mascarenhas, Vesna Najfeld, Vivek Subbiah, Hagop Kantarjian, Guillermo Garcia-Manero, Srdan Verstovsek & Naval Daver (2018). “Myeloid/lymphoid neoplasms with FGFR1 rearrangement”. Leukemia & lymphoma. 59 (7): 1672–1676. doi:10.1080/10428194.2017.1397663. PMID 29119847. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
27. ↑ Ximena Montenegro-Garreaud, Roberto N. Miranda, Alexandra Reynolds, Guilin Tang, Sa A. Wang, Mariko Yabe, Wei Wang, Lianghua Fang, Carlos E. Bueso-Ramos, Pei Lin, L. Jeffrey Medeiros & Xinyan Lu (2017). “Myeloproliferative neoplasms with t(8;22)(p11.2;q11.2)/BCR-FGFR1: a meta-analysis of 20 cases shows cytogenetic progression with B-lymphoid blast phase”. Human pathology. 65: 147–156. doi:10.1016/j.humpath.2017.05.008. PMID 28551329. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
28. ↑ Paola Villafuerte-Gutierrez, Montserrat Lopez Rubio, Pilar Herrera & Eva Arranz (2018). “A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation”. Case reports in hematology. 2018: 5724960. doi:10.1155/2018/5724960. PMID 30647980.CS1 maint: Multiple names: authors list (link)
29. ↑ Kamiya-Matsuoka C, Garciarena P, Amin HM, Tremont-Lukats IW, de Groot JF (December 2013). “B lymphoblastic leukemia/lymphoma presenting as seventh cranial nerve palsy”. Neurol Clin Pract. 3 (6): 532–534. doi:10.1212/CPJ.0b013e3182a78ef0. PMC 6082360. PMID 30107017.
30. ↑ Zhang X, Rastogi P, Shah B, Zhang L (September 2017). “B lymphoblastic leukemia/lymphoma: new insights into genetics, molecular aberrations, subclassification and targeted therapy”. Oncotarget. 8 (39): 66728–66741. doi:10.18632/oncotarget.19271. PMC 5630450. PMID 29029550.
31. ↑ Germing U, Kobbe G, Haas R, Gattermann N (November 2013). “Myelodysplastic syndromes: diagnosis, prognosis, and treatment”. Dtsch Arztebl Int. 110 (46): 783–90. doi:10.3238/arztebl.2013.0783. PMC 3855821. PMID 24300826.
32. ↑ Gangat N, Patnaik MM, Tefferi A (January 2016). “Myelodysplastic syndromes: Contemporary review and how we treat”. Am. J. Hematol. 91 (1): 76–89. doi:10.1002/ajh.24253. PMID 26769228.
33. ↑ Islam A, Catovsky D, Goldman JM, Galton DA (September 1985). “Bone marrow biopsy changes in acute myeloid leukaemia. I: Observations before chemotherapy”. Histopathology. 9 (9): 939–57. PMID 3864727.
34. ↑ Orazi A (2007). “Histopathology in the diagnosis and classification of acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic/myeloproliferative diseases”. Pathobiology. 74 (2): 97–114. doi:10.1159/000101709. PMID 17587881.
35. ↑ F. Julia, T. Petrella, M. Beylot-Barry, M. Bagot, D. Lipsker, L. Machet, P. Joly, O. Dereure, M. Wetterwald, M. d’Incan, F. Grange, J. Cornillon, G. Tertian, E. Maubec, P. Saiag, S. Barete, I. Templier, F. Aubin & S. Dalle (2013). “Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients”. The British journal of dermatology. 169 (3): 579–586. doi:10.1111/bjd.12412. PMID 23646868. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
36. ↑ Livio Pagano, Caterina Giovanna Valentini, Alessandro Pulsoni, Simona Fisogni, Paola Carluccio, Francesco Mannelli, Monia Lunghi, Gianmatteo Pica, Francesco Onida, Chiara Cattaneo, Pier Paolo Piccaluga, Eros Di Bona, Elisabetta Todisco, Pellegrino Musto, Antonio Spadea, Alfonso D’Arco, Stefano Pileri, Giuseppe Leone, Sergio Amadori & Fabio Facchetti (2013). “Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study”. Haematologica. 98 (2): 239–246. doi:10.3324/haematol.2012.072645. PMID 23065521. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
37. ↑ Joseph D. Khoury (2018). “Blastic Plasmacytoid Dendritic Cell Neoplasm”. Current hematologic malignancy reports. 13 (6): 477–483. doi:10.1007/s11899-018-0489-z. PMID 30350260. Unknown parameter |month= ignored (help)
38. ↑ Shinichiro Sukegawa, Mamiko Sakata-Yanagimoto, Ryota Matsuoka, Haruka Momose, Yusuke Kiyoki, Masayuki Noguchi, Naoya Nakamura, Rei Watanabe, Manabu Fujimoto, Yasuhisa Yokoyama, Hidekazu Nishikii, Takayasu Kato, Manabu Kusakabe, Naoki Kurita, Naoshi Obara, Yuichi Hasegawa & Shigeru Chiba (2018). “[Blastic plasmacytoid dendritic cell neoplasm accompanied by chronic myelomonocytic leukemia successfully treated with azacitidine]”. [[[Rinsho ketsueki] The Japanese journal of clinical hematology]]. 59 (12): 2567–2573. doi:10.11406/rinketsu.59.2567. PMID 30626790.CS1 maint: Multiple names: authors list (link)
39. ↑ Patnaik MM, Tefferi A (June 2016). “Chronic myelomonocytic leukemia: 2016 update on diagnosis, risk stratification, and management”. Am. J. Hematol. 91 (6): 631–42. doi:10.1002/ajh.24396. PMID 27185207.
40. ↑ Parikh SA, Tefferi A (June 2012). “Chronic myelomonocytic leukemia: 2012 update on diagnosis, risk stratification, and management”. Am. J. Hematol. 87 (6): 610–9. doi:10.1002/ajh.23203. PMID 22615103.
41. ↑ Benton CB, Nazha A, Pemmaraju N, Garcia-Manero G (August 2015). “Chronic myelomonocytic leukemia: Forefront of the field in 2015”. Crit. Rev. Oncol. Hematol. 95 (2): 222–42. doi:10.1016/j.critrevonc.2015.03.002. PMC 4859155. PMID 25869097.
42. ↑ Dao KH, Tyner JW (2015). “What’s different about atypical CML and chronic neutrophilic leukemia?”. Hematology Am Soc Hematol Educ Program. 2015: 264–71. doi:10.1182/asheducation-2015.1.264. PMC 5266507. PMID 26637732.
43. ↑ Muramatsu H, Makishima H, Maciejewski JP (February 2012). “Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: novel pathogenetic lesions”. Semin. Oncol. 39 (1): 67–73. doi:10.1053/j.seminoncol.2011.11.004. PMC 3523950. PMID 22289493.
44. ↑ Aricò M, Biondi A, Pui CH (July 1997). “Juvenile myelomonocytic leukemia”. Blood. 90 (2): 479–88. PMID 9226148.
45. ↑ Hasle H (March 1994). “Myelodysplastic syndromes in childhood–classification, epidemiology, and treatment”. Leuk. Lymphoma. 13 (1–2): 11–26. doi:10.3109/10428199409051647. PMID 8025513.
46. ↑ Patnaik MM, Tefferi A (March 2017). “Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management”. Am. J. Hematol. 92 (3): 297–310. doi:10.1002/ajh.24637. PMID 28188970.
47. ↑ Alshaban A, Padilla O, Philipovskiy A, Corral J, McAlice M, Gaur S (2018). “Lenalidomide induced durable remission in a patient with MDS/MPN-with ring sideroblasts and thrombocytosis with associated 5q- syndrome”. Leuk Res Rep. 10: 37–40. doi:10.1016/j.lrr.2018.08.001. PMID 30186759.
48. ↑ Bouchla A, Papageorgiou SG, Tsakiraki Z, Glezou E, Pavlidis G, Stavroulaki G, Bazani E, Foukas P, Pappa V (2018). “Plasmablastic Lymphoma in an Immunocompetent Patient with MDS/MPN with Ring Sideroblasts and Thrombocytosis-A Case Report”. Case Rep Hematol. 2018: 2525070. doi:10.1155/2018/2525070. PMC 6247723. PMID 30524760.
49. ↑ You MJ, Medeiros LJ, Hsi ED (September 2015). “T-lymphoblastic leukemia/lymphoma”. Am. J. Clin. Pathol. 144 (3): 411–22. doi:10.1309/AJCPMF03LVSBLHPJ. PMID 26276771.
50. ↑ Patel KJ, Latif SU, de Calaca WM (March 2009). “An unusual presentation of precursor T cell lymphoblastic leukemia/lymphoma with cholestatic jaundice: case report”. J Hematol Oncol. 2: 12. doi:10.1186/1756-8722-2-12. PMC 2663564. PMID 19284608.
51. ↑ Elreda L, Sandhu M, Sun X, Bekele W, Cohen AJ, Shah M (2014). “T-cell lymphoblastic leukemia/lymphoma: relapse 16 years after first remission”. Case Rep Hematol. 2014: 359158. doi:10.1155/2014/359158. PMC 4005062. PMID 24822133.
52. ↑ Sedick Q, Alotaibi S, Alshieban S, Naheet KB, Elyamany G (2017). “Natural Killer Cell Lymphoblastic Leukaemia/Lymphoma: Case Report and Review of the Recent Literature”. Case Rep Oncol. 10 (2): 588–595. doi:10.1159/000477843. PMID 28868017.
53. ↑ Jain N, Lamb AV, O’Brien S, Ravandi F, Konopleva M, Jabbour E, Zuo Z, Jorgensen J, Lin P, Pierce S, Thomas D, Rytting M, Borthakur G, Kadia T, Cortes J, Kantarjian HM, Khoury JD (April 2016). “Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype”. Blood. 127 (15): 1863–9. doi:10.1182/blood-2015-08-661702. PMC 4915808. PMID 26747249.
54. ↑ Haydu JE, Ferrando AA (July 2013). “Early T-cell precursor acute lymphoblastic leukaemia”. Curr. Opin. Hematol. 20 (4): 369–73. doi:10.1097/MOH.0b013e3283623c61. PMC 3886681. PMID 23695450.

Template:Hematology

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2], Rim Halaby, M.D. [3], Carlos A Lopez, M.D. [4], Shyam Patel [5]; Grammar Reviewer: Natalie Harpenau, B.S.[6]

In 2015, the incidence of acute myeloid leukemia was approximately 6.5 per 100,000 individuals with a case-fatality rate of approximately 50% in the United States. The incidence of acute myeloid leukemia increases with age; the median age at diagnosis is 63 years. Males are more commonly affected by acute myeloid leukemia than women. The male to female ratio is approximately 1.3 to 1. Incidence of acute promyelocytic leukemia is relatively rare. It predominantly affects people of Latin American descent and least commonly affects African Americans. It is more common in older adults.

• Acute myeloid leukemia is a relatively rare cancer. There are approximately 20,500 new cases each year in the United States, and the incidence rate has remained stable from 1995 through 2005.
• Acute myeloid leukemia accounts for 1.2% of all cancer deaths in the United States.
• The case fatality rate of acute myeloid leukemia is approximately of 50% in the United States.
• In 2011, the age-adjusted incidence of acute myeloid leukemia was 4.05 per 100,000 persons in the United States.^[1]
• The incidence of acute myeloid leukemia overall is estimated to be 6.5 per 100,000 individuals in the United States.
  • In infants younger than 1 year old, the incidence is 1.5 per 100,000 persons.^[2]
  • In patients above the age of 80, the incidence of acute myeloid leukemia is 25 per 100,000 persons.^[2]
  • In the first decade of life, the incidence is 0.4 cases per 100,000 persons.^[2]
  • In the second decade of life, the incidence is 1 case per 100,000 persons.^[2]

Acute promyelocytic leukemia is a sub-category of acute myeloid leukemia and has a slightly different demographics than other forms of acute myeloid leukemia.

• The incidence of acute promyelocytic leukemia is 0.2 to 0.26 per 100,000 annually in the United States, which corresponds to 600-800 cases of acute promyelocytic leukemia per year.^[3]
• Acute promyelocytic leukemia affects approximately 1,500 people per year in the United States.^[4]
• Caucasians are more commonly affected by acute promyelocytic leukemia than African Americans.^[3] The incidence in Caucasians is 0.18 per 100,000, while the incidence with African Americans is 0.14 per 100,000.^[3]
• Asians and Pacific islanders are more commonly affected by acute promyelocytic leukemia than African Americans.^[3]
• The incidence is higher in people of Latin American descent compared to Caucasian descent.
• Acute promyelocytic leukemia represents 10-15%% of all cases of acute myeloid leukemia in adults.^[5] The median age is approximately 40 years, which is considerably younger than the other sub-types of acute myeloid leukemia (70 years).
• The incidence of acute promyelocytic leukemia has increased over time from 1975-2008.^[3]

• The incidence of acute myeloid leukemia increases with age; the median age at diagnosis is 63 years.
• Acute myeloid leukemia accounts for about 90% of all acute leukemias in adults but is rare in children.
• The rate of therapy-related Acute myeloid leukemia (that is, acute myeloid leukemia caused by previous chemotherapy) is rising. Therapy-related disease currently accounts for about 10–20% of all cases of acute myeloid leukemia.^[6]
• While the overall age-adjusted incidence of acute myeloid leukemia in the United States between 2007 and 2011 is 3.8 per 100,000, the age-adjusted incidence of acute myeloid leukemia by age category is:^[1]
  • Under 65 years: 1.8 per 100,000
  • 65 and over: 17.5 per 100,000
• Similarly, older patients are more likely to develop acute promyelocytic leukemia than younger patients.
• The incidence of acute promyelocytic leukemia in people above age 60 is 0.36 per 100,000. The incidence in people under age 20 is 0.06 per 100,000.

• Acute myeloid leukemia is slightly more common in men, with a male-to-female ratio of 1.3:1.^[7]

• In the United States, the age-adjusted incidence of acute myeloid leukemia by gender on 2011 is:^[1]
  • In males: 4.97 per 100,000 persons
  • In females: 3.32 per 100,000 persons

• Shown below is an image depicting the observed incidence of myeloid leukemia by gender the United States between 1975 and 2011. These graphs were adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[1]
• In acute promyelocytic leukemia, men are more commonly affected than women. The incidence per year in men is 0.19 per 100,000, while for women is 0.17 per 100,000.^[3]

• There is some geographic variation in the incidence of acute myeloid leukemia. In adults, the highest rates are seen in North America, Europe, and Oceania.
• In contrast, childhood acute myeloid leukemia is less common in North America.
• In the United Kingdom, acute myeloid leukemia accounts for 34% of all leukemia cases, and around 2,900 people were diagnosed with the disease in 2011.^[8]

• Adult acute myeloid leukemia is more rare in Asian and Latin American countries.^[9][10]
• Childhood acute myeloid leukemia is less common in India than in other parts of Asia.^[11]

These factual differences may be due to population genetics, environmental factors, or a combination of the two.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2], Carlos A Lopez, M.D. [3], Shyam Patel [4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

Common risk factors in the development of acute myeloid leukemia are advanced age, benzene exposure, prior myelodysplastic syndrome, germline mutations, and other conditions like aplastic anemia.

A number of risk factors for developing acute myeloid leukemia have been identified including:

• Advanced age: This is the most common risk factor for acute leukemia. Elderly patients are more likely to develop myeloid leukemia, due to a longer duration and opportunity for mutations to accumulate in cells. These mutations are more likely to accumulate in hematopoietic stem cells through a process called clonal evolution.^[1]
• Benzene^[2]: Benzene is a chemical solvent and aromatic hydrocarbon, for which exposure is a significant risk factor for acute leukemia.^[2]
• Prior myelodysplastic syndrome: Myelodysplastic syndrome is a disorder characterized by ineffective hematopoiesis, defective maturation of blood cells, and peripheral cytopenias. Antecedent myelodysplastic syndrome is implicated in some forms of acute leukemia, such as acute myeloid leukemia. Myelodysplastic syndrome is a precursor for leukemia, as this disease is characterized by the presence of dysplastic or cancerous cells that do not meet the requirements for a formal diagnosis of leukemia.^[3]
• Germline mutations: In general, germline predisposition to acute promyelocytic leukemia is rare. In patients with acute myeloid leukemia, germline mutations in the RUNX1 gene can predispose to the development of the cancer.^[4]
• Other conditions: Other causes include myeloproliferative syndromes, aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, chemical exposure and several congenital conditions such as Down syndrome, Bloom syndrome, Fanconi anemia, and neurofibromatosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]; Grammar Reviewer: Natalie Harpenau, B.S.[3]

There are currently no guidelines for screening for acute myeloid leukemia. Monitoring of the complete blood count is done routinely.

There are currently no guidelines for screening for acute myeloid leukemia. Routine monitoring of complete blood count (CBC) once yearly is sufficient for screening for hematologic diseases in general.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2], Carlos A Lopez, M.D. [3], Shyam Patel [4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

The natural history of acute myeloid leukemia involves the commencement of symptoms including fatigue, bleeding, and infection. Some patients will also present with disseminated intravascular coagulation in which bleeding and thrombosis occurs simultaneously. Complications of acute myeloid leukemia include infection, hemorrhage, venous thromboembolism, and therapy-related complications. The prognosis of acute myeloid leukemia is largely based upon on the European LeukemiaNet (ELN) classification system. The natural history of acute promyelocytic leukemia is also related to defective normal blood cell production, which include fatigue, bleeding, and infection. Complications include thrombosis and hemorrhage, which eventually occur in a significant proportion of patients. Early death is common and is related to bleeding complications. Therapy-related complications of acute promyelocytic leukemia include differentiation syndrome, QT interval prolongation, and cardiomyopathy. The prognosis of acute promyelocytic leukemia was previously poor, but the advent of arsenic trioxide and all-trans retinoic acid has rendered the prognosis to be far more favorable in the recent years.

• Acute myeloid leukemia usually begins with a variety of symptoms including fatigue, bleeding, and infections (such as upper respiratory tract infection).
• complete blood count usually reveals a low white blood cell count, low hemoglobin, and/or low platelet count.
• Bone marrow biopsy is usually done to work up the abnormal laboratory values, and a diagnosis of acute myeloid leukemia is made.
• The median survival in the absence of treatment is typically 6-8 weeks.
• In patients with acute promyelocytic leukemia, in the first few days to weeks of the disease, there is a high risk of bleeding due to disseminated intravascular coagulation.^[1]
• The median survival in the absence of treatment of acute promyelocytic leukemia is typically one week, due to bleeding complications contributing to mortality.^[2]
• The high early mortality rate was previously a major part of the natural history of the disease, prior to the advent of rapid diagnostic and therapeutic interventions for this disease.^[3]
• In areas of the United States with limited healthcare or highly specialized academic centers, bleeding diathesis continues to remain a major part of the natural history of the disease.
• Such bleeding complications include gingival bleeding (very common), bruising (very common), epistaxis, menorrhagia (less common).
• In areas of the United States with readily available healthcare and specialized academic medical centers, the natural history of the disease takes a favorable trajectory, as the cure rate is quite high if appropriate induction therapy is initiated.^[3]

Common complications of acute myeloid leukemia and promyelocytic leukemia include:

Infection:

• Infection is the most common complication of acute myeloid leukemia. Infection arises due to impaired function of white blood cells. In patients with acute myeloid leukemia, most white blood cells are immature and cannot differentiate into mature neutrophils. The differentiation block prevents the body from producing infection-fighting cells. Patients are at increased risk for the following types of infections:
  • Bacterial: Patients may require workup including imaging and blood cultures. Treatment includes intravenous antibiotics such as cefepime, piperacillin-tazobactam, or meropenem.
  • Viral: Patients may require workup including imaging, serologies, and viral titers. Treatment includes anti-viral agents such as acyclovir.
  • Fungal: Patients may require workup including imaging and fungal cultures. Treatment includes anti-fungal agents such as isovuconazole, posaconazole, or voriconazole.

Hemorrhage

• Acute myeloid leukemia, especially the promyelocytic sub-type, is frequently associated with bleeding caused by disseminated intravascular coagulation (DIC).
• Hemorrhagic and bleeding diathesis is the major cause of early complications that can lead to immediate death in patients with acute promyelocytic leukemia.

Venous thromboembolism

• Thrombus formation is a major cause of morbidity in acute promyelocytic leukemia.
• Thrombosis in the setting of acute promyelocytic leukemia is associated with a worse outcome compared to non-cancer-related thrombosis.^[4]
• Studies have shown that nearly 80% of patients with venous thromboembolism and cancer die within 6 months of the diagnosis of venous thromboembolism.
• The reason for this correlation between thrombosis and death in acute promyelocytic leukemia is that thrombosis is a surrogate marker for disease progression.

• • Procoagulants: There is increased production of procoagulant molecules such as thrombin from cancer cells. Furthermore, mucins and cytokines produced by malignant promyelocytes can induce endothelial cells to increase tissue factor production, and tissue factor functions in the extrinsic pathway to promote coagulation.
  • Platelets: There is a increased platelet activation in acute promyelocytic leukemia.
  • Fibrin: There is decreased fibrinolytic activity in acute promyelocytic leukemia, and this results in presence of excess fibrin. Fibrin is also known as factor I of the coagulation cascade and functions to binds platelets together via their GpIIb/IIIa receptors. This is one of the final steps in coagulation.
  • Natural anticoagulants: There is decreased production of natural anticoagulants, and this results in increased propensity for thrombosis.
  • Catheters: Central venous catheters can serve as a nidus for thrombosis since there is localized tissue and endothelial damage at the site of catheter insertion. and along the catheter within the body.^[4] Patients with acute promyelocytic leukemia are more likely to have central venous catheters, compared to patients with other conditions, since chemotherapy usually requires the presence of a central catheter to be placed.
  • Immobility: Patients with acute promyelocytic leukemia are frequently confined to a hospital bed during induction therapy, and venous stasis contributes to thrombosis. Obesity can also contribute to thrombosis.
  • Erythropoiesis-stimulating agents: Patients with acute promyelocytic leukemia frequently have anemia. Some patients receive erythropoiesis-stimulating agents, such as erythropoietin, which can increase red blood cell production and exacerbate thrombotic complications.

• In a 2015 study from MD Anderson Cancer Center, it was shown that the annual incidence of venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, was 6.1-42%, which is the highest amongst all leukemia sub-types.^[4]
• In contrast, the incidence of venous thromboembolism in chronic myeloid leukemia was only 1.5%.

Disease	Thrombotic Incidence
Acute myeloid leukemia	3.7%
Acute promyelocytic leukemia	6.1-48%
Chronic lymphocytic leukemia	2.7%
Acute lymphoblastic leukemia	2.1-13%
Chronic myeloid leukemia	1.5%

Therapy-related complications:

Treatment of acute myeloid leukemia can result in a variety of complications which are somewhat unique to the disease.

• • Rash: Cytarabine-related rash is very common after induction chemotherapy. This can be treated with corticosteroids.
  • Cerebellar toxicity: Patients treated with high-dose cytarabine (greater than 2-3g/m2) can develop cerebellar toxicity and thus require routine neurologic exams during consolidation chemotherapy.
  • Conjunctival toxicity: Patients treated with high-dose cytarabine (greater than 2-3g/m2) can develop conjunctivitis and thus require routine ocular exams and prophylactic steroid eye drops during consolidation chemotherapy.
  • Cardiomyopathy: Patients receiving chemotherapy with anthracyclines, such as idarubicin or daunorubicin, are at risk for short-term cardiac-related complications such as arrhythmias and long-term cardiac-related complications such as systolic dysfunction and heart failure. The highest risk of these complications occurs in patients with underlying cardiomyopathy such as congestive heart failure, atrial fibrillation, or other cardiac issues. The cardiotoxicity of anthracyclines is dose-dependent and generally irreversible.
  • Differentiation syndrome: In patients with relapsed or refractory acute myeloid leukemia harboring the IDH2 mutation treated with enasidenib, differentiation syndrome can result. The incidence of differentiation syndrome overall after enasidenib treatment is about 10%, and the incidence of grade 3 or higher differentiation syndrome is 7%. It also occurs in patients with acute promyelocytic leukemia after treatment with all-trans retinoic acid.^[5] This condition is characterized by weight gain, peripheral edema, hypoxia, dyspnea, renal failure, fever, and hypotension. The syndrome is thought to be due to systemic inflammation induced by the release of cytokines from malignant promyelocytes. This results in endothelial cell damage with resultant capillary leakage. Malignant promyelocytes are then able to adhere to tissue that is perfused by the microcirculation.^[5] Patients with a high white blood cell count are at highest risk for differentiation syndrome, since all-trans retinoic acid will result in release of a large amount of cytokines if there is a high leukemia burden. Differentiation syndrome is a major complication that must be recognized early on, such that proper corrective measures can be taken. These include the use of dexamethasone 10mg PO twice daily, plus supportive treatment for any underlying respiratory distress. Diruesis may be needed to help eliminate excess fluid accumulation.
  • QT interval prolongation: In patients with relapsed or refractory acute myeloid leukemia harboring the IDH1 mutation treated with ivosidenib, QT interval prolongation occurs in approximately 8% of patients. In patients with acute promyelocytic leukemia, arsenic trioxide can result in prolonged QT interval, which carries a risk for cardiac-related complications such as arrhythmias. Patients who are treated with arsenic trioxide must have routine electrocardiograms (EKGs) done to ensure that the corrected QT interval remains less than 500 milliseconds. In patients who are treated with concomitant chemotherapy and arsenic trioxide, such as patients with high-risk acute promyelocytic leukemia, there is a higher risk for cardiac-related complications. Chemotherapy and intravenous fluids can alter electrolyte such as potassium levels. Hypokalemia (low potassium) can exacerbate QT prolongation.

The European LeukemiaNet classification from 2017 represents the most recent prognostic scheme for acute myeloid leukemia.^[6] This prognostic scheme is based on cytogenetic and molecular features of the disease. Prognostic categories as determined by European LeukemiaNet 2017 classification include favorable prognosis, intermediate prognosis, and poor prognosis.

Name	Description
Favorable prognosis	Includes: AML with translocations between chromosome 8 and chromosome 21 [t(8;21)] (ICD-O 9896/3); RUNX1/RUNX1T1 AML with inversions in chromosome 16 [inv(16)] (ICD-O 9871/3); CBFB/MYH11 AML with mutant NPM1 and wild-type FLT3 AML with biallelic CEBPalpha mutation
Intermediate prognosis	Includes: AML with mutant NPM1 and mutant FLT3 (FLT3-ITD) AML with wild-type NPM1 and wild-type FLT3 (no FLT3-ITD) AML with translocations between chromosome 9 and chromosome 21 (MLLT3-KMT2A) AML with cytogenetic abnormalities not classified as favorable or adverse
Adverse prognosis	Includes: AML with translocations between chromosome 6 and chromosome 9 AML with inversion of chromosome 3 AML with translocations involving chromosome 11q23 AML with translocations between chromosome 6 and chromosome 9 AML with monosomy 5 or 7 AML with complex karyotype (2 or more cytogenetic abnormalities) AML with mutant RUNX1, mutant ASXL1, or mutant TP53

Acute myeloid leukemia is a curable disease; the chance of cure for a specific patient depends on a number of prognostic factors.^[7] The first publication to address cytogenetics and prognosis was the MRC trial of 1998:^{[8][9][10][11]}

Later, the Southwest Oncology Group and Eastern Cooperative Oncology Group,^[12] and later still, Cancer and Leukemia Group B published other, mostly overlapping lists of cytogenetics prognostication in leukemia^[13]

• Prior to the introduction of readily available diagnostics and targeted therapeutics, the prognosis of acute promyelocytic leukemia was previously very poor, especially in the early phase of the disease.
• The poor prognosis was due to high bleeding risk and death from hemorrhagic complications due to disseminated intravascular coagulation.
• Death typically occurs with a few days to weeks in the absence of treatment.
• The early death rate is estimated to be 17.3%, based on a large population-based analysis conducted in the United Stated between 1992-2007.^{[14] [2]}
• The 5-year survival rate is only 30-40% after 5 years in younger patients.^[5]
• In the current era of medicine (after the introduction of all-trans retinoic acid and arsenic trioxide), the prognosis of acute promyelocytic leukemia carries a much better prognosis.^[3]
• Patients can achieve long-term, durable remission if treated appropriately in an expedited manner with medications such as all-”trans” retinoic acid, arsenic trioxide, or cytotoxic chemotherapy.
• The current overall survival rate is 86-97%, and the complete remission rate is 90-100%.^[5]
• In a multi-center study published in 2017 evaluating long-term outcomes of patients with acute promyelocytic leukemia, the complete remission rate was 96%.^[15]
• Induction mortality is low at 4%.^[15]

• Antecedent myelodysplastic syndrome or myeloproliferative disorder: Acute myeloid leukemia which arises from a pre-existing myelodysplastic syndrome or myeloproliferative disease (so-called secondary AML) has a worse prognosis, as does treatment-related AML arising after chemotherapy for another previous malignancy. Both of these entities are associated with a high rate of unfavorable cytogenetic abnormalities.^[16][17][18] In some studies, age > 60 years and elevated lactate dehydrogenase level were also associated with poorer outcomes.^[19] As with most forms of cancer, performance status (i.e. the general physical condition and activity level of the patient) plays a major role in prognosis as well.
• Therapy-related leukemia: Acute myeloid leukemia which arises after receipt of chemotherapy for another type of cancer has a worse prognosis compared to de novo acute myeloid leukemia.
• Age: Older age portends a worse prognosis for patients with acute myeloid leukemia.

Age group	5-year overall survival[20]
15-24 years old	53%
60-69 years old	13%
70-79 years old	3%
80 years and beyond	0%

• Cure rates in clinical trials have ranged from 20–45%;^[21][22] however, it should be noted that clinical trials often include only younger patients and those able to tolerate aggressive therapies. The overall cure rate for all patients with acute myeloid leukemia (including the elderly and those unable to tolerate aggressive therapy) is likely lower. Cure rates for promyelocytic leukemia can be as high as 98%.^[23]

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