Acute Myeloid Leukemia




Abstract


Acute myeloid leukemia (AML) accounts for approximately 20% of childhood leukemia, yet is responsible for a majority of the deaths from leukemia. Children present with a wide range of signs and symptoms, ranging from anemia to life-threatening coagulopathy, complications from tumor lysis syndrome or leukemic infiltration. Patients with AML are at an increased risk of infection and should receive prophylactic antimicrobials. Cytarabine, daunorubicin, and etoposide remain the backbone of AML therapy. Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) are utilized for relapsed/refractory AML. Hematopoietic stem cell transplantation is recommended for high-risk and relapsed patients. Therapies targeting novel molecular and cytogenetic markers are under investigation. Acute promyelocytic leukemia, a unique subtype of AML, is treated with all-trans retinoic acid and arsenic trioxide, with very good response. Myeloid leukemia in Down syndrome is another unique subtype of AML; patients typically have a GATA1 mutation and have an excellent response to reduced intensity regimens. Methods with increased sensitivities are being utilized for the detection of occult disease below the level of morphologic detection, referred to as minimal residual disease (MRD). Treatment protocols utilize MRD to assess response to therapy and guide future therapy.




Keywords

Acute myeloid leukemia, acute promyelocytic leukemia, AML, APML, FLT-3, GATA-1, minimal residual disease, MRD, myeloid malignancy

 


Acute myelogenous leukemia (AML) is characterized by the abnormal proliferation and differentiation of myeloid precursors in the bone marrow. While the etiology of primary AML is unknown, certain predisposing factors can lead to secondary AML as discussed below. While AML is the less common of the two acute leukemias of childhood, it is responsible for most acute leukemia deaths.




Incidence and Epidemiology





  • Leukemia accounts for 25–30% of all childhood cancers.



  • AML accounts for 20% of childhood leukemia.



  • Incidence: 500 new cases of childhood AML in the United States per year.



  • Age distribution: Peaks in neonatal period and during adolescence.





Etiology and Predisposing Conditions


Development of AML is thought to follow a multihit hypothesis. An initial oncogenic mutation creates a “preleukemic” cell that eventually develops into a leukemic cell via a second promotional mutation. Genetic and molecular mutations resulting in AML are classified as Class I and Class II mutations as listed in Table 19.1 .



Table 19.1

Categories of Genetic and Molecular Mutations Resulting in Acute Myeloid Leukemia
















Mechanism Examples
Class I mutations Proliferative and/or survival advantage to cells, without altering cellular differentiation RAS, FLT-3, KIT, CBL
Class II mutations Impair differentiation and dysregulate apoptosis RUNX1, MLL, PML/RARA

MLL , mixed lineage leukemia.


Table 19.2 lists the predisposing conditions associated with an increased risk of developing AML.




  • Fanconi anemia: Patients have a 50% risk of developing AML. They have increased toxicity from chemotherapy, necessitating protocol modifications.



  • Severe congenital neutropenia: Patients have a 21% risk of developing AML, most often preceded by a mutation in the granulocyte colony-stimulating factor receptor gene. Partial or total loss of chromosome 7 occurs in half of the patients.



  • Shwachman–Diamond syndrome (SDS): Patients have a 30% risk of developing AML associated with abnormalities of chromosome 7.



Table 19.2

Conditions Predisposing to Acute Myeloid Leukemia












Inherited conditions Acquired conditions Environmental exposures



  • Down syndrome



  • Fanconi anemia



  • Severe congenital neutropenia



  • Diamond–Blackfan anemia



  • Dyskeratosis congenital



  • Neurofibromatosis-1



  • Bloom syndrome



  • Shwachman–Diamond syndrome



  • Li–Fraumeni syndrome



  • Ataxia telangiectasia



  • Twinning




  • Aplastic anemia



  • Myelodysplastic syndrome



  • Myeloproliferative syndrome



  • Acquired amegakaryocytic thrombocytopenia



  • Paroxysmal nocturnal hemoglobinuria




  • Ionizing radiation



  • Alkylating chemotherapeutic agents



  • Epidophyllotoxin chemotherapeutic agents



Therapy-related myelodysplastic syndrome and therapy-related AML (t-AML) typically present within 3–5 years after treatment but cases up to 10 years or more have been described. Patients with t-AML tend to have a worse prognosis than patients with de novo disease with identical cytogenetics. t-AML related to topoisomerase II inhibitors have a short latency (6–36 months).




  • Epipodophyllotoxins: Exposure typically results in French–American–British (FAB) M4 or M5 AML and often involves a mixed lineage leukemia ( MLL ) gene rearrangement (11q.23).



  • Anthracyclines: Often involves an MLL gene rearrangement.



  • Alkylating agents: Often results in AML with poor-risk cytogenetics.



Twin concordance




  • Concordance studies on identical twins show that an identical twin is twice as likely as the general population to develop leukemia if his/her twin developed leukemia before age 7.



  • If the affected identical twin was diagnosed as an infant, the concordance rate is nearly 100%.



  • Analysis of unique genomic fusion gene sequences of the leukemias suggests a common clonal origin.





Clinical Features


See Chapter 18 on ALL for some of the common clinical features that may occur in all cases of acute leukemia.


Children with AML may present with a wide range of signs and symptoms, ranging from fever, anemia, or thrombocytopenia to life-threatening coagulopathy or complications from extramedullary disease (EMD) resulting in organ dysfunction.


EMD consists of a collection of myeloblasts or immature myeloid cells outside of the bone marrow. It is seen in approximately 10–20% of patients with AML. It can occur as a myeloid sarcoma (MS), previously referred to as a chloroma, or as the presence of leukemic cells in the cerebrospinal fluid (CSF). The most common presentations are gingival hypertrophy, lymphadenopathy, and leukemia cutis. MS is also seen within the central nervous system (CNS) and the orbit, periorbital areas, and paraspinal areas. EMD typically occurs concurrently with AML but occasionally may present as the first manifestation, even before bone marrow involvement. Even in the absence of bone marrow involvement EMD should be treated using an AML protocol. EMD has been associated with t(8;21), inv(16), and 11q23 MLL rearrangements. CNS disease is associated with a high white blood cell (WBC) and is more often seen with M4 and M5 AML.




Diagnosis


Laboratory Studies


Blood count and bone marrow





  • Leukocytosis: Median WBC count at diagnosis is 20,000/mm 3 .



  • Approximately 20% of patients present with WBC count above 100,000/mm 3 .



  • Auer rods, needle-shaped intracytoplasmic azurophilic inclusion bodies are often, but not always seen in AML, particularly in M2 or M3 AML.



  • Anemia: Hemoglobin <9 g/dl in 50% of patients.



  • Thrombocytopenia: Platelets <100,000/mm 3 in 75% of patients.



  • The WHO classification of AML defines that 20% blasts are required for the diagnosis of AML, patients with clonal cytogenetic abnormalities including t(8;21) (q22;q22), inv(16) (p13;q22) or t(16;16) (p13;q22) and t(15;17) (q22;q12) are considered to have AML regardless of the blast percentage.



  • Special bone marrow studies, which help in detailed cell classification, include: histochemistry, immunophenotying, and cytogenetics.



The morphologic features of myeloblasts and the cytochemical features of AML are shown in Tables 19.3 and 18.3 (see previous chapter), respectively.



Table 19.3

Morphologic Characteristics of Lymphoblasts and Myeloblasts




















































Characteristic Lymphoblasts Myeloblasts
Size 10–20 mm 14–20 mm
NUCLEUS
Shape Round or oval Round or oval
Chromatin Smooth, homogeneous Spongy, loose, finely developed meshwork
Nucleoli 0–2 and indistinct 2–5 and distinct “punched-out”
Nuclear membrane Smooth, round Irregular
Nuclear–cytoplasmic ratio High Low
CYTOPLASM
Color Blue Blue-gray
Amount Thin rim More abundant
Granules Absent Present
Auer rods Absent Present


Cerebrospinal fluid (CSF) : The diagnosis of CSF leukemia is the same as described for ALL (see Chapter 18 ).


CNS involvement at diagnosis and at relapse is seen in 5–10% of pediatric AML patients. See Table 19.4 for factors associated with CNS leukemia. Unlike acute lymphoblastic leukemia (ALL), CNS disease in AML is not a factor within the AML risk group stratification because it does not affect overall survival (OS), although those with CNS disease have an increased incidence of isolated CNS relapse. Intrathecal (IT) chemotherapy is given to all patients, including those without any detectable CNS involvement. Patients with CNS involvement at diagnosis receive additional intensified IT chemotherapy consisting of weekly IT chemotherapy until blasts clear from the CSF and monthly thereafter until the end of therapy.



Table 19.4

Factors Associated with Central Nervous System Disease











Hyperleukocytosis
Monocytic leukemia (FAB M4 or M5, including M4eo with inv(16))
MLL rearrangement
Younger age (<2 years)

FAB, French–American–British; MLL , mixed lineage leukemia.


Coagulation profile : Decreased coagulation factors that frequently occur are hypofibrinogenemia, decreased levels of factors V, IX, and X.


Monitor for tumor lysis syndrome: The extent of electrolyte disturbances and degree of tumor lysis varies depending on the leukemic burden and rate of cell turnover. Tumor lysis syndrome occurs less frequently in AML than in ALL, and is more often seen in FAB M4 or M5 AML than other subtypes. Complete metabolic panel, including lactic dehydrogenase and uric acid should be sent at diagnosis (see Chapter 32 ).


Cardiac function assessment: Electrocardiogram and echocardiogram should be performed at baseline and with each cycle of chemotherapy to monitor for cardiotoxicity.


Infectious disease evaluation: Patients often present with fever, thought to be due to pyrogens released by leukemic cells and as an inflammatory response. Blood cultures should be drawn and antibiotics initiated (see Chapter 33 for details). Viral studies should be sent including: varicella antibody titer, cytomegalovirus antibody titer, herpes simplex antibody, and hepatitis antibody screening at baseline.




Classification of AML


Acute leukemia can be classified based on morphologic characteristics, cytochemical features, immunologic characteristics, and cytogenetic and molecular characteristics. Table 19.5 lists the WHO classification of acute myeloid leukemia and related neoplasms.



Table 19.5

WHO Classification of Myeloid Neoplasms and Acute Leukemia







ACUTE MYELOID LEUKEMIA AND RELATED NEOPLASMS


  • 1.

    Acute myeloid leukemia with recurrent genetic abnormalities



    • a.

      AML with t(8;21)(q22;q22); RUNX1-RUNX1T1


    • b.

      AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11


    • c.

      APL with t(15;17)(q22;q12); PML-RARA


    • d.

      AML with t(9;11)(p22;q23); MLLT3-MLL


    • e.

      AML with t(6;9)(p23;q34); DEK-NUP214


    • f.

      AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1


    • g.

      AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1


    • h.

      Provisional entity: AML with mutated NPM1


    • i.

      Provisional entity: AML with mutated CEBPa



  • 2.

    Acute myeloid leukemia with myelodysplasia-related changes


  • 3.

    Therapy-related myeloid neoplasms


  • 4.

    Acute myeloid leukemia, not otherwise specified



    • a.

      AML with minimal differentiation


    • b.

      AML without maturation


    • c.

      AML with maturation


    • d.

      Acute myelomonocytic leukemia


    • e.

      Acute monoblastic/monocytic leukemia


    • f.

      Acute erythroid leukemia



      • i.

        Pure erythroid leukemia


      • ii.

        Erythroleukemia, erythroid/myeloid



    • g.

      Acute megakaryoblastic leukemia


    • h.

      Acute basophilic leukemia


    • i.

      Acute panmyelosis with myelofibrosis



  • 5.

    Myeloid sarcoma


  • 6.

    Myeloid proliferations related to Down syndrome



    • a.

      Transient abnormal myelopoiesis


    • b.

      Myeloid leukemia associated with Down syndrome



  • 7.

    Blastic plasmacytoid dendritic cell neoplasm




Table 19.6 lists the FAB classification of AML.



Table 19.6

French–American–British Classification of Acute Myeloid Leukemia







  • 1.

    Type M0 —acute undifferentiated leukemia


  • 2.

    Type M1— myeloblastic leukemia without maturation; morphologically indistinguishable from L2 morphology


  • 3.

    Type M2— myeloblastic leukemia with differentiation


  • 4.

    Type M3— acute promyelocytic leukemia; most cells abnormal hypergranular promyelocytes; cytoplasm contains multiple auer rods


  • 5.

    Type M3V— microgranular variant of acute promyelocytic leukemia; cells with deeply notched nucleus; typical hypergranular promyelocytes less frequent


  • 6.

    Type M4— both myelocytic and monocytic differentiation present in varying proportions


  • 7.

    Type M4EOS— associated with prominent proliferation of eosinophils


  • 8.

    Type M5— monocytic leukemia containing poorly differentiated and/or well-differentiated monocytoid cells (the M4 and M5 subtypes are particularly common in children under 2 years of age)


  • 9.

    Type M6— erytholeukemia (Di Guglielmo disease)


  • 10.

    Type M7— megakaryoblastic leukemia; associated with myelofibrosis; frequently observed in children with trisomy 21. M7 leukemia has the following characteristics:



    • a.

      The blast morphology is heterogeneous in appearance, resembling L1 or L2 cells with or without granules and having one to three nucleoli; the cytoplasm has blebs


    • b.

      Immunophenotype is CD41-, CD42-, CD61-positive—in addition to CD13 and CD33 positivity


    • c.

      Electron microscopy demonstrates positive platelet peroxidase reaction localized exclusively on the nuclear membrane and the endoplasmic reticulum




FAB M5 and M7 are more common in early childhood, while older children are more likely to have FAB M 0 , M 1 , M 2 , and M 3 . AML in patients with Down syndrome (DS) is frequently associated with FAB M7 (megakaryoblastic leukemia).


Table 19.7 shows the WHO classification of acute leukemias of ambiguous lineage which are discussed below.



Table 19.7

2008 WHO Classification: Acute Leukemias of Ambiguous Lineage
















Lineage Marker
Myeloid


  • Myeloperoxidase OR



  • Monocytic differentiation (at least two of the following):




    • NSE



    • CD11c



    • CD14



    • CD64



    • Lysozyme


T lineage


  • Cytoplasmic CD3 OR



  • Surface CD3

B lineage


  • Strong CD19 AND



  • At least two of the following with strong expression of




    • CD79a



    • Cytoplasmic CD22



    • CD10 OR




  • Weak CD19 AND



  • At least two of the following with strong expression of




    • CD79a



    • Cytoplasmic CD22 OR



    • CD10



NSE, Non-specific esterase.


The quantitative bone marrow criteria for the diagnosis of acute myeloblastic leukemia are summarized in Table 19.8 .



Table 19.8

Quantitative Bone Marrow Criteria for the Diagnosis of Acute Myeloblastic Leukemia Subtypes a

















































Bone marrow cells M1 (%) M2 (%) M4 (%) M5 (%) M6 (%)
BLASTS
All nucleated cells >30 >30 <30 or >30
Nonerythroid cells 90 >30 >30 >80 b >30
Erythroblasts<all nucleated cells <50 <50 >50
Granulocytic component c <nonerythroid cells <10 >10 >20 d <20 Variable
Monocytic component e <nonerythroid cells <10 <20 >20 >80 b Variable

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Jul 3, 2019 | Posted by in HEMATOLOGY | Comments Off on Acute Myeloid Leukemia

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