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Flashcards in Acquired Marrow Failure Syndromes Deck (24):
1

What is the definition of bone marrow failure?

  • Bone marrow failure is defined by the inability to make adequate normal blood cells to meet the needs of the body
  • Marrow failure can be acquired, such as in aplastic anemia or due to replacement of the bone marrow by cancerous cells in AML, ALL, or myelodysplastic syndrome, or congenital, such as in Fanconi anemia

2

What is the definition of aplastic anemia and what are the classifications of severity?

  • Aplastic anemia (AA) is a type of bone marrow failure caused by an inappropriate response by the immune system
  • AA is characterized by a hypocellular bone marrow without evidence of an abnormal infiltrative process or fibrosis and pancytopenia or decrease in all blood counts
  • It is classified by the severity of the cytopenias:
    • Moderate AA is defined as decreased bone marrow cellularity and decrease in at least 2 of 3 hematopoietic cell lines, not fulfilling the criteria for severe AA
    • Severe AA is defined by bone marrow cellularity <30% and decrease in at least 2 of 3 hematopoietic cell lines, including absolute neutrophil count <0.5 x 109/L, transfusion dependence with absolute reticulocyte <60 × 109/L, or platelet count <20 × 109/L
    • Very severe AA is defined by an absolute neutrophil count of <0.2 × 109/L
  • There are not typically cytogenetic (chromosome) abnormalities in AA
    • If the patient has an abnormal karyotype a diagnosis of hypocellular myelodysplastic syndrome should be considered

3

What is the epidemiology of aplastic anemia?

  • AA occurs in approximately 2 patients per million persons in the United States
  • The incidence of the disease peaks in children and young adults and then again in patients 60 years and older

4

What is the etiology of primary aplastic anemia?

  • Most cases of acquired AA are idiopathic or have unknown causes
    • They are thought to be due to a T cell mediated autoimmune process
  • In vitro studies have demonstrated that when lymphocytes from AA patients are cultured with normal marrow they can inhibit hematopoiesis
    • Further, expansions of CD8+ T cells have been found in patients with idiopathic aplastic anemia
    • One study reported decreased T-cell receptor zeta chain expression patients with AA, comparable to that seen in other autoimmune diseases
  • Infrequently, aplastic anemia is reported in pregnant patients
  • AA in pregnancy typically resolves spontaneously with delivery

5

What is the etiology of secondary aplastic anemia?

  • AA is a diagnosis of exclusion and you must evaluate for other causes of pancytopenia to determine if this is primary AA or a secondary process
  • Several drugs have been implicated in causing aplastic anemia
    • Commonly reported drugs in AA are:
      • indomethacin
      • chloramphenicol
      • sulfonamides
      • antiepileptics (valproic acid, phenytoin, carbamezapine)
      • nifedipine
    • Aplastic changes are typically reversible with removal of the causative agent
  • Chemicals such as solvents and pesticides (i.e. benzene) have long been associated with aplastic anemia
  • Radiation exposure, whether iatrogenic or accidental, causes AA likely due to direct damage to stem cells
  • While parvovirus B19 most commonly causes isolated pure red cell aplasia due to attacks on proerthyroblasts, it can also cause AA
  • Hepatitis associated AA occurs more commonly in Asia, where higher rates of viral hepatitis are reported
  • However, up to 30% of patients undergoing orthotopic liver transplant for noninfectious fulminant hepatitis will have AA
  • Other commonly reported viruses in secondary AA are EBV, CMV, and HIV
  • Systemic illnesses such as hypothyroidism and anorexia nervosa can also cause pancytopenia
  • Additionally, patients with autoimmune diseases have higher rates of aplastic anemia than the general population, supporting the likelihood of an immune process inhibiting the marrow

6

What is the cell morphology in aplastic anemia?

  • Bone marrow biopsy is the gold standard for evaluating for AA
  • The bone marrow appears hypocellular and mostly absent of hematopoietic cells
  • Typically, only fat cells, fibrous stroma, and scatters or clusters of lymphocytes or plasma cells are present
  • Peripheral blood will have decreased numbers of red cells, platelets, neutrophils and lymphocytes

7

What is the clinical presentation of aplastic anemia?

  • Symptoms are slow in onset
  • Patients experience symptoms and complications related to cytopenias
    • Neutropenia presents as severe or recurrent infections, fevers, chills
    • Anemia causes:
      • fatigue
      • pallor
      • shortness of breath
      • chest pain
      • palpitations
      • dizziness
      • syncope
    • Thrombocytopenia can result in:
      • bruises
      • petechiae
      • bleeding
  • If young age, family history of cytopenias, or abnormal exam findings such as short stature, skeletal or skin abnormalities, consider familial or inherited disorder such as Fanconi anemia or dyskeratosis congenita
    • If concern for Fanconi anemia evaluate with chromosome fragility test
    • If concern for dyskeratosis congenita evaluate with telomere length analysis

8

What is the pathogenesis of aplastic anemia?

  • Pluripotent stem cells are responsible for generating hematopoiesis and lymphopoiesis
    • When stem cell levels are extremely low, they cannot maintain their normal functions of self-renewal and differentiation
  • Inappropriately increased lymphocyte activation inhibits hematopoiesis
    • Interferon-gamma or its stimulation of cytokines may play a role in lymphocyte activation and hematopoiesis inhibition
  • Hematopoietic progenitor cells express the Fas death receptor, which is increased in AA patients
    • Activated T cells produce interferon-gamma and tumor necrosis factor alpha, which may play a role in increasing Fas receptor expression
    • When the ligand or Fas antigen binds the Fas receptor on hematopoietic stem cells this induces apoptosis
    • Fas antigen levels are increased in bone marrow cells of patients with AA
  • Natural killer T cells are decreased in AA, as well as many autoimmune diseases, suggesting they may play a role in regulating the immune system
  • An increase in T helper cells that produce the cytokine IL-17 has been noted in both AA patients and patients with autoimmune diseases
    • These cells have been shown to cause cell-mediated cytotoxicity in autoimmune diseases
  • In addition to immune dysregulation, recent data suggests that there may be acquired genetic mutations in hematopoietic stem cells similar to those seen in congenital disorders
    • Some patients demonstrate mutations in TERC and TERT genes, which encode telomerase, and are more commonly seen in children with dyskeratosis congenita
    • Telomerase dysfunction causes shortened telomeres and cell death

9

What is the treatment of aplastic anemia?

  • Some of these patients spontaneously recover marrow function
  • Severe AA requires treatment to prevent complications of cytopenias
  • For patients < 20 years old allogeneic hematopoietic stem cell transplant from an Human Leukocyte Antigen(HLA)-matched sibling donor is the preferred treatment
  • Because AA is likely an autoimmune based process, the primary treatment for patients who cannot receive a stem cell transplant is antithymocyte globulin (ATG)
    • ATG consists of human T cells injected into a horse or rabbit, leading to production of anti-T cell antibodies that can be harvested and used to treat the autoimmune process
    • In clinical trials horse ATG has produced better hematologic responses and survival outcomes than rabbit ATG
  • Other commonly used immunosuppressive agents include cyclosporine and cyclophosphamide

10

What is myelodysplastic syndrome (MDS)?

  • MDS includes a heterogeneous group of clonal, malignant hematopoietic stem cell disorders that cause dysplastic and ineffective blood cell production and carry a risk of transformation to acute leukemia
  • Diagnostic criteria require dysplastic features in the peripheral blood and ≥10% of bone marrow precursor cells in one or more cell lineages—erythroid, myeloid, or megakaryocytic
    • All patients with MDS must have < 20% blasts in the marrow or blood, otherwise they meet diagnostic criteria for leukemia
  • Patients should also be ruled out for other causes of cytopenias, such as B12, folate or copper definiciency, alcohol abuse, and medication effects

11

What is the epidemiology and etiology of MDS?

  • Approximately 10,000 cases of MDS are diagnosed in the United States annually
  • The median age at diagnosis is > 65 years old. It is unusual to see MDS in a patient < 50 years old
    • If MDS is noted in children, it is most commonly seen in Down Syndrome or congenital disorders such as Fanconi anemia and Shwachman Diamond
  • There are slightly higher rates of MDS in men compared to women, possibly related to historical occupational exposures such as chemicals, in particular benzene
    • However, MDS with deletion of the long arm of chromosome 5 (5q syndrome) is typically seen in women
  • Approximately 85% of MDS cases arise de novo and the etiology is unknown
  • Some patients develop therapy related MDS (t-MDS) after treatment with chemotherapy or radiation for other cancers
    • Chemotherapies that alkylate DNA bases (eg, chlorambucil, cyclophosphamide, melphalan) can cause MDS 5-7 years after treatment
    • Topoisomerase II inhibitors (eg, topotecan, etoposide, anthracyclines) cause MDS within a shorter time frame of 1-3 years
  • There are rare cases of familial MDS, which are associated with germ line mutations in RUNX1, CEBPA, TERC, TERT, and GATA2 genes

12

What is the cell morphology of MDS?

  • The bone marrow is usually hypercellular in MDS
  • Because patients have low peripheral blood counts, this suggests ineffective hematopoiesis in the bone marrow of abnormal cells that undergo apoptosis before reaching the peripheral blood
  • A hypocellular marrow suggestive of hypoplastic MDS can be difficult to distinguish from AA, but cells with dysplasia should be present
  • Red blood cells are larger than their stage of maturation (megaloblastoid) with a large nucleus that is asynchronous with the cytoplasm
    • Red blood cell precursors with mitochondria full of iron are called ringed sideroblasts and will be highlighted by a Prussian blue stain
  • Platelet precursors, megakaryocytes, can be small or large and have hyper or hypolobated nuclei
    • Neutrophil precursors, granulocytes, have dysplasia in the nucleus or have increased immature forms
    • In the peripheral blood RBCs will be normocytic or macrocytic
    • Neutrophils may have hyperlobated nuclei with decreased granulation in the cytoplasm
    • They may have decreased nuclear segmentation, which is called a pseudo Pelger Huet abnormality
    • Platelets are often enlarged and hypogranulated

13

What is the clinical presentation of MDS?

  • Similar to the presentation of AA, patients with MDS have symptoms related to their cytopenias
    • Neutropenia presents as:
      • severe or recurrent infections
      • fevers
      • chills
    • Anemia causes:
      • fatigue
      • pallor
      • shortness of breath
      • chest pain
      • palpitations
      • dizziness
      • syncope
    • Thrombocytopenia can result in:
      • bruises
      • petechiae
      • bleeding
  • Many patients are asymptomatic and concern for MDS arises based on abnormal blood count, in particular macrocytic anemia

14

What is the pathogenesis of MDS?

  • Generally, the pathogenesis of MDS is not understood
    • We hypothesize that acquired mutations occur in hematopoietic stem cells, resulting in clonal production of abnormal, dysplastic cells that produce ineffective hematopoiesis
    • This is supported by the fact that most patients with MDS have chromosome abnormalities, which cause genomic instability
  • In patients with t-MDS after alkylating chemotherapy agents or radiation often have losses of a portion of chromosomes 5 or 7
  • Patients who received topoisomerase inhibitor chemotherapy may have 11q23 translocations, which lead to transcription of a fusion protein involving the mixed-lineage leukemia (MLL) gene
  • We have identified a few mutations that appear to cause specific types of MDS
    • The SF3B1 gene encodes elements of RNA splicing
      • Mutations in SF3B1 have been noted in patients with refractory anemia with ringed sideroblasts and refractory anemia with thrombocytosis
    • Loss of the long arm of chromosome 5 in patients with 5q syndrome leads to haploinsufficiency of the ribosomal protein, RPS14
      • This causes ineffective erythropoiesis, resulting in macrocytic anemia
    • Gene promoter regions in MDS are frequently hypermethylated, which causes them to be silenced
      • This is called epigenetic modulation of DNA when there can be a change in gene expression without directly changing the DNA
    • Mutations in genes TET2, IDH1, and IDH2 have been identified in MDS
      • These genes code for enzymes involved in DNA methylation
  • It is not understood how DNA methylation causes MDS, however patients respond to hypomethylating chemotherapies, suggesting this is an important disease process in MDS

15

What is the prognosis of MDS?

  • Validated prognostic tools, including the International Prognostic Scoring System and the World Health Organization Prognostic Scoring System, account for factors such as:
    • degree of cytopenias
    • cytogenetics
    • marrow blast percentage
  • Provides information regarding survival and risk of transformation to AML
  • Patients can be generally classified as low, intermediate or high risk disease
  • Treatment selection is based on prognostic stage

16

What is acute myeloid leukemia (AML)?

  • AML is a clonal stem cell malignancy in which abnormal immature hematopoietic cells inappropriately survive, replicate, and accumulate in bone marrow, peripheral blood, and sometimes other tissues
  • Because the leukemia cells replace the bone marrow, patients do not have normal cells for active hematopoiesis, leading to:
    • neutropenia
    • anemia
    • thrombocytopenia
    • clinical features of bone marrow failure
  • AML is defined as greater than or equal to 20% clonal blasts (immature white blood cells) in the peripheral blood or bone marrow, except in patients with the following cytogenetic abnormalities, who are classified as having AML irrespective of blast count:
    • t(8;21)(q22;q22)
    • inv(16)(p13q22)
    • t(16;16)(p13;q22)
    • t(15;17)(q22;q12)
  • These and other genetic abnormalities are utilized in the World Health Organization (WHO) classification of AML
  • Immunophenotypic characterization by flow cytometry using cell surface antigens is important to identify AML from another acute leukemia and may include progenitor-associated antigens (eg, human leukocyte antigen-DR [HLA-DR], CD34, CD117) and myeloid antigens (eg, CD13, CD33)

17

What is the epidemiology and etiology of AML?

  • AML is the most common acute leukemia in adults
  • There were approximately 13,000 new AML cases and 9,000 deaths in the United States in 2009
  • The annual incidence increases with age
    • The median age at diagnosis is 67 years
    • Unfortunately, survival rates are poor, with 5-year survival <5% in patients >65 years of age at diagnosis
    • In children, AML is more rare, but overall survival has improved to ~60%
  • Most cases of AML have no known cause
  • Known risk factors include prior exposure to radiation or chemotherapy, particularly topoisomerase II inhibitors and alkylating agents
    • This is thought to cause therapy-related AML (t-AML), and accounts for ~10%-20% of all cases
    • AML can develop 5-10 years after exposure to alkylating agents or radiation and is associated with and unbalanced loss of genetic material involving chromosomes 5 or 7
    • t-AML related to topoisomerase II inhibitors will develop sooner within 1-5 years, and may be associated with balanced recurrent chromosomal translocations involving 11q23 (MLL) or 21q22 (RUNX1)
  • Benzene is considered to be an environmental risk factor for AML
  • Patients with congenital bone marrow failure syndromes (eg, Fanconi anemia, Shwachman-Diamond syndrome), genetic disorders (eg, Down syndrome), and adult MDS and myeloproliferative disorders are also at increased risk of developing AML and do not respond well to standard chemotherapy treatments

18

What is the morphology of AML cells?

  • The bone marrow is often hypercellular in AML due to replacement by clonal blast cells, which are seen in the peripheral blood as well in most patients when diagnosed
  • Myeloblasts are immature cells with large nuclei, prominent nuceloli, and granules in the cytoplasm
    • Sometimes the granules form rods called Auer rods
    • The myeloblasts will stain positive for myeloperoxidase by immunohistochemistry
  • APL blasts contain granules with proteolytic enzymes, when released this causes severe coagulopathy, hemorrhage and thrombosis

19

What is the pathogenesis of AML?

  • AML develops due to several genetic mutations in the hematopoietic stem cell, leading to clonal immature and abnormal cells replicating, but have lost the ability to differentiate into mature cells such as neutrophils
  • There is a “two hit” hypothesis for AML based on the idea of two mutations
    • The first or class I mutations such as FLT3-ITD, KRAS, and KIT drive cell proliferation
    • The second or class II mutation, such as CEBPA or IDH, impair the cell’s ability to differentiate or mature into functional cells
  • Drugs are being developed to inhibit FLT3-ITD and IDH gene mutations
  • The most common chromosome rearrangements t(8;21) and inv(16) involve core binding factor genes that leads to abnormal transcription, leading to hematopoietic failure
    • t(15;17) drives acute promyelocytic leukemia by creating a fusion gene between the transcription factor, retinoid acid receptor alpha, and the promyelocytic leukemia protein
    • This suppresses differentiation of the cells
    • The vitamin A derivative all trans retinoid acid overcomes this and allows maturation of cells, resuming normal hematopoiesis
  • Arsenic trioxide also appears to degrade the PML-RARA fusion
  • The bone marrow microenvironment through CXCR4 signaling is thought to interact with and protect the AML cells

20

What is acute lymphoblastic leukemia/lymphoma (ALL)?

  • ALL is an aggressive clonal malignancy of lymphoid hematopoietic stem cells
    • ALL can arise from either B or T lineage lymphocyte precursor cells
  • Flow cytometry of the blood or peripheral blood can help differentiate between the two lineages:
    • B cell surface markers include CD19, CD22, CD20 and CD79a
    • T cell markers include CD7, CD3, CD5, CD2, CD1a, CD4 and/or CD8.

21

What is the epidemiology and etiology of ALL?

  • ALL is the most common leukemia in children (representing 23% of all cancer diagnoses and 76% of leukemias among children <15 years of age) but accounts for only 20% of adult acute leukemia
    • This may be due to the fact that the number of normal bone marrow pre-B lymphoblasts (the cell of origin) peaks in childhood
  • T ALL occurs in adolescence when the thymus reaches its maximum size
    • Incidence is higher in men and Hispanics

22

What is the clinical presentation of ALL?

  • Patients can present with symptoms from their cytopenias when the ALL involves the bone marrow and is a leukemia
  • ALL can also involve the lymph nodes, commonly the mediastinum, and is then referred to as acute lymphoblastic lymphoma
    • Patients may also develop:
      • palpable lymph nodes or chest pain
      • facial swelling due to SVC compression
      • difficulty swallowing due to a mediastinal mass
  • T ALL often presents as a young man with a mediastinal mass

23

What is the morphology of cells in ALL?

  • On peripheral blood smears, lymphoblasts vary from
    • small cells with scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli
    • larger cells with moderate amounts of cytoplasm, dispersed chromatin, and multiple nucleoli
  • Unlike AML, granules are rare and there are never Auer rods
  • Immunohistochemistry will stain positive for terminal deoxynucleotidyltransferase (TDT), as special DNA polymerase found on B and T lymphoblasts

24

What is the pathogenesis of ALL?

  • Like AML, ALL is thought to be caused by a series of acquired genetic mutations
  • Hyperdiploidy (> 50 chromosomes) is common in children and associated with a favorable prognosis
  • In B ALL the t(9;22) or Philadelphia chromosome is present in 50% of adult patients and leads to the fusion of 2 genes and the creation of the the BCR/ABL1 protein
    • This causes activation and proliferation of the leukemia cell
    • This mutation can be targeted with tyrosine kinase inhibitors such as dasatinib, which are also used in CML
  • Chromosome 11q23 abnormalities can also occur and cause mutations in the mixed lineage leukemia (MLL) gene, leading to increased cell survival and proliferation
  • The t(12;21) is common in childhood B ALL and fuses the ETV6 (TEL) gene with the RUNX1/AML1 gene, resulting in the production of a fusion protein that drive the production of dysfunctional cells
  • Recently more gene mutations have been identified in ABL, JAK, CRLF2, and PDGFR
  • Clinical trials are underway to use new drugs to target these gene mutations