Acquired and Inherited BMFS

Question 1

Syndromes associated with AA

Answer 1

Schwann diamond (pancreatic insuff)
Fanconi anaemia (short, pigmentation, radial Ray)
Dyskeratosis congenita (nails, leukoplakia, skin pigmentation)
TAR
DIamond Blackfan
(RSP19 gene)
Congenital amegakaryocytic thrombocytopenia
(MPL gene mutation)

Question 2

AA cytogenetic abnormality

Answer 2

Del 13q
Trisomy 8
Monosomy 7

Question 3

The diagnosis of Aplastic Anemia usually requires the presence of pancytopenia defined as:

Neutrophil count:
Platelet count:
Hemoglobin:
Absolute Reticulocyte count:

accompanied by a hypocellular marrow without abnormal or malignant cells or fibrosis

Answer 3

Neutrophil count: fewer than 1.5 × 109/L
Platelet count: fewer than 50 × 109/L
Hemoglobin: less than 100 g/L
Absolute Reticulocyte count: fewer than 40 × 109/L

Question 4

Degree of Severity of Acquired Aplastic Anemia

Moderately severe:
Severe:
Very severe:

Answer 4

Moderately severe: Hgb <100 g/L ARC <40.0 × 109/L NC <1.5 × 109/L PC <50.0 × 109/L

Severe: Hgb <90 g/L ARC <30.0 × 109/L NC <0.5 × 109/L PC <30.0 × 109/L

Very severe: Hgb <80 g/L ARC <20.0 × 109/L NC <0.2 × 109/L PC <20.0 × 109/L

Moderately severe: At the time of diagnosis at least 2 of 3 blood counts should meet these criteria

Question 5

The highest frequency of aplastic anemia occurs in persons between the ages of_______years; a second peak occurs between the ages of ________years.

Answer 5

15 and 25 years

65 and 69 years

Question 6

The male-to-female incidence ratio of aplastic anemia in most studies is approximately

Answer 6

One

Question 7

Toxins that cause AA

Answer 7

• Benzene
• Chlorinated hydrocarbons
• Organophosphates

Question 8

Viruses that cause AA

Answer 8

• Epstein-Barr virus
• Non-A, -B, -C, -D, -E, or -G hepatitis virus
• HIV

Question 9

Inherited Causes of AA

Answer 9

• Fanconi anemia
• Dyskeratosis congenita
• Shwachman-Diamond syndrome
• Other rare syndromes

Question 10

The final common pathway to the clinical disease is

Answer 10

A decrease in blood cell formation in the marrow

Question 11

Reduced hematopoiesis in most cases of aplastic anemia results from

Answer 11

Cytotoxic T-cell–mediated immune suppression of very early CD34+ hematopoietic multipotential progenitor or stem cells

Question 12

A relationship between acquired aplastic anemia and hereditary aplastic anemia (FA or dyskeratosis congenita) has been suggested because of the defects in _______________________

Answer 12

Telomerase and telomere repair

Question 13

The most notorious drug documented to cause aplastic anemia

Answer 13

Chloramphenicol

The occurrence of aplastic anemia appears to be idiosyncratic, perhaps related to an inherited sensitivity to the nitroso-containing toxic intermediates.

Question 14

Anti-malarial with evidence that it cause AA

Answer 14

Quinacrine (Atabrine)

The aplasia occurred during administration of the offending agent and was preceded by a characteristic rash in nearly half the cases

Question 15

Causes AA because there is delayed oxidation and clearance of a related compound, acetanilide

Answer 15

Phenylbutazone

Question 16

A histamine H2-receptor antagonist, is occasionally implicated in the onset of cytopenias and aplastic anemia, perhaps owing to a direct effect on early hematopoietic progenitor cells

Answer 16

Cimetidine

There is drug interactions or synergy with: carmustine and chloramphenicol

Question 17

Drugs Associated with Aplastic Anemia - High Risk

Answer 17

Antineoplastic drugs:
Alkylating agent
Antimetabolite
Cytotoxic antibiotic

Question 18

Was the first chemical linked to aplastic anemia, based on studies in factory workers before the 20th century

Answer 18

Benzene

Question 19

An uncommon connective tissue disorder with painful swelling and induration of the skin and subcutaneous tissue, has been associated with aplastic anemia

Has been largely unresponsive to therapy

Answer 19

Eosinophilic fasciitis

Question 20

Total-body exposure to radiation between _______Gy leads to gastrointestinal symptoms and depression of leukocyte counts, but most patients recover.

Answer 20

1 and 2.5 Gy

Question 21

Although unusual, severe marrow aplasia can follow use of the alkylating agent,________, and may persist indefinitely.

Answer 21

Busulfan

Marrow aplasia may develop in patients 2–5 years after discontinuation of alkylating agent therapy.

These cases often evolve into hypoplastic myelodysplastic syndromes.

Question 22

A rare exception to the negligible pathogenetic role of hematopoietic growth factors in the etiology of aplastic anemia is the homozygous or mixed heterozygous mutation of the TPO receptor gene, MPL, which can cause

Answer 22

Amegakaryocytic thrombocytopenia

Evolves later into aplastic anemia

Eltrombopag, a TPO receptor agonist, can stimulate mono- or, in some patients, bilineage or trilineage recovery of blood counts that may be sustained off therapy

Question 23

TRUE OR FALSE

Lymphadenopathy and splenomegaly are not features of aplastic anemia; such findings suggest an alternative diagnosis such as a clonal myeloid or lymphoid disease.

Answer 23

TRUE

Lymphadenopathy and splenomegaly are not features of aplastic anemia; such findings suggest an alternative diagnosis such as a clonal myeloid or lymphoid disease.

Question 24

TRUE OR FALSE

Significant qualitative changes of red cell, leukocyte, or platelet morphology on the blood film are features of classical acquired aplastic anemia.

Answer 24

FALSE

Significant qualitative changes of red cell, leukocyte, or platelet morphology on the blood film are not features of classical acquired aplastic anemia.

Question 25

# TRUE OR FALSE The plasma contains high levels of hematopoietic growth factors, including EPO, TPO, and myeloid colony-stimulating factors.

Answer 25

TRUE The plasma contains **high** levels of hematopoietic growth factors, including EPO, TPO, and myeloid colony-stimulating factors. ## Footnote Other findings: * Macrocytes may be present in the blood film and the mean cell volume increased. * Platelets function normally. * Occasionally only one cell line is depressed initially

Question 26

# TRUE OR FALSE Plasma iron values are usually high, and Fe clearance is prolonged, with decreased incorporation into red cells.

Answer 26

TRUE Plasma **iron** values are usually **high**, and **Fe clearance** is **prolonged**, with decreased incorporation into red cells.

Question 27

Marrow Findings in Aplastic anemia

Answer 27

Numerous spicules with empty, fat-filled spaces, and relatively few hematopoietic cells

Question 28

Refers to spicules that are cellular or even hypercellular

Answer 28

“hot spots” ## Footnote These focal areas of residual hematopoiesis *do not appear to be of prognostic significance.*

Question 29

Cytogenetic analysis in aplastic anemia is

Answer 29

Normal ## Footnote **Clonal cytogenetic abnormalities** in otherwise apparent aplastic anemia is indicative of an underlying **hypoplastic clonal myeloid disease.**

Question 30

Imaging that can be used to **distinguish between marrow fat and hematopoietic cells**

Answer 30

Magnetic resonance imaging ## Footnote Magnetic resonance imaging studies of bone may be useful in differentiating severe aplastic anemia from clonal myeloid syndromes. The former gives a fatty signal and the latter a diffuse cellular pattern.

Question 31

A reticulocyte percentage of less than ______% is strongly indicative of aplastic erythropoiesis and, when coupled with leukopenia and thrombocytopenia, points to aplastic anemia.

Answer 31

0.5%

Question 32

As many as_____ of patients with otherwise typical aplastic anemia have evidence of **glycosylphosphatidylinositol molecule defects and diminished phosphatidylinositol-anchored protein** on leukocytes and red cells as judged by flow cytometry, analogous to that seen in PNH.

Answer 32

50%

Question 33

As many as____% of patients with aplastic anemia have a five-year probability of myelodysplasia developing.

Answer 33

20%

Question 34

Mutations that are increased in prevelance with patient age

Answer 34

ASXL1 and DNMT3A

Question 35

Mutations that were of similar frequency in all age groups

Answer 35

BCOR, BCORL1, and PIGA

Question 36

Three principal options: for treatment in AA

Answer 36

(1) syngeneic or allogeneic hematopoietic cell transplantation (2) combination immunosuppressive therapy with ATG and cyclosporine, and (3) eltrombopag

Question 37

# TRUE OR FALSE In general, transplantation is the preferred treatment for children and most otherwise healthy younger adults.

Answer 37

TRUE In general, **transplantation** is the preferred treatment for children and most otherwise healthy younger adults.

Question 38

The preferred stem cell source

Answer 38

A histocompatible sibling matched at the HLA-A, -B, -C, and -DR loci ## Footnote An allele-level HLA-matched unrelated donor can be used in younger patients

Question 39

# TRUE OR FALSE Red cell and platelet transfusions be used sparingly in potential transplant recipients to minimize sensitization to histocompatibility antigen

Answer 39

TRUE Red cell and platelet transfusions be used sparingly in potential transplant recipients to minimize sensitization to histocompatibility antigen

Question 40

Packed red cells to alleviate symptoms of anemia usually are indicated at hemoglobin values:

Answer 40

Below 80 g/L

Question 41

# TRUE OR FALSE It is important to transfuse patients with red cells (or platelets) from family members if transplantation within the family is possible

Answer 41

FALSE It is important **not to transfuse** patients with red cells (or platelets) **from family members** if transplantation within the family is remotely possible ## Footnote Because this approach may **sensitize patients to minor histocompatibility antigens**, increasing the risk of graft rejection after hematopoietic cell transplantation.

Question 42

Preferred platelet unit for previously pregnant or transfused patients who are already **allosensitized** or who become so after treatment with leukoreduced platelets

Answer 42

Single-donor HLA-matched apheresis-harvested platelets

Question 43

The major curative approach in AA

Answer 43

Hematopoietic Cell Transplantation ## Footnote The results of transplantation are best in patients **younger than age 20 years (80%–90% long-term survival)** but decrease every decade of increasing age thereafter. Optimal with **HLA-matched sibling** transplantation.

Question 44

# TRUE OR FALSE Marrow stem cells perform better than blood stem cells when used as a source for patients with aplastic anemia, although this is under continued study.

Answer 44

TRUE **Marrow stem cells** perform **better** than blood stem cells when used as a source for patients with aplastic anemia, although this is under continued study.

Question 45

In patients older than age 40 years, survival in matched-sibling transplant is reduced to approximately________%.

Answer 45

50%

Question 46

Regimen that appear to improve outcome by **decreasing the frequency of chronic graft-versus-host disease**, which could make it useful in treating **older** patients.

Answer 46

Alemtuzumab-containing regimens

Question 47

If there is an HLA mismatch at one or more loci, especially _____or ____, the outcome is compromised,and immunosuppression with combined therapy may be preferred initially

Answer 47

HLA-A or -DRB1

Question 48

Act principally by **reducing cytotoxic T cells** **Release hematopoietic growth factors** from T cells

Answer 48

Antilymphocyte and Antithymocyte Globulin

Question 49

# TRUE OR FALSE Rabit ATG is superior to equine and, if available, is recommended as the first line of therapy

Answer 49

FALSE **Equine** ATG is superior to rabbit and, if available, is recommended as the first line of therapy

Question 50

# TRUE OR FALSE ATG treatment may accelerate platelet destruction, reduce the absolute neutrophil count, and cause a positive direct antiglobulin (Coombs’) test.

Answer 50

TRUE ATG treatment may accelerate **platelet destruction, reduce the absolute neutrophil count**, and cause a **positive direct antiglobulin (Coombs’) test**.

Question 51

Characterized by spiking fevers, skin rashes, and arthralgia, commonly occurs **7–10 days** from the first dose

Answer 51

Serum sickness

Question 52

Management of Serum sickness

Answer 52

* Glucocorticoid (eg, prednisone 1 mg/kg) from day one of ATG treatment and for two weeks thereafter * Fever, rigors, rash, hypotention, and hypoxia can be minimized by administration of acetaminophen and diphenhydramine before each dose of ATG. * Supplementation with intravenous hydration for hypotension and oxygen administration for hypoxia. * In cases of severe reactions, the administration of ATG can be slowed or temporarily discontinued until improvement occurs, and then reinstituted at a slower rate of infusion if necessary.

Question 53

Approximately _______of patients no longer require transfusion support after treatment with ATG alone.

Answer 53

One-third

Question 54

A cyclic polypeptide that **inhibits IL-2 production** by T lymphocytes and prevents expansion of cytotoxic T cells in response to IL-2

Answer 54

Cyclosporine

Question 55

Initial dose of Cyclosporine

Answer 55

**10–12 mg/kg per day **for at least** 6 months** and with downward dose modification after six months for as long as **12 months**. ## Footnote Responses usually are seen by **three months** and may range from achieving transfusion independence to complete remission

Question 56

Trough blood levels of Cyclosporine

Answer 56

200–400 ng/mL

Question 57

A **TPO receptor agonist** used to stimulate platelet production in patients with immune thrombocytopenia May **expand stem cell numbers** and **promote DNA repair**

Answer 57

Eltrombopag ## Footnote **Multilineage hematopoietic response** occurred, leading to restoration of granulopoiesis, erythropoiesis, and megakaryocytopoiesis with a subsequent increase in neutrophil, erythrocyte, and platelet counts, sometimes to normal levels **MPL receptors** are present on hematopoietic stem cells A **higher dose of eltrombopag (150 mg/day)** and **longer treatment (at least 24 weeks)** increases the likelihood of response

Question 58

Combination Immunotherapy

Answer 58

* ATG (40 mg/kg per day) for 4 day * Cyclosporine (6 mg/kg per day in divided doses every 12 hours) for 6 months * Methylprednisolone (1 mg/kg per day) for 2 weeks * Eltrombopag is given at 150 mg from day 1 for 6 months

Question 59

# TRUE OR FALSE G-CSF added to the combined immunosuppressive therapy does not increase response rate or survival.

Answer 59

TRUE G-CSF added to the combined immunosuppressive therapy does not increase response rate or survival.

Question 60

A monoclonal **anti-CD52** antibody that targets that antigen on T lymphocytes, has been an effective immunosuppressive agent in both **relapsed and refractory patients**

Answer 60

Alemtuzumab

Question 61

An alternative thrombopoietin receptor agonist that is a **larger** molecule than eltrombopag and requires **parenteral** administration It binds to the thrombopoietin receptor site, **cMPL**

Answer 61

Romiplostim

Question 62

Alemtuzumab produces profound and persistent___________.

Answer 62

Lymphopenia

Question 63

Stimulate the **production of EPO**, and their metabolites stimulate erythropoiesis when added to marrow cultures in vitro. May be useful in the treatment of aplastic anemia syndromes resulting from **shortened telomeres**.

Answer 63

Androgens

Question 64

Therapy with myeloid growth factors is probably best reserved for

Answer 64

Episodes of severe infection As a preventive measure before dental work or other procedures that would compromise mucosal barriers in patients who have not responded to hematopoietic cell transplant or immunotherapy ## Footnote * Generally, prophylactic use of growth factors is not warranted.

Question 65

# TRUE OR FALSE Prophylactic use of growth factors is warranted.

Answer 65

FALSE Prophylactic use of growth factors is not warranted.

Question 66

The most important prognostic feature

Answer 66

Absolute neutrophil count

Question 67

Hematopoietic cell transplantation is curative for approximately: Patients younger than 20 years of age: Between the ages of 20 and 40 years: Older than age 40 years:

Answer 67

Patients younger than 20 years of age: 80%–90% Between the ages of 20 and 40 years: 70% Older than age 40 years 50%

Question 68

The best outcomes occur in patients who have:

Answer 68

* Allele-based HLA-matched sibling * Have not been exposed to immunosuppressive therapy before transplantation * Have not been exposed and sensitized to blood cell products * Have had a marrow rather than a blood stem cell donor product, and * Have not been subjected to high-dose radiation in the conditioning regimen for transplantation

Question 69

Predictive of a better response to therapy

Answer 69

* Higher initial absolute reticulocyte and lymphocyte counts * High proportion of Treg B cells

Question 70

AD Rare Inherited Syndromes Associated with Aplastic Anemia

Answer 70

* Ataxia-pancytopenia (myelocerebellar disorder) * WT syndrome ## Footnote The rest autosomal recessive

Question 71

The most common form of constitutional aplastic anemia The great majority of patients have mutations of FANCA, FANCC, or FANCG

Answer 71

Fanconi anemia (FA)

Question 72

First step in understanding the genetic basis of FA

Answer 72

Diepoxybutane test ## Footnote In this test, diepoxybutane results in **chromosome fragmentation** in the cells of patients with FA.

Question 73

Hereditary cause of AA: pancreatic insufficiency, steatorrhea

Answer 73

Schwaman Diamond Syndrome

Question 74

Approximately 5% of patients with FA exhibit the _____________ phenotype

Answer 74

VACTERL with hydrocephalus (VACTERL-H) ## Footnote This requires having **3 of 8** features, including vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula, esophageal atresia, renal abnormalities, limb abnormalities, and hydrocephalus

Question 75

Hereditary cause of AA: nail dystrophy, mucosal leukoplakia A predisposition to malignant transformation The disease is a reflection of **telomere complex dysfunction** and results from defective telomerase activity resulting from mutations in the telomerase-related genes

Answer 75

Dyskeratosis congenita

Question 76

Responsible for the X-linked recessive form of Dyskeratosis congenita

Answer 76

DKC1 gene ## Footnote DKC1 encodes **dyskerin**, which is a conserved multifunctional protein component of the telomerase complex

Question 77

Homozygous recessive mutations in the **TERT** gene produce a severe variant of dyskeratosis, referred to as the

Answer 77

Hoyeraal-Hreidarsson syndrome

Question 78

Used to confirm Dyskeratosis congenita

Answer 78

Genetic analysis for telomerase complex gene mutations

Question 79

# TRUE OR FALSE In Dyskeratosis congenita, transplantation might improve the cytopenias, but not the abnormalities of other organs or the frequency of secondary nonhematopoietic cancer.

Answer 79

TRUE In Dyskeratosis congenita, **transplantation might improve the cytopenias, but not the abnormalities of other organs** or the frequency of secondary nonhematopoietic cancer. ## Footnote The incidence of **squamous cell carcinoma** of mucosal sites is increased, and the squamous cell carcinoma often originates in sites of leukoplakia in the skin, gastrointestinal, or genitourinary tracts.

Question 80

Manifests as exocrine pancreatic insufficiency with secondary steatorrhea, blood cell deficiencies, and skeletal abnormalities Results from mutations in the **SBDS gene on chromosome 7q11**, which induces accelerated cellular apoptosis via the FAS pathway

Answer 80

Shwachman-Diamond syndrome

Question 81

# Shwachman-Diamond syndrome Pancreatic insufficiency can be established by

Answer 81

Low serum trypsinogen ## Footnote in patients younger than 3 years of age

Question 82

Cytogenetic abnormalities involving chromosomes _________ have been described in marrow cells of patients with Shwachman-Diamond syndrome

Answer 82

Chromosomes 7 and 20 ## Footnote Have a significant risk of progression to a myelodysplastic syndrome or AML

Question 83

Results from mutations in the TPO receptor gene, **MPL**

Answer 83

Congenital (hereditary) amegakaryocytic thrombocytopenia (CAMT) ## Footnote * **CAMT I** with mutations leading to **complete loss-of-function of the TPO receptor**, resulting in more severe thrombocytopenia and a rapid progression to pancytopenia (aplastic anemia) * **CAMT II**, resulting from a variety of missense mutations, in which affected children have an increase in platelet count above 50 × 109/L with time and much slower progression to and sometimes less severe pancytopenia

Question 84

Hereditary cause of AA: cafe au lait spots, VACTERL phenotype

Answer 84

Fanconi anemia

Question 85

Hereditary cause of AA: bilateral sensorineural deafness, agranulocytosis, SCID Results from a pluripotential stem cell defect as both lymphoid and granulocytic progenitors are affected.

Answer 85

Reticular dysgenesis

Question 86

Results from mutations in the **ATR** gene, and marrow cells exhibit **heightened sister chromatid exchange**

Answer 86

Seckel syndrome

Question 87

# TRUE OR FALSE Inherited aplastic anemias can be treated by hematopoietic cell transplantation but, if successful, this step does not correct somatic abnormalities, only the hematopoietic and immunologic defect.

Answer 87

TRUE Inherited aplastic anemias can be treated by **hematopoietic cell transplantation** but, if successful, this step **does not correct somatic abnormalities**, **only the hematopoietic and immunologic defect**.