87 Acute Myelogenous Leukemia Flashcards
(226 cards)
1
Q
4 environmental factors are established causal agents of AML
A
- high-dose radiation exposure
- chronic, high-dose benzene exposure (≥40 parts per million [ppm]-years)
- chronic tobacco smoking
- chemotherapeutic (DNA-damaging) agents
2
Q
An endogenous factor that increases risk is obesity. Studies in North America show an increased risk of AML in men and women with elevated body mass index, and this is particularly notable for __________________
A
Acute promyelocytic leukemia (APL)
The precise mechanisms are still unclear but may be related, in part, to elevated leptin levels, decreased adiponectin levels, shortened telomeres, alterations in lipid metabolism, associated inflammation and as yet unknown factors in obese subjects
3
Q
The most compelling data indicate that the bulk of AML cases arise from 1 of 2 predominant CD34+ cell populations:
A
CD34+CD45RA+CD38−CD90− (multipotential myeloid progenitor)
or
CD34+CD38+CD45RA+CD110+ (granulocyte–monocyte progenitor)
4
Q
Chromosome changes involving CBF
A
t(8;21), inv(16), t(16;16), or t(15;17)
A more favorable outcome
5
Q
Increased in frequency in patients over 60 years of age and in cases that develop after cytotoxic therapy
A
Deletions in chromosome 5 and 7 and complex cytogenetic abnormalities
6
Q
Mutations with favorable outcomes
A
- t(8;21)(q22;q22.1); RUNX1-RUNX1T1
- inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFβ-MYH11
- Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow
- Biallelic mutated CEBPa
7
Q
Mutations with poor outcome
A
- t(6;9)(p23;q34.1); DEK-NUP214
- t(v;11q23.3); KMT2A rearranged
- t(9;22)(q34.1;q11.2); BCR-ABL1
- inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
- −5 or del(5q); −7; −17/abn(17p)
- Complex karyotype, monosomal karyotype
- Wild-type NPM1 and FLT3-ITDhigh
- Mutated RUNX1or ASXL1 without good risk karyotype
- Mutated TP53
8
Q
TRUE OR FALSE
Patients with CBF leukemias expressing KIT have a good prognosis.
A
FALSE
Patients with CBF leukemias expressing KIT have a worse prognosis.
9
Q
TRUE OR FALSE
A monosomal karyotype is associated with a decreased chance of achieving remission or survival, especially when combined with TP53 mutations.
A
TRUE
A monosomal karyotype is associated with a decreased chance of achieving remission or survival, especially when combined with TP53 mutations.
10
Q
Approximately _______of AML cases have a normal karyotype
A
45%
11
Q
Most frequently mutated gene in AML (50%)
Allogenic transplantation not needed in first
remission if this mutation occurs in absence
of mutated FLT3-ITD
A
NPM1
NPM1 mutation is not associated with better duration of complete remission in those treated with hypomethylating agents.
12
Q
An ITD of FLT3 on chromosome 13 occurs in approximately ____ of adult AML cases
A
25%
FLT3-ITD expression is often higher at relapse.
13
Q
Point mutations in the TKD of FLT3 mutations occur in approximately ____% of AML cases
A
6%
Have little impact on outcomes
14
Q
The FLT3-ITD mutation confers a poor prognosis if the ratio of mutant to wild-type expression is (LOW/HIGH).
A
High (≥0.51)
15
Q
A leucine zipper transcription factor involved in myeloid differentiation.
A
CEBPα
16
Q
TRUE OR FALSE
CEBPα-double, but not CEBPα-single, mutation patients had a significantly better overall survival at 8 years than wild-type, CEBPα-single, or CEBPα-double and FLT3-ITDpositive patients.
A
TRUE
CEBPα-double, but not CEBPα-single, mutation patients had a significantly better overall survival at 8 years than wild-type, CEBPα-single, or CEBPα-double and FLT3-ITDpositive patients.
17
Q
Catalyze oxidative decarboxylation of isocitrate into α-hemoglutarate
A
IDHs
18
Q
Found to predict for the presence of IDH1/IDH2 mutations
A
Serum 2hydroxyglutarate
- A level of 700 ng/mL was found to discriminate mutated from nonmutated
- Those with levels greater than 20 ng/mL at the time of remission had shorter overall survival.
19
Q
These mutations are highly enriched in therapy-related AML and in those with complex karyotype.
A
TP53 Mutations
20
Q
The detection of persistent leukemia-associated mutations in at least ______% of marrow cells in day 30 remission marrow cell samples is associated with a high risk of relapse.
A
5%
21
Q
Gene mutations associated with familial AML
A
- GATA2
- CEBPα and DDX41
- Telomerase RNA (TERC) or telomerase reverse transcriptase component (TERT)
22
Q
AML is the predominant form of leukemia during the: (Neonatal OR childhood OR adolescence)period
A
Neonatal period
23
Q
AML is more common in (males/females)
A
Males
24
Q
The acute promyelocytic variant of AML is somewhat more common in __________ (race)
A
Latinos
25
# Immunologic Phenotype
CD11b, CD13, CD15, CD33, CD117,
HLA-DR
Myeloblastic
26
# Immunologic Phenotype
CD11b, CD13, CD14, CD15, CD32, CD33,
HLA-DR
Myelomonocytic
27
# Immunologic Phenotype
Glycophorin, spectrin, ABH antigens,
carbonic anhydrase I, HLA-DR, CD71
(transferrin receptor)
Erythroid
28
# Immunologic Phenotype
CD13, CD33
Promyelocytic
| No CD34 and HLADR
29
# Immunologic Phenotype
CD11b, 11c, CD13, CD14, CD33, CD65,
HLA-DR
Monocytic
30
# Immunologic Phenotype
CD34, CD41, CD42, CD61, anti–von
Willebrand factor
Megakaryoblastic
31
# Immunologic Phenotype
CD11b, CD13, CD33, CD123, CD203c
Basophilic
32
# Immunologic Phenotype
CD13, CD33, CD117
Mast cell
33
**Palpable splenomegaly or hepatomegaly** occurs in approximately ______of patients.
25%
34
**Lymphadenopathy** is extremely uncommon, except in the ______________ variant of AML
Monocytic variant of AML
35
**Extramedullary involvement** is most common in____________________leukemia.
Monocytic or myelomonocytic leukemia
36
Skin involvement in AML may be of 3 types:
* Nonspecific lesions
* Leukemia cutis
* Granulocytic (myeloid) sarcoma of skin and subcutis
37
A necrotizing inflammatory lesion involving the terminal ileum, cecum, and ascending colon, can be a presenting syndrome or occur during treatment
Ileotyphlitis (enterocolitis)
38
A tumor composed of myeloblasts, monoblasts, or megakaryocyes
Myeloid sarcoma
Synonyms: granulocytic sarcoma, chloroma, myeloblastoma, monocytoma
## Footnote
The tumors originally were called **chloromas** because of the **green color imparted by the high concentration of the enzyme myeloperoxidase** present in myelogenous leukemic cells.
39
Most frequent cytogenetic disturbance in myeloid sarcomas
Abnormalities in chromosome 8
40
(Systemic chemotherapy or local therapy), should be used for treatment of myeloid sarcoma, although the long-term outcome in such cases usually is poor.
Systemic chemotherapy
## Footnote
Systemic chemotherapy, rather than local therapy, should be used for treatment, although the long-term outcome in such cases usually is **poor**.
41
Mutations with propensity to develop extramedullary leukemia
AML with t(8;21) or inv16
42
Principal cause of anemia in AML
Inadequate production of red cells
43
Mechanism of thrombocytopenia in AML
Inadequate production and decreased survival of platelets
44
Are elliptical cytoplasmic inclusions, approximately 1.0–1.5 μm long and 0.5 μm wide, that derive from azurophilic granules
Auer rods
## Footnote
APL: higher proportion of cells have Auer rods and some have multiple (bundles) of rods (so-called **faggot cells**).
Present in the blast cells of approximately **15%** of cases
45
The WHO has invoked an arbitrary threshold of______of marrow nucleated cells being blast cells to distinguish polyblastic AML from oligoblastic myelogenous leukemia
20%
46
**Relapse** of AML can be identified as any increase in blast count greater than _______
2%
47
# TRUE OR FALSE
Any distinctions between MDS and AML in survival are a function of age, cytogenetic risk category, and molecular features, and the blast count.
FALSE
Any distinctions between MDS and AML in survival are a function of age, cytogenetic risk category, and molecular features, **not the blast count**.
48
Myeloblasts are distinguished from lymphoblasts by any of 3 pathognomonic features:
* Reactivity with specific histochemical stains
* Auer rods in the cells
* Reactivity with a panel of monoclonal antibodies against epitopes present on myeloblasts (eg, CD13, CD33, CD117)
49
Leukemic myeloblasts give positive histochemical reactions for:
Myeloperoxidase, Sudan black B, or naphthyl AS-D-chloroacetate esterase
50
Blast cells may express :
Granulocytic surface antigens __________________ or
Monocytic surface antigens _____________
Granulocytic surface antigens **(CD15, CD65)** or
Monocytic surface antigens **(CD11b, CD11c, CD14, CD64)**
51
AML associated with intense fibrosis
Megakaryoblastic leukemia
52
Associated with marrow basophilia
t(6;9)
53
Associated with marrow eosinophilia
inv16 or t(16;16)
54
Associated with in cases of AML following chemotherapy or radiotherapy
Loss of part or all of chromosomes 5 and 7
55
Chromosome abnormality very common in **acute myeloblastic leukemia**
Trisomy 8
56
**t(9;22) (q34; q22) in BCR-ABL1 gene** is present in ______ of patients with AML
~2%
57
Often **acute myelomonocytic** phenotype; associated with increased marrow
**eosinophils**; predisposition to cervical lymphadenopathy, better response to
therapy
Inv(16) (p13.1;q22) or
t(16;16) (p13.1;q22)
58
~1% of cases of AML
Approximately 85% of cases with normal or increased platelet count
Marrow has increased dysmorphic, hypolobulated megakaryocytes.
Hepatosplenomegaly more frequent
Inv(3) (q21q26.2) /RPN1-EVI1
59
Approximately ______% of cases of AML contain cells that are **cytogenetically normal**.
45%
60
Serum uric acid and lactic dehydrogenase levels are higher in___________________AML than in other AML phenotypes
Myelomonocytic and monocytic AML
61
Are associated with **hypofibrinogenemia** and other indicators of activation of coagulation or fibrinolysis
APL and acute monocytic leukemia
62
Hyperleukocytosis is a markedly elevated blood blast cell count, usually greater than _____________
100 × 10 9 /L
63
Subsets of AML are associated with a greater likelihood of presenting with hyperleukocytosis
Myelomonocytic, acute monocytic, the microgranular variant of APL, and AML with inv16, 11q23 rearrangements, or FLT3-ITD
64
The circulations most sensitive to the effects of leukostasis
CNS, lungs, and penis
65
Approximately **10%** of patients with AML present with a syndrome that includes **pancytopenia**, often with inapparent blood blast cells, and absence of hepatic, splenic, or lymph nodal enlargement
Hypoplastic Leukemia
## Footnote
Approximately 75% of these patients are **men older than 50 years.**
66
Marrow necrosis is uncommon but approximately _________ of cases are associated with lymphoid or myeloid malignancies and about ____________ of cases occur in patients with AML
two-thirds
one-fourth
67
Two most common symptoms or signs of **marrow necrosis**
**Bone pain** (approximately 80% of patients)
**Fever** (approximately 70% of patients)
68
Marrow findings in marrow necrosis
The marrow aspirate is often **watery and serosanguineous.**
An amorphous extracellular eosinophilic background with disintegrating cells that have lost their staining characteristics with indistinct margins and varying degrees of pyknosis and karyorrhexis
## Footnote
Both technetium scanning and MRI can point to areas of intact marrow that may be used to make a diagnosis of the underlying disease, if it is unknown.
69
Four myeloproliferative syndromes related to AML have been identified in the neonate:
* Transient myeloproliferative disorder
* Transient leukemia
* Congenital leukemia
* Neonatal leukemia
## Footnote
Transient myeloproliferative disorder and transient leukemia are considered to represent the same phenomenon.
70
Can be present at birth, or occur shortly thereafter, in approximately **10% of infants with Down syndrome**.
The blast cells usually have the immunophenotype of **megakaryocytes**.
Transient myeloproliferative disease (TMD)
71
In Transient myeloproliferative disease (TMD), the elevated white cell and blast cell counts disappear in most patients (approximately 80%) over a period of _____________
Weeks to months
72
Approximately _______of newborns with Down syndrome and transient leukemia develop______________________ in the first __________years of life.
25%
Acute megakaryocytic leukemia
First 4 years of life
73
Mutations that have been found in **nearly all** patients with TMD and in acute megakaryocytic leukemia in Down patients
GATA1 mutations
74
# TMD
Treatment suggested for those patients with severe hepatic fibrosis, very high white cell counts, or hydrops fetalis
Very-low-dose cytarabine
75
# TMD
Children with Down syndrome have either a ______-fold risk of AML or an approximately ________-fold of ALL by age 5 years
150x (AML)
40x (ALL)
76
Myelogenous leukemia in patients with Down syndrome often has what phenotype of leukemia
Megakaryoblastic or erythroid phenotype
77
A rare syndrome, occurs 10 times more often in newborns with Down syndrome than in newborns without trisomy 21
The disease has been diagnosed prenatally.
Congenital or neonatal leukemia
78
The most common phenotype and karyotype in congenital or neonatal leukemia
Monocytic leukemia and t(4;11)
## Footnote
The presence of a cytogenetic abnormality on band **q23 of chromosome 11** is a very poor prognostic sign.
79
Cases of biphenotypic leukemia that are morphologically or cytochemically indicative of myelogenous leukemia
LY+AML
## Footnote
The WHO now classifies some of these disorders as mixed phenotype acute leukemia (MPAL).
80
Cases of biphenotypic leukemia that are more indicative of lymphocytic leukemia
MY+ALL
## Footnote
The WHO now classifies some of these disorders as mixed phenotype acute leukemia (MPAL).
81
2 notable syndromes are associated with hybrid leukemias:
**(a) the myeloid leukemia and natural killer cell hybrid (CD56+, CD7+, CD13+, CD33+)**
**(b) the lymphoma, eosinophilia, and t(8;13) myeloid leukemia hybrid.**
## Footnote
* The hybrids can appear de novo or after relapse of a lymphoma, T-cell leukemia, or blast crisis of CML.
* The hybrid leukemias usually have a poor prognosis.
82
Often **simulates APL, with hypergranular cytoplasm** present but an **abnormality of chromosome 17 is absent**
Myeloid–natural killer cell leukemia
83
Lymphoid and myeloid cells are present simultaneously but are derived from separate clones, or sequential myeloid and lymphoid leukemia are present, but the 2 lineages are derived from separate clones
Mixed Leukemias
84
An unusual but significant concordance has been reported between **nonseminomatous mediastinal germ cell tumors** and AML, especially the _________________ variant.
Megakaryoblastic
85
Most common in adults, and most frequent variety in infants.
Three morphologic– cytochemical types (M0, M1, M2).
Acute myeloblastic leukemia
## Footnote
The WHO has divided acute myeloblastic leukemia not otherwise specified, into 3 types: AML without differentiation, AML without maturation, and AML with maturation.
86
Approximately 15% of patients with AML
More likely to have **extramedullary infiltrates** in gingiva, skin, or CNS than are patients with acute myeloblastic leukemia
Acute Myelomonocytic Leukemia
87
# FAB Classification of Acute Myelomonocytic Leukemia
Variant of myelomonocytic leukemia has increased numbers of marrow **eosinophils (10–50%), Auer rods in blast cells, and inversion or rearrangement of chromosome 16**
Has an **increased risk of CNS involvement**, it carries a more favorable prognosis
M4Eo
88
Translocations involving ______________ are associated with **Acute Myelomonocytic Leukemia**
Chromosome 3
89
Erythroid leukemia is arbitrarily divided into 3 degrees of severity:
(a) **Erythroleukemia** in which more than 50% of the marrow cells are dysmorphic
(b) **Erythroblasts admixed with myeloblasts**, the latter composing approximately 20% of nonerythroid cells or approximately 5% to 10% of total marrow cells
(c) **Pure erythroid leukemia**, in which more than 80% of marrow cells are dysmorphic erythroblasts with a trivial granulocytic proportion of cells and very few if any myeloblasts
90
Features of erythroblasts in Acute Erythroid leukemia
Glycophorin A, spectrin, carbonic anhydrase I, ABH blood group antigens, and other antigens that occur on early erythroid progenitors, such as the transferrin receptor (CD71)
Antihemoglobin antibody and antihuman erythroleukemic cell line antibody often are positive
91
# TRUE OR FALSE
The more predominant the erythroid component and the lower the proportion of myeloblasts, the better the response to therapy.
TRUE
The **more predominant the erythroid** component and the lower the proportion of myeloblasts, the **better the response** to therapy.
92
APL occurs with greater frequency among (nationality)
Latinos from Europe and South and Central America
93
APL is also increased among persons with an (increased or decreased) body mass index.
Increased
## Footnote
Upregulation of polyunsaturated fatty acid metabolism genes has been noted, and in APL patients with obesity, **FLT3 mutations are higher.**
94
Promyelocytes with multiple Auer rods have been referred to as:
Faggot cells
95
Leukemic promyelocytes stain intensely with myeloperoxidase and Sudan black and express
CD9, CD13, and CD33
**BUT NOT CD34 or HLA-DR**
96
**Microgranular** cases represent approximately _____ of patients with promyelocytic leukemia.
The leukemic cells may mimic promonocytes with convoluted or lobulated nuclei.
20%
## Footnote
The total WBC often is highly elevated, and severe coagulopathy is prominent in microgranular cases.
97
The most frequent cytogenetic abnormality (**>95%**) in APL
t(15;17)(q22;q21)
98
Other variant translocations in APL
Chromosome 3, 5, or 11 and chromosome 17 or isochromosome 17
99
Rearrangement of the RARα gene that is **retinoid responsive**
t(15;17), PML–RARα fusion
t(5:17), NPM–RARα fusion
t(3;17), TBLR1–RARα fusion
100
Rearrangement of the RARα gene that is **retinoid resistant**
t(11;17), PLZF–RARα fusion
101
Mutation in APL where **Auer rods are absent** and **CD56** expression usually is present
t(11;17)
102
The PML–RARα gene has 2 isoforms that produce a short-type and a long-type fusion mRNA, respectively.
Patients with the__________ isoform may have a worse outcome
Short
## Footnote
FLT3 mutations are frequently found in human disease, especially in the hypogranular variant.
103
# APL
Approximately 5% to 10% of patients die during remission induction, most of
Hemorrhage
often into the brain
104
Have a higher prevalence (50%) of **extramedullary tumors**
Hepatomegaly, splenomegaly, and lymphadenopathy are more frequent
Acute Monocytic Leukemia
105
In Acute Monocytic Leukemia, monocytic cells react for nonspecific esterase stains, α-naphthyl acetate esterase, and naphthol AS-D-chloroacetate-esterase; in a cytochemical or chemoluminescence assay; or with monoclonal antibodies against monocyte surface antigens, especially ____
CD14
## Footnote
Immunoreactivity of cells for **lysozyme** is characteristic.
106
Results in the **MOZ-CBP** fusion gene, is characterized by **mildly granular promonocytes (simulating hypogranular promyelocytes)**, intense phagocytosis of red cells, erythroblasts, and sometimes neutrophils and platelets in blood and marrow, **simulating macrophagic hemophagocytic syndrome, intravascular coagulation or primary fibrinolysis**, and a high frequency of **extramedullary disease**
Acute monoblastic leukemia with t(8;16)
107
# TRUE OR FALSE
In acute monocytic leukemia, , examination of cerebrospinal fluid is often recommended, even in the absence of symptoms, when remission has been achieved
TRUE
In **acute monocytic leukemia**, **examination of cerebrospinal fluid is often recommended**, even in the absence of symptoms, when remission has been achieved
## Footnote
Greater incidence of CNS or meningeal disease
108
AML prevalent variant of AML that develops in patients with **Down syndrome** or in patients with **mediastinal germ cell tumors** and coincident AML
Has **severe myelofibrosis**
The serum **lactic acid dehydrogenase level frequently is strikingly increased** and has an isomorphic pattern unlike that seen with other acute leukemias.
Acute Megakaryoblastic (Megakaryocytic) Leukemia
## Footnote
Maturing megakaryocytes with agranular cytoplasm with cytoplasmic protrusions, clusters of platelet-like structures, or shedding of cytoplasmic blebs
109
Markers of Acute Megakaryoblastic (Megakaryocytic) Leukemia
Antibodies to von Willebrand factor or to platelet glycoprotein Ib (CD42), IIb/IIIa (CD41), or IIIa (CD61)
## Footnote
Confirmation of their megakaryoblastic maturation requires immunocytologic studies for the presence of **von Willebrand factor** and the immunoreactivity to **CD41, CD42, or CD61.**
110
Chromosal abnormalities associated with Acute megakaryocytic leukemia
chromosome 3
Infants with t(1;22)(p13;q13)
111
The eosinophilic cells are dysmorphic and the cytoplasm hypogranulated with smaller-than-normal eosinophilic granules.
Acute Eosinophilic Leukemia
## Footnote
**Increased eosinophils in the marrow, but not in the blood**, is a variant of **acute myelomonocytic leukemia and inversion 16 or other abnormalities of chromosome 16**, but is not considered an acute eosinophilic leukemia.
112
# Acute eosinophilic leukemia
A specific histochemical reaction, _______________________, permits identification of leukemic cells with eosinophilic differentiation and diagnosis of acute eosinoblastic leukemia in some cases of AML with fewer identifiable eosinophils in blood or marrow.
Cyanide-resistant peroxidase
113
Proposed as a means of distinguishing acute eosinophilic leukemia from a polyclonal, reactive eosinophilia
Overexpression of WT gene expression
114
# TRUE OR FALSE
Patients with acute eosinophilic leukemia do not usually develop bronchospastic signs, neurologic signs, and heart failure from endomyocardial fibrosis as is seen in chronic eosinophilic leukemia
TRUE
Patients with acute eosinophilic leukemia do not usually develop bronchospastic signs, neurologic signs, and heart failure from endomyocardial fibrosis as is seen in chronic eosinophilic leukemia
## Footnote
Probably because those tissue changes are the result of release of toxins in the granule crystalloid, **absent in most eosinophils in acute eosinophilic leukemia** and because of the **shorter duration of survival** in acute eosinophilic leukemia.
115
Appropriate choice for treatment for Acute eosinophilic leukemia
Cytarabine and an anthracycline
116
Most cases evolve from the **chronic phase of CML**
Characterized by presence of **CD9, CD25**, or both
Elevated blood and urine histamine and urinary methylhistamine levels
Acute basophilic leukemia
## Footnote
In some cases of **acute myelomonocytic leukemia associated with t(6;9)(p23;q34)**, basophils may be increased in the marrow, but not in the blood.
117
# Acute basophilic leukemia
The cells stain with ____________ and the basophilic granules can be most striking in myelocytes.
Toluidine blue or Astra blue
118
Related to a mutation of the **KIT gene**
Plasma tryptase is elevated
Naphthol AS-D-chloracetate-esterase–positive, CD11b-negative, CD117-positive, CD123-negative
Mast cell leukemia
119
The key laboratory distinctions between acute basophilic leukemia and acute mast cell leukemia
**Basophilic leukemia:** naphthol AS-Dchloracetate- esterase–negative, CD11b positive, CD117 negative or weakly positive, CD123 positive, have no increase in cell or plasma tryptase
**Mast cell leukemia:** naphthol AS-D-chloracetate-esterase–positive, CD11b-negative, CD117-positive, CD123-negative, have an increase in cell and plasma tryptase
120
Defined as elimination of the leukemic cell population in marrow as judged by microscopy and flow cytometry and the restitution of marrow hematopoiesis resulting in a normal or virtually normal white cell, hemoglobin, and platelet concentrations in the blood
Remission
121
Any suspicion of **APL**, however, should lead to urgent administration of ________________
ATRA
122
# TRUE OR FALSE
Age is a contraindication to treatment, and septuagenarians and octogenarians who are fit cannot enter remissions.
FALSE
**Age per se is not a contraindication to treatment**, and septuagenarians and octogenarians who are fit can enter remissions.
123
More extensive evaluation of coagulation factors should be made if:
(a) clotting times are abnormal
(b) bleeding is exaggerated for the level of the platelet count
(c) APL or acute monocytic leukemia is the phenotype
124
Therapy for hyperuricemia is required if:
(a) the pretreatment uric acid level is greater than 7 mg/dL (0.4 mmol/L)
(b) the marrow is packed with blast cells, or
(c) the blood blast cell count is moderately or markedly elevated
125
Dose of Allopurinol
Allopurinol 300 mg/day
126
Allopurinol can cause allergic dermatitis and should not be used if the uric acid level is less than_________ and the total white cell count is less than approximately _______, as long as hydration is adequate and urine flow is high (>_______ mL/h)
less than 7 mg/dL
total white cell count is less than approximately 20 × 109/L
>150 mL/h
## Footnote
Thus, allopurinol should be discontinued after the risk of acute hyperuricosuria or tumor lysis has passed (usually **4 to 7 days**).
127
Reduce plasma urate levels by approximately **80%** within 4 hours of the first drug dose.
Recommended dose is **0.2 mg/kg daily for 5–7 days IV**
Recombinant urate oxidase (rasburicase)
128
The primary goal of induction therapy in AML
Complete remission
* <2% blasts in the marrow)
* A neutrophil count greater than 1 × 109/L
* Platelet count greater than 100 × 109/L
129
Current standard induction treatment for non-APL AML
Anthracycline or Anthraquinone and Cytarabine
130
The two most important variables in remission-induction therapy
* Age of the patients
* Proportion of patients with therapy-induced leukemia or an antecedent clonal myeloid disease (clonal evolution)
131
Anthracycline that **does not induce P-glycoprotein expression** -> drug resistance is reduced
Idarubicin
132
May be given during induction to **reduce the risk of cardiotoxicity** in patients at higher-than-usual risk because of a history of coronary artery disease or congestive heart failure
Dexrazoxane
133
# TRUE OR FALSE
High-dose cytarabine does not increase complete remission rates and increases toxicity compared to conventional doses, especially in patients over 60 years of age
TRUE
**High-dose cytarabine does not increase complete remission rates and increases toxicity** compared to conventional doses, especially in patients over 60 years of age
134
The effect of induction chemotherapy is usually assessed by marrow aspirate and biopsy _______days after completion of chemotherapy.
7–10 days
“day 14 marrow”
## Footnote
Hypocellular marrow and no evidence of residual leukemic blasts: recovery of normal counts is awaited
Hypocellular marrow and a small number of residual blasts: additional therapy may be delayed until count recovery or until another marrow assessment often recommended at a 1 week interval after the “day 14 marrow” examination.
Sgnificant amounts of leukemic cells remaining: repeating the original induction therapy or use of a high-dose cytarabine regimen
135
# TRUE OR FALSE
There are insufficient data to determine whether use of the same regimen or advancing to a high-dose cytarabine-containing regimen is the superior approach.
TRUE
There are insufficient data to determine whether use of the same regimen or advancing to a high-dose cytarabine-containing regimen is the superior approach.
136
Approximately ____ of patients with persistent AML after 1 course of induction therapy have a complete remission after a second course, and disease-free survival at 5 years is approximately ___
40%
10%
137
A multitargeted kinase inhibitor, was approved by the FDA in 2017 for use in AML patients with FLT3 ITD or TKD point mutations
Midostaurin (ITD or TKD)
Sorafenib (ITD)
138
Second-generation FLT3 inhibitor
Gilteritinib and crenolanib
139
A humanized **anti-CD33** monoclonal antibody conjugated to calicheamicin that has now been approved for addition to 7+3 chemotherapy
Gemtuzumab ozogamicin (GO)
## Footnote
**3 mg/m2 on days 1, 4, and 7**
140
The main toxicity of Gemtuzumab ozogamicin (GO)
Prolonged thrombocytopenia
141
A liposomal preparation of **daunorubicin hydrochloride and cytarabine liposome** in a fixed **1:5 molar ratio**, was approved for use by the FDA in 2017 for patients **over 60 years** with AML and in those with **secondary AML or MDS-related cytologic findings**
CPX-351
## Footnote
Toxicity: longer duration of cytopenia
142
Use has been primarily in patients **over 60 years deemed unfit for standard induction chemotherapy**
Hypomethylating Agents
Decitabine
5-Azacytidine
143
Oral bioavailable small molecule **inhibitor of BCL-2**
Demonstrated synergistic activity with hypomethylating agents
Approved in the United States for use in previously untreated AML patients **older than 75 years** in combination with low-intensity chemotherapy,
Venetoclax
## Footnote
Mechanisms of resistance to venetoclax include **overexpression of BCL-2A1, BCL-xL, and MCL-1,738** as well as through alterations in metabolic pathways.
144
A **hedgehog pathway inhibitor** approved by the FDA in 2018 for oral administration in combination with low-dose cytarabine for newly diagnosed AML patients **75 years old and older or who have comorbidities** that preclude use of intensive induction chemotherapy
Glasdegib
145
Toxicity of Glasdegib
Muscle cramps, dysgeusia, and prolonged QT interval
146
Oral inhibitor of IDH2:
Oral inhibitor of IDH1:
Oral inhibitor of IDH2: **Enasidenib**
Oral inhibitor of IDH1: **Ivosidenib**
## Footnote
Only **ivosidenib** has been approved for initial therapy
147
Side effects of hypomethylating agents
Constipation
148
Side effect of Ivosidenib
Differentiation syndrome
149
Most serious complications of hyperleukocytosis:
Intracranial hemorrhage or pulmonary insufficiency
150
In management of hyperleukocytosis: - Hydration should be administered promptly to maintain urine flow greater than ____________
100 mL/h per m2
151
Hydroxyurea dose for Cytoreduction
Hydroxyurea **1.5–2.5 g** orally **every 6 hours (total dose 6–10 g/day)** for approximately **36 hours**
## Footnote
Appropriate remission-induction therapy should be initiated as soon as possible after the leukocyte count has been decreased significantly.
152
Simultaneous_____________________ can decrease blast cell concentration by approximately _______ within several hours without contributing to uric acid or cellular phosphate release.
Leukapheresis
30%
153
____________________ may improve the hypoxemia related to hyperleukocytosis
Inhaled nitric oxide
154
**Granulocyte transfusion** should not be used prophylactically for neutropenia but may be used in patients with :
* high fever, rigors, and bacteremia unresponsive to antibiotics
* with blood fungal infections
* with septic shock
155
# TRUE OR FALSE
Patients with evidence of intravascular coagulation or exaggerated primary fibrinolysis should be considered for platelet and fresh-frozen plasma administration before antileukemic therapy is started.
TRUE
Patients with evidence of intravascular coagulation or exaggerated primary fibrinolysis should be considered for **platelet and fresh-frozen plasma administration before antileukemic therapy is started**.
156
Infusion of cryoprecipitate can be used for fibrinogen levels less than approximately ____________
125 mg/dL
157
Intravascular coagulation or primary fibrinolysis may occur in patients with _____________
APL and acute monocytic leukemia
158
Management of CNS disease
Prophylactic therapy usually is not indicated, but **examination of the spinal fluid after remission** should be considered in:
(a) monocytic subtypes;
(b) cases with extramedullary disease;
(c) cases with inversion 16 and t(8;21) cytogenetics;
(d) CD7+ and CD56+ (neural cell adhesion molecule) immunophenotypes; and
(e) patients who present with very high blood blast cell counts
159
# TRUE OR FALSE
Prophylactic intrathecal chemotherapy is not recommended if low-dose cytarabine is used for consolidation.
FALSE
Prophylactic intrathecal chemotherapy is NOT recommended if **high-dose cytarabine** is used for consolidation.
160
Treatment of meningeal leukemia
* High-dose IV cytarabine (which penetrates the blood–brain barrier)
* Intrathecal methotrexate
* Intrathecal cytarabine
* Cranial radiation
* Chemotherapy and radiation in combination
161
If CNS leukemia is present, intrathecal therapy is often given:
Twice per week until blasts are cleared, and then once per week for 4–6 weeks
## Footnote
This therapy can be accomplished via the lumbar puncture route or through placement of an Ommaya reservoir.
162
If there is a mass present treatment can be:
Radiation or high-dose cytarabine with glucocorticoids
163
# TRUE OR FALSE
Unless the patient has neurologic symptoms, lumbar puncture generally is deferred until blood blast cells have cleared.
TRUE
Unless the patient has neurologic symptoms, lumbar puncture generally is deferred until blood blast cells have cleared.
## Footnote
No consensus exists on a trigger for platelet transfusion in adults with AML undergoing lumbar puncture; a **platelet count of less than 20 × 109/L** has been proposed as such a trigger, but many therapists use a **higher platelet count (eg, 50 × 109/L)** as a safety threshold for lumbar puncture.
164
Myeloid sarcoma may be the presenting finding in approximately ____ of patients with AML.
1%
## Footnote
Patients with **trisomy 8** have poorer survival rates.
165
Treatment for Nonleukemic Myeloid Sarcoma
Intensive AML induction therapy
166
Post remission therapy for patients with **good risk cytogenetics** and can also be considered in those with **intermediate-risk cytogenetics**
4 cycles of high-dose cytarabine
167
Post remission therapy for patients with **poor-risk cytogenetics**
Allogeneic HSC transplantation
168
Associated with benefit from high-dose cytarabine therapy:
## Footnote
A cycle is typically **3 g/m2 twice daily on days 1, 3, and 5**, providing 6 doses per cycle
* RAS mutations
* CBF leukemias, such as t(8;21)
* Patients 60 years or younger, if they have adequate renal function
* NPM1 mutation without FLT3-ITD mutation
* Biallelic CEBPα mutations
## Footnote
KIT mutations in CBF AML are associated with a poorer prognosis.
169
High-dose cytarabine frequently causes **conjunctivitis and photophobia** hence this should be given
Glucocorticoid eyedrops are usually used every 6 hours for 24–72 hours after the last dose of the drug
170
May decrease the likelihood of severe **cerebellar toxicity** associated with Cytarabine
1-hour duration infusion of high-dose or reduced-dose (eg, 2 g/m2) cytarabine
## Footnote
Patients over age 60 years and patients with renal insufficiency require dose attenuation (ie, to 1–2 g/m2).
171
Can be used for AML who achieve a remission, do not have a compatible stem cell donor, and are into the eighth decade of life
**Autologous marrow or blood stem cell rescue**
172
An adoptive immunotherapy with donor mononuclear cell infusions is sometimes used to treat relapse of leukemia after allografting
Donor Leukocyte Infusion
## Footnote
Most effective in **early relapses** and in the **absence of extensive of chronic GVHD.**
173
The major complications of Donor Leukocyte Infusion
GVHD and marrow aplasia
174
After patients complete consolidation therapy, they are generally followed with blood counts every _______________
Every 3 months for 2 years, and then every 3–6 months for 5 years
175
A predictive factor for relapse
Time taken to enter complete remission after induction
176
# TRUE OR FALSE
In patients who relapse more than 1 year after the first remission, the original remission-induction regimen can be readministered or a combination salvage chemotherapy regimen can be administered.
TRUE
In patients who relapse **more than 1 year** after the first remission, the **original remission-induction regimen** can be readministered or a combination salvage chemotherapy regimen can be administered.
177
Defined as leukemia that does not respond to **2 initial induction** chemotherapy treatments with cytarabine and an anthracycline or anthraquinone.
Refractory leukemia
178
# TRUE OR FALSE
A retrospective study suggested that clofarabine-based versus fludarabine-based regimens had a higher complete remission rate and a longer survival
TRUE
A retrospective study suggested that **clofarabine-based versus fludarabine-based regimens** had a **higher complete remission rate and a longer survival**
179
Leukemia that reoccurs following a remission
Relapsed leukemia
180
The probability of a second remission is approximately _% in **younger (ages 15–60 years)** patients, and approximately _% in **older (ages 60–80 years)** patients, but the duration of remission is nearly always much shorter than the first remission.
40%
25%
181
Second-generation DNA methylation inhibitors
Guadecitabine
182
Can promote histone acetylation and gene transcription in RUNX1/ETO-positive leukemic cells
Depsipeptide
183
An aminonucleoside inhibitor of DOT1L histone methyltransferase activity is under clinical investigation in MLL-rearranged leukemias.
Pinometostat
184
Are small molecule inhibitors of MDM2 (Murine Double Minute 2), a negative regulator of p53
Nutlins / Idasanutlin
185
An oral exportin-1 inhibitor
Selinexor
186
A CDK6 inhibitor has activity in MLL-rearranged leukemias
Palbociclib
187
A CDK9 inhibitor, is being examined as an MCL-1 inhibitor
Alvocidib
188
Has been studied in CBF leukemias with a KIT mutation in conjunction with chemotherapy
Dasatinib (Sprycel)
189
Inhibitor of oxidative phosphorylation
Metformin
Mubritinib
190
An oral iron chelator, inhibits leukemic CD34+CD38− cells through NF-κB inhibition and reactive oxygen species generation
Deferasirox (Exjade)
191
# TRUE OR FALSE
Patients who are suspected APL based on morphology and presence of coagulopathy should begin ATRA without waiting for definitive FISH or molecular confirmation.
TRUE
Patients who are suspected APL based on morphology and presence of coagulopathy should begin ATRA without waiting for definitive FISH or molecular confirmation.
192
In APL, those with WBC of ________________ or higher are considered to have high-risk disease
10 × 109/L
193
Used alone, ATRA can induce a short-term remission in at least _______ of patients.
80%
194
**Leukocytosis during ATRA–arsenic trioxide therapy** in patients with white cell counts higher than 10 × 109/L can be treated with _____________.
Hydroxyurea or idarubicin
195
Chemotherapy for APL
Low-risk disease:
High-risk patients:
Chemotherapy for APL
Low-risk disease: A combination of ATRA plus arsenic trioxide, ATRA plus idarubicin alone, or ATRA plus daunorubicin plus cytarabine
High-risk patients: ATRA plus daunorubicin and cytarabine, ATRA plus idarubicin, or ATRA and arsenic trioxide with idarubicin (dose-adjusted based on age)
196
Cause of mortality for APL despite treatment with ATRA
Fatal intracranial hemorrhage
## Footnote
5%
**High white count** has been found to be a predictor of early hemorrhagic death.
197
Variant of APL, in which the promyelocytic leukemia zinc finger (PLZF) gene is fused to RARα, **DOES NOT respond to ATRA.**
t(11;17)
198
With ATRA, leukemic promyelocytes disappear from the blood in ______weeks, and a normal marrow aspirate maybe obtained in ______ weeks.
2–4 weeks
4–10 weeks
199
A rapid increase in the total blood leukocyte count to as high as 80 × 109/L in the first several weeks of therapy of APL
Differentiation syndrome
(previously called the **retinoic acid syndrome**)
200
Key feature or symptom of Differentiation Syndrome
Respiratory distress
## Footnote
The syndrome consists of fever, weight gain, dependent edema, pleural or pericardial effusion, and bouts of hypotension.
201
Treatment of differentiation syndrome
Early use of cytotoxic chemotherapy and glucocorticoid administration
Dexamethasone 10 mg IV every 12 hours
202
Prophylactic glucocorticoids should be given to those:
* With a WBC higher than 10 × 109/L or
* Those receiving both ATRA and arsenic trioxide
203
# APL
Targeted levels for
Platelet counts:
Fibrinogen:
Platelet counts: 30–50 × 109/L
Fibrinogen: 1.5 g/L or higher
204
# TRUE OR FALSE
Arsenic trioxide can trigger apoptosis of APL cells at low concentrations and maturation at high concentrations.
FALSE
Arsenic trioxide can trigger **apoptosis of APL cells at high** concentrations and **maturation at low** concentrations.
205
Consolidation therapy for APL
Arsenic trioxide plus ATRA or an anthracycline plus ATRA
## Footnote
High Risk: the addition of **cytarabine** or use of **arsenic trioxide** can be used to diminish the rate of relapse
High-risk patients may require **intrathecal chemotherapy** during consolidation to prevent central nervous system relapse.
206
At the end of consolidation, molecular remission in the marrow should be assessed by
Reverse transcriptase–polymerase chain reaction (RT-PCR)
207
# TRUE OR FALSE
In those patients treated with ATRA plus arsenic trioxide, and white cell count lower than 10 × 109/L at diagnosis, no maintenance is required.
TRUE
In those patients treated with **ATRA plus arsenic trioxide**, and white cell count **lower than 10 × 109/L** at diagnosis, **no maintenance** is required.
## Footnote
For others, ATRA maintenance with chemotherapy is recommended
Best results were achieved when **ATRA** was combined with **6-mercaptopurine and methotrexate.**
208
APL maintenance is usually recommended for ______ years.
2 years
## Footnote
During maintenance, PCR monitoring on blood samples is recommended.
If the PCR is positive in blood, a marrow examination should be done.
209
# APL High Risk
**MRD monitoring** should be performed every ___ months in high-risk patients up to ___ years after completion of consolidation therapy.
3 months
3 years
210
# TRUE OR FALSE
Secondary AML responds more poorly to chemotherapy and allogeneic HSC transplantation than does de novo AML.
TRUE
'
**Secondary AML** responds more **poorly** to **chemotherapy and allogeneic HSC transplantation** than does de novo AML.
211
Exposure to wha drugs can lead to AML with **MLL gene rearrangements on chromosome 11q32.**
Topoisomerase II inhibitors (eg, etoposide, mitoxantrone, amsacrine)
212
Latency period for development of AML after:
Topoisomerase II Inhibitors :
Alkylating Agents and Cisplatin :
Topoisomerase II Inhibitors : **2 years**
Alkylating Agents and Cisplatin : **6 years**
## Footnote
Topoisomerase II Inhibitors : No relationship with higher cumulative dose has been identified.
Alkylating Agents and Cisplatin : The risk is related to cumulative alkylating agent dose.
213
The most common cytogenetic changes in secondary **AML from Alkylating Agents and Cisplatin**
Deletions of all or part of chromosome 5 or 7
214
Other drugs that may increase the risk of secondary leukemias:
* Low-dose weekly methotrexate for rheumatoid arthritis
* Etanercept therapy
* Temozolamide
* Growth hormone administration
* G-CSF given to patients with congenital, but not idiopathic or cyclic neutropenia
215
Characteristics of AML older than 60 years old
* More frequent CD34 expression
* High frequency of unfavorable cytogenetic findings (32%)
* Higher MDR1 expression (71%)
* Functional drug efflux (58%)
216
Leukemia (AML, ALL, CML) is the _________ most common malignancy of women in the childbearing age group
Second
217
# AML in Pregnancy
If the pregnancy is not terminated,_______________ might be useful in the__________________ trimester, when chemotherapy poses a high risk to the embryo.
Leukapheresis
First
218
The preferred anthracycline to treat pregnant women as it has **lower transplacental transfer**
Doxorubicin
219
# TRUE OR FALSE
Leukemic infiltrates can be found on both the maternal side of the placenta and the villi.
FALSE
Leukemic infiltrates can be found on the maternal side of the placenta, but usually **not in the villi.**
220
The risk of serious cardiac effects is correlated with
* Increasing dose of anthracycline
* Increasing patient age
* Presence of underlying heart disease.
221
The incidence of congestive heart failure is **dose related** and ranges from approximately:
5% at ____mg/m2
Greater than 30% at ____ mg/m2
5% at 550 mg/m2
Greater than 30% at 600 mg/m2
222
Diagnosis of Neutropenic Enterocolitis is confirmed by
Sonography or CT scanning
## Footnote
Mucosal thickening and polypoid appearance
223
Management of Neutropenic Enterocolitis
Bowel rest, nasogastric suction, fluids, and antibiotics
## Footnote
* *Parenteral alimentation is sometimes used but is generally not helpful.*
* **Right hemicolectomy** is usually done only in the absence of resolution and if hemodynamic stability is lost
224
Definition of Remission
* Neutrophil count greater than 1 × 109/L
* Platelet count greater than 100 × 109/L
* Less than 5% blasts in the marrow by microscopy
* Absence of extramedullary AML
## Footnote
**Remission with incomplete platelet recovery CRplatelets (CRp)** has all these requirements, but the platelet count does not reach 100 × 109/L.
225
Early death can occur during induction chemotherapy, and ____________and ___________are the most important predictors of treatment-related mortality.
Performance status and age
226
The two most compelling determinants of a poor outcome in AML
Older age and less-favorable cytogenetic risk
