Translocation t(9;22) (q34;q11)(BCR-ABL1 [Abelson murine leukemia viral oncogene homologue 1]) Philadelphia chromosome, now called the Ph chromosome

82 Classification and Clinical Manifestations of the Clonal Myeloid Disorders Flashcards by Amelie Avenido

Refers to the relationship of the disease in question to normal cellular differentiation and maturation and the regulation of cell population homeostasis (birth and death rates)

Deviation

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Preclinical and Minimally-Deviated Clonal Myeloid Diseases

A. Clonal hematopoiesis of indeterminate potential (CHIP)
B. Clonal hematopoiesis of oncogenic potential (CHOP)
C. Clonal cytopenias of unknown significance (CCUS)

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Moderate-deviation neoplasms (no increase in blast cells [<2%] are evident in marrow)

A. Underproduction of mature cells is prominent
* 1. Clonal anemia
* 2. Clonal bi- or tricytopenia
* 3. Paroxysmal nocturnal hemoglobinuria

B. Overproduction of mature cells is prominent
* 1. Polycythemia vera
* 2. Essential thrombocythemia

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Moderately-severe-deviation neoplasms (very small percentage of leukemic blast cells present in marrow [usually ≤6%])

A. CML
* 1. Philadelphia (Ph) chromosome–positive, BCR rearrangement–positive (~90%)
* 2. Ph chromosome–negative, BCR rearrangement–positive (~6%)
3. Ph chromosome–negative, BCR rearrangement–negative (~4%)

B. Primary myelofibrosis (chronic megakaryocytic leukemia)

C. Chronic eosinophilic leukemia
* 1. PDGFR rearrangement–positive
* 2. FGFR1 rearrangement–positive

D. Chronic neutrophilic leukemia
* 1. CSF3R rearrangement–positive
* 2. CSF3R and SETBP1 rearrangement–positive
* 3. JAK2V617F rearrangement–positive

E. Chronic basophilic leukemia

F. Systemic mastocytosis (chronic mast cell leukemia)
* 1. KITD816V mutation–positive (~90%)
* 2. KITV560G mutation–positive (rare)
* 3. FILIPI-PDGFRα

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Severe-deviation neoplasms (usually moderate
concentration of leukemic blast cells present in marrow)

A. Oligoblastic myelogenous leukemia (myelodysplastic syndrome)

B. Chronic myelomonocytic leukemia
* 1. PDGFR rearrangement–positive (rare)
*
C. Atypical myeloproliferative disease (syn. atypical CML)

D. Juvenile myelomonocytic leukemia

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Very-Severe-deviation neoplasms (leukemic blast or early progenitor cells frequent in the marrow and blood)

A. Phenotypic variants of AML
* 1. Myeloblastic (granuloblastic)
* 2. Myelomonocytic (granulomonoblastic)
* 3. Promyelocytic
* 4. Erythroid
* 5. Monocytic
* 6. Megakaryocytic
* 7. Eosinophilic
* 8. Basophilic
* 9. Mastocytic
* 10. Histiocytic or dendritic

B. Higher-frequency genotypic variants of AML [t(8;21), Inv16 or t(16;16), t(15;17), or (11q23)]

C. Myeloid sarcoma

D. Acute biphenotypic (myeloid and lymphoid markers) leukemia

E. Acute leukemia with lymphoid markers evolving from a prior clonal myeloid disease

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Clonal hematopoiesis as a result of a somatic mutation in a clone of marrow cells, but marrow and blood cells without any phenotypic evidence of a blood cell disorder, that is, normal marrow and blood cell morphology and normal blood cell counts.

CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP)

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A somatic mutation in which an unequivocally abnormal cytopenia is or cytopenias are present

Clonal cytopenia of unknown significance (CCUS)

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Definition of cytopenias in clonal cytopenia of unknown significance (CCUS)

Hemoglobin :
Absolute neutrophil count :
Platelet count :

Hemoglobin : <100 g/L
Absolute neutrophil count : <1.8 × 10 9 /L
Platelet count : <100 × 10 9 /L

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A somatically mutated clonal disorder without a phenotype but with more concerning somatic mutations

Clonal hematopoiesis of oncogenic potential (CHOP)

In the case of CHOP, the mutations are disease-related or even disease-specific mutations and have a higher propensity to undergo clonal evolution to a progressive neoplasm.

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TRUE OR FALSE

In the cases of CHIP and CHOP, the definition includes absence of evidence of paroxysmal nocturnal hemoglobinuria or clonal lymphocytosis or cytologic dysmorphia.

TRUE

In the cases of CHIP and CHOP, the definition includes absence of evidence of paroxysmal nocturnal hemoglobinuria or clonal lymphocytosis or cytologic dysmorphia.

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Most frequent specific gene mutations which make up about 75% of CHIP

DNMT3A, TET2, ASXL1, and JAK2

12 specific gene mutations so far identified

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Mutations that are more frequently detected in secondary AML, following MDS or CMML

TET2
ASXL1

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Associated with deletions in the long arm of chromosome 11 and with the presence of ring sideroblasts in MDS.

SF3B1

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The variant allele frequency (VAF) by definition is above ____ %

Above 2%

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TRUE OR FALSE

Age-related clonal hematopoiesis (ARCH) is in essence a synonym for CHIP but denotes the effect of aging

TRUE

Age-related clonal hematopoiesis (ARCH) is in essence a synonym for CHIP but denotes the effect of aging

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The rate of progression of CHIP to a clinically evident neoplasm is approximately 0.75% of affected persons per year, of which the majority are __________ neoplasms

Myeloid neoplasms

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TRUE OR FALSE

A coexisting significant finding in patients with CHIP is a predisposition to cardiovascular morbidity and mortality.

TRUE

A coexisting significant finding in patients with CHIP is a predisposition to cardiovascular morbidity and mortality.

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The vascular occurrences in CHIP may relate to the mutations of genes such as __________

TET2 and JAK 2

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Defined as an idiopathic cytopenia(s) without a detectable somatic mutation.

Idiopathic cytopenias of undetermined significance (ICUS)

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Diseases include one group in which late precursor apoptosis (ineffective myeloproliferation) is characteristic (the clonal cytopenias) and one group in which proliferation is exaggerated and cellular maturation approximates normal (effective myeloproliferation)

MODERATE-DEVIATION CLONAL MYELOID DISEASES

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Essential characteristic of moderate-deviation clonal myeloid diseases

Cytopenias resulting from exaggerated apoptosis of marrow late precursors (referred to as “ineffective hematopoiesis”)

Variable dysmorphogenesis of blood cells

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The blood cell abnormalities, characteristic of the clonal cytopenias and oligoblastic myelogenous leukemia, include abnormalities of:

(a) red cell size (macrocytosis, anisocytosis), shape (poikilocytosis), and cytoplasm (basophilic stippling, pathologic sideroblasts);

(b) neutrophil nuclear or organelle structure (cytoplasmic hypogranulation, nuclear hypolobulation or hyperlobulation, and condensation)

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Blast percentage in:

AML:
MDS:

Blast percentage in:

AML: 20% or more
MDS:5%–20%

The use of an arbitrary boundary of 20% blasts has no pathobiologic basis.

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# TRUE OR FALSE In severe inflammatory states with leukemoid reactions, the marrow myeloblast percent is usually increased .

FALSE In severe inflammatory states with leukemoid reactions, the marrow myeloblast percent is usually **DECREASED** because in this circumstance, precursor cell expansion in the myelocyte pool is far greater, such that the percent of blast cells decreases.

# TRUE OR FALSE Three percent or 4% blast cells in the marrow at the time of presentation, after therapy, or suspected relapse should not be considered “normal” and is evidence of leukemic hematopoiesis.

TRUE **Three percent or 4% blast cell**s in the marrow at the time of presentation, after therapy, or suspected relapse should **not be considered “normal”** and is evidence of leukemic hematopoiesis.

# TRUE OR FALSE Polycythemia vera and essential thrombocythemia show morphologic evidence of leukemic hematopoiesis

FALSE Polycythemia vera and essential thrombocythemia **DO NOT show morphologic evidence of leukemic hematopoiesis** ## Footnote The proportion of blast cells in the marrow is never increased above normal, and blast cells are never present in the blood.

# Percentage of Janus kinase 2 (JAK2) gene mutation in: PV: ET:

PV: 95% ET: 50%

Other mutations in ET aside from JAK2

Wild-type JAK2 gene Calreticulin (CALR) gene Myeloproliferative leukemia virus gene (MPL)

The most constant feature in primary myelofibrosis

Abundance of neoplastic, dysmorphic megakaryocyte Predisposition to marrow reticulin and collagen fibrosis, osteosclerosis, extramedullary fibrohematopoietic tumors, splenomegaly, and teardrop-shaped red cells (dacryocytes) in virtually every oil immersion field ## Footnote The megakaryocytic abnormalities are so dominant and consistent in this disorder that it could be considered **chronic megakaryocytic leukemia**

Gene mutations in PMF

JAK2 gene (50%) CALR gene (30%) MPL mutation (10%)

Percentage with “triple negative” mutation in PMF

10%

Cause of fibrosis in PMF

Cytokines released by neoplastic (leukemic) megakaryocytes

Gene mutation in CML

Translocation t(9;22) (q34;q11)(BCR-ABL1 [Abelson murine leukemia viral oncogene homologue 1]) ## Footnote Philadelphia chromosome, now called the Ph chromosome

Percentage of patients with CML with t(9;22) mutation

90%

Percentage of CML patients do not have the rearrangement

Primary myelofibrosis terminates in acute leukemia in approximately _____% of patients.

15%

# TRUE OR FALSE Therapy is required in all cases of CML and primary myelofibrosis at the time of diagnosis.

FALSE Therapy is required in **all cases of CML**, and in **most, but not all, cases of primary myelofibrosis** at the time of diagnosis.

Gene mutation in Chronic neutrophilic leukemia

Colony-stimulating factor 3 receptor gene (CSF3R) 30% CSF3R and a SET binding protein gene (SETBP1) mutation 60% JAK2 V617F mutation 10%

Previous name of Chronic eosinophilic leukemia

Hypereosinophilic syndrome with evidence of clonal hematopoiesis involving eosinopoiesis

Gene mutation in Chronic eosinophilic leukemia

PDGFR-β gene PDGFR-α gene (FIP1L1–PDGFR-α fusion gene)

Treatment for Chronic eosinophilic leukemia

Imatinib mesylate (or a congener)

FIP1L1–PDGFR-α fusion gene mutation is inferred by

Deletion in the CHIC2 gene ## Footnote detected during FISH

# TRUE OR FALSE A clonal myeloid syndrome that includes eosinophilia and a translocation between 8p11, at the site of the tyrosine kinase domain of the fibroblast growth factor receptor-1 (FGFR1) gene, and several different partner chromosomes, is responsive to imatinib mesylate

FALSE A clonal myeloid syndrome that includes eosinophilia and a **translocation between 8p11**, at the site of the **tyrosine kinase domain of the fibroblast growth factor receptor-1 (FGFR1) gene**, and several different partner chromosomes, is **NOT responsive to imatinib mesylate**

Gene mutation in Systemic mastocytosis

KIT gene mutation

# KIT V560G or KIT D816V is sensitive to imatinib mesylate

KIT V560G ## Footnote KIT D816V is insensitive to imatinib but may be responsive to second-generation tyrosine kinase inhibitors.

These disorders fall into a group that **progresses less rapidly than acute leukemia and more rapidly than CML**; have a predisposition to develop with a granulocytic and monocytic phenotype, either morphologically or cytochemically

SEVERE-DEVIATION CLONAL MYELOID DISEASES ## Footnote Include oligoblastic myelogenous leukemia (formerly designated refractory anemia with excess blasts), chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia

Characteristics of atypical myeloproliferative disease or atypical CML (aCML)

* Seen in older patients (>65 years) * Low myeloblast percentage in marrow (<5%) and blood * Never have a rearrangement in the BCR gene * Not responsive to tyrosine kinase inhibitors * Have a poor prognosis (median survival of 5–20 months)

Atypical myeloproliferative disease (aCML) has a relatively high frequency of ______ gene mutations

CSF3R

# TRUE OR FALSE In AML, knowing the cytogenetic alteration is useful for estimating the probability of entering a sustained remission (risk category)

TRUE In AML, knowing the cytogenetic alteration is useful for estimating the probability of entering a sustained remission (risk category)

Cytogenetics in AML with favorable outcome; more likely to enter a prolonged remission or be cured with therapy

t(8;21) t(15;17) t(16;16) inv(16)

Treatment for patients with t(15;17) AML

All-trans-retinoic acid and arsenic trioxide

Useful for determining subclinical (minimal) residual disease and monitoring therapy in cases in which an appropriate genetic marker is available, such as the t(8;21) or t(15;17)

Polymerase chain reaction

Gene expression studies in AML are important because:

(a) identify genes that cooperate or interact to result in a fully malignant phenotype, (b) provide potential new targets for therapy, (c) help identify patients who might benefit from early hematopoietic stem cell transplantation, (d) may be used to measure minimal residual disease, and (e) may permit analysis of the mutational evolution from the earliest neoplastic cell without malignant potential to cells with additional mutations capable of developing lethal clones

# TRUE OR FALSE Currently, prognostic group stratification of AML has value, principally in assessing the utility of using allogeneic hematopoietic stem cell transplantation as an early therapy.

TRUE Currently, prognostic group stratification of AML has value, principally in assessing the utility of using allogeneic hematopoietic stem cell transplantation as an early therapy.

Likelihood of clonal myeloid disases progressing to florid (polyblastic) AML (a very-severe-deviation neoplasm) PNH: Clonal anemia: Clonal bi- or tricytopenia: Oligoblastic myelogenous leukemia: ET: PV: PMF:

PNH: less than 1% Clonal anemia: 10% Clonal bi- or tricytopenia: 35% Oligoblastic myelogenous leukemia: 66% ET: 5% (rises to 10% over 25 years) PV: 12% PMF: 20% ## Footnote Virtually all patients with CML have the potential to progress to acute leukemia of any subtype, including in about a quarter of cases to lymphoid phenotypes

Likelihood of polycythemia vera evolving to a syndrome indistinguishable from primary myelofibrosis

15%

Term used for **exposures** that result in the development of AML, presumably without a preexisting predisposing mutation, such as exposure to **chemotherapy or radiation therapy**

Secondary AML

Term used for AML that results from clonal evolution of a less advanced neoplasm (eg, CHIP, CHOP, CCUS, MDS, CMML, CNL, or a MPN)

ceAML (clonal evolution to AML)

# TRUE OR FALSE A severe block in maturation is characteristic of AML, whereas a high proportion of leukemic primitive multipotential cells mature into terminally differentiated cells of all lineages in patients with CML.

TRUE A severe block in maturation is characteristic of AML, whereas a high proportion of leukemic primitive multipotential cells mature into terminally differentiated cells of all lineages in patients with CML.

AML associated with tissue infiltration, including into the CNS

Monocytic leukemia

AML associated with disseminated intravascular coagulation, fibrinolysis, and hemorrhage

Promyelocytic leukemia *Monocytic leukemia (to lesser extent)

AML associated with hepatosplenomegaly

Eosinophilic leukemia

AML associated with mediator-release syndromes

Basophilic or mast-cell leukemia

AML associated with predisposition to myeloid sarcomas

AML with t[8;21] or inv[16] cytogenetic abnormalities

AML associated with intense marrow fibrosis

Megakaryocytic leukemia

Identification of markers unique for erythroid cells

CD 71

Identification of markers unique for megakaryocytic cells

CD41, CD42, or CD61

Gene mutation in Paroxysmal nocturnal hemoglobinuria

PIG-A gene on the active X chromosome ## Footnote The mutation causes a highly specific alteration in blood cell membranes, a deficiency in the **glycosylphosphatidylinositol anchor**, with **decreased cell-surface CD59**, rendering the blood cells exquisitely sensitive to complement lysis.

Discrete tumors of leukemic cells that form in skin and soft tissues, breast, periosteum and bone, lymph nodes, mediastinum, lung, pleura, gastrointestinal tract, gonads, urinary tract, uterus, central nervous system, and virtually any other site

Myeloid (granulocytic) sarcomas (also called chloromas or myeloblastomas)

One of four histopathologic patterns usually is evident by immunocytochemistry in Myeloid (granulocytic) sarcomas

Myeloblastic, monoblastic, myelomonoblastic, or megakaryoblastic

AML with these cytogenetics has a predisposition to form myeloid sarcomas

t(8;21) and inv(16)

Patients with this type of AML has more diffuse collections of leukemic promonocytes or monoblasts can invade the skin, gingiva, anal canal, lymph nodes, CNS, or other tissues

Monocytic subtype

AML with features of microvascular thrombosis

Acute promyelocytic Acute monocytic Acute myelomonocytic leukemia

A very rare presenting feature or complication of leukemia but has occurred in the setting of hyperleukocytosis and as a presenting feature of acute promyelocytic leukemia.

Large-vessel arterial thrombosis

Proportion of patients with AML and CML that manifest extraordinarily high blood leukocyte counts.

AML (5%–15%) CML (10%–20%)

Hyperleukocytic Syndromes occur when counts are greater than: AML: _____________ CML: ______________

AML:100 × 109/L CML:300 × 109/L

In AML with hyperleukocytosis, _________________ and _________________ are the most serious manifestations in predicting early death

Intracerebral hemorrhage and the impairment of pulmonary function

# TRUE OR FALSE In CML, there is a very close negative correlation of hematocrit with leukocrit, preventing an increase in bulk viscosity.

TRUE In CML, there is a very close negative correlation of hematocrit with leukocrit, preventing an increase in bulk viscosity.

Initial management of hyperleukocytosis

Hydration, leukapheresis, and/or cytotoxic therapy

A consequence of rapid cell lysis, usually as a result of cytotoxic therapy, and the resultant release of potentially toxic intracellular contents, resulting in **hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia**

Tumor Lysis Syndrome

It has been proposed that the risk of tumor lysis syndrome can be predicted most accurately by the ______________ level

Serum uric acid

Another marker of high tumor burden

Serum lactic dehydrogenase

The major vascular manifestations of thrombocythemia

Arterial vascular insufficiency and venous thromboses

Patients with essential thrombocythemia who have the _________ mutation have a significantly **lower risk of thrombotic disease**

CALR mutation

Thrombotic complications occur in approximately _____% of patients with polycythemia vera.

40%

Erythrocytosis and thrombocytosis may interact and cause hypercoagulability, especially in the _________________ circulation.

Abdominal venous circulation

Nearly ____________ of patients with paroxysmal nocturnal hemoglobinuria have thrombosis, especially in the venous system.

Half

# TRUE OR FALSE Thrombosis is more common in patients with paroxysmal nocturnal hemoglobinuria–aplastic anemia hybrid than in those with the paroxysmal nocturnal hemoglobinuria with the classical hemolytic syndrome

FALSE **Thrombosis** is more common in patients with paroxysmal nocturnal hemoglobinuria with the **classical hemolytic syndrome** than in those with the paroxysmal nocturnal hemoglobinuria–aplastic anemia hybrid

# TRUE OR FALSE Fever during cytotoxic therapy, when neutrophil counts are extremely low, is nearly always a sign of infection

TRUE Fever during cytotoxic therapy, when neutrophil counts are extremely low, is nearly always a sign of infection

Acid–base disturbances occur in approximately 25% of patients, the majority having _______________.

Respiratory or metabolic alkalosis

FACTITIOUS LABORATORY RESULTS in leukemia

High K Low glucose Low arterial blood oxygen

# TRUE OR FALSE In AML, palpable splenomegaly is present in approximately one-third of cases, but usually is slight in extent.

TRUE In AML, palpable splenomegaly is present in approximately **one-third** of cases, but usually is **slight in extent**.

# Percentage of splenomegaly in MPNs: PV: CML: PMF: ET:

PV: 80% CML: 90% PMF: 100% ET: 30%

# TRUE OR FALSE Extensive marrow necrosis, an uncommon event, can occur in any clonal myeloid disease, especially AML, and less often, primary myelofibrosis, CML, essential thrombocythemia, and polycythemia vera.

TRUE Extensive **marrow necrosis**, an uncommon event, can occur in any clonal myeloid disease, especially **AML**, and less often, primary myelofibrosis, CML, essential thrombocythemia, and polycythemia vera.

Most common symptoms in marrow necrosis

Bone pain and fever ## Footnote **Anemia and thrombocytopenia** are very common, as are nucleated red cells and myelocytes in the blood **(leukoerythroblastic reaction)**

Findings in marrow necrosis

Hypocellularity with loss of marrow cell structural definition (blurred staining of residual cells), evidence of cell necrosis, gelatinous transformation of marrow, and, often, an amorphous eosinophilic material throughout

The mechanism in marrow necrosis

Microvascular dysfunction

82 Classification and Clinical Manifestations of the Clonal Myeloid Disorders Flashcards

(98 cards)