82 Classification and Clinical Manifestations of the Clonal Myeloid Disorders Flashcards
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
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)
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
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
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
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
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)
A somatic mutation in which an unequivocally abnormal cytopenia is or cytopenias are present
Clonal cytopenia of unknown significance (CCUS)
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
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.
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.
Most frequent specific gene mutations which make up about 75% of CHIP
DNMT3A, TET2, ASXL1, and JAK2
12 specific gene mutations so far identified
Mutations that are more frequently detected in secondary AML, following MDS or CMML
TET2
ASXL1
Associated with deletions in the long arm of chromosome 11 and with the presence of ring sideroblasts in MDS.
SF3B1
The variant allele frequency (VAF) by definition is above ____ %
Above 2%
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
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
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.
The vascular occurrences in CHIP may relate to the mutations of genes such as __________
TET2 and JAK 2
Defined as an idiopathic cytopenia(s) without a detectable somatic mutation.
Idiopathic cytopenias of undetermined significance (ICUS)
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
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
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)
(c) platelet variation in size (megathrombocytes) and granulation (hypogranulation or abnormal granulation)
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.
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 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 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
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
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])
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
4%
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
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
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
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%
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
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
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
