85 Primary Myelofibrosis Flashcards
TRUE OR FALSE
The the fibrosis in PMF is secondary, not primary
TRUE
The the fibrosis in PMF is secondary, not primary
The only cancer in the medical lexicon not so designated; rather, it is named for an epiphenomenon in the extracellular matrix
PMF
Central pathologic change in PMF
Neoplastic (dysmorphic) megakaryocytopoiesis
Mutations in PMF
50% JAK2 gene
25% Calreticulin (CALR) gene
~5%Thrombopoietin receptor (C-MPL) gene
Percentage of triple-negative PMF
10%
In infants, the disorder can mimic the classic disease or show certain features but not others, such as ________________
Absence of hepatosplenomegaly
TRUE OR FALSE
In young and middle-age adults, PMF is similar to that in older subjects, although the proportion of indolent cases may be higher, and the disease occurs in boys twice as frequently as in girls.
FALSE
In young and middle-age adults, PMF is similar to that in older subjects, although the proportion of indolent cases may be higher, and the disease occurs in girls twice as frequently as in boys.
TRUE OR FALSE
In adults, the disease occurs with about equal frequency in men as in women.
TRUE
In adults, the disease occurs with about equal frequency in men as in women.
Exposure to high concentrations of __________ or __________________ preceded the development of PMF in a very small number of cases in the past.
Benzene
Very-high-dose ionizing radiation
Benzene in exposures greater than __________ is associated with an increased relative risk of acute myelogenous leukemia (AML) but not of chronic myelogenous leukemias.
40–200 ppm-years
TRUE OR FALSE
Most lymphocytes, and especially most long-lived T-lymphocytes are formed before acquired JAK2 V617F mutational event and are thus not part of PMF clone.
TRUE
Most lymphocytes, and especially most long-lived T-lymphocytes are formed before acquired JAK2 V617F mutational event and are thus not part of PMF clone.
JAK2 gene mutation in exon 12 account for _____ of PMF
~1%
JAK2 V617F is a dominant, gain-of-function mutation in the gene residing on chromosome _________
Chromosome 9p24
Percentage of JAK2 Mutation in:
PV:
PMF:
ET:
Percentage of JAK2 Mutation in:
PV: 98%
PMF: 60%
ET: 55%
Absent in most healthy individuals
A negative regulator of three important pathways in hematopoiesis—JAK2/STAT5, AKT, and MAPK—as well as in inflammation
LNK protein
Non-Driver Somatic Mutations that predict an inferior prognosis
ASXL1/SRSF2
Non-Driver Somatic Mutations associated with progression to AML from an MPN
RUNX1, TP53, NRAS, WT1, FLT3, IDH1/2, and TET2
High levels of fibroblastic factors __________________ resulted in intense fibrosis in animal models.
TGF-β 1 and platelet-derived growth factor [PDGF]
Increased ______________ was thought to be the principal cause of osteosclerosis
Osteoprotegerin
In PMF, it is the most prominent alteration in this clonal myeloid disease and is responsible for most of its major manifestations
Neoplastic megakaryopoiesis
Constitutive mobilization and circulation of CD34+ cells are prominent features of the clonal expansion.
TRUE OR FALSE
Microvessel density and marrow blood flow are increased in patients with PMF.
TRUE
Microvessel density and marrow blood flow are increased in patients with PMF.
Causes of anemia in PMF
- Decreased erythropoiesis
- Shortened red cell survival
- Effects of splenomegaly on the distribution of red cells in the circulation
- Hemolysis
Synonym for PMF
Megakaryocytic myelosis
Chronic megakaryocytic leukemia
Four of the five major types of collagen are present in normal marrow:
- Type I in bone
- Type III in blood vessels
- Types IV and V in basement membranes
The fine reticulin fibers that appear after silver impregnation of marrow are principally _________ collagen
Type III collagen
They do not stain with trichrome dyes
The thicker collagen fibers are principally ____________ collagen and stain with trichrome dyes, but do not impregnate with silver.
Type I collagen
Collagen types I, III, IV, and V are increased in PMF , but _______________ is increased uniformly and preferentially.
Type III collagen
In terms of fibroplasia, all are increase except for
Collagenase
Plasma level of matrix metalloprotein III
Marrow fibrosis in PMF is most closely correlated with _____________________.
Increased neoplastic and dysmorphic megakaryocytes in the marrow
TRUE OR FALSE
The increased pathologic emperipolesis (the entry of neutrophils and other marrow cells into the canalicular system of megakaryocytes), evident in human PMF and in mouse models, suggests this may be an additional mechanism of α-granule injury and release of TGF-β and PDGF.
TRUE
The increased pathologic emperipolesis (the entry of neutrophils and other marrow cells into the canalicular system of megakaryocytes), evident in human PMF and in mouse models, suggests this may be an additional mechanism of α-granule injury and release of TGF-β and PDGF.
TRUE OR FALSE
The fibroblastic proliferation in marrow is not an intrinsic part of the abnormal clonal expansion of hematopoiesis.
TRUE
The fibroblastic proliferation in marrow is not an intrinsic part of the abnormal clonal expansion of hematopoiesis.
Extramedullary hemopoiesis is almost always present in what organs
Liver and spleen
Pathophysiology of extramedullary hematopoiesis
Escape of progenitor cells from marrow and their lodgment in other organs
TRUE OR FALSE
Reversion of the liver and spleen to their fetal hematopoietic functions (metaplasia) is a major factor in extramedullary hematopoiesis, and quantitatively significant, effective hematopoiesis occur outside of the marrow
FALSE
Reversion of the liver and spleen to their fetal hematopoietic functions (metaplasia) is NOT a MAJOR factor in extramedullary hematopoiesis, and quantitatively significant, effective hematopoiesis DOES NOT occur outside of the marrow
The most frequent self-reported complaint and is disproportionate to the degree of anemia.
Fatigue
Severe left upper quadrant or left shoulder pain can occur from __________________
Splenic infarction and perisplenitis
Occasionally, bone pain is prominent, especially in the ________________.
Long bones of the lower extremities
Fatigue, weight loss, cachexia, night sweats, and bone pain are more frequent later in the course of the disease and are related to the ______________________ that are a key feature of the disease
Increase in circulating inflammatory cytokines
TRUE OR FALSE
Splenomegaly is present on palpation or imaging studies in some of patients at the time of diagnosis, and hepatomegaly is detectable in two-thirds of patients.
FALSE
Splenomegaly is present on palpation or imaging studies in almost ALL patients at the time of diagnosis, and hepatomegaly is detectable in TWO-THIRDS of patients.
Proportion of splenomegaly
Mildly:
Moderately enlarged:
Massive:
Mildly: one-fourth
Moderate: half
Massive: one-fourth
A syndrome that closely mimics the raised and tender plaques of Sweet syndrome
Neutrophilic dermatosis
- The dermatopathology of neutrophilic dermatosis is different from leukemia cutis and is unrelated to infection or vasculitis.
- The predominant histologic lesion is an intense polymorphonuclear neutrophilic infiltrate.
These cutaneous lesions in PMF may have myeloid cells with giant cells carrying ________ markers characteristic of megakaryocytes
CD61
Percentage of patient with Prefibrotic Primary Myelofibrosis
Without overt reticulin fibrosis in the marrow
25%
Constant finding in prefibrotIc PMF
Thrombocytosis
The most important distinction or prefibrotIc PMF with ET
In PMF, bizarre changes are evident with wide variation in megakaryocyte size, from very small to giant size cells.
Nuclear lobulation is abnormal, with bulky multilobulation, hypolobulation, and free megakaryocyte nuclei in the marrow spaces.
In ET, megakaryocytes are increased, but they do not display the dysmorphia observed in PMF.
Symptoms or signs leading to diagnosis of Extramedullary (Fibrohematopoietic) Tumors
(1) identification of a mass on imaging regardless of location
(2) appearance of signs or symptoms of an effusion in the thorax or abdomen
(3) unexpected neurologic signs
(4) another finding that appears unexpected in a patient with PMF
TRUE OR FALSE
Portal vein thrombosis is a complication of PMF and occasionally precedes disease onset.
TRUE
Portal vein thrombosis is a complication of PMF and occasionally precedes disease onset.
TRUE OR FALSE
Abnormalities of humoral immune mechanisms have been observed in as much as half of patients with PMF.
TRUE
Abnormalities of humoral immune mechanisms have been observed in as much as half of patients with PMF.
Causes of nonclonal secondary myelofibrosis
Lupus erythematosus, Vasculitis, polyarteritis nodosa, ulcerative colitis, scleroderma, biliary cirrhosis, Sjögren syndrome, and acute reversible myelofibrosis responsive to glucocorticoids
Imaging that can uncover evidence of new bone formation and periosteal thickening (osteosclerosis)
MRI
Imaging that provide evidence for increased bone formation, bone thickening, and higher proportions of cancellous and of woven bone.
Lumbar spine dualenergy x-ray absorption studies and quantitative computed tomography
Approximately _____ of patients with PMF will experience a significant thrombotic event during the ___________ of the disease.
10%
First four years
The two principal risk factors for thrombosis are :
Elevated leukocyte count and age
Not platelet count
The combination of the JAK2 mutation, leukocytosis, and age predicted the highest incidence of thrombosis.
The JAK2 mutational analysis is positive in: (%)
Idiopathic hepatic vein thrombosis:
Idiopathic portal vein thrombosis:
Idiopathic hepatic vein thrombosis: 35%
Idiopathic portal vein thrombosis: 25%
TRUE OR FALSE
Normocytic–normochromic anemia is present in all patients with PMF
FALSE
Normocytic–normochromic anemia is present in most, but not all, patients
Anisocytosis and poikilocytosis are a constant finding.
TRUE OR FALSE
In some cases, teardrop-shaped red cells (dacrocytes) are present in sufficient number to be found in few oil immersion field
FALSE
In all cases, teardrop-shaped red cells (dacrocytes) are present in sufficient number to be found in every oil immersion field
Approximately ________% of patients present with pancytopenia because of severe impairment of hematopoiesis affecting each cell lineage, coupled with sequestration in a massively enlarged spleen.
10%
Pancytopenia usually is associated with intense marrow fibrosis.
The________________________in the blood is correlated with the extent of marrow reticular fiber density
Frequency of hematopoietic progenitor cells in the blood
Megakaryocytes also are present in the systemic venous blood.
An (Increase/Decrease) in blood CD34+ cells is very characteristic of PMF, and the concentration of these cells lends weight to the diagnosis.
Increase
The height of the CD34+ cell count is correlated with the extent of disease and disease progression.
A concentration greater than __________ blood CD34+ cells is virtually diagnostic of PMF
15 × 10 6 /L
Patients with greater than ___________ CD34+ cells have more rapid progression of disease than patients with fewer CD34+ cells.
Greater than 300 × 10 6 /L CD34+ cells
CD34+ cells have impaired in vitro differentiation to natural killer cells, which appears to be related to a dysregulation in control of _______
IL-15
Stain for collagen fibrosis; characteristically stains green
Gomori trichrome stain
Characteristic of megakaryocytes in BMA of PMF
Giant megakaryocytes and micromegakaryocytes, abnormal nuclear lobulation, and naked megakaryocyte nuclei
Thrombopoietin receptors are (decreased/increased) on megakaryocytes and platelets.
Decreased
Characteristic of granulocytes in BMA of PMF
Hyperlobulation and hypolobulation of the nucleus, acquired Pelger–Huët anomaly, nuclear blebs, and nuclear–cytoplasmic maturation asynchrony
Microvessel density is significantly (decreased/increased) in approximately 70% of patients
Increased
Scale used in grading of the degree of PMF
Bauermeister scale (0-4)
European grading scale (0–3)
Marrow finding in prefibrotic stage
Increased proportion of late neutrophil precursors (myelocytes, metamyelocytes, bands)
Myeloblasts and CD34+ cells are inconspicuous
Erythropoiesis may be slightly decreased
Increased and abnormal megakaryocytopoiesis :hallmark of this phase
Chromosome abnormalities of hematopoietic cells are evident in approximately______of patients at the time of diagnosis.
40%
Most frequent cytogenetic findings
- partial trisomy 1q
- Interstitial deletion of a segment of the long arm of chromosome 13
- del(13)(q12–22), which bears the retinoblastoma gene
- del 20q
- trisomy 8
The______abnormality is more prevalent in PMF than any other MPNs.
5q–
Cytogenetic findings that are associated with PMF but are not exclusively seen in patients with PMF.
del(13) and der(6)t(1;6)(q21–23;p21.3)
15% of patients present with unfavorable karyotypes namely:
Three or more abnormalities
+9
–7/7q–
5/5q–
i(17q)
inv(3)
12p–
11q23
An unfavorable karyotype is associated with a ___________greater risk of acute leukemic transformation than a favorable karyotype.
Sixfold
Finding on MRI of PMF as cellularity and fibrosis progress
Hypointensity of T1-weighted and T2-weighted images
TRUE OR FALSE
MRI can identify the uncommon periosteal reactions that usually occur in the distal femur, proximal tibia, or ankle.
TRUE
MRI can identify the uncommon periosteal reactions that usually occur in the distal femur, proximal tibia, or ankle.
The reactions represent expansion of marrow cellularity into normally inactive regions of long bones or extramedullary spaceoccupying lesions of fibrohematopoietic tissue.
MRI finding of patchy or diffuse osteosclerosis
“sandwich vertebrae”
The findings of sodium-fluoride positron emission tomography can be virtually specific for osteosclerosis of PMF
INCREASE OR DECREASE:
Serum levels of uric acid, lactic dehydrogenase, bilirubin, alkaline phosphatase, and high-density lipoprotein
INCREASE
INCREASE OR DECREASE
Serum levels of albumin and cholesterol
DECREASE
Serum________________ is often decreased and is a negative prognostic factor
Cholesterol
INCREASE OR DECREASE
Thrombopoietin and IL-6
Serum-soluble IL-2 receptor and serum VEGF
Urinary excretion of calmodulin
INCREASED
Thrombopoietin and IL-6 do not correlate with either platelet or megakaryocyte mass.
TRUE OR FALSE
In PMF, the white cell count usually is less than 30 × 109/L at the time of diagnosis.
TRUE
In PMF, the white cell count usually is less than 30 × 10 9 /L at the time of diagnosis.
In CML, the white cell count is usually greater than 30 × 10 9 /L in almost all patients and greater than 100 × 10 9 /L in half of patients.
Condition characterized by intense marrow fibrosis and an increase in marrow polyclonal T and B lymphocytes.
Primary autoimmune myelofibrosis
Conditions that can induce reactive marrow fibrosis and occasionally simulate PMF
- Metastatic carcinoma, especially a primary carcinoma of breast or prostate
- Disseminated mycobacterial infection
TRUE OR FALSE
All clonal hematopoietic diseases (AML, CML, oligoblastic myelogenous leukemia [myelodysplastic syndrome], lymphomas) may have increased marrow reticulin fibers but only infrequently have collagen fibrosis.
TRUE
All clonal hematopoietic diseases (AML, CML, oligoblastic myelogenous leukemia [myelodysplastic syndrome], lymphomas) may have increased marrow reticulin fibers but only infrequently have collagen fibrosis.
Leukemia accompanied by intense marrow fibrosis
Acute megakaryoblastic leukemia
Transition into PMF
PV:
ET:
Transition into PMF
PV: 15%
ET: 7-15%
The principal initial reasons for therapy
Constitutional symptoms, anemia, thrombocytopenia, and splenomegaly
Predictors of more rapid progression of disease
- Hemoglobin less than 100 g/L
- White blood cell count less than 4.0 × 10 9 /L or greater than 30.0 × 10 9 /L
- Patelet count under 100 × 10 9 /L
- Bllasts above 1% of total leukocytes
Staging prognostic systems used in PMF
Dynamic international prognostic scoring system (DIPSS plus)
Componennt of Dynamic international prognostic scoring system (DIPSS plus)
- Age older than 65 years
- Constitutional symptoms
- White blood cell count over 25 × 10 9 /L
- Hemoglobin less than 100 g/L
- Blood blasts greater than 1%
- Unfavorable karyotype, including +8, -7/7q-, i(17q), -5/5q-, 12p-, inv(3), or 11q23 rearrangement
- Transfusion dependency;
- Platelet count lower than 1 × 10 9 /L
Options for treatment of anemia in PMF
- BT
- Recombinant erythropoietin
- Luspatercept
- Androgen therapy
TRUE OR FALSE
Use of erythropoietin for anemia is usually disappointing in over 50% of PMF patients.
TRUE
Use of erythropoietin for anemia is usually disappointing in over 50%of PMF patients.
Patients selected by their inappropriately low serum erythropoietin levels (<125 U/L) for the degree of anemia—beneficial effects can result.
A recombinant protein that is composed of a modified extracellular domain of activin receptor type IIb linked to the IgG1 fc domain. It inhibits several ligands in the TGF-β superfamily.
This inhibition results in an accelerated maturation and proliferation of LATE erythroid precursors.
Luspatercept
Administered subcutaneously in doses up to 1.75 mg/kg every 21 days
Side effects of Luspatercept
High blood pressure (11%)
Bone pain (8%)
Diarrhea (4%)
TRUE OR FALSE
Severe anemia may improve with androgen therapy in some patients but, generally, it is less effective than erythropoietin.
TRUE
Severe anemia may improve with androgen therapy in some patients but, generally, it is less effective than erythropoietin.
Dose of Danazol
Danazol 600–800 mg/day orally for up to 6 months
The drug is tapered to the minimum effective dose or discontinued if no significant response occurs.
TRUE OR FALSE
Androgens are less effective in splenectomized patients or those with less splenic enlargement.
FALSE
Androgens are more effective in splenectomized patients or those with less splenic enlargement.
Patients undergoing androgen therapy should have periodic assessment of ________ size by physical examination, measurement of_________ and, if appropriate, ultrasonographic imaging
Liver
Liver function tests
TRUE OR FALSE
Evaluation of male patients for prostatic enlargement or cancer is prudent before starting androgen therapy.
TRUE
Evaluation of male patients for prostatic enlargement or cancer is prudent before starting androgen therapy.
Patients with significant hemolytic anemia may benefit from
Glucocorticoid therapy
Prednisone 25 mg/m2 per day
If tolerated, the dose can be continued for 1–2 months and then tapered gradually.
In children, high-dose glucocorticoid therapy can ameliorate marrow fibrosis and improves hematopoiesis.
The most striking and consistent effect with JAK2 V617F Kinase Inhibitors
Decrease in spleen size and reversal of constitutional symptoms
JAK2 Inhibitors often suppress blood cell counts, and _______________& can be dose-limiting.
Thrombocytopenia
In 2011, _____________, an oral JAK2 inhibitor, was approved by the FDA for use in patients with intermediate- or high-risk PMF.
Ruxolitinib
Ruxolitinib should not be administered if platelet counts fall to less than ______________
50 × 10 9 /L
Drug not FDA approved for starting platelet counts of 50–100 × 10 9 /L
Dose of Ruxolitinib
PC >200
20 mg BID
Dose of Ruxolitinib
PC 100-200
15 mg BID
Dose of Ruxolitinib
PC 50-100
5 mg twice daily
Increasing each month by 5 mg daily until maximal splenic size reduction, only if platelet count stays above 40 × 109/L
JAK32 inhibitor that crosses the brain barrier and unlike in ruxolitinib therapy, Wernicke encephalopathy has been encountered with this therapy, and thiamine deficiency needs to be ruled out before initiation of therapy
Fedratinib
If encephalopathy is suspectedin Fedratinib, ____________ therapy must be initiated
Parenteral thiamine
Indications for using Hydroxyurea
- Exaggerated accumulation of platelets
- Occasional very high leukocyte counts
- Troublesome areas of extramedullary hematopoiesis
- Symptomatic splenomegaly
Dose of Hydroxyurea in PMF
0.5–1.0 g/day or 1–2 g orally 2-3 times per week
Patients on HU should be evaluated for dose adjustment at least _____________ and, if appropriate, eventually extended to evaluation every 3 months.
Every week for one month
TRUE OR FALSE
Thalidomide is poorly tolerated at optimal doses of approximately 800 mg/day.
TRUE
Thalidomide is poorly tolerated at optimal doses of approximately 800 mg/day.
- Most patients receive about half that amount and are tapered to the lowest effective dose.
- In subsequent studies, lower doses of thalidomide (50 mg/day) administered together with prednisone were more tolerable
Drug has also been useful in patients with PMF who have a 5q– cytogenetic abnormality
Lenalidomide
Most troubling side effects of Lenalidomide
Neutropenia and thrombocytopenia
Although largely ineffective in later stages of PMF, it has shown efficacy in the early myeloproliferative stage of PMF with mild to moderate marrow fibrosis
Interferons
Uses of Cytarabine in PMF
Ascites resulting from peritoneal hematopoietic implants has been treated with intraperitoneal cytarabine.
Intrasplenic cytarabine administered via a splenic artery catheter has resulted in significant improvement in a patient
Used in bone pain in PMF
Etidronate 6 mg/kg per day on alternate months
Clodronate 30 mg/kg per day for several months
Indications for radiotherapy
- Severe splenic pain (splenic infarctions)
- Massive splenic enlargement with contraindication to splenectomy (eg, thrombocytosis)
- Treating ascites resulting from myeloid metaplasia of the peritoneum
- Focal areas of severe bone pain (periostitis or the osteolysis of a myeloid sarcoma)
- Extramedullary fibrohematopoietic tumors, especially of the epidural space
Repeated doses of 0.5–2.0 Gy to the spleen can ameliorate the pain.
Splenic radiation can result in further cytopenias or worsening cytopenias, especially thrombocytopenia, referred to as
Abscopal effect
Major indications for splenectomy
(1) painful enlarged spleen (~50% of patients)
(2) excessive transfusion requirements or refractory hemolytic anemia (~25% of patients)
(3) portal hypertension (~15% of patients)
(4) severe thrombocytopenia (~10% of patients)
Splenectomy in PMF
Perioperative mortality:
Postoperative morbidity:
Infection, especially pneumonia:
Perioperative mortality: 10%
Postoperative morbidity: 30 %
Infection, especially pneumonia: 10%
Useful for exaggerated thrombocytosis post splenectomy
Hydroxyurea or aspirin and anagrelide
Leukemic blast transformation occurs in approximately _______of patients after splenectomy.
15%
Median survival after splenectomy
18 months
The only curative approach to PMF.
Hematopoietic cell transplantation
Patients usually considered for transplantation
- Younger than age 50 years, with a DNA-based matched-sibling donor
- Progressive disease
- Poor prognostic findings, such as :
- Hemoglobin less than 100 g/L
- Blast cells greater than 1% of blood cells
- Unfavorable cytogenetics (eg, abnormalities involving chromosome 5, 7, or 17, or cells with three or more abnormalities)
The rate of disease progression is associated with at least 16 variables measured at the time of diagnosis, namely:
1. Older age
2. Severity of anemia
3. Exaggerated leukocytosis (>25 × 10 9 /L) or leukopenia (<4.0 × 10 9 /L)
4. Constitutional symptoms of fever, sweating, or weight loss at the time of diagnosis
5. Proportion of blast cells in the blood (≥1%)
- Male gender
- Severity of thrombocytopenia
- Proportion of CD34+ cells in the blood
- The presence of the V617F mutation in JAK2
- Monocytosis
- A decreased proliferating cell nuclear antigen index and a decreased apoptotic index by in situ end labeling
- Degree of liver enlargement
- Extent of marrow fibrosis
- Postsplenectomy spleen histology
- WT1 expression in CD34+ cells; and
- Certain clonal cytogenetic abnormalities, especially involving chromosome 5, 7, or 17, or with three or more abnormalities
The most consistent predictive variables appear to be advanced age, severity of anemia, and higher-risk clonal cytogenetic abnormality at the time of diagnosis, each of which represents a poor prognostic indicator.
The major causes of death in PMF
Infection, hemorrhage, postsplenectomy mortality, and acute leukemic transformation
Months of survival
Low risk:
Low-intermediate risk:
High-intermediate risk:
High risk:
Low risk: 135 months
Low-intermediate risk:95 months
High-intermediate risk: 48 months
High risk: 27 months
Gene mutations have been associated with prognosis in patients with PMF, either overall survival or risk of conversion to AML
IDH, EZH, ASXLI, and SRSF2
