Leukocyte disorders: part 1- Exam 2 Flashcards
What are some indications to order a bone marrow biopsy?
dx/staging bone marrow disorders
increase or decrease in hematologic cell lines
lymphoma
evaluation of iron metabolism
fever of unknown origin
unexplained splenomegaly
What is the CI to bone marrow biopsy? What is NOT a CI?
severe bleeding disorders
thrombocytopenia is NOT a CI, but you would give a plt transfusion first
What is the preferred site for a bone marrow biopsy? What is the second area?
posterior iliac crest
anterior iliac crest
What sites are commonly used for bone marrow aspiration? Which one is commonly used in infants? morbidly obese?
tibia: MC site used in infants
sternum between 2nd and 3rd ICS: reserved for only >12 yrs old and morbidly obese
_____ a malignant disorder that originates in a single lymphocyte progenitor (lymphoblast) and results from an abnormal expression of genes, often as a result of chromosomal translocation
Acute Lymphoblastic Leukemia (ALL)
**What is the pathophysiology behind ALL?
abnormal lymphoblasts that are resist to death, keeping making more and more, no longer needs the stem cell to replicate, abnormal lymphoblasts in the BM suppress normal hematopoiesis, abnormal lymphoblasts accumulate in other organs and the organs are enlarged upon PE
rapid cell proliferation/self-renewal
reduction in normal cell proliferation
block in cell differentiation
increase resistance in cell apoptosis
What are the risk factors for ALL?
In utero radiation exposure
Chemicals (questionable): pesticides, tobacco, alcohol, nitrites, chemotherapy
High birth weight - increased insulin-like growth factor (IGF - 1)
Lack of exposure to infections in the first few weeks/months of life¹
Only 5% are linked to genetics
______ is MC in children less than 5 years old and older than 60. Most deaths are in what pt population? What ethnicity and gender?
ALL
more deaths in adults
Slightly more common in males
Caucasian > African Americans
What is the clinical presentation of ALL?
fever of unknown origin
related to bone marrow infiltration
neutropenia, anemia, thrombocytopenia
lymphadenopathy
bone pain
LUQ abdominal fullness, early satiety (splenomegaly)
mediastinal mass: chest pain, dysphagia, or dyspnea
swelling of the neck, face, and upper limbs
painless testicular swelling/mass
Leukostasis: WBC> 100K that leads to inadequate circulation
What are some s/s of leukostasis?
HA, altered mental status, blurred vision, dyspnea, priapism
increased risk of intracranial hemorrhage
risk persists for at least 1 week after reduction of WBC
What is the mortality of leukostasis is not treated properly in 2 days?
40% within 2 days
What tests should you order on a pt if you suspect ALL?
CBC
CMP
blood cultures
CXR
CT/MRI of the brain w/o contrast
additional:
peripheral smear
LDH
CT chest with contrast
CSF analysis
Flow cytometry
bone marrow aspiration and biopsy
What will the CBC look like on a pt with ALL?
decreased RBC, platelet and neutrophils
WBC may be normal, high or low
Why do you order a CXR if you suspect ALL?
r/o pneumonia as a source of infection, assess for signs of mediastinal mass
What would you expect to find on a peripheral smear of a pt wit ALL?
pancytopenia with circulating lymphoblasts
Why would you order a chest ct with contrast on a pt with ALL?
assess lymphadenopathy, further assess mediastinal mass
Pt has ALL with neuro s/s and you do a CSF analysis, what would you expect to find? What will flow cytometry show?
(+) lymphoblast cells in CSF - with spinal infiltration of dz.
atypical antigens confirmation
How do you definitively dx ALL?
Bone marrow biopsy with greater than 20% lymphoblasts
What is the management for ALL?
Refer to hematology/oncology
Screen and treat for active infections in febrile patients
ALL treatment begins with “induction chemotherapy” and CNS prophylaxis, followed by post-remission therapy with or without stem cell transplantation
What is the goal of induction chemo? What are the guidelines?
Multi-drug chemotherapy over the course of 4-6 weeks
Initiated in the hospital¹
Goal: remission induction
Complete remission achieved at 65-85%
When treating ALL, _____ is vital during all stages to prevent CNS recurrence
Intrathecal therapy
After the induction phase of chemo, what are the next treatment steps based off of?
Based upon patient age and toleration of
induction chemo
What is the post-remission therapy for young patients with tolerable effects of chemo?
readministration of induction regimen or other high dose chemotherapeutic agents after normal hematopoiesis is restored for 4-8 months
continue less intensive weekly/daily maintenance therapy for 2-3 years
What is the post-remission therapy for older patients or unable to tolerable the effects of chemo?
Allogeneic Stem Cell Transplantation
Patient receives intensive chemotherapy prior to transplant to ensure destruction of as many cancer cells as possible.
IV transplantation of stem cells over an hour
Stem cells travel to the bone marrow and begin to produce new blood cells
What is the management of leukostasis in ALL?
prophylaxis for tumor lysis syndrome via IV hydration and hypouricemic agents
emergent chemotherapy
leukapheresis
For ALL, what is the cure rate in children? Adults?
90% in children
50% in adults
What is considered a relapse for ALL? What is the common timeframe?
a reappearance of leukemic cells at any site
most often occurs within first 2 years
What are good prognostic factors for ALL?
No chromosomal abnormalities¹
Age younger than 39 years
White blood cell (WBC) count of < than 30,000/μL
Complete remission within 4 weeks
What are poor prognostic criteria for ALL?
Chromosomal abnormalities
Age older than 60 years
Precursor B-cell WBCs with WBC count > than 100,000/μL
Failure to achieve complete remission within 4 weeks
_______ a malignant lymphoid neoplasm that is characterized by the accumulation of long-lived, functionally incompetent, small mature B cells
Chronic Lymphocytic Leukemia (CLL)
______ results from dysfunction in the maturation of the B-cell. Results in B-cells that are unable to respond to immunologic stimulation
Chronic Lymphocytic Leukemia (CLL)
_____ is the MC form of leukemia in the US
Chronic Lymphocytic Leukemia (CLL)
_____ mainly occurs after the age of 50, median age of onset is 72
Chronic Lymphocytic Leukemia (CLL)
What is the clinical presentation of CLL?
slow onset
lymphadenopathy
recurrent infections (usually viral)
HSM
anemia/thrombocytopenia
What tests would you order if you suspect CLL? **What will the tests show?
**CBC: WBC >20,000 cell/µL
isolated absolute lymphocytosis (hallmark)
persists for > 3 months
+/- decreased RBC, platelets
peripheral smear: predominantly small mature lymphocytes, (+) smudge cells¹, may see prolymphocytes
CMP: to asses liver/renal function
flow cytometry
bone marrow aspiration/biospy
**What is a hallmark finding on a CBC with a CLL pt?
isolated absolute lymphocytosis (hallmark)
persists for > 3 months
What do you expect to find on a peripheral smear for a CLL pt?
predominantly small mature lymphocytes, **(+) smudge cells¹, may see prolymphocytes
What are the 2 direct predecessor of a B lymphocyte?
small lymphocyte then prolymphocyte
How is a CLL dx confirmed? What would you expect to see?
Peripheral blood via flow cytometry - confirms diagnosis
confirms the presence of various abnormal B-lymphocyte surface antigens
What will the bone marrow bx show of a pt with CLL? Is it required?
infiltrated with small lymphocytes
NOT always required to make diagnosis
**What is the staging system for CLL? Describe how to stage a pt.
Revised Rai staging system
Low risk:
Stage 0: Lymphocytosis alone
lymphocyte > 15,000/μL, and > 40% lymphocytes in the bone marrow
Intermediate risk:
Stage I: Lymphocytosis with enlarged node(s) in any site,
Stage II: splenomegaly or hepatomegaly or both
High risk:
Stage III: Anemia (hemoglobin level < 11.0 g/dL)
Stage IV: Thrombocytopenia (platelets < 100,000/μL)
aka look at blood levels and organs involved to determine stage
LESHAT
What is the management for CLL based on?
staging
If a pt is low risk pt for CLL, what is the management? What would change that?
observation
symptoms would increase risk: worsening fatigue, symptomatic lymphadenopathy/HSM, anemia, or thrombocytopenia
What are treatment options for CLL? What is the curative therapy?
multidrug chemo
growth factors to decrease duration of neutropenia following chemo
allogeneic stem cell transplant:reserved for patients who are not controlled with standard therapies Most elderly patients are NOT able to tolerate transplant after first round of cehmo
splenectomy: indicated for refractory splenomegaly and pancytopenia
stem cell transplant is the only known curative therapy
What are the complications of CLL?
Obstructive lymphadenopathy - compressing on internal organs
Transformation into aggressive large cell lymphoma (Richter Syndrome)
Autoimmune hemolytic anemia or thrombocytopenia¹
a pt with CLL who is a low risk stage, what is the average survival?
Intermediate/high risk?
low: average survival 10-15 years
Intermediate/high risk: 2 year survival is > 90%, 5-year survival is > 70%
_____ A malignant disease of the bone marrow resulting from an arrest in the early development of myeloid precursors
Acute Myelogenous Leukemia (AML)
What is the pathophysiology of AML?
rapid proliferation of myeloblast without differentiation into mature cells
abnormal myeloblasts are resistant to apoptosis
accumulation of myeloblasts in marrow, blood, spleen, liver
reduction of normal hematopoiesis due to marrow accumulation
aka loss of neutrophils, eosinophils, basophils and monocytes
What is the pathogenesis of AML? Who is the MC pt population?
chromosomal translocations and other genetic mutations
median age is 70, white, men, developed countries
What is the MC risk factor for AML? Describe what is happening?
Myelodysplastic Syndrome (MDS)
bone marrow disease of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years
Congenital/Genetic Disorders such as Trisomy 21, Bloom’s syndrome, Fanconi anemia are associated with _____
AML
What would a CBC of a pt with AML show?
**peripheral smear?
decreased RBC, platelet and neutrophils
WBC may be normal, high or low
**pancytopenia with predominantly circulating myeloblasts
**Auer rod - eosinophilic needle-like inclusion in the cytoplasm of myeloblasts
**_____ confirms the presence of AML
auer rod on peripheral smear
What will bone marrow bx look like on a pt with AML?
hypercellular, predominant myeloblasts
How do you differentiate AML from ALL?
flow cytometry: AML will have myeloid antigens on the cell surface and ALL will not
AML work up includes ____ and ______. When are they indicated?
Brain MRI/CT - indicated for neurologic symptoms (leukostasis)
Lumbar Puncture - symptomatic patients only, looking for CNS infiltration, CNS infiltration is rare for pts with AML
What is the broad management for AML?
refer to hem/onc
multi-drug chemo
intrathecal chemo if CNS is involved
AML pts, induction: multi-drug chemotherapy will induce remission in _____ of patients who are < 60 y/o and ____ in patients > 60 y/o
80-90%
50-60%
AML pts: Post-remission therapy includes _____ and/or _____
standard chemotherapy
stem-cell replacement (can be autologous or allogeneic)
What factors contribute towards a good prognosis for AML pts? Poor prognosis factors?
Good:
less than 60 yrs old
remission after first chemo
Poor:
older than 60 yrs old
poor response to first chemo treatment
abnormal genetics/chromosomes detected in AML cells
______ A disorder characterized by dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with normal differentiation
Chronic Myeloid Leukemia (CML)
What is the Philadephia chromosome? What disorder is it associated with?
results from a single specific genetic mutation
translocation t (9:22)
Chronic Myeloid Leukemia (CML)
What is the genetic bcr/abl known as? What does it possess?
translocation t(9:22) - Philadelphia chromosome
bcr/abl gene produces a protein that possess overactive tyrosine kinase (TK) activity
What is TK responsible for? What disorder is it associated with?
controlling cell growth, differentiation, metabolism and apoptosis
Chronic Myeloid Leukemia (CML)
Chronic Myeloid Leukemia (CML) average age of onset is ______. What is associated with?
55 y/o - “middle-aged”
increased risk with exposure to ionizing radiation
What are the phases of CML? Chronic myeloid leukemia
First (chronic)
Second (accelerated)
Third (terminal blast crisis)
CML that is found in the chronic phase is found _____
incidentally
CML in the third “blast” phase, what is happening?
immature myeloid cells rapidly proliferate (fatal)
pruritus, diarrhea, flushing, gastrointestinal ulcers seen with elevated basophils due to overproduction of _____. What disorder are they associated with?
histamine
CML: Chronic myeloid leukemia
What is the clinical presentation of CML?
Fever of unknown origin, bone pain, splenomegaly, signs of leukemia: anemia, neutropenia, thrombocytopenia
What is the MC PE finding for CML?
splenomegaly
What does the CBC of CML patient in the chronic phase look like? accelerated phase?
chronic phase:
average white count 100,000-150,000 cells/μL
granulocytosis with marked increase in mature neutrophils, mild increase in basophils and eosinophils
accelerated phase:
reduced platelets, RBC, increase in myeloblasts
What does the peripheral smear of CML patient in the chronic phase look like? accelerated phase?
chronic phase: confirmation of CBC findings
accelerated phase : peripheral myeloblast cells, promyelocytes visualized
What two “things” are associated with leukostasis?
increased WBC AND signs of end organ damage
What will the Leukocyte Alkaline Phosphatase (LAP) stain tell you? What does it look like in CML?
a type of alkaline phosphatase found inside WBC’s
LAP will be high in an infection
will be DECREASED in CML
**What will a bone marrow biopsy look like in a CML pt?
hypercellular with increased granulocyte cells and their progenitors
Blast phase: >20% blasts compromise BM cells
**What will a PCR test look like with CML?
can be performed on blood or marrow aspirate
identifies bcr/abl DNA segment (aka Philadelphia Chromosome)
What is the definitive way to diagnosis CML?
bone marrow bx and PCR to check for the presence of the Philadelphia Chromosome
What is the management of chronic phase CML?
tyrosine kinase inhibitor - single drug chemotherapy
_____ results in CML cell death leaving healthy cells less affected compared to standard chemotherapy
tyrosine kinase inhibitor
_____ describes the dependency of certain tumor cells on a single activated oncogenic protein or pathway to maintain their malignant properties.
oncogene addiction
What are the parameters in order to be considered in hematologic remission of CML? How long does it normally take?
often seen within 3 months
normal CBC and physical exam
What are the parameters in order to be considered in cytogenetic remission of CML? How long does it normally take?
seen within 3-6 months
normal chromosome returns with < 10 % positive (Ph+) cells
What are the parameters in order to be considered in molecular remission of CML? How long does it normally take?
within 12 months
negative PCR result for the mutational bcr/abl mRNA (absence of Ph+ cells)
How long do you need to continue therapy after molecular remission is reached in CML?
Continue therapy for 2 years after molecular remission is reached
What is the treatment for accelerated or blast phase CML?
TKI + multidrug chemotherapy
consider allogeneic stem cell transplantation
transplant is also indicated if lack of response to TKI
What is the treatment for symptomatic leukostasis?
emergent chemotherapy, leukapheresis, prophylaxis for tumor lysis syndrome
What are some signs of transition from chronic CML to accelerated CML?
splenomegaly
inadequate decrease in granulocytes with standard therapy
blast cells and promyelocytes in peripheral smear
anemia, basophilia and thrombocytopenia
new cytogenetic abnormalities or myelofibrosis seen on bone marrow biopsy
What is the prognosis for CML?
depends on the response to TKI
100% survival at 9 years with good response to TKI
_________ a neoplastic proliferation of plasma cells producing an overproduction of nonfunctional monoclonal immunoglobulins
multiple myeloma
Multiple Myeloma is preceded by a premalignant plasma cell proliferative disorder known as ???? What does it result from?
Monoclonal Gammopathy of Undetermined Significance (MGUS)
abnormal plasma cell response to antigenic stimulation
What are the risk factors for multiple myeloma? Who is at the highest risk?
older age, immunosuppression, and environmental exposures
radiation, benzene, organic solvents, herbicides, and insecticides
median age: 65 years old
M>F
African American > Caucasian/Hispanics > Asian/Pacific Islanders
in MM, Proliferation of neoplastic plasma cells in the bone marrow results in _____
diminished hematopoiesis
What do neoplastic plasma cells of MM look like? What happens as a result?
monoclonal
resulting in a lack of adequate immunoglobulin response to infection
Neoplastic plasma cells increase _____, ______ and _____ formation
osteoclastic activity, hypercalcemia, bone tumor
What do neoplastic plasma cells secrete? What does it harm?
an antibody called myeloma proteins which are harmful to the kidneys, nerves and other organs
What are plasmacytomas? What are they made of specifically?
a discrete solitary mass of neoplastic monoclonal plasma cells found in bone (MC vertebrae) or extramedullary spaces (upper airway/sinus being MC - other soft tissue locations possible)
What is the clinical presentation of Multiple myeloma?
Skeletal system: MC axial
bone pain: MC back, hips and ribs
spinal cord compression: back pain, weakness, numbness, or dysesthesias in the extremities
pathologic fractures
hypercalcemia due to skeletal destruction
signs of anemia, neutropenia, thrombocytopenia
renal: impaired function/failure, proteinuria, oliguria
neuro: radiculopathy or neuro deficits from spinal nerve compression
peripheral nerve compression - MC median nerve (Carpal Tunnel Syndrome)
Plasmacytomas:
bleeding, obstruction
aerodigestive tract (MC), orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal
What will the CBC of MM look like? peripheral blood smear? bone marrow bx?
pancytopenia
RBC rouleaux formation
infiltration by monoclonal plasma cells which are often morphologically abnormal
What are some specific tests that you want to order for multiple myeloma? What will be present to help dx MM?
Serum protein electrophoresis¹ (SPEP):
(+) paraprotein (M-protein) found
24 hour urine collection with urine protein electrophoresis (UPEP):
(+) Bence Jones protein²
Quantitative immunoglobulin levels:
suppression of the non-myelomatous immunoglobulins (IgG, IgA, IgM)
prognostic testing for MM is _____. What does it tell you?
Beta-2 microglobulin
elevated - level is directly related to tumor burden
Why would you order x-rays for MM? Where are the MC places?
assess for lytic lesions and pathologic fractures
MC seen in skull, spine, long bones
What is the management for MM?
chemo
chemo then autologous stem cell transplant (usually in younger patients)
localized radiation: to target bone pain related to tumor formation
stabilize the bone due to pathological fractures
IV steroids/neurosurgery consult to help reduce spinal cord compression
How do you manage bone disease/hypercalcemia in MM?
use bisphosphonates¹ (IV Reclast) in symptomatic patients with intact renal function
How do you manage anemia in MM? renal impairment?
initiate EPO therapy if persistent anemia when other causes have been ruled out
plasmapheresis to remove M-proteins from circulation
What is the prognosis for MM?
Median survival is 3 years
better survival rates in younger patients
