Leukemia and other Myeloproliferative disorders Flashcards
These make up the cellular components of
our immune system
Leukocytes
Innate vs. Adaptive immunity
○ Innate: Present and circulating, always on
the offensive against pathogens
○ Adaptive: Adapt to presence of pathogen by
activating and creating
mechanisms for tagging
Neutropenia
● Abnormally low number of Neutrophils.
● Neutropenic patients are at significantly
increased risk of infection, especially
from bacteria and fungi.
Some Possible causes of neutropenia:
● Aplastic anemia
● Overwhelming septicemia
● Marrow obliteration by malignancy or cancer treatment
● Drugs (more than 70, including PCN,
phenytoin, etc)
● Dialysis
● Folate/Vitamin B12 Deficiency
● Familial neutropenia
● Idiopathic
Neutrophilia
● Increased number of Neutrophils.
● Some causes of neutrophilia are not
pathologic, but just in response to normal physiologic processes.
Some Possible causes of neutrophilia
● Steroid therapy
● Bacterial infection
● Early Viral infection
Lymphocytosis
● Increase in the number of Lymphocytes
Some Possible causes of lymphocytosis
● Viral infections
● Thyrotoxicosis
● Lymphoid leukemia
● Chronic infection
● Drug reactions
● Allergic reactions
● Autoimmune diseases
Lymphocytopenia
● Decreased number of Lymphocytes.
● Lymphocytopenia is considered a normal
variant in about 22% of the healthy
population
Some Possible causes of Lymphocytopenia
● Normal variant
● Idiopathic
● Human Immunodeficiency Virus infection
● AIDS
● Bone marrow suppression after Chemotherapy
● Some drugs
● Burns
● Trauma
Monocytosis
● Increased number of Monocytes.
● Mature Monocytes are phagocytic and a
key player in the innate immune
response
Half of our total
number of Monocytes
are stored in the
____
spleen
Some Possible causes of Monocytosis
● Inflammation
● Infection
● Malignancy
● Tuberculosis
● Myeloproliferative Disorders
Eosinophilia
● Increased number of Eosinophils.
● One of the granulocytes.
● Present in relatively small number
throughout the body.
Some Possible causes of Eosinophilia
● Allergic reactions
● Asthma
● Drug reactions
● Parasitic infections (sometimes)
● Fungal infections (sometimes)
● Addison’s Disease
● Malignancy
Basophilia
● Increased number of Basophils.
● Also one of the granulocytes.
● The least prominent of the white blood
cell type
Circulates in the blood and will release
histamine when stimulated by inflammation or
infection
Basophils
Some Possible causes of basophilia
● Hypersensitivity reactions
● Drug reactions
● Inflammatory reactions
● Chronic myeloid leukemia
● Hodgkin’s Disease sometimes
Malignancy of blood cell origin = ____ Malignancies
Hematologic
Malignancies of the Myeloid Progenitor line (erythrocyte, granulocyte,
platelet) are typically called _____
Myeloid, Myelogenous, or Myeloproliferative
Malignancies of the Lymphoid Progenitor line are typically called
_____
Lymphoid or Lymphoblastic
f the malignancy arose in the bone marrow and may involve the peripheral blood, we refer to it as a ____
Leukemia
Most Acute Leukemias arise with no ____
clear cause
There are two main types of Acute Leukemia:
○ ALL: Acute Lymphoblastic Leukemia
○ AML: Acute Myelogenous Leukemia
Similarities in ALL and AML
Symptoms are very similar
○ Physical exam signs are similar
○ Diagnostic findings are similar, but a few
very important differences (know these!)
○ Treatment is similar as well
_____: Lymphoid Progenitor Cells in the bone marrow become malignant and begin to replicate wildly
ALL
______: Myeloid Progenitor Cells (precursor to RBCs, granulocytes, monocytes, platelets) become malignant and proliferate wildly
AML
May be classified as B-cell or T-cell in origin
ALL
____ is the most common childhood malignancy
ALL
___ has a Known connection to Down Syndrome
ALL
ALL epidemiology
○ Hematologic malignancy commonly referred to as ALL.
○ The incidence of ALL peaks at the age of 5 years (3-7).
AML Epidemiology
○ Hematologic malignancy commonly known as AML.
○ Accounts for 80% of all new cases of adult acute leukemias.
○ Cause is unknown in most cases, but
has been connected to radiation,
chemo, and Down Syndrome.
○ Can be preceded by Myelodysplastic
Syndrome (MDS) or CML
Median age of AML
■ Primarily occurs in adults over 50 years of age (median = 60)
Signs and Symptoms (both AML and ALL)-
○ Most patients have been ill only for days or weeks.
○ Chief complaint may be fever, fatigue, weight loss, irritability, arthralgias, bleeding (often from gums).
○ If CNS involvement, may have headache, stiff neck, visual disturbances, or vomiting
○ Gingival hypertrophy from leukemic infiltration is common
Physical exam of both AML and ALL may reveal
■ Pallor
■ Petechiae
■ Ecchymosis
■ Hepatosplenomegaly (more common
with ALL)
■ Lymphadenopathy (more common
with ALL)
■ Papilledema
■ Retinal hemorrhages
■ Focal neurologic deficits
The most dramatic presentation of acute leukemias is that of ____
Hyperleukocytosis (“Leukostasis”)
Hyperleukocytosis (“Leukostasis”)
Extremely high level of circulating
blasts in the blood leads to clumping of blasts in capillaries
● Impaired circulation
● Headache, confusion
● Dyspnea, respiratory distress
Requires emergent Leukapheresis
and chemotherapy
Acute Leukemias diagnosis
○ Bone Marrow Biopsy: Marrow will be Hypercellular with > 20% Blasts
○ CBC will generally show a normocytic anemia, thrombocytopenia, and often Neutropenia.
○ WBC count can be low, normal, or high- Sometimes very high (even > 100,000 cells/mm 3 )
○ Hallmark of both:
■ Pancytopenia with Circulating Blasts (immature WBCs)
● Circulating Lymphoid or Myeloid blasts
○ Terminal Deoxynucleotidyl transferase is also diagnostic for ALL
Hallmark of both ALL and AML
Pancytopenia with Circulating Blasts (immature WBCs)
● Circulating Lymphoid or Myeloid blasts
Chest X-ray in ALL may reveal
an _____
Anterior Mediastinal mass,
suggestive of a T-cell ALL
(Malignant enlargement of the thymus)
Peripheral Blood Smear in AML may show _____
Auer Rods
- Pathognomonic and diagnostic for AML
Treatment for both ALL and AML includes _____
“Induction Chemotherapy”, which is essentially aggressive combination chemo with the goal of “inducing” remission
(Taking out the bone marrow until it is essentially wiped out, hoping it will recover without the leukemia re-manifesting)
Acute Leukemia should be Tx’d by _____
Hematology Oncologist
Acute Leukemia is considered a ____, especially
among younger patients without significant comorbidities
curable disease
*in patients up tp 60 YOA
For AML, treatment produces complete remission in ____% of those under 60 YOA, and ____% in older patients
80-90; 50-60
For ALL, treatment produces complete remission in _____% of pediatric cases, and in about ___% of adult cases
95-98; 90
Chemotherapy for CNS infiltration
Intrathecal chemotherapy (cranial
or lumbar) is becoming common practice,
even for prophylaxis in some
_____ is sometimes needed and may
be the best chance for a cure in many patients
Allogeneic stem cell replacement
T/F Once acute leukemia has recurred after initial chemotherapy, the
prognosis is poor
T
Chronic Myelogenous Leukemia
● CML is a disease of the middle aged (45-60, mean of 50-55 yrs).
● Accounts for approximately 15% of adult leukemia
There has been increased incidence of CML among persons with history of ____
exposure to high level ionizing radiation
Chronic Myelogenous Leukemia is Characterized by the ____
Philadelphia Chromosome
○ Translocation between long arms of chromosomes 9 and 22
○ Moves the protooncogene abl next to breakpoint cluster (bcr)
○ bcr/abl fusion gene encodes for pathologic novel protein
Chronic Myelogenous Leukemia Pathophysiology
○ Proliferation of myeloid cells that retain their
capacity to differentiate initially.
Phases of CML
○ Initially, the Chronic Phase:
■ WBCs > 100,000, with < 5% blasts
■ Does not behave like malignancy
■ If left untreated, is inherently unstable
and will progress to Accelerated Phase
○ Accelerated Phase:
■ > 5% blasts, but still < 30%
■ 4-6 months before entering Blast Phase
○ Blast Crisis Phase (acute phase):
■ The aggressive, acute stage of the
disease process
■ Blood or Marrow shows > 30% blasts
This is a form of Secondary Acute
Leukemia and is often
indistinguishable from AML clinically
CML in a blast crisis phase
Most patients diagnosed in the Blast
Phase of CML have poor response to therapy
and _____
die within 1-2 years
Chronic Myelogenous Leukemia S/S
○ May be asymptomatic, especially if in Chronic or Accelerated phases.
○ May have LUQ pain secondary to enlarged spleen.
○ May have fever, weight loss, arthralgias, bleeding
○ Physical exam usually reveals obvious splenomegaly, ecchymosis, and/or bone tenderness.
○ Rarely patients will present with blurred vision, neuro deficits, or pulmonary distress secondary to leukostasis
Diagnosis of CML
CBC for suspected CML will show WBC increased, often > 100,000.
■ Increased granulocytes (especially Neutrophils)
○ May see normocytic anemia
Bone Marrow Biopsy for CML would be ____-
hypercellular with a left shift, even if <5% blasts
Hallmark of CML
PCR detects bcr/abl gene from the Philadelphia Chromosome
Most people (90%) are diagnosed with CML while in _____
Chronic Phase
Treatment and Referral for CML
○ Should be managed early by Hematology Oncologist.
○ Treatment during Chronic Phase is important to delay conversion to Blast Phase.
○ Treatment is chemotherapy class called Tyrosine Kinase Inhibitors (Imatinib [Gleevec] is most common, although there are others) with or without Allogeneic Stem Cell Transplant
Prognosis of CML
○ Patients with good molecular response to the tyrosine kinase
inhibitor treatment have excellent prognosis.
■ Essentially 100% survival based on recent studies
○ More than 80% of later recurrences occur 6-8 months after stopping tyrosine kinase inhibitor therapy.
■ 90-95% of recurrences regain remission with re-treatment
○ Average life expectancy for CML diagnosed while in the acute
Blast Phase is poor at approximately 3 months
Chronic Lymphocytic Leukemia
● CLL usually occurs in adults over the age of 50 years.
○ Median age is 70 years
○ Twice as common in males
● Most common form of adult leukemia in Western world
Pathophysiology of CLL
○ CLL is a clonal malignancy of B-Lymphocytes.
○ The disease process is indolent with slowly progressive accumulation of lymphocytes.
○ Eventually, immunosuppression and bone marrow failure develop,
with possible lymphocytic organ infiltration
Chronic Lymphocytic Leukemia S/S
○ Many patients are asymptomatic and this is diagnosed incidentally on routine CBC (asymptomatic lymphocytosis).
○ If symptomatic, may have weakness, fatigue, and/or infections.
○ Physical examination may reveal lymphadenopathy (80%) and/or
hepatosplenomegaly (50%).
CLL is a clonal malignancy of _____
B-Lymphocytes
CBC findings for CLL
CBC classically shows WBC count of > 15,000/mm 3 .
■ Many may be as high as 100,000/mm 3 .
○ CBC Differential reveals the predominant WBC to be small Mature Lymphocytes.
○ Normocytic anemia is common.
PBS findings for CLL
Peripheral blood smear shows mature
lymphocytes with some characteristic Smudge
Cells (disintegrating Lymphocytes).
Bone marrow biopsy findings of CLL
> 30% well-differentiated Lymphocytes.
CBC giveaway for CLL
CBC Differential reveals the predominant WBC
to be small Mature Lymphocytes.
The lymphocytes are high as opposed to other cells
Treatment and Referral for CLL
○ Because CLL is so indolent, we do not generally treat those who
are asymptomatic with stable disease.
■ Watchful waiting for Sxs is usually initial treatment plan
About 10% of CLL patients may develop associated _____
Autoimmune Hemolytic Anemia (Positive Coombs Test)
Steroids would be the treatment in this case
Treatment and Prognosis of CLL
○ Targeted chemotherapy agents have improved the prognosis in recent years.
■ Patients who are asymptomatic or early stage at diagnosis generally have a life expectancy of 10-15 years and can be reassured they can live a normal life.
○ Patients diagnosed in later stages (generally symptomatic) have a 5-year survival of more than 50%
○ Allogeneic Stem Cell Transplant are reserved for those with high-risk and resistant forms of CLL
Hairy Cell Leukemia
● Rare form of Leukemia that usually presents in late middle aged
(median age of 55 years).
○ 5 times more common in males
Hairy Cell Leukemia pathophysiology
○ Malignancy of hematopoietic stem
cells differentiated as mature
B-Lymphocytes with hairy cytoplasmic
projections.
○ Usually see Pancytopenia with anemia,
thrombocytopenia, and neutropenia
Hairy Cell Leukemia S/S
○ Most patients present with gradual
onset of fatigue.
○ Some present with concerns of
massively enlarged spleen
○ The disease is indolent and usually
plagued with recurrent infections,
including Mycobacterial
Some present with concerns of
massively enlarged spleen in what?
Hairy cell leukemia
Hairy Cell Leukemia diagnosis
Pancytopenia is the hallmark.
■ Anemia, Thrombocytopenia, Neutropenia
○ Peripheral Blood Smear may reveal “Hairy Cells”
○ Bone Marrow biopsy confirms characteristic
appearance of the B-Lymphocytes in the marrow
Treatment for hairy cell leukemia
○ A short course of chemotherapy is often very beneficial and more than 80% experience significant remission
○ More than 95% live longer than 10 years after diagnosis
Myeloproliferative Disorders include the following
○ Polycythemia Vera
○ Essential Thrombocytosis
○ Chronic Myelogenous Leukemia
○ Acute Myelogenous Leukemia
○ Myelodysplastic Syndromes
Myeloproliferative Disorders
Multiple disorders due to acquired
clonal abnormalities of the Myeloid
progenitor cell line.
all ______ may progress to life-threatening
Acute Myelogenous Leukemia.
Myeloproliferative Disorders
Polycythemia Vera is also known as
Primary Erythrocytosis: this is an acquired
myeloproliferative disease resulting in overproduction of RBCs.
______is due to chronic hypoxia states like smoking, COPD, cyanotic heart disease, etc
Secondary Erythrocytosis (AKA “polycythemia”)
Polycythemia Vera characteristic mutation
A mutation in the JAK2 signalling molecule is demonstrated in 95% of cases
In polycythemia vera, RBC production happens independently of _____ and
____ is actually low in most cases
Erythropoietin; Epo
Polycythemia Vera S/S
○ Patients complain of episodes of headache, blurred vision, and pruritus (especially after a hot shower/bath).
○ Frequent epistaxis is common, likely
due to engorgement of the mucosal
blood vessels.
○ May have engorged retinal veins.
○ The spleen is usually palpable and is
essentially always enlarged on imaging
○ PV patients have an increased tendency
to experience thrombotic events.
○ May see Erythromelalgia- burning and
throbbing sensation of the hands/feet
Polycythemia Vera Diagnosis
○ Hematocrit is elevated, >49%.
○ WBC is usually elevated, most often between 10 and 20,000.
○ Platelet count is sometimes elevated, occasionally as high as 1,000,000
○ Erythropoietin level is responsively suppressed.
○ Diagnosis should be confirmed by checking the JAK2 mutation
○ Bone Marrow Biopsy is not necessary, but would reveal panhyperplasia.
○ Iron stores are often depleted - burning up iron to make more RBCs
Polycythemia Vera Treatment
Treatment of choice is regular Therapeutic Phlebotomy.
○ Occasionally myelosuppressive chemotherapy is indicated
○ Low-dose Aspirin (81 mg) is also recommended, as this reduces
the risk of thrombosis
○ Antihistamines can help with pruritus.
When is myelosuppressive chemotherapy indicated in polycythemia?
■ For those not responding to or tolerating phlebotomy.
■ Hydroxyurea is widely used, historical preference.
■ Two newer drugs are showing possibly superior results:
● The JAK2 inhibitor Ruxolitinib
● The novel interferon Ropeginterferon Alpha-2b
● These are best for patients with refractory hematocrit without splenomegaly, and are now recommended in front of Hydroxyurea.
Most common cause of death in polycythemia vera?
Arterial thrombosis
Essential Thrombocytosis
● An uncommon myeloproliferative disorder.
● The underlying cause is unknown.
● Significant proliferation of megakaryocytes in the bone marrow
occurs and leads to an elevated platelet count.
Similarity between Essential Thrombocytosis and polycythemia vera
As in Polycythemia Vera, there is a high
frequency of JAK2 mutation (about 50%
of cases)
Essential Thrombocytosis incidence
● The median age at presentation is 50-60 years.
● ET is slightly more common in females than males
S/S of Essential Thrombocytosis
○ Often asymptomatic (most commonly)
○ Thrombosis may be presenting sign
■ The risk of thrombosis increases with age
■ May occur at unusual sites, such as hepatic or portal vein
○ Some may experience erythromelalgia (relieved by aspirin)
○ Splenomegaly is present in at least 25% of cases
Essential Thrombocytosis hallmark
Elevated platelet count
Peripheral blood smear may
reveal abnormally large platelets.
Is hematocrit normal or elevated in Essential thrombocytosis?
Normal (key differentiator from PV)
In the absence of a JAK2 mutation, also check for ____
CALR and MPL mutations
Treatment of Essential Thrombocytosis
■ The treatment of choice is oral Hydroxyurea
■ This can lower the platelet count, with the goal of having
platelets under 500,000
In Essential Thrombocytosis patients with lower risk of thrombosis, _____ reduces the risk and also treats erythromelalgia
Low-dose Aspirin
Myelodysplastic Syndromes
● A group of acquired clonal disorders of the hematopoietic stem cells, all considered premalignant (can become AML).
● Idiopathic in most cases, but sometimes linked to prior chemotherapy or radiation treatment.
● Patients are usually over the age of 60 years
Myelodysplasia is characterized by the following
○ Cytopenias
○ Usually hypercellular bone marrow
○ Morphologic dysplasia
○ Genetic abnormalities
Myelodysplastic Syndromes S/S
○ Often asymptomatic - Discovered with incidental finding of abnormal CBC
○ Most common symptomatic presentations are generally related to bone marrow failure:
■ Fatigue
■ Recurrent or abnormal infections
■ Bleeding
○ Splenomegaly and pallor are also commonly found.
Myelodysplastic Syndromes Diagnosis
○ There is no specific, pathognomonic finding.
○ Anemia is generally present
○ The bone marrow is characteristically hypercellular, helping to differentiate this from Aplastic Anemia.
■ Cytogenetic and histologic testing of bone marrow sample helps confirm the dysplasia and diagnosis
○ Separated from AML by less than 20% blasts circulating.
Myelodysplastic Syndromes treatment
○ Treatments may include blood product transfusions, chemotherapy treatments, and/or stem cell transplants.
○ Prognosis is poor; the course is ultimately fatal, with survival years ranging significantly.
■ The only curative treatment is allogeneic stem cell transplant, which is successful 30-60% of the time
Should always be referred to hematology
