5. Leukemia/Lymphoma Flashcards
Myeloproliferative diseases – Polycythemia vera
• Clonal proliferation of hematopoietic ____ cells
• Erythrocytosis
– May be associated with ____ and ____
• ____ mutations
- I’ll start the discussion today by talking about red blood cell disorders, specifically and most commonly, Polycythemia vera.
- Myeloproliferative disease includes an array of different diseases, all of which affect red blood cells.
- There are some rare forms and some not-so-rare forms. In the grand scheme of things, all cancer is unusual and uncommon, but of the cancers that occur of the red blood cells, this is by far the most ____. (“This” being Polycythemia vera.) This represents a clonal proliferation of a stem cell that is differentiating into RBCs.
stem leukocytosis thrombocytosis somatic JAK2 tyrosine kinase common
Myeloproliferative dx - Polcythemia vera
Conversely, in anemia, there’s fewer RBCs relative to blood volume, and that’s a lower ____
So, Polycythemia is the exact opposite of ____ in regards to hematocrit effects In a blood smear, look at a microliter or a pin prick that you spread on a slide of normal or anemic blood.
You would see far more cells in polycythemia in the same amount of volume in a smear than you would in anemic. Because there are more RBCs, hemoglobin is ____, and then by extension, iron is ____.
One of the treatments for this disease is actually ____ blood from the body to reduce
blood volume and hence reducing the risk for iron overload. This is one of the main
treatments we use apart from medication.
Again, understanding signaling - if EPO is used to activate RBC formation, and too many red blood cells already formed, the EPO should be ____. And that’s exactly what happens.
So, because there’s so many RBCs in the system, there’s less EPO that needs to be released
from kidney to stimulate more synthesis. So, you’re stopping additional synthesis.
ESR (Erythrocyte Sedimentation Rate) will be reduced. Will discuss in a second. Clinically, you will see the effects that occur as a result of too many red blood cells.
They may ____ more frequently (thrombosis)
◦
The body is in overdrive trying to kill off the excess RBCs, so they will have ____ as a result.
Patients are systemically itchy all over (pruritus). As a palliative measure, the patients are
typically prescribed ____ to reduce itchiness.
hematocrit
anemia
elevated
elevated
drawing
decreased
clot
antihistamines
Erythrocyte sedimentation rate
• Rate at which red blood cells sediment in ____ hour (mm / hr)
• Balance between ____-sedimentation factors (eg fibrinogen) vs
factors resisting sedimentation (eg negative charge on RBCs)
• Reduced in ____ and sickle cell anemia
ESR=Erythrocyte Sedimentation Rate
An “intuitive test because the name itself is what it actually is in terms of the test.”
◦ What you do: take a blood draw, put it into tube, and let it sit at room temperature for an hour.
RBCs will drop to bottom of the tube via ____ alone. Will sediment to the bottom of the tube.
◦ You are measuring the total length of the ____ volume in relation to the ____ volume.
That is Erythrocyte Sedimentation Rate It’s measured as a function of ____
◦
◦
one
pro
polcythemia
gravity
RBC
total tube
time
Finding the ESR = measuring the amount of that tube that is ____ of RBCs after 1 hour Measure the difference in millimeters per unit time Very quick and easy test - nothing required beyond taking the blood sample There are different factors that affect how quickly those RBCs drop:
____
◦ ____ WBCs and cytokines in bloodstream ◦ ◦
◦The more “dirt,” the more foreign stuff you have in your bloodstream, the ____ likely the
ESR will be reduced.
The more dirt, the ____ the distance between the initial volume to where the RBCs end
up. Why? Because you have ____.
devoid inflammation excess less shorter interference
Conversely, if you have certain factors in your bloodstream that promote excessive sedimentation, it will ____ ESR.
For example, excessive RBCs in your original blood sample will cause a reduced ESR
Having more RBCs in your sample, the length will be ____
◦ Why Sickle Cell? Because cells are abnormal and tend not to sediment as readily as regular cells. So, the blood distance remains ____ than it would be normally.
◦
So really there is only 2 conditions where the ESR is reduced:
____
____
increase
shorter
polycythemia
sickle cell anemia
Myeloproliferative diseases – Polycythemia vera
• Weekly ____
– To reduce blood thickness and maintain HCT < ____%
• ____
– To limit blood clots
• Cytoreductive therapy with ____ – To reduce RBC production in bone marrow
So to treat this condition, want to do one of two things:
Either reduce ____ activation (done medicinally), OR
◦
Do something that requires ____ intervention - reducing the amount of blood in the
body. Patients go to laboratories every couple of weeks and have blood drawn from their
bodies to reduce their blood volume.)
Palliatively and prophylactically, they are given ____ to prevent blood clots. Cannot ____ this blood because its a cancer of the bloodstream itself
Another option of treatment is Hydroxyurea, which we’ve discussed in the context of Sickle Cell Anemia to destroy any additional red cell formation.
It’s ____; can destroy other elements in the bloodstream
phlebotomy
45
aspirin
hydroxyurea
JAK2 technical aspirin donate nonspecific
Myeloproliferative diseases – Essential thrombocythemia
• Overproduction of platelets due to more ____
• Usually identified on ____ blood test
• ____, leukocytosis, reduced RBCs
– Platelets > ____ / µL for at least two months
• ____, thrombosis, splenomegaly
• ____ or ____ mutations
– Dysregulate ____ pathway
A second myeloproliferative disease is called Essential thrombocythemia This is a cancer of ____. Megakaryocytes give rise to platelets. Therefore, patients have too many platelets in the bloodstream Platelets are not cells; do not have ____. Megakaryocytes are the originating cells of platelets. Megakaryocytes are the malignant cells in this context
So patients with thrombocythemia have a risk for significant, random blood ____ - a potential life-threatening condition. Rarely is this disease strictly ____.
megakaryocytes thrombocytosis 450,000 bleeding JAK2 calreticulin STAT
megakaryocytes
nuclei
clotting
megakaryocytes
Myeloproliferative diseases - essential thrombocythemia
When the stem cells differentiate, and a mutation occurs, it will will dictate which cell types will be affected in that lineage.
If the mutation occurs early in the stem cell, then all the lineages that derive from that
stem cell will be affected.
So, oftentimes patients will have leukocytosis, erythrocytosis, may have some ____ as well.
Conversely, some patients have ____ RBCs, depending if the mutation occurs later in that stream of events. All depends on which stage of differentiation the mutation occurred in. Will dictate
This disease is often clinically ____. Many patients don’t realize they are experiencing blood clots until it’s too late for them.
Oftentimes, this disease is found in indirectly routine blood tests - manifesting as In addition to thrombotic events, these patients may also experience increased bleeding or spontaneous bleeding. Because sometimes their platelets don’t work properly.
____ bleeding may occur in gums, may be present in urine or feces, etc. which phenotypes the patient manifests with.
◦
excessive platelets. Platelet levels would be higher than normal
____ oftentimes are enlarged
◦ Like polycythemia, there is an attempt by the body to try to destroy some of this excess material.
◦
polycythemia reduced asymptomatic spontaneous spleens
Myeloproliferative diseases – Essential thrombocythemia
Like Polycythemia vera, ____ plays a role in this pathway as well.
So does a 2nd protein called ____
◦
If either of these proteins is mutated, it will trigger the same phenotype
◦ Calreticulin does NOT play a role in polycythemia. But it may play a role in this condition, thrombocythemia
In both cases, both proteins regulate the same downstream cascade (____ signaling)
STAT is a transcription factor that regulates a bunch of downstream genes
◦ Understand that Calreticulin doesn’t play any role in Polycythemia vera, but does play a role in Essential Thrombocythemia. How to treat?
◦
◦
There is a treatment for JAK2, as we alluded to when discussing Polycythemia. No treatment for ____ mutations - must do treatment that is indirect, not direct
Indirect=get ____ drawn to reduce platelet loads. May get ____ therapy
‣
to reduce formation of karyocytes in the bone marrow. So, it’s not a direct
treatment.
JAK2 calreticulin STAT calreticulin blood hydroxyurea
Leukemia • AML – acute myeloid leukemia • CML – chronic myeloid leukemia • CMML – chronic myelomonocytic leukemia • ALL – acute lymphoblastic leukemia • CLL – chronic lymphocytic leukemia
Some literature describes Essential Thrombocythemia as a form of Leukemia, and
technically it sort of is. But from our standpoint, it’s not.
We are specifically talking about cancers of ____ elements (neutrophils, eosinophils, basophils, and monocytes). Leukemias are categorized as acute vs. chronic, myeloid vs. lymphoid
Acute and chronic - not the typical “acute” and “chronic” definitions we are used to. Onset doesn’t dictate this. The nomenclature we use describes cancer that’s exquisitely ____ (as acute leukemias are) versus those that are not as
aggressive as the ____ typically are.
So in this case, Acute and Chronic is not reflective of quick onset vs. late onset vs. ◦
protracted onset. It’s more reflective of ____ vs less aggressivity.
myeloid
aggressive
chronic leukemias
aggressivity
Leukemia
Acute Myeloid Leukemia could be a cancer of ____, a cancer of eosinophils, a cancer of basophils.
They all fall into same category of AML.
v
◦ We have CLL, chronic lymphocytic leukemia - the least ____ cancer of all subtypes. This chart is from 2014, but the numbers hold true even to today, whereby the vast majority of new cancers, new leukemias diagnosed every year are of the AML category.
Of the cancers that are most prevalent in the population - ____
There is a difference between incidence and prevalence
____ = new onset
____ = how many patients in the population have that cancer
Of all ____, AML is most common. In ____, ALL is most common. Of all patients
across all leukemia subtypes, ____ is by far the most common leukemia that is formed.
neutrophils
aggressive
CLL incidence prevalence patients kids AML
Leukemia – Acute myeloid leukemia
• Excessive production of immature ____ (myeloblasts)
• Most common ____
– Highest ____ rate
AML is defined as….reads first bullet point Again, ____, ____, and/or ____
Again, of all subtypes, this is the most common acute adult form of leukemia
In kids, it’s ____. We’ll talk about that in a second.
WBCs
acute adult leukemia
incidence
neutrophils
eosinophils
basophils
ALL
Risk factors • \_\_\_\_ • Prior chemo- or radiotherapy • Exposure to \_\_\_\_ bomb or benzene • Aplastic anemia • Genetic mutations – \_\_\_\_ syndrome – high \_\_\_\_ rates – \_\_\_\_
Signs and symptoms • \_\_\_\_ • Spontaneous bleeding / petechiae • \_\_\_\_ pain • Splenomegaly • Masses – \_\_\_\_
Patients who have ____ are also at a high risk for developing leukemia, AML specifically.
Why? Because patients with Aplastic Anemia have lost the ability to produce normal erythroid and myeloid elements. As a result, their body is trying to
compensate. At some point during the course of their disease, a cell will experience a
____ that will propel it to become malignant.
AML is one of the most common cancers when it gets into the Aplastic Anemia background.
There are a plethora of molecular changes associated with AML. In fact, we categorize leukemia on ____ and molecular ____.
Molecular cytogenetics may play a role in ____
Patients with Neurofibromatosis Type 1 also have an increased risk for AML but with a very ____ prognosis. We don’t know exactly why. How do leukemias manifest? Nothing specifically. reads the bullets under “Signs and Symptoms” but he adds “increased infection”
There’s nothing about the way that these patients present clinically that is indicative
◦
of leukemia ____
smoking nuclear down cure NF1
anemia
bone
myeloid sarcoma
aplastic anemia mutation morphology cytogenetics prognosis poor specifically
Clinically, they may look like ____ The small nodule on the nose was initially thought to be basal cell carcinoma. Upon biopsy, turned out to be leukemia. Rash on hand - upon biopsy, turned out to be leukemia Leukemia of the orbit - not systemic (can get leukemia in ____ sites as opposed to systemically)
anything
soft tissue
Baby developed leukemia in utero. The baby’s physical response was one of ____ - the attempt on the baby’s part to form blood outside of the blood marrow. These babies are born with bluish papules on the skin - called “____ baby” because the papules kind of look like blueberries.
extramedullary hematopoeisis
blueberry muffin
Myelocytic and myelomonocytic most common leukemic variants in mouth
So these are what we would call Extramedullary Lesions. If they have solitary lesions, we tend to call them \_\_\_\_. (Goes back to the previous slide and points out 2nd photo from the right - this young girl has Myeloid Sarcoma of the Orbit.) These two patients (the two photos show different cases) - limited to the oral cavity. There are several different subtypes of AML. Two of them most commonly occur in the oral cavity: \_\_\_\_ version of AML ◦ \_\_\_\_ version of AML ◦
It’s important to differentiate AML Myelomonocytic from CMML. They are two very different cancers. In this picture, we’re talking only about AML Myelocytic and Myelomonocytic variant occurring within the oral cavity
myeloid sarcomas
myelocytic
myelomonocytic
Myelocytic and myelomonocytic most common leukemic variants in mouth
Photo on the left
Patient had green gums, green fibrotic enlarged gums of both maxillary and mandibular ◦
◦
gingiva. It turned out to be leukemia.
Leukemia may result in a ____ discoloration of the tissue. Why? Because
myeloperoxidase (an enzyme found within neutrophils) may oxidize ____ to
give off a green coloration.
‣
These are called a “____” because of the green color.
Clinically, they may be mass-forming, they may be diffuse, they may be localized. Nothing about the clinical presentation is ____ to these cancers. These versions are strictly morphologic variants, which may dictate how they are treated therapeutically. (Therapy is based on ____ and ____.)
greenish free radicals chloroma unique morphology molecular genetics
Leukemia – Acute myeloid leukemia
• Categorized based on ____ levels and ____
• Chemotherapy / stem cell transplant
• Curable in up to 40% of patients < 60 years
Treatments are based on ____ findings now. In fact, these are one of the cancers that are routinely analyzed at the molecular level in all cases.
Why? Because certain molecular changes impart or correlate with prognosis. And certain molecular changes can be treated specifically and directly against that molecular change.
What does that mean? Well, there are some ____ that produce, for example, hybrid proteins - for which there are now treatments specifically against those hybrid
proteins.
In other cases, some of these mutations don’t have treatments for them. So, they are treated indirectly (routine ____)
maturation cytogenetics molecular translocations chemotherapy
Leukemia - acute myeloid leukemia
Chemotherapy is ____-line therapy in all cases. If chemotherapy doesn’t work, oftentimes the patient will undergo ____ transplantation to clear the body of all their damaged and malignant stem cells.
Sometimes, even after chemotherapy, they may still undergo ____ transplantation to ensure there’s no further risk.
Stem cell transplantation is ____ a cure-all for all patients
AML used to be a death sentence.
It’s still not a good prognosis - only 40% of all patients under age 60 will survive their disease with treatment. But this is across all AMLs. Some versions of AML with very
distinct molecular changes are much more ____, and these have a better prognosis
than those that don’t have targetable forms of the disease.
first stem cell stem cell not treatable
Leukemia – Chronic myeloid leukemia • Rarely affects \_\_\_\_ • 50% patients \_\_\_\_ • t(\_\_\_\_) – Philadelphia chromosome – \_\_\_\_ fusion
CML=Chronic Myeloid Leukemia - almost always occurs in ____ patients.
AML can occur in kids - then, very ____
◦
But, kids rarely get CML
◦ At least half of all patients are ____ and don’t know they have the disease. Instead, they present with a longstanding history of ____ findings (ex: tired, bruising, bleeding, gums bleeding, etc.)
◦
So most patients do have symptoms, but they’re low-grade non-aggressive symptoms. These patients don’t seek treatment until they become bothersome.
CML is almost always characterized by a unique molecular change that was discovered here at Penn back in the 60’s - that’s why it’s called the Philadelphia Chromosome.
The translocation is Chromosomes 9 to 22, resulting in a fusion protein between the
◦
BCR gene and the ABL1 gene
The BCR-ALB1 fusion protein is a ____
◦
children asymptomatic 9;22 adult aggressive asymptomatic non-specific
tyrosine kinase
Leukemia – Chronic myeloid leukemia
• BCR-ABL1 constitutively active ____
In patients that have CML, this tyrosine kinase is constitutively activated (as it is in ____). Therefore, it’s constantly producing new ____. That’s how leukemia develops. This was the first ____ protein for which a treatment was developed specifically for this leukemia. This was the first targetable cancer for which a drug was created specifically for this one protein and only in this context.
Context=CML; drug=____
◦
tyrosine kinase polcythemia vera neutrophils/WBCs targetable gleevac
Leukemia – Chronic myeloid leukemia
• Targeted therapies improved 10 year survival from 20% to 80-90% - ____
Gleevec prevents the binding site of ____ to trigger the kinase reaction. All tyrosine kinases need energy to perpeturate the functionality.
Gleevac binds in the place of ATP to prevent activation of that Tyrosine Kinase. It only works on this one specific ____ of Tyrosine Kinase that is unusual and only forms in this context. Upon binding of ATP, the Tyrosine Kinase doesn’t activate sufficiently, therefore the cell can’t grow. Name of drug: Gleevec (Imatinib)
CML also at one time was a death sentence. Now, it’s one of the most treatable forms of leukemia. Patients respond very well to this drug. This is first generation; there are now ~4 generations of drugs since then that specifically target BCR-ABL1
imatinib
ATP
type
Leukemia – Chronic myelomonocytic leukemia
• Monocyte count > \_\_\_\_ per cubic millimeter blood – May also see \_\_\_\_ in blood • Disease of \_\_\_\_ – Male : female \_\_\_\_ • Prior \_\_\_\_ increases risk • May progress to \_\_\_\_
CMML - this is different than what I described before. In the context of oral leukemias, it’s typically AML of the myelomonocytic lineage or the myelocytic lineage. CMML is a wholly different cancer altogether. CMML is a cancer of ____
Patients get ____ - have far many more monocytes in the bloodstream than they normally should have.
Precursor to Monocytes is ____. The defect is occurring in an early precursor that is in the lineage toward monocyte development.
1000 monoblasts elderly 2:1 chemotherapy AML
monocytes
monocytosis
monoblast
Leukemia – Chronic myelomonocytic leukemia
This cancer may may develop on its own, but patients have distinct risk for this cancer if they’ve had a previous cancer that was treated with chemotherapy
Chemotherapy is not a targeted treatment; it’s very ____ and is aimed at killing a whole bunch of rapidly proliferating cells.
Chemotherapy for any type of cancer increases the risk for ____
◦ CMML patients may progress on to ____. (Going from a chronic, slow-forming disease to a more acutely aggressive disease) CMML is actually quite a difficult cancer to treat. ____ don’t respond well to treatment, therefore, typically these patients are treated with whole-body nonspecific chemotherapy.
◦ There is no ____ forms of treatment for this version of the disease.
non-specific CMML AML monocytes targetable
Leukemia – Acute lymphoblastic leukemia
• Most common \_\_\_\_ cancer • 75% of childhood leukemias are ALL – \_\_\_\_ lineage or \_\_\_\_ lineage • Cytogenetics have prognostic value – Subset harbor \_\_\_\_ chromosome • \_\_\_\_ association – \_\_\_\_ outcome • \_\_\_\_ >>> adult 5 year survival
ALL - most common form of pediatric cancer. This is a treatable form of pediatric cancer Only those cancers that have distinct molecular changes that are targetable by treatment
Some patients don’t have distinct changes, which makes it harder to treat them and
worse prognosis
Of all childhood leukemias, they are most commonly ALL. The rest are typically AML.
The chronic versions are less likely….CML vs CLL
If it’s ALL, then it’s either B or T lineage ____ lineage may also occur in some patients. That’s the exquisitely aggressive cancer - often very difficult to treat.
B ALL and T ALL are actually treatable forms of cancer depending on the changes.
pediatric B T philadelphia down syndrome poor childhood
NK
Leukemia - ALL
As with all leukemias, cytogenetics have an important prognostic role here
They are prognosticators
◦ If Leukemia has molecular change X, versus molecular change Y, whatever X and Y represent, X may have a better prognosis and be much more treatable than the Y version of that same cancer if it’s the same cell type. So, molecular ____ are evaluated on each and every patient with leukemia irrespective of subtype. Some of these same patients may also have the same 9:22 chromosomal translocation (the Philadelphia Chromosome)
Yet, may not be CML - may be ALL If they have ____ onset mutation, may develop ALL instead of CML with exact same cytogenetics
Down Syndrome patients are at risk for leukemias. AML in that context is a treatable
cancer; very high response rates.
Why don’t know why - research group at CHOP studying why Down Syndrome is only
risk for ____ and not solid cancers (liver cancer, head/neck cancer, etc.).
AML is treatable and much more ____. ALL is a very ____ cancer in these patients.
If these same patients were to develop ALL, it is a very poor prognosis ◦ ◦
cytogenetics early leukemia curable deadly
