MPDs, Lymphomas, and Leukemias - Weir 03.24.15 Flashcards
What mutation is central to the dx of PV?
JAK-2 mutation
What medicine is most important in treating CML?
TKI
What is a common cause of elevated platelets?
Splenectomy
What are some common causes of erythrocytosis?
-
Reduction of plasma volume (relative erythrocytosis):
1. Acute - vomiting, diarrhea, burns, diabetic ketoacidosis, protracted fever
2. Chronic - prolonged, inappopriate use of diuretics - Appropriately increased sEPO levels: COPD, cyanotic heart disease, smokers, sleep apnea, high altitude, obesity, drugs (androgens, corticosteroids), EPO dope
- Inappropriately increased sEPO levels: renal cell carcinoma, non-neoplastic renal lesions, cerebellar hemangioblastoma, hepatocellular carcinoma, uterine fibroma, renal transplant, pituitary adenoma
What are the most common causes of neutrophilia?
- HISTORY IS REALLY IMPORTANT
- Sick? Infection
- Not sick? Obesity or cigarette smoking
- Additional:
1. MPDs: CML, PV, myelofibrosis
2. Drugs: corticosteroids, i.e., injection for back pain or lithium, e.g., as anti-depressant
3. Inflammation
4. Malignancy
How does morphology affect classification of myeloid malignancies, generally speaking?
- Myeloproliferative neoplasms: fully mature cells that look fairly normal
- Myelodysplasia: clonal cells that take over bone marrow, but are sick
- Acute leukemias: can’t mature at all
- NOTE: these are all linked, but manifest themselves in different ways
What words are key in defining myeloproliferative disorders?
- Increased cell mass
- Clonal origin
- Committed stem cell mutations: allows escape from proliferation limitation, but still permits maturation
- Full maturation
What are the common driving mutations in myeloproliferative disorders?
- JAK-2 mutation
- CALR mutation
- MPL mutation
- NOTE: in almost all MPDs, we can determine a driving mutation, and these help us define the disease
What’s going on with this dude?
- Facial plethora in 65 y/o man: reddish complexion due to excess blood
- Due to PV, in this case
- Labs:
1. Hb: 22, WBC: 17 x 10^9, PLT: 550 x 10^9
What are some common physical findings in PV?
- Splenomegaly: 70% (you may not always be able to feel this)
- Skin, conjunctival plethora
- Engorged retinal vessels
- Hepatomegaly
- HTN
What are some common symptoms in PV?
- Headache: 48%
- Weakness
- Pruritis: itchiness
- Dizziness
- Diaphoresis: perspiring profusely
- Visual disturbances
- Weight loss, paresthesias, dyspnea, joint, epigastric discomfort
What are the major causes of death in PV? Median survival?
- THROMBOSIS (+ thromboembolism = 31%) basically the thing we treat, prevent
- Also, AML (19%), other malignancy, hemorrhage, MF
- Median survival 14 years from initiation of phlebotomy
What might this be? Describe it.
- Polycythemia vera
- Lots of platelets, and may be big (almost as big as red cell in some cases)
- Commonly associated with iron deficiency: tend to have chronic blood loss -> hypochromic microcytes
- White cells may be left-shifted, and show slight basophilia (not as numerous as in CML)
- PLT counts can exceed 600,000, which may lead to confusion with ET
What do you see here?
- PV: proliferative phase
- Hypercellular bone marrow with loose clusters of pleomorphic megakaryocytes -> packed with cells; ought to see adipose, but we don’t here
What are the predictors for thrombosis with PV?
- Age >65
- Previous thrombosis
- Elevated leukocyte count (>15,000); something about inflammatory products of neutrophils
- CV risk factors
- Elevated Hct: >45%
- NOTE: we can’t change age, but can change Hct and leukocytes
What are the WHO criteria for PV?
1 ) Elevated red cell mass >25% above mean normal predicted value, or Hgb >18.5 M or >16.5 F, or >99th %ile of reference range for age, sex, and altitude
2) No cause of secondary erythrocytosis
3) Splenomegaly
4) Clonal gene abnormality other than BCR-ABL
5) Endogenous erythroid colony formation
- NOTE: not just red cells up, which may help you distinguish from other factors, i.e., smoking, where only red cells should be up
- Also tend to have elevated B12
What are the proposed revised WHO criteria for PV?
-
Major
1. Hg >18.5 M, >16.5 F or other evidence of INC red cell volume
2. JAK2617V>F or other functionally similar mut (i.e., exon 12 mut) -
Minor
1. Marrow biopsy w/hypercellularity for age and trilineage growth (erythroid, granulocyte, megakaryocyte)
2. Serum EPO level below normal
3. Endogenous erythroid colony formation in vivo
What kind of testing might you do if you suspect PV?
- Check JAK-2 and EPO levels
1. If EPO high, then you know its not PV
2. If EPO down, and JAK2 negative, may be another mutations, i.e., exon 12 JAK2 mutation
Know this chart.
Good job!
REMEMBER: you can be a smoker who has PV. Hepatocellular carcinoma can elevate EPO via paraneoplastic syndrome.
What are the various treatments for PV?
- Phlebotomy: goal to make pts iron deficient, so they hold their own blood count down (target 45%)
- Aspirin: 100 mg/d significantly lowers risk of CV death, non-fatal MI & stroke, major thromboembolism (HR: 0.4; RR of major bleeding with ASA: 1.6)
- Hydroxyurea: very effective in reducing thrombosis; target Hct 45%, w/WBC >3,000; supp w/phlebotomies, if needed -> NO clear increase in leukemic transformation (Busulfan reasonable in older pts)
-
Interferon: 3 million u/d until response, then lower (or peg-INF) -> can control PLT and Hct in majority of pts, reduce spleen size, and alleviate pruritis
1. May work when hydroxyurea fails - Jak-2 inhibitors: don’t elim disease, but relieve symptoms
54 y/o AAM cough, no fever. Healthy. Normal WBC and Hgb, but platelets 930,000 and MCV low. What is differential diagnosis of this thrombocytosis? What test should you order?
- Ferritin: because one of most common causes of increased platelets is iron deficiency
What should be in your differential dx for elevated platelets?
- Inflammation
- Trauma
- Malignancy
- Iron deficiency
- Splenectomy
- Myeloproliferative neoplasm
What is Budd-Chiari syndrome?
- Budd-Chiari syndrome: uncommon condition induced by thrombotic or non-thrombotic obstruction of hepatic venous outflow -> hepatomegaly, ascites, and abdominal pain
1. 40-58% of B-C syn and 33% with portal (splanchnic) vein thrombosis JAK2 V617F positive
2. Blood counts may not be up with portal HTN
3. Testing recommended for all SVT (if you have JAK2 V617F mut, you HAVE PV) - NOTES: thrombosis is a big deal in MPD
What is going on here?
- Erythromelalgia due to ET
- Severe burning pain and hot, red congestion of forefoot and toes in 39 y/o man
What do you see here?
- Essential thrombocythemia
- Peripheral blood findings in ET include thrombocytosis with LARGE AND GIANT PLATELETS and normal erythrocytes
- Mild leukocytosis (usually <30,000 also may be present, as can circulating megakaryocyte nuclear fragments or micromegakaryocytes
What’s going on here?
- ET
- Hypercellular bone marrow biopsy with marked increase in #’s of megakaryocytes arranged in loose clusters throughout the marrow
- Megakaryocytes in ET are larger than those in reactive conditions or CML, and contain nuclear cloud-like lobations
- Mild increase in thin, reticulin fibers
What are the proposed WHO criteria for ET?
- NOTE: harder to diagnose, but if platelets up and you don’t have other cause, then probably ET. If you can find Jak-2, MPL, or Cal-R mutation, that will help you diagnose. There is a lot of rule-out.
- CRITERIA:
1. Sustained platelet count >450 x 10^9
2. Bone marrow biopsy specimen w/proliferation mainly of megakaryocyte lineage and increased #’s of enlarged, mature megas; no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis
3. Not meeting WHO criteria for the other MPDs
4. JAK2617V>F or other clonal marker, or in absence of clonal marker, no evidence for reactive thrombocytosis
How migh pts with ET aquire bleeding problems? What should you do, in this case?
- Pts w/platelets > 1.5 million may acquire von Willebrand’s disease w/loss of large VWF multimers; responds to platelet reduction
-
For major bleeding problems:
1. Correct thrombocytosis
2. Withdraw ASA and antithrombotics
3. May respond to DDAVP, antifibrinolytics, plasma products that contain vWF
What is the treatment for ET?
- High-risk pts need platelet reduction
- Hydroxyurea (inhibits all cell lines), as in PV
-
Anagrelide (very specific for megakaryocytes)
1. As effective in lowering platelets
2. Decreased venous thrombosis
3. Increased arterial thrombosis, major bleeding, and myelofibrotic transformation
4. Now hydroxyurea is primary treatment (new study results) - Interferon, like in PV -> probably safe in pregnancy
- Can’t bleed platelets off
What is high-risk PV vs. low-risk?
- ANY ONE of the following:
1. Age >60 yrs
2. Previous documented thrombosis, erythromelagia (if resistant to aspirin)
3. Platelets > 1,000 x 10^9/L
4. Diabetes or HTN requiring meds
5. Significant/symptomatic splenomegaly - Low-risk PV: pts w/none of the above risk factors
What is high-risk ET?
- Only treat if high-risk
- ANY ONE of the following:
1. Age >60
2. Platelet count >1500 x 10^9
3. Previous thrombosis, erythomelagia (if resistant to aspirin
4. Previous hemorrhage related to ET
5. Diabetes or HTN requiring meds - Low-risk: <40 w/none of the above
- Intermediate risk: 40-60 w/none of the above
What are some clinical findings at diagnosis for pts with chronic idiopathic myelofibrosis?
- Very common findings (>50% cases): splenomegaly, hepatomegaly, fatigue, anemia, leukocytosis, thrombocytosis
- Common: asymptomatic, weight loss, night sweats, bleeding, splenic pain, leukocytopenia
- Uncommon: peripheral edema, portal HTN, jaundice, LAD, gout
- NOTE: these people FEEL BAD. May have high or low platelet count. Extra medullary hematopoiesis in spleen and liver. HISTORY and EXAM markedly change way you will go in diagnostic lab testing for these disorders.
Is fibrosis of the bone marrow the same thing as primary myelofibrosis?
No
What are some conditions in which myelofibrosis may occur?
- Neoplastic conditions: chronic MPDs, myelodysplasia with fibrosis, AML, ALL, hairy-cell leukemia, myeloma, carcinoma, systemic mastocytosis
- Non-neoplastic conditions: granulomatous disease, hypoparathyroidism, hyperparathyroidism, osteoporosis, Vit D deficiency, SLE, systemic sclerosis
What do you think is going on here?
- Chronic idiopathic myelofibrosis (CIM)
- Thrombocytosis with giant and bizarre platelets
- Anemia typically w/mild reticulocytosis, dacrocytes, and nucleatd RBCs
- Variable platelet count, and usually a left-shifted leukocytosis of 15-30,00 uL (basophilia or eosinophilia in 10-30% of cases)
- Dacrocyte: teardrop cell (almost always see this in myelofibrosis) -> think BONE MARROW when you see this
- Nucleated red cells: in cases of extreme outpouring of blood (i.e., hemolysis, bleeding) or distorted marrow architecture (i.e., primary myelofibrosis)
What do you see here?
- Chronic idiopathic myelofibrosis
- Lots of fibrosis, collagen
What do you see here? What is a common translocation associated with a poor prognosis?
- If you see a blood smear like this, it is CML. Key cell is the myelocyte. If you start seeing myelocytes in non-sick patient in the blood, you need to start thinking CML. Normally, you will not see these in peripheral blood.
- Think BCR-ABL1 (Philadelphia Chromosome) -> bad prognosis
1. One of the few things with ONE driving mutation that activates everything (most cancers have backup pathways)
Know this.
Good job!
What is cerebral lymphoma?
- Was AIDS-related, but now increasing with older people
- Treatable/curable in maybe 1/3rd of people
What is the staging system for lymphomas?
- Stage I: single node or lymphoid structure
- Stage II: two or more lymph regions 1 side diaphragm
- Stage III: both sides of diaphragm
- Stage IV: extranodal beyond E {sole site of disease}, outside of the lymph node structures
***Highly aggressive lymphoma will often present as Stage IV
What do you think these masses are?
- Generalized lymphadenopathy
- In this case, due to diffuse large B-cell lymphoma
- Right axillary mass on the left image; left renal vein (retroperitoneal) mass on the right image
What kind of imaging is this?
Fused PET/CT scan
What does this tell you?
- Difference between autologous transplant post-R failure and conventional therapy (more chemo)
- Clearly, autologous transplant had much better outcomes here
Note the trends here.
Good job!
Chronic skin rash and skin biopsy with lymphoma. What is it?
MYCOSIS FUNGOIDES. Indolent lymphoma.
What’s going on here?
Sezary syndrome: hard to get rid of, or limit, this
What are these characteristic of?
- Sezary syndrome
- Abnormal cells in the peripheral blood have characteristic, cerebriform, large, and clefted nuclei with fine chromatin pattern and scant cytoplasm
What is this?
- Adult T-cell Leukemia/lymphoma
- Japan and Caribbean and southern USA
- HTLV-1 RNA retrovirus
What is this?
R-S Cell (on every test ever, according to Dr. Weir)
What is this cell characteristic of? What are the details we need to know about this one?
- Hairy cell leukemia: indolent B cell lymphoproliferative disorder
- Male: Female = 4:1
- Splenomegaly, pancytopenia, decreased cell-mediated immunity
- Tartrate-resistant Acid Phosphatase (TRAP)
- CD 19,20,22,11c,25,103
Antigen-dependent B-cell receptor (BCR) signaling and its targeting by small-molecule inhibitors. Antigen binding induces the aggregation of the BCR with its coreceptors CD79A and B, which become phosphorylated by the tyrosine kinases LYN and SYK. SYK activates phosphoinositide 3–kinase (PI3Kδ), which in turn converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate PIP3. PIP3 serves as a docking site for the cytoplasmic kinases Bruton’s tyrosine kinase (BTK) and AKT. BTK phosphorylates and thereby activates phospholipase C gamma 2 (PLCγ2), which in turn generates a set of second messengers to activate protein kinase C beta (PKCβ). PKCβ phosphorylates IκB kinase (IKK) to activate nuclear factor κB (NF-κB) transcription factors that regulate gene expression of several survival factors. The kinases inhibited by small molecules with promising clinical activity are indicated.
What is the MOA of Rituximab?
- Ab binds CD20, which is widely expressed on B cells, but is absent on terminally differentiated plasma cells
- Rituximab tends to stick to one side of B cells, where CD20 is, forming a cap and drawing proteins over to that side. The presence of the cap changed the effectiveness of natural killer (NK) cells in destroying these B cells. When an NK cell latched onto the cap, it had an 80% success rate at killing the cell. In contrast, when the B cell lacked this asymmetric protein cluster, it was killed only 40% of the time
- The Fc portion of rituximab mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity(CDC).
Rituximab has a general regulatory effect on the cell cycle.
It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
It elicits shedding of CD23.
It downregulates the B cell receptor.
It induces apoptosis of CD20+ cells.
The combined effect results in the elimination of B cells (including the cancerous ones) from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.
