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
Should you get a bone marrow biopsy in people with suspected CIM?
- Yes
- ALWAYS get a bone marrow biopsy in these folks to make a diagnosis - > prove its not CML, and look at mutational analysis (you will find something about 75% of the time now)
What are the WHO criteria for CIM?
- Presence of mega proliferation and atypia, usually w/reticulin and/or collagen fibrosis, or (if no fibrosis) hypercellular bone marrow (granulocytic, and often DEC erythropoiesis -> pre-fibrotic cellular-phase disease)
- Not meeting WHO criteria for other MPDs
- JAK2617V>F mutation
- Additional minor criteria: leukoerythroblastosis, INC serum LDH, anemia, palpable splenomegaly
- NOTE: always get a bone marrow biopsy in these folks to make dx. Prove its not CML and look at mutational analysis (you will find one about 75% of the time now).
How do you manage tx of MF?
- HIgh-risk: allo SCT, JAK2 inhibitor
- Intermediate risk: some combo of JAK2 inhibitors, IMID, hypomethylators, etc.
- Low-risk: selective observation
- NOTE: No way to reverse disease in a tangible way. Jak-2 inhibitors the upfront drugs for treatment -> don’t take away clone, but turns off Jak-2, taking away the cytokines that make people feel terrible, and relieving splenomegaly. Chronically taken drug, but eventually it will quit working due to genetic instability.
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)
How do CML patients present? How do you dx them? What is their prognosis?
- Pts present w/elevated neutrophil count, usually not ill
- Often a palpable spleen
- Blood smear shows early neutrophils, esp. myelocytes
- Dx by FISH or PCR for BCR-ABL fusion transcripts (both very sensitive), or by bone marrow with above and cytogenetics for 9:22 translocation
- Prognosis was 3-4 years survival with 25% converting to AML each year; allogeneic transplant was only cure and treatment of choice for those able, but now we have tyrosine kinase inhibitors (TKIs) -> IMATINIB
What is a potential form of resistance to Imatinib?
- Mutation in the ATP-binding site -> there are now second and third-line treatments for this
What is the goal in TKI treatment for CML?
- Complete cytogenetic response, eliminating the clone completely (unlike PV) - no evidence of BCR-ABL
- If you get down to 0.1%, you are going to do VERY WELL -> some people cured this way, and able to come off therapy
- If tx fails, direct gene sequencing to identify mutation, and select alternative TKI. If this fails, allogeneic bone transplant. Add’l therapies: hydroxyurea and alpha IFN (good for ALL MYELOPROLIFERATIVE DISORDERS)
Know this.
Good job!
What is the Ddx for eosinophilia?
- Idiopathic (most of the time) Eosinophilia
- Reactive (DRUGS or ALLERGIES) Eosinophilia
-
Hypereosinophilic syndrome: >1500; > 6 months; organ damage (LUNG and HEART)
1. Idiopathic Hypereosinophilic Syndrome
2. Chronic Eosinophilic Leukemia: molecular or cytogenetic evidence of monoclonal eosinophils and/or increased blasts in blood or BM
3. Hematopoietic neoplasms accompanied by eosinophilia
1. T cell clonal disorders
2. AML -> INVERSION OF 16
3. MPN or MPD-eos (MP = myeloproliferative)
What are some complications associated with eosinophilia?
- Myocarditis
- Lung infiltration
- Enteritis
- Encephalopathy, neuropathy
- Thromboses
- Eczema, angioedema
What should you include in your evaluation for eosinophilia?
- Drugs
- Stool for parasites
- Strongyloidiasis
- Dermatitis, respiratory illnesses, vasculitides
- Solid tumors
- Tissue damage, pulmonary function
- Echocardiogram, troponins
***Secondary causes include: drug hypersensitivity, infection, hypoadrenalism, solid organ neoplasm, etc.
What is the therapy for eosinophilia?
- Key: Which patients respond to imatinib?
- FIP1L1-PDGFRA (cryptic translocation you can’t detect by routine cytogenetics -> need FISH) by FISH, RT-PCR
- May be present in mastocytosis with eosinophilia or in hypereosinophilic syndrome/CEL or in MPD with eosinophilia (PDGFRB by cytogenetics)
- If organ damage: glucocorticoids, hydroxyurea, IFN
If worried about CML and cytogenetics come back normal, should you do FISH?
- Yes
- Only about 90% detected by routine cytogenetics, and false negative rate is high
What stage is lymphoma patient with lymph nodes in 2 locations on one side of diaphragm?
Two
What is the most common leukemia of adults in the Western world?
CLL
What virus is commonly associated with Burkitt?
EBV
Why is the stage of differentiation of the original cell important when considering lymphomas?
- Because it can help you categorize/define the lymphoma
- In general (at least with B-cell lymphomas), the less differentiated the original cell, the more aggressive the cancer
What does lymphoma do?
- Mass: LAD, ureteral obstruction, cord compression
- Replacement: pancytopenia
- Reduction: hypogammaglobulinemia
- Tumor products: uric acid, Ca (from tumor cell), lysis
- Paraneoplastic: autoimmune hemolytic anemia (AHA), idiopathic thrombocytopenic purpura (ITP), neuropathy
- Psychosocial/economic: broke and alone
- Toxicity of therapy: infected, numb, short of breath
What 4 things will help you determine if you can help, or cure a patient with lymphoma?
- Tumor histology: indolent, aggressive, highly aggressive, B or T-cell
- Tumor stage
- Condition of patient
- Available therapies
Can you watch indolent lymphoma until it bothers the patient?
Absolutely
What are the defining characteristics of indolent (low grade) lymphomas?
- Higher stage
- Slower progression
- Response to simple therapies
- Incurable, except stages I-II
- Survival independent of early treatment
- Treat when symptomatic
What are some examples of indolent lymphomas?
- Follicular: BCL-2, 14:18; apoptosis inhibitor
-
Small lymphocytic/CLL
1. CLL in blood, SLL not; 17p del = bad, p53 - MALT lymphomas (11:18)
- Mycosis fungoides: gastric, mucosa around eye, lungs; T-cell cutaneous
If a pt has an aggressive (high grade) or highly aggressive lymphoma, what is their prognosis?
- These people are probably going to die (30-50%)
- Stage 1 you could cure with radiation, but otherwise you probably can’t
What are the defining characteristics of agressive (high grade) lymphomas?
- Often lower stage
- Rapid progression
- Require complex therapies
- Potential cure
- Early therapy required
What are some examples of agressive lymphomas?
- Diffuse large cell (most common of these)
- Mantle cell: t(11;14), Cyclin D translocation
- Peripheral T-cell lymphoma: NOS, angioimmunoblastic, anaplastic
What are some highly aggressive lymphomas?
- Burkitt (or Burkitt-like): t(8;14), c-MYC
- T-Cell lymphoblastic lymphoma
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 tests might you use for staging a lymphoma?
- History and exam
- CAT scan chest, abdomen and pelvis
- Bone marrow aspirate and biopsy with flow cytometry
- PET scan (fructose)
- Chemistries, CBC,LDH
- CSF if high risk disease
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 is the most common lymphoma in the US?
- Diffuse large B-cell
- Together with follicular lymphoma, make up the BIG 2
What are the IPI staging categories?
-
APLES
1. Age >60
2. P (performance)-status
3. LDH elevated
4. Extranodal sites
5. Stage III-IV - Each category worth one point (as you add points, risk goes up, and chances of survival go down; about 50% between 2 and 3)
What are the Follicular IPI staging categories?
-
ANLSH
1. Age >60
2. Nodal sites
3. INC LDH
4. Stage III-IV
5. Hgb <12 - 0-1 = 90% 5 yr sv; 2 = 77% 5 yr sv; 3-5 = 52% 5 yr sv
- Not necessarily helpful in decision-making, but good for clinical trial matching. Different treatments based on prognosis would make this helpful, but that is not currently the case for most of these.
What is the therapy for indolent lymphomas?
- You don’t cure them, so don’t try (unless Stage I)
- Local irradiation
- Alkylators and predisone
- Anthracyclines
- Fludarabine
- Antibody therapy
- Radiation labeled antibodies
- Combo Chemo: CHOP, Fludarabine + Mitoxantrone
What is the therapy for aggressive lymphomas?
- Chance to cure if you are aggressive. Rituximab (CD20 MAb) + CHOP most common (REMEMBER THIS) -> remarkably improve cure rate when Ritux added, but cells eventually become immune and compensate
- Combo Chemo: CHOP, HyperCVAD
- Antibody therapy plus CHOP
- Radio-immunotherapy
- Short course chemo + radiation
- Marrow transplant for relapse (can use allogeneic, but primarily autologous)
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!
Name 4 targeted therapies.
- CD 52: alemtuzumab (very effective drug, particularly against T-cells; very immunosuppressive, so hard to use due to secondary infections)
- CD 30: brentuximab vedotin (targeted chemotherapy); think Hodgkin
- Bruton Tyrosine Kinase: ibrutinib (think Mantle Cell Lymphoma)
- CD 22: Inotuzumab ozogamicin
What virus is commonly associated with lymphoma after transplant?
EBV
What infections are associated with lymphomas?
- HIV: primary CNS, other aggressive B-cell lymphomas
- HHV8: Kaposi’s, primary peritoneal lymphoma, Castleman’s disease
- HTLV-1: T-cell lymphomas
- EBV: Burkitt, post-transplant
- H. Pylori: MALT lymphomas, GI lymphomas
- Chlamydia: ocular lymphoma
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)
Compare Hodgkin’s and NHL. How do you treat Hodgkin’s?
- Different mode of progression (sequential), but same staging and staging tests
- Early stage: treat with short course chemo and focal radiation to area of disease or radiation alone or chemo alone (much more sensitive to radiation and chemo - highly curable disease)
-
Late stage: treat with chemotherapy -> ABVD (every 2 weeks for 6 months)
1. Good prognosis
What are some of the late complications of Hodgkin’s treatment?
- Problem is pts have long-term complications of their treatment -> 1% per year risk of developing second malignancy over a 30-year period
- Acute leukemia (in the first three years, and small chance) and myelodysplasia
- Solid tumors-breast (in yng women who got radiation), lung, stomach, bone, soft tissues
- Coronary artery disease (radiation)
- Radiation and chemotherapy pneumonitis (Bleomycin)
- Infertility (don’t forget to ask people about this b/c ppl need to store stuff - not as bad w/ABVD as older tx)
- Hypothyroidism
- Don’t use alkylators anymore due to secondary malignancies
What is CLL?
- Low-grade B cell malignancy usually in pts > 50 yo
- Often asymptomatic (# of presentations; usually feel fine)
- Lymphocytosis, LAD, splenomegaly, anemia
- Autoimmune cytopenias (high risk -> up to 15%)
- Hypogammaglobulinemia (can have almost no lymphocytes and have this problem)
- Smudge cells
How do Rai and Binet staging work for CLL?
- Rai (more common): 0 = lymphocytosis, 1 = enlarged lymph nodes, 2= hepatosplenomegaly, 3 = Hgb < 10 (non-immune), 4 = Platelets <100,000 (non-immune)
- Binet: A=0-2 areas, B=> 2 areas, C= Hgb<10 or plts< 100,000
- Higher stages really the ones you need to be worried about, i.e., folks with anemia and/or thrombocytopenia
What are the POOR prognostic indicators for CLL?
- High Stage
- Increased rate of lymphocyte doubling time
- Beta 2 microglobulin
- Deletion 17p or other TP53 mutations, 11q deletion
- Un-mutated VH genes, ZAP-70, CD 38 (because less differentiated original cell)
- 17p del also in multiple myeloma
What is the treatment for CLL?
- Alkylator: Chlorambucil, cyclophosphamide, bendamustine
- Purine analogues: Fludarabine
- Chemo combos: FCR (young people -> may plateau and be cured; fludarabine, cyclophosphamide, ritux)
- Immunotherapy: rituximab (CD 20; there are also new, better drugs for CD20), alemtuzumab (CD 52)
- Radiation
- Corticosteroids
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
What are the treatment indications for Hairy Cell Leukemia?
- BRAF inhibitor (Vemurafenib) can now be used for hairy cell (new devo)
-
Treatment Indications:
1. Cytopenias: ANC < .5-1.0, HGB < 8-10, PLT <50-100,000
2. Symptomatic splenomegaly, lymphadenopathy - Very high, enduring response rates to 2- chlorodeoxy-adenosine and deoxycoformycin
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.
