MPDs, Lymphomas, and Leukemias - Weir 03.24.15 Flashcards

Question

What do you see here?

Answer 1

- 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

Answer 2

- 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

Answer 3

- 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

Answer 4

- 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

Answer 5

- 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

Answer 6

- 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

Answer 7

- 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

Answer 8

- _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.

Answer 9

- _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

Answer 10

- 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)

Answer 11

- Chronic idiopathic myelofibrosis - Lots of fibrosis, collagen

Answer 12

- 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)

Answer 13

1. 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) 2. Not meeting WHO criteria for other MPDs 3. 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).

Answer 14

- _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_.

Answer 15

- 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)

Answer 16

- 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**

Answer 17

- Mutation in the ATP-binding site -\> there are now second and third-line treatments for this

Answer 18

- 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)

Answer 19

- 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)

Answer 20

- Myocarditis - Lung infiltration - Enteritis - Encephalopathy, neuropathy - Thromboses - Eczema, angioedema

Answer 21

- 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.

Answer 22

- 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

Answer 23

- Yes - Only about 90% detected by routine cytogenetics, and false negative rate is high

Answer 24

- 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

Answer 25

- _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

Answer 26

- Tumor histology: indolent, aggressive, highly aggressive, B or T-cell - Tumor stage - Condition of patient - Available therapies

Answer 27

Absolutely

Answer 28

- Higher stage - Slower progression - Response to simple therapies - **Incurable**, except stages I-II - _Survival independent of early treatment_ - **Treat when symptomatic**

Answer 29

- _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

Answer 30

- These people are probably going to die (30-50%) - Stage 1 you could cure with radiation, but otherwise you probably can’t

Answer 31

- Often lower stage - Rapid progression - Require complex therapies - Potential cure - Early therapy required

Answer 32

- _Diffuse large cell_ (most common of these) - _Mantle cell_: t(11;14), Cyclin D translocation - _Peripheral T-cell lymphoma_: NOS, angioimmunoblastic, anaplastic

Answer 33

- _Burkitt_ (or Burkitt-like): t(8;14), c-MYC - _T-Cell lymphoblastic lymphoma_

Answer 34

- Was AIDS-related, but now increasing with older people - Treatable/curable in maybe 1/3rd of people

Answer 35

- _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

Answer 36

- 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

Answer 37

- 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

Answer 38

Fused PET/CT scan

Answer 39

- Diffuse large B-cell - Together with follicular lymphoma, make up the BIG 2

Answer 40

- _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)

Answer 41

- _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.

Answer 42

- 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

Answer 43

- 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_)

Answer 44

- Difference between autologous transplant post-R failure and conventional therapy (more chemo) - Clearly, autologous transplant had much better outcomes here

Answer 45

- _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

Answer 46

- _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

Answer 47

MYCOSIS FUNGOIDES. Indolent lymphoma.

Answer 48

Sezary syndrome: hard to get rid of, or limit, this

Answer 49

- Sezary syndrome - Abnormal cells in the peripheral blood have characteristic, cerebriform, large, and clefted nuclei with fine chromatin pattern and scant cytoplasm

Answer 50

- _Adult T-cell Leukemia/lymphoma_ - Japan and Caribbean and southern USA - HTLV-1 RNA retrovirus

Answer 51

R-S Cell (on every test ever, according to Dr. Weir)

Answer 52

- 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

Answer 53

- 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

Answer 54

- 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**

Answer 55

- **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

Answer 56

- 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

Answer 57

- _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_

Answer 58

- 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

Answer 59

- 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

Answer 60

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.

Answer 61

- 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.