HemeOnc Diseases

Disease General Class Causes/Genetics Pathophysiology Symptoms

B12 deficiency

Folate deficiency

Iron deficiency Hypoproliferative Anemia

Anemia of chronic disease Hypoproliferative Anemia regular anemia symptoms

Beta thalassemia minor Often asymptomatic

Beta thalassemia

α-/α- (trans) OR αα/-- (cis) mild anemia

α-/--

all minuses

Hypoproliferative Anemia- Megaloblastic (problem w/ DNA production)

Diet (Vegan), Inadequate secretion of IF (post GI surgery, pernicious anemia), lack of gastric acid, Competition for B12 (tapeworm, bacterial overgrowth), pancreatic insufficiency, Crohn's

eat --> B12 binds to R protein --> gastric parietal cells release intrinsic factor --> pancreatic proteases degrade R, so B12 is free to bind to IF --> B12-IF binds to terminal ileum receptors -> endocytosed & enters circulation (so problems w/ any of this cause deficiency)

Beefy red tongue; Neurological symtpoms (spinal cord degeneration --> loss of position & vibration sense; dementia, psychosis, personality changes)

Hypoproliferative Anemia- Megaloblastic (problem w/ DNA production)

Diet, Malabsorption, Increased requirement (pregnancy, lactation, hemolysis, psoriasis), Drugs

eat raw leafy green veggies --> absorbed in small intestines --> stored in liver

Beefy red tongue (glossitis)

Usually due to blood loss, but also due to growth, pregnancy, lactation or poor diet, absorption, transferrin function

iron absorbed thru intestines, bound to transferrin, stores in liver as ferritin, to bone marrow to make Hgb, thru circulation on RBC; macrophages engulf; back to liver

Glossitis, Angular cheilititis (ulcers at mouth corners), Esophageal webs, Koilonychia (nail spooning), Pica

Cytokines want to sequester iron away from blood stream

inflammatory states, cytokines increase hepcidin production --> less Fe absorption from gut, less Fe export from liver stores, less transferrin & TIBC

Quantitative hemoglobinopathy ββ+ or ββ0

the mutations in thalassemias partially or completely inactivate chain production

Quantitative hemoglobinopathy

Intermedia: β+β+ or β+β0

and Major (aka- Cooley's anemia) β0β0

deficiency in 1 chain type --> excess in other type --> ineffective erythropoesis & destruction of produced RBCs

Splenomegaly, skeletal deformities (frontal bossing), iron overload

Alpha thalassemia (cis and trans)


deficiency in 1 chain type --> excess in other type --> ineffective erythropoesis & destruction of produced RBCs

Alpha thalassemia- Hemoglobin H disease


forms a beta 4 tetramer --> unstable, so it precipitates out as a Heinz body, leaving a bite cell behind + hemolytic anemia

Variable presentation, often like beta thal intermedia (see above)

Alpha thalassemia- Hydrops fetalis


loss of all 4 alpha genes, main type is Hemoglobin Barts, w/ gamma4 tetramers

intrauterine death w/o transfusion

Structural hemoglobinopathy

Hemoglobin C Structural hemoglobinopathyColumn1 Column2 Column3 Column4 Column5

Herediatry spherocytosis Hemolytic Anemia- congenital Autosomal dominant

Hemolytic Anemia- congenital X-linked

Pseudothrombocytopenia not an actual disease

Sickle Cell disease (may want to refer to study sheet b/c lots of info on this)

6th aa on β chain from glutamate --> valine

HbS polymerizes when hypoxic -> blood depolymerizes when it returns to lungs -> multiple sickling/desickling cycles -> cell dehyrdration -> cells before irreversible sickled & block small vessels

Chronic anemia, thromboses (increased risk for venous clots), painful crises, aplastic crises, infection esp w encapsulated organisms b/c functionally asplenic

6th aa on β chain from glutamate --> lysine

increased cellular dehydration -> mild hemolysis

mild hemolysis, splenomegaly

defect in RBC membrane skeleton protein (spectrin, ankryin) -> patients cant anchor lipids -> lipids pinched off -> spherocytes form + hemolysis

see list of hemolytics; increased hemolysis + abdominal pain w/ trivial infectious illnesses

G6PD Deficiency (Glucose 6 Phosphate Dehydrogenase)

low G6PD -> ineffective PPP -> low NADPH levels -> Hb not proteted from oxidative damage -> Hb oxidized & precipitates out as Heinz body -> bite cell left behind

see list of hemolytics; hemolysis usually triggered by drugs/infection

Warm antibody Hemolytic Anemia

Immune Mediated Hemolytic Anemia

can be primary or secondary to another disorder; or drug induced; Evan's syndrome: when it's associated w/ immune platelet destruction

IgG antibodies against RBC membrane molecules form --> IgG antibodies coat RBC --> RBC engulfed by macrophages --> spherocytes form

See list of hemolytics;symptoms vary depending on rate of fall in Hb

Cold antibody Hemolytic anemia

Immune Mediated Hemolytic Anemia

associated w/ infection from Mycoplasma & Mononucleosis; or lymphoproliferative disease

IgM antibodies bind to RBC in cooler extremities --> fix complement --> complement-coated RBCs are lysed in or out of vessel & RBC agglutination

cyanosis; ischemia of extremities

Microangiopathic Hemolytic Anemia (MAHA)

Non-immune hemolytic anemia

TTP, HUS, DIC, malignant HTN, vasculitis, OB trouble

shear damage to RBC's due to endothelial cell activation or damage

certain pt's make a substance that causes platelets to clump in test tubes --> artifically low platelet count

no actual bleeding consequences

DIC (disseminated intravascular coagulation)

Thrombocytopenia: peripheral destruction- non-immune mediated

Gram negative sepsis, severe burns, OB disaters, certain leukemias/tumors, shock, venom, cancer

abnormal activation of coagulation, thrombin generation, clotting factor consumption, platelet destruction, fibrinolysis activation

histologic finding is always thrombosis

Heparin

Thrombocytopenia

Splenic Sequestration Thrombocytopenia splenomegaly

Hemophilia A Hemophilia

Hemophilia B Hemophilia same as Hemophilia A

VWF deficiency Hemophilia Autosomal dominant

Thrombophilia "gain of function"

Factor V leiden Thrombophilia "loss of function"

TTP (thrombocytopenic purpura)


can be sporadic (ADAMTS-13), familial, drug induced (quninine, cyclosporine, tacrolimus) , increased in pregnancy/AIDS

of sporadic: pt's make antibody against ADAMTS-13, a protease that cleaves long chains of VWF -> platelets get stuck to long vwf chains -> abnormal platelet aggregation + schistocytosis

fever, neuro symptoms, kidney symptoms

HUS (hemolytic uremia syndrome)


diarrheal illnesses (E. coli 0157:H7 & Shigella)

shiga toxin binds to kidney endothelial cells --> cell death

like TTP, but w/ less neuro and more renal

HIT (Heparin Induced Thrombocytopenia)

Thrombocytopenia: peripheral destruction- immune mediated

antibodies against the complex of heparin & PF4 --> can lead to thrombosis

ITP (Immune/Ideopathic Thrombocytopenic Purpura)

lupus, HIV, CLL may be involved; in kids, usally provoked by viral illness

Portal HTN from cirrhosis, malignancy, sarcoidosis, chronic hemolytic disease

splenic enlargement, from any cause, can lead to displacement of platelets from peripheral ciculation -> splenic pool

X-linked deficiency of Factor 8

Factor 8 is part of the clotting cascade in secondary hemolysis

hemarthrosis, bleeding in muscle, CNS, retroperitoneum, oro/naso pharynx, surgical sites, urinary tract

X-linked deficiency of Factor 9

Factor 9 is part of the clotting cascade in secondary hemolysis

deficiency/dysfunction of VWF, which helps w/ platelet adhesion and carries/stabalizes factor 8 in plasma -> bleeding

muco-cutaneous bleeding (menorrhagia, epistasis, GI bleeds), excess bleeding w/ trauma

Prothrombin 20210 mutation

point mutation in prothrombin gene -> increased prothrombin levels -> greater chance of clots

a risk factor for thrombosis, not a disease

point mutation in factor 5 gene at place where activated protein C cleaves 5a -> 5a relatively resistant to deactivation


Thrombophilia

Polycythemia vera A clonal disorder

unclear

Myelofibrosis

Myelodysplasia

antiphospholipid antibody syndrome

2 types of antibodies are possible: The Lupus Inhibitor & Anticardiolipid Antibody

mechanisms of thrombosis are controversial


Myeloproliferative Disorder (these are all stem cell disorders leading to autonomous production of hematopoietic cells from all 3 lineages)

JAK2 mutation -> unregulated GF signaling in absence of epo -> lots of erythrocytosis

Pruritis after bathing, Erythromlelalgia, Hypermetabolic syndrome, thrombosis, hemorrhage; Hyperviscosity syndrome (headaches, visual change, tinnitus, dizzy, parasthesias, low mental acuity);

Essential Thrombocythemia


1/2 have clonal disorder; 1/2 have polyclonal increase in megakaryocytes

major complication = thrombosis; many pt's asymptomatic; digistal ischemia; erythromelalgia; pruritis; hemorrhage in 40%


Clonal stem cell disorder affecting mainly megakaryocytes

all myeloproliferative disordres can result in a spent phase that looks like preliminary MF

anemia & thrombocytopenia symptoms; fever, sweat, weight loss; massive splenomegaly (can cause abdominal pain, early satiety), hepatomegaly

condition where there is disordered maturaion in 1+ cell lines, usually -> cytopenias

disordered maturation in 1+ cell lines; can be due to cytogenic abnormalities

disordered maturation -> cytopenia -> the clone can either remain stable or progess, making worse clones

some asymptomatic pt's diagnosed b/c of low counts; others present w/ symptoms of anemia/thrombocytopenia

Hematology Labs Diagnosis Treatment Other

Oral or IM B12

Microcytosis

none needed

MCV<80

microcytosis MCV <80 watch out for having kids

MCV <80

macrocytosis, hypersegmented PMNs

Retic index <2%; Absolute retic count <75,000; MCV >100; elevated PMNs

Increased homocysteine & methylmalonic acid; decreased B12

takes 3-4 yrs to deplete stores in liver

macrocytosis, hypersegmented PMNs

Retic index <2%; Absolute retic count <75,000; MCV >100; elevated PMNs

Increased homocysteine only; decreased serum and red cell (months) folate

Give folate orally, even w/ malabsorption; Prophylactic folate to risk groups

only takes 2-5 months to deplete stores

Hypochromatic, Microcytosis, Thrombocytosis (increased platelets)

1st- high RDW, 2nd- MCV <80; Low ferritin; Retic index <2%; Absolute retic count <75,000; high platelet count

In a healthy outpatient, ferritin = best study for iron deficiency; BM biopsy = gold standard

Correct underlying cause; Oral iron (nausea, constipation), IV iron, blood transfusion

no excretion so be careful about giving too much

Low serum iron levels, also low Transferrin and TIBC; Ferritin can be normal or high; MCV<80

AOCD has low TIBC, while Fe deficiency has high TIBC; also, ferritin not decreased in AOCD

TIBC = total iron binding capacity

Microcytosis, target cells, basophilic strippling, hypochromatic

Hgb is normal or minimally decreased, MCV <75, RBC count high

Hb electrophoresis shows increased HbA2 = hallmark

more common in Mediterranean region

Microcytosis, Target Cells, Howell-Jolly bodies, nucleated red cells, schistocytes, basophilic strippling, teardrops

Hb electrophoresis shows increased HbA2 = hallmark

Transfuse regularly, chelate for iron overload; stem cell transplant = only curative model

more common in Mediterranean region

w/ molecular techniques only (see below!)

trans = Africans; cis = Asians

Bite cells, Heinz bodies, microcytosis, target cells

MCV <80 , low MCH, high RDW

Hb eletrophoresis cannot detect the presence of alpha thalassemia trait past infancy

Blood transfusions, chelate for iron overload; stem cell transplant = only curative model

exchange transfusion in utero

Sickle Cells, Poikilocytosis leukocytosis, thrombosis

Column6 Column7 Column8 Column9 Column10

Spherocytes

Bite Cells or blister cells

Schistocytes high LDH, high bilirubin

they show low platelets

Schistocytes

sickle prep screening test to detect sickle cells; Hb electropphoresis to detect abnormal Hb; PCR can be done prenatally

hydroxyurea but not in pregnancy or w/ poor follow up b/c it suppresses BM; treat pain, give O2, folate; sometimes transfusion; BM transplant=only cure

complications = acute chest syndrome, pulmonary HTN, stroke ~age 5, problems w/ transfusion, etc

Target Cells, Microcytosiscan complicate HbS by increasing dehydration

low MCV, high MCHC, high reticulocyte count; high LDH, high unconj bilirubin

increased osmotic fragility (spherocytic cells are more dense, so more susceptible to lysis in distilled water)

folate supplementation; splenectomy will stop hemolysis but spherocytes persist

complication: aplastic crisis w/ Parvovirus B19

high LDH, high unconj bilirubin

G6PD levels; Note: immediately after a hemolytic episode, G6PD levels in patients w/ A- may be normal

Folate supplement +Avoid oxidant agents (anti-malarials, sulfa drugs, Dapson, Vit K, Fava beans, moth balls)

2 normal G6PD variants: B = most common, A = 20% healthy AA's

Spherocytes; Polychromasia

positive Coomb's test (direct & indirect); high retic, high bilirubin, high LDH; high MCHC

Spherocytes & Positive Coomb's Test

immunusuppresants = mainstay; 1st line- corticosteroids 2nd- splenectomy 3rd- stronger immunosuppresants (Rituximab, Cytoxan)

RBC agglutination; Spherocytes; polychromasia

positive Coomb's test ; high MCHC

RBC agglutination, spherocytes, Positive Coomb's Test

keep patient warm; may need immunosuppression & transfusion

steroids and splenectomy are ineffective

rule this out when evaluating thrombocytopenia

high PT, high PTT if progressed, low platelets, low fibrinogen, high fibrin degradation products/D-dimers

high PT, low platelets, low fibrinogen, increased in D Dimers

treat underlying cause! May support w/ platelet transfusion, replace clotting factors w/ FFP, replace fibrinogen w/ cryoprecipitate

Schistocytes

Schistocytes

Megakaryocytes in marrow low platelets

low platelets

1-2% of Caucasians

MAHA (high LDH, high bilirubin), low platelets

"The Pentad"- 1. must have MAHA (see above) 2. must have thrombocytopenia 3. fever 4. neuro 5. renal

plasma exchange! Avoid platelet transfusions b/c this fuels the fire; remove inciting agents, corticosteroids, splenectomy may be needed

>90% fatal w/o therapy, 80-90% survive w/ therapy; 1/3 survivors relapse, most in 1st month after Dx

like TTP; often called TTP/HUS

may respond less well than TTP to plasma exchange

more common in pediatric pts; better prognosis

platelet counts do not have to be abnormal! Just fallen by 30-50%

platelet drop 7-10 days after heparin started

if platelets fall on heparin, stop heparin immediately!

1-3% of patients treated w/ heparin

diagnosis of exclusion w/ no diagnostic test

for kids: spontaneously remits; for adults, 1st- corticosteroids & IVIg (can give Anti-D/Win Rho to Rh+ pts), 2nd- splenectomy; 3rd- stronger immunosuppressor

remember to immunize against encapsulated organisms (Strep pneumo, H influenzae, Strep meningitidis) before taking spleen out

platelet transfusion is wasteful b/c they will also go to the spleen; reserve for severe bleeding

increased PTT corrected w/ 1:1 mix

Factor 8 replacement via recombinant factors or plasma derived; DDAVP = Desmopressin Acetate help mild cases only

increased PTT corrected w/ 1:1 mix

Factor 9 replacement via recombinant factors or plama derived

increased bleeding time (PFA), inreased PTT corrected w/ 1:1 mix, decreased VWF antigen and activity

increased bleeding time (PFA), inreased PTT corrected w/ 1:1 mix, decreased VWF antigen and activity, decreased Factor 8 activity

DDAVP can help; Humate P is enriched w/ VWF

most common inherited bleeding disorder

prophylaxis at times of increased risk; avoid triggers; after 1st event- warfarin/heparin


5% Caucasians are heterozygous, but 90% never get VTE

for LI: prolonged PL dependent clotting tests, esp PTT, that don't correct on 1:1 mix but correct w/ excess plasma; for AA: detect w/ ELISA

Need 1-thrombosis (venous or arterial) or recurrent miscarriage AND 2- persistent anti-PL antibody(s)


Basophilia (tear drops cells in spent phase)

low epo levels, positive JAK2 V617F mutation, high Hgb, (can have High WBC or platelets), basophilia, high uric acid & B12 (facial plethora, splenomegaly, hepatomegaly, distention of retinal veins)

low or undetectable epo levels; JAK2 mutation

1st line- phlebotomy (increases thrombosis risk, doesn't affect progression to spent phase) 2nd- hydroxyurea; give low dose aspirin to all patients

5% in pt's <40; 1.) Asymptomatic Latent Phase 2.) Proliferative phase (hypermetabolic, hyperviscosity, thrombosis) 3.) Spent Phase (anemia, leukopenia, myelofibrosis, increased liver & spleen size, tear drops cels)

large/bizarre shaped platelets; clusters of abnormal megakaryocytes in BM, Basophilia

normal Fe and ESR; pseudohyperkalemia & pseudohypoglycemia if plts very high

1st rule out secondary causes of thrombocytosis (Fe def, cancer, infection, bleeding); platelet count >600 on 2 separate occasions

goal = lower plt count to decrease thrombosis risk; treat pt's who have/at risk for thrombosis, those >65 yo, or w/ plts >1 mil; w/ hydroxyurea, Anagrelide, IFN-alpha

20% pt's <40 yo *may progress to myelofibrosis

Teardrop cells, nucleated RBCs, early granulocytes; Basophilia

low Hgb, low plts, low WBC; "dry tap", increased collagen and reticulin fibrosis on BM biopsy

no definitive therapy; BM transplant on young patients; supportive therapy w/ transfusion; splenectomy for abdominal pain

Median survival = 5 years; transforms to AML in 5-20%;

Monocytosis, Macrocytosis of RBC, neutrophils can be hypogranular or biloped, and/or large platelets

MCV >100; can have low platelet count

Marrow features: megaloblastic erythropoeisis, ringed sideroblasts, dyserythropoeisis, small megakaryocytes w/ abnormal nucleus, blast cells <20% marrow cells (>20 = AML)

supportive; transfuse w/ RBCs and plts as needed, growth factors (epo, G-CSF) help cytopenias; thalidomide, DNA hypomethylators

disease of the elderly; once the pt develops AML, the chances of remission is much less

Disease General Class Epidemiology Risk Factors Symptoms

RadiationChromic Myeloid Leukemia (CML)

Myeloproliferative neoplasm; transforms

hematopoietic pluripotent cell

Median Diagnosis Age= 66 (some in kids)

Hypermetabolic syndrome(sweat, fever, weight

loss, anorexia), fatigue, abnominal fullness, early

satiety; 1/3 incidental findings

Chronic Lymphocytic Leukemia (CLL)- aka SLL

when in lymph

Malignancy of mature B cells

Older patients; most common adult leukemia;

median diagnosis age = 72

Family history, exposure to Agent Orange

Fatigue, weakness, fever, night sweat, malaise, abdominal

fullness, early satiety; increased infections,1/5 incidental

findings

Acute Myeloid Leukemia (AML)

Malignancy of committed myeloid progenitor cells

Median diagnosis age =68, but some kids

Prior radiation, prior chemo (alkylating agents, topo II inhibitor), Benzene, Down syndrome, Fanconi anemia

Hypermetabolic syndrome, severe anemia (fatigue, dyspnea), opportunistic

infections, bruises & bleeding, mental status changes, CXR

infiltrates, APL type associated w/ DIC

Acute Lymphoblastic Leukemia (ALL)

Malignancy of committed lymphoid progenitor cells

(pre-T or pre-B)

Median diagnosis =11, most common cancer in children, peak incidence

2-5

Prior radiation, prior chemo, Down Syndrome

Hypermetabolic syndrome, fatigue, SOB, opportunistic infections, bruises/bleeding,

mediastinal mass (esp in precursor T-cell), CNS

involvemnt, testicular involvement

Physical Exam Labs Morphology Pathogenesis Diagnosis

Bcl-2 overexpression -> blocks apoptosis

Splenomegaly, hepatomegaly

Leukocytosis w/ neutrophilia (left shift), basophilia, eosinophilia; anemia; thrombosis (plts

increased or normal)

Peripheral blood: lots of immature granulocytes

+ basophils; heterogeneity; Bone

Marrow aspirate is hypercellular w/ high M:E,

decreased fat

t(9,22) -> Philidelphia Chromosome/BCR-ABL, with

constitutive tyrosine kinase activity -> more proliferation, less apoptosis;

P210 bcr-abl is seen most

Philidelphia chromosome necessary + sufficient; 95% by cytogenics; 5% only by FISH;

PCR detects bcr/abl transcript; Flow cytometry is

not helpful until blast crisis myeloid vs lymphoid

Lymphadenopathy, splenomegaly, sometimes

hepatomegaly

Lymphocytosis >5000; anemia, thrombocytopenia, hypogammaglobulinemi

a -> infections

Accumulation of mature, homogenous lymphocytes;

smudge cells; homogeneous BM

Usually by peripheral smear; Flow Cytometry is key! CD19 light chain restriction, CD5+, 19+, 20+, 23+; Cytogenetics

often show deletion of 13

Ecchymoses, petechiae, Bilateral infiltrates on CXR,

hepatomegaly

Cytopenia- Severe neutropenia, severe

thrombocytopenia (in contrast to CML), severe anemia, hyperleukocytosis

Auer rods = AML; Monotonous population of myeloblasts: large w/

open chromatin, prominent nucleoli, scant cytoplasm in

peripheral blood; can often see granules

Type 1 mutations -> proliferative advantage (ie- activate FLT-3, a TK); Type 2 mutations block cell differentiation (eg-t(15,17) PML-RARα, a transcriptional

repressor that recruits a nuclar co-repressor complex to block genes

involved in differentiation, called Acute Promyelocytic Leukemia, APL)

AL Dx requires >20% blood or BM are blasts; Auer rods;

look for t(15,17) w/ cytogenetics; look for CD33 (myeloid), CD34 = blasts

Hepatosplenomegaly; lymphadenopathy

Severe anemia, severe neutropenia, severe

thrombocytopenia (bc bone marrow is just making

leukocyte blasts)

Peripheral blood luekocytosis w/ numerous

lymphoblasts; homogenous BM

aspirate: large cells, open chromatin, prominent nucleoli, monotonous

t(12,21), most common childhood one, good prognosis, recruits NCoR; BCR-ABL p190, worse prognosis, 1/3 of adult

cases, 4% of kids

Cytogenetics showing t(12,21), Do flow to tell from AML,

CLL! It shows CD10+ CD19+ CD34+; cytochemical stains

negative

Progression Treatment Prognosis Details

good, a very treatable disease

1- asymptomatic chronic phase; 2- accelerated phase

(more blasts, WBCs, splenomegaly, basophilia); 3- Blast crisis: turns into AML

(or ALL)

1st: Imatinib (Gleevec), a BCR-ABL tyrosine kinase

inhibitor, binds to inactive conformation; 2nd- Nilotinib works if resistance occurs; Allogenic SCT = only cure

Autoimmunity can occur (AIHA- 20%, ITP- 2%); Stage 0 =

lymphocytosis only; Stage 1: + lymphadenopathy; Stage 2: +splenomegaly; Stage 3:

+anemia; Stage 4: + thrombocytopenia

Not curable; treatment of asymptomatic CLL has no

survival advantage; Chemo (Rituximab) if symptoms

worsen

good long-term prognosis, many die w/ it not of it; deletion of 13q14 = good prognosis; deletion of 11q23

and 17p13 (involves p53)= bad prognosis

Note: the FAB classification for t(15,17) AML = M3; will stain strongly w/ MPO cytochemical

staining

Curable (30-40%); "7+3 chemo"; consider STM (for

APL, 80% curable = chemo + all-trans

retinoic acid)

Good: t(15,17) mutation associated with M3; Bad: old age, chromo deletion, secondary to other

disease/chemo/radiation, FLT-3, monosomy 5,7 or 11q23 (MLL)

Complication = tumor lysis syndrome: life-threatening due

to high cell turnover, causes renal failure, hyperuricemia,

hyperkalemia, hyperphosphatemia,

hypocalcemia; treat w/ IV hydration, allopurinol,

rasburicase

Very complex; cure rates 80% in kids, 20-40% in

adults; treat w/ vincristine, daunorubicin, L-

asparaginase, prednisone; allogenic SCT reserved for

high risk disease

Good: Age 2-10, t(12,21), hyperdiploidy, B cell Bad: Age

<1 or >10, t(9,22), 11q23 hyodiploidy, T cell, high WBC

count

Lymphoma Grade Epidemiology Histology Labs

"Low Grade" Not curable

Low Grade Older adults Not curable

Intermediate Grade

Burkitt Lymphoma High grade

Molecular Abnormalities

Curability &Treatment

Small Lymphocytic Lymphoma

Older adults; same as CLL but in lymph nodes

Small, round, mature lymphocytes (B cells) that obliterate normal architecture

Flow cytometry: CD5+, CD19+, CD20+, CD22+, CD23+, light chain restriction

Follicular (Small Cleaved) Lymphoma

Small, cleaved lymphocytes; lots of germinal center cells

Flow cytometry: CD10+, CD19+, CD20+, CD22+,light chain restriction

t(14,18) -> high BCL2 -> blocks apoptosis

Diffuse Large Cell Lymphoma

most common type of adult NHL; in children & adults; can relate to impaired immune function (HIV)

Large B cells spread throughout lymph node

30% have 3q27 mutation causing BCL-6 abnormality

100% have high BCL-6 -> no arrested development

Curable- treat with "R-CHOP" sometimes w/ XRT (Rituximab/ Cyclophosphamide/ Adriamycin/ Vincristine/ Prednisone); radiation early stage, chemo late stage

Mostly children. 1- Endemic (kids, jaw, Africa, EBV) 2- Non-endemic (worldwide, ab mass, 15% EBV), increased incidence w/ HIV/AIDS

Macrophages form "starry sky" & cytoplasmic vacuoles

Cytogenetics: t(8,14) t(2,8) or t(8,22) b/c myc is on chromosome 8

high MYC -> proliferation

>80% curable, unlikely to relapse after remission for 2+ years

High grade

Hodgkin's Lymphoma

Lymphoblastic Lymphoma

Children & young adults (similar to ALL)

Homogenous middle size cells (90% involve T cells, 10% B cells); blasts

T cell type Flow: CD3+ CD4+ CD8+ Tdt+

Curable- treat w/ ALL therapy including CNS treatment

"Intermediate Grade"

EBC 50% of cases, bimodal (peak in 20s then past 50)

Reed-Sternberg Cells, are the minority of cells in smear

Immunohistochemistry for Dx: CD30+ CD15+ CD45-, flow + cytogenetics look normal

Note: spread to adjacent nodes

60-95% curable with ABVD "Adriamycin, Bleomycin, Vinblastine, Decarbazine"; 2/3 have mass after treatment, late relapses occur

Prognosis

Pt's often die w/, not of it

Pt's often die w/, not of it; 13q14 is good, Trisomy 12 is bad

International Prognostic Index: +1 for high LDH, age >60, 2+ performance, Stage 3 or 4, Extranodal 4 yr survival: 0 = 95% 1-2 = 80% 3-5= 55%

Staging for lymphomas: 1- 1 node or extranodal site; 2- 2+ nodes on same side of diaphram 3- 2+ nodes above and below diaphram 4- liver or BM involved E= extranodal, B= any B symptoms

Complication: Superior Vena Cava Syndrome, treat w/ radiation

* Lymphocyte predominance: great prognosis, older pt's *Nodular Sclerosis- good prognosis, younger *Mixed Cellularity- intermiedate prognosis *Lymphocyte depletion= bad

Disease Symptoms Physical Exam Labs Morphology Diagnosis

Multiple Myeloma Compression fractures

Smoldering Myeloma None Normal N/A

None Normal N/A

Amyloidosis

CRAB (high Ca, renal insufficiency, anemia, bone disease w/ lytic lesions), recurrent bacterial infections, rare hyperviscosity

elevated ϒ on SPEP/UPEP, IEF shoes monoclonal disorder; lesions on skeletal survey; normochronic, normocytic anemia; high creatinine, high P:A ratio, low anion gap

Rouleaux Formation, lots of plasma cells in bone marrow

1.) 3+ g/dl Ig OR 10+% plasma cells in BM (CD138+ stains for plasma cells) and 2.) CRAB symptoms

elevated ϒ on SPEP/UPEP, IEF shows monoclonal disorder

1.) 3+ g/dl Ig OR 10+% plasma cells in BM and 2.)Asymptomatic

MGUS (Monoclonal Gammopathy of Unknown Significance)

somewhat elevated ϒ on SPEP/UPEP, IEF shows monoclonal disorder

1.) <3 g/dl Ig AND <10% plasma cells in BM and 2.) asymptomatic

Big Tongue, Periorbital Hemorrhage, Carpel Tunnel, Foamy Urine

Many organs involved (kidney, liver, spleen, GI tract, heart, skin, nervous system, respiratory system, blood), Peripheral Neuropathy, Cardiac Arrithmias

elevated ϒ on SPEP/UPEP, IEF shows monoclonal disorder, but only on light chains; proteinuria

Eosinophilic homogenous material on light microscopy; "Apple green birefringence" on Congo Red Stain using polarized light; Tissue Biopsy shows β-sheets; Fibrillar appearance on EM

1.) <3 g/dl Ig AND <10% plasma cells in BM and 2.) Symptoms

Waldenstron's Macroglobulinemia

B symptoms, Fatigue, Hyperviscosity Syndrome: Headache, Blurred Vision

Hepatosplenomegaly, Lymphadenopathy, Retinal Vessel Sausaging, Peripheral Neuropathy

elevated ϒ on SPEP/UPEP, IEF shows monoclonal increase in IgM; CD20+ CD138+, can have positive Coomb's b/c Hemolytic Anemia; high serum viscosity

Plasma and B cells in bone marrow biopsy

IgM monoclonal gammopathy AND >10%bone marrow w/ lymphoplasmacytic lymphocytes (S IgM+ CD19+ CD20+ CD138+)

Prognosis Treatment

Stage 1- β2 microglobulin <3.5, albumin >3.5 = 5.2 yrs; Stage 2- β2 micro <3.5, albumin <3.5 OR β2 micro 3.5-5.5 = 3.7 yrs; Stage 3- β2 micro >5.5 = 2.4 years; also cytogenetics

No cure, use multiple treatments & combos

10% risk of progression per year

Observation only until symptomatic

A pre-malignant condition (10-25% progress to myeloma, 1-1.5%/year of progression)

Observation only until symptomatic

Can progress to myeloma, but damage done is often fatal before myeloma develops

main type: AL amyloidosis (due to Ig light chains, associated w/ monoclonal plasma cells)- treat similar to myeloma

"lymphoplasmacytic lymphoma", progresses like CLL; disease of adults, men

Not curable, so treat like a low grade lymphoma; can treat symptoms w/ plasmaphoresis (plasma exchange)

Drug General Class Mechanism

Methotrexate (MTX)

5-fluorouracil (5-FU)

same at 6-MP

Cytarabine (ara-C)

Antitumor antibiotic intercalates in DNA

Antitumor antibiotic

Bleomycin Antitumor antibiotic

Antitumor antibiotic

Antimetabolite (inhibits DNA synthesis)

Folic acid analog that inhibits dihydrofolate reductase →↓ dTMP → ↓ DNA & ↓ protein synthesis


Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid; this complex inhibits thymidylate synthase →↓ dTMP → ↓ DNA & ↓ protein synthesis

6-mercaptopurine (6-MP)


Purine (thiol) analog →↓ de novo purine synthesis; activated by HGPRTase

6-thioguanine (6-TG)



Pyrimidine analog → inhibition of DNA polymerase

Dactinomycin (Actinomycin D)

Doxorubicin (Adriamycin, daunorubicin)

Generate free radicals; noncovalentaly intercalate in DNA → breaks in DNA → ↓ replication

induces free radical formation → breaks in DNA strands

Etoposide (VP-16), teniposide

inhibits topoisomerase II → ↑DNA degradation

Alkylating agent

Alkylating agent

Busulfan Alkylating agent Alkylates DNA

Microtubule inhibitor


Cross-link DNA

Hydroxyurea

Prednisone

Cyclophosphamide, ifosphamide

covalently X-link (interstrand) DNA at guanine N-7. requires bioactivation in liver

Nitrosoureas (carmustine, lomustine, semustine, streptozocin)

Requires bioactivate; cross BBB into CNS

Vincristine, Vinblastine

alkaloids that bind to tubulin in M-phase and block polymerization of MT's so that mitotic spindle can't form

Paclitaxel, other Taxols

hyperstabalize polymerized MTs in M-phase so the mitotic spindle can't break down (no anaphase)

Cisplatin, Carboplatin

inhibits ribonucleotide reductase → ↓DNA synthesis

may trigger apoptosis; may even work on nondividing cells

Tamoxifen, raloxifene

SERMs- receptor antagonists in breast and agonists in bone; block the binding of estrogen to estrogen receptor + cells

Imatinib (Gleevec)

Rituximab

Trastuzumab (Herceptin)

monoclonal antibody against HER-2 (erb-B2), a TK; helps kill breast cancer cells that overexpress HER-2

Philidelphia chromosome bcr-abl TK inhibitor

monoclonal antibody against CD20, which is found on most B-cell neoplasms

Clinical Use Toxicity

myelosuppression

Cancers (leukemias, lymphomas, choriocarcinoma, sarcoma)

Myelosuppression, reversible w/ leucovorin; macrovesicular fatty changes in liver, mucositis, teratogenic

Colon cancer & other solid tumors, basal cell carcinoma (topical); synergy w/ MTX

Myelosuppression, not reversible w/ leucovorin; Overdose "rescue" w/ thymidine; photosensitivity

Leukemias, lymphomas (not CLL or Hodgkins)

Bone marrow, GI, liver; metabolized by xanthine oxidase so increased toxicity w/ allopurinol

Acute Lymphoid Leukemia

Bone marrow depression, liver; can be given w/ allopurinol

AML, ALL, high-grade non-Hodgkin's lymphoma

Leukopenia, thrombocytopenia, megaloblastic anemia

Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma; used for children's tumor

Hodgkin's lymphoma, myelomas, sarcomas, solid tumors (breast, ovary, lung)

Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia; toxic to tissues w/ extravasation; Dexrazoxane (iron chelating agent) used to prevent cardo toxicity

Testicular cancer, Hodgkin's lymphoma

Pulmonary fibrosis, skin chances, minimal myelosuppression

small cell carcinoma of lung & prostate, testicular carcinoma

Myelosuppression, GI irritation, alopecia

CNS toxicity (dizziness, ataxia)

Non-Hodkin's lymphoma, breast & ovarian carcinomas; also immunosuppressants

myelosuppression; hemorrhagic cysitis, partially prevented w/ mesna (thol group of mesna binds toxic metabolite)

Brain tumors (including glioblastoma multiforme)

CML. Also used to ablate pt's bone marrow before BM transplant

pulmonary fibrosis, hyperpigmentation

Hodgkin's lymphoma, Wilm's tumor, choriocarcinoma, ALL

Vincristine: neurotoxicity (areflexia, peripheral neuritis), paralytic ileus; Vinblastine: bone marrow suppression

MT's are the "vines" of your cells ; vin blastine blasts BM

ovarian and breast carcinomas

Myelosuppression, hypersensitivity

it is TAXing to stay polymerized

testicular, bladder, ovary, and lung carcinomas

Nephrotoxicity, acoustic nerve damage; prevent nephrotoxicity w/ amifostine (free radial scavenger) and chloride diuresis

melanoma, CML, sickle cell

bone marrow suppression, GI upset

usually in glucocorticoid cancer chemo; used in CLL, Hodkgin's (part of MPOPP regimen)

Cushing symtpoms; immunosuppression, cataracters, acne, osteoperosis, HTN, peptic ulcers, hyperglycermia, psychosis

breast cancer; and to prevent osteoperosis

Tamoxifen: may ↑risk of endometrial cancer via partial agonist effects; hot flashes

metastatic breast cancer cardiotoxicity

CML, GI stromal tumors fluid retention

Non-Hodgkins lymphomas, rheumatoid arthritis

Drug General Class Mechanism Toxicity

Typical Alkylating Agent

Antimetabolite

Antimetabolite

Cytarabine (ara-C) Antimetabolite

Antimetabolite Myelosuppression

Bendamustine Antimetabolite

Cyclophosphamide, Ifosphamide, Melphalan

Direct cross-linking of base pairs

Myelosuppression; Hemorrhagic cysitis- Ifosphamide especially; Acrolein is a metabolite of these drugs that causes damage, prevent w/ mesna

Cisplatin, Carboplatin, Oxaliplatin

Atypical Alkylating Agents: Platinum Agents

Inhibits DNA synthesis thru formation of DNA crosslinks

1- Peripheral neuropathies (all) 2- Nephrotoxic (cisplatin), prevent w/ hydration, forced dieresis, mannitol, we see increased creatinine and Mg wasting 3.) Nausea/Vomiting (all, but Cisplatin has highest level of ANY drug) 4- Thrombocytopenia w/ Carboplatin

Nitrosoureas (BCNu = carmustine, CCNu = lomustine)

Atypical Alkylating Agents

First derived chemo after WW2 mustard gas toxicity

Pulmonary, Myelosuppression, Nausea/Vomiting, CNS

Methotrexate (MTX)

Folic acid analog that inhibits dihydrofolate reductase →↓ dTMP → ↓ DNA & ↓ protein synthesis; tumors rely solely on endogenous folate for growth, so they can't grow; High dose range

Myelosuppression, reversible w/ leucovorin; Mucositis

5-fluorouracil (5-FU)

Pyrimidine analog →↓ dTMP → ↓ DNA & ↓ protein synthesis

Dose limiting toxicities (the way you deliver it changes toxicity); Continuous infusion -> GI (mucositis, diarrhea); Bolus (myelosuppression);

Pyrimidine analog → inhibition of DNA polymerase

Toxicity associated with HIDAC (high dose): Cerebellar toxicity (increased incidence w/ renal dysfunction) & conjunctivitis

6-mercaptopurine (6-MP)

Purine (thiol) analog →↓ de novo purine synthesis; acts as false base for DNA replication

has mechanisms of action, including traits of alkylating agents and purine antimetabolites

Microtubule inhibitor MT destruction


Topo Inhibitor

Topo Inhibitor

Anthracyclines

Differentiation Agents

Bleomycin Traditional Chemo

Traditional Chemo

Vincristine, Vinblastine (Vinca Alkaloids)

Cumulative neurotoxicities esp peripheral neuropathy, Variable myelosuppression (vinblastine > vincristine bc it "blasts" the BM), FATAL IF ADMINISTERED INTRATHECALLY (thru spinal cord)

Taxanes (Paclitaxel, Docetaxel)

MT stabalization (opposite of Vinca alkaloids)

Peripheral Neuropathies, Myelosuppression, Hypersensitivity

Camptothecins (Topotecan, Irinotecan)

inhibit Topoisomerase I, the enzyme responsbile for relaxing supercoiled DNA to allow transcription to occur

Myelosuppression (both), Diarrhea ("I ran to the can")- early onset: treat w/ atropine; late onset = life threatening, treat aggressively w/ loperamide (no max daily dose)

Etoposide (VP-16), teniposide

inhibits topoisomerase II, the enzyme responsible for recoiling DNA after transcription → ↑DNA degradation

Myelosuppression, Secondary Malignancies (ie- AML), Dose dependent mucositis

Doxorubicin, Daunorubicin, Mitoxantrone

Intercalates DNA and inhibits topoisomerase; free radical damage; some alkylation

Cardiotoxicity- All cause cumulative, dose-dependent biventricular heart failure (CHF-like); Extravasation (when drug gets into peripheral tissue, causing severe damage to surrounding skin, get plastic surgeon ASAP); myelosuppression, mucositis, secondary malignancies

All-trans-retinoic acid (ATRA), Arsenic trioxide

Promote maturation of arrested cell line, mostly used to treat APL (AML, M3)

Cardiotoxicity from Arsenic; Differentiation syndrme from both

induces free radical formation → breaks in DNA strands

Pulmonary fibrosis**** Pulmonary toxicity

Bortezomib, Carfilzomib

Proteasome Inhibitors (proteosomes are responsbile for protein degradation) so you disrupt the effect on regulatory proteins needed for tumor growth

Fatigue, weakness, malaise, neuropathy, thrombocytopenia

Hormone Therapies

Hormone Therapies

Rituximab Monoclonal Antibody

Monoclonal Antibody

Cetuximab Monoclonal Antibody

Bevacizumab Monoclonal Antibody Proteinuria, GI perforation

Imatinib (Gleevec) Targeted Therapy fluid retention

Thalidomide, Lenalidomide

Immunomodulating Agents

Antiangiogenesis --> inhibition of cell adhesion mechanisms

Neuropathy, Thromboembolism (when combined w/ steroids), Constipation, thalidomide = teratogen

Flutamide, Bicalutamide, Nilutamide

Antiandrogens used in Prostate Cancer

Leuprolife, Goserelin

LHRH agonists used in prostate cancer

monoclonal antibody against CD20, which is found on most B-cell neoplasms; used against lymphomas

"imab" is chimeric, 33% mouse, so more infusion rxns

Trastuzumab (Herceptin)

monoclonal antibody against HER-2 (erb-B2), a TK; helps kill breast cancer cells that overexpress HER-2

"umab" is humanized, so fewer infusion rxns

Monoclonal antibody directed against EGFR, used for solid tumors

Severe hypersensitivity rxns, Acneiform rash (correlates w/ survival)

Against VEGF-R, used against solid tumors

Philidelphia chromosome bcr-abl TK inhibitor, revolutionalized CML treatment

Other

Note: Antimetabolites are structurally similar to compounds needed for normal cell function; they ultimately inhibit DNA replication or repair; S phase specific

commonly used in combo w/ leucovorin for potentiation

Continuous infusion and high dose (HIDAC)

Note: all MT inhibitors are Cell cycle dependent to M phase; MT's are the "vines" of your cells ; vin blastine blasts BM

Note: Abraxane has least risk of hypersensitivity rxns, but increase risk of neuropathies compared to other taxanes; it is TAXing to stay polymerized

murine (-onab) -> chimeric (-imab) -> humanized (-umab) -> human (-mumab)

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HemeOnc Diseases