Download - 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)
Quantitative hemoglobinopathy
deficiency in 1 chain type --> excess in other type --> ineffective erythropoesis & destruction of produced RBCs
Alpha thalassemia- Hemoglobin H disease
Quantitative hemoglobinopathy
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
Quantitative hemoglobinopathy
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)
Thrombocytopenia: peripheral destruction- non-immune mediated
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)
Thrombocytopenia: peripheral destruction- non-immune mediated
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
a risk factor for thrombosis, not a disease
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
a risk factor for thrombosis, not a disease
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
Myeloproliferative Disorder (these are all stem cell disorders leading to autonomous production of hematopoietic cells from all 3 lineages)
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%
Myeloproliferative Disorder (these are all stem cell disorders leading to autonomous production of hematopoietic cells from all 3 lineages)
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
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)
prophylaxis at times of increased risk; avoid triggers; after 1st event- warfarin/heparin
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
Antimetabolite (inhibits DNA 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)
Antimetabolite (inhibits DNA synthesis)
Purine (thiol) analog →↓ de novo purine synthesis; activated by HGPRTase
6-thioguanine (6-TG)
Antimetabolite (inhibits DNA synthesis)
Antimetabolite (inhibits DNA synthesis)
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
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
Microtubule inhibitor
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)