Therapeutics Anemia

Types
o
o
o

of anemia
Iron-deficiency anemia
Folic acid deficiency
Vitamin B12 deficiency
Pernicious anemia
o Anemia of chronic disease
Anemia of chronic kidney disease
o Aplastic anemia
Cancer- and chemotherapy-induced anemia
o Inherited anemias: sickle cell disease and thalassemias
o Hemolytic anemia
Intro: what is anemia?
o Decrease in hemoglobin or volume of red blood cells (RBCs) decreased O2carrying capacity of blood
Hgb < 13.0 g/dL (M) or < 12.0 g/dL (F)
o High prevalence groups (NHANES)
Women
African Americans
Elderly
Low-income persons
Why do we care?
o Cause of 4,852 deaths in 2010
65 % in patients 75 years or older
o Increased risk of:
Cardiac comorbidities
Arrhythmias, HF
o Cognitive dysfunction
o Surgical complications
o Decreased quality of life
o Indirect and direct healthcare costs
Indirect time out of work, QOL
Direct transportation, blood work
Special populations: pregnancy
o Increased risk of
Low birth weight
Preterm delivery
Perinatal mortality
Postpartum depression
Special populations: geriatrics
o Percent of residents with anemia
Assisted living or other residential facilities: 9.6 %
Nursing homes: 18.6 %
o Associated with
Gastrointestinal cancer
Increased hospitalization and mortality
Decreased quality of life and physical function
o If IDA present, folic acid or vitamin B12 deficiency also likely

Reference Ranges for Normal Hematologic Labs by Age Group (Dipiro

2008)

Lab

2-6 years

6-12 years

12-18
years

18-49
years

Hemoglobin
(g/dL)

11.5-15.5

11.5-15.5

M 13.0-16.0

M 13.517.5

F 12.0-16.0

F 12.0-16.0
Hematocrit (%)

MCV (fl)

34-40

75-87

35-45

77-95

M 37-49

M 41-53

F 36-46

F 36-46

M 78-98

80-100

F 78-102
MCHC (%)

-----

31-37

31-37

31-37

MCH (pg)

24-30

25-33

25-35

26-34

RBC
(million/mm3)

3.9-5.3

4.0-5.2

M 4.5-5.3

M 4.5-5.9

F, female; M, male; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular

hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell;
RDW, red blood cell distribution; TIBC, total iron-binding capacity.

Reference Ranges for Normal Hematologic Labs by Age Group (Dipiro

2008)
Lab

2-6 years

6-12 years

12-18
years

18-49
years

Reticulocyte
count, absolute
(%)

-----

-----

-----

0.5-1.5

Serum iron
(mcg/dL)

-----

50-120

50-120

M 50-160

TIBC (mcg/dL)

250-400

250-400

250-400

250-400

RDW (%)

-----

-----

-----

11-16

Ferritin (ng/mL)

7-140

7-140

7-140

M 15-200

F 40-150

F 12-150
Folate (ng/mL)

-----

-----

-----

1.8-16.0*

Vitamin B12
(pg/mL)

-----

-----

-----

100-900*

Erythropoietin
(mU/mL)

-----

-----

-----

0-19

*May vary based on assay method

F, female; M, male; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular
hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell;
RDW, red blood cell distribution; TIBC, total iron-binding capacity.
o Serum ferritin is an acute phase reactant and may increase in the presence of
chronic infection or inflammation. Iron may be present in these illnesses but not
available for erythropoiesis. It is, however, specific for IDA ferritin decreases only
with IDA.
o Vitamin B12 may be falsely low due to folate deficiency, pregnancy, and use of
OCPs.
Calculation of transferrin saturation (TSat)
o TSat (%) = (serum iron/TIBC) x 100
o Interpretation:
Adults (normal): 20-50 %
< 20 % indicates iron deficiency
> 50 % may indicate iron overload
Children (normal): > 16 %
Signs and symptoms of anemia
o Not everyone has symptoms!
o Acute-onset anemia
Tachycardia, lightheadedness, dyspnea
That great feeling you get after donating blood when you were right at the
hemoglobin cut-of
o Chronic anemia
Weakness, fatigue, headache, vertigo, faintness, low body temperature,
and/or pallor
S/x similar to hypothyroidism
Iron deficiency anemia (Hyperchromic, microcytic)
Iron deficiency anemia (IDA)
o Common in young children (1-2) and women
o Hematologic values
Decreased ferritin* (most specific), serum iron, transferrin saturation
Decrease in Hgb/Hct follows
Increase in TIBC (total iron binding capacity)
Causes of IDA
o Diet lacking iron vegetarian or vegan
o Significant physical exercise
o Gastrointestinal illnesses
Ulcers
Colon polyps or cancer
Crohns disease
Celiac disease
o Infections
o Surgery
o
o

Severe injury or trauma

Chronic use of meds
Aspirin
NSAIDS
BC/Goodys Powder common in the South
Anticoagulants
Daily recommended dietary allowances (U.S. DHHS) ELEMENTAL IRON!
o Women needs more 14-50 y/o 15/18mg
Who needs more iron?
o Pregnant women
o Women of childbearing age
o Teenage girls
o Preterm and low birth weight infants
o Athletes intense exercise causes tiny bleeds in intestines require 30% more iron
o Vegans/vegetarians
o Gastrointestinal disorders/malabsorption
o Older adults with chronic disease
Dietary sources of iron
o Lean red meat (heme iron: more absorbable)
o Liver (heme iron)
o Turkey (heme iron)
o Fish (heme iron)
o Eggs
o Dairy products
o Quinoa, couscous
o Lentils and beans
o Nuts
o Tofu
o Oysters
o Green, leafy vegetables (i.e. spinach)
o Dried fruits (i.e. apricots, prunes, raisins)
o Iron-fortified foods (i.e. cereal)
Foods and iron absorption
o Aid absorption
Orange juice
Strawberries
Broccoli
Other fruits/vegetables with vitamin C
o Hinder absorption
Cofee or tea with meals
Concomitant calcium
Folic acid and vitamin B12 deficiency
Food fads/diets (cutting out iron and other nutrients)
Treatment of IDA
o Correct underlying condition if possible
o Oral iron supplementation is standard of care (parenteral second choice)
Adults: 120 mg day x 3 months
o Parenteral therapy
1st choice if patient cannot absorb oral iron therapy
GI disorders, gastric surgeries
nd
2 choice if patient cannot tolerate oral therapy
o
o

E.g. cant swallow, significant GI side efects, worsening s/x of IBD,

unresolved bleed, renal failure-induced anemia treated with EPO,
insufficient oral absorption from Celiacs
(1) Ferrous iron salts (NIH Office of Dietary Supplements 2007)
o Ferrous fumarate 33 % (0.26$)
o Ferrous sulfate 20% (0.09$)
o Ferrous gluconate 12% (0.09$)
Guess that formulation
o Ferretts is 325 mg of ferrous fumarate 106 mg of elemental iron
o Feosol is 325 mg of ferrous sulfate 65 mg of elemental iron
o Flintstones with Iron contain ferrous fumarate, but a smaller amount 45 mg, which
is 15 mg of elemental iron for 4 years and older, or tablet which is about 7.5 mg
of elemental iron for 2-3 years old.
o High potency Fergon contains ferrous gluconate approx. 225 mg or 27 mg of
elemental iron per tablet
Dosing & administration of oral iron
o Frequency of dosing
One tablet twice daily of ferrous sulfate sufficient for adults = 130 mg/day
o Gastrointestinal side efects - n/v/d, constipation, abd pain, dark colored stools
o Pros and cons to administration with food decrease SE but also decrease
absorption
o Pros and cons to use of delayed release or enteric coated formulations less
incidence of SE but not absorbed as well
Drug-drug interactions
o Decease Iron absorption
Proton pump inhibitors
H2 blockers
Cholestyramine
Tetracyclines, doxycycline (both agents sufers)
Antacids
Al-, Mg-, Ca2+
o Drugs decreased by iron
Levodopa
Methyldopa
Levothyroxine
Penicillamine
Fluoroquinolones
Tetracyclines, doxycycline
Mycophenolate
Monitoring of oral iron therapy
o Hemoglobin usually increases within 2-3 weeks
Increase of 1 g/dL in one month represents adequate response and confirms
that IDA was the problem; there could be something else going on (e.g. B12
and folic acid deficiency)
If Hgb does not increase by 1 g/dL, something else is wrong
o Reticulocyte count increases in a few days
o Hematocrit and ferritin should be monitored too
D/C treatment three months after these labs normalize
o Check CBC periodically thereafter after treatment
If values abnormal, reevaluate underlying causes and consider IV iron or
transfusion
o Waiting three months allows iron stores to become replenished

o Transfusion reserved for those who are symptomatic

Treatment of IDA parenteral therapy
(2) Iron dextran complex TEST DOSE
o IV formulations for adults and pediatrics
Dexferrum 50 mg/mL (1 mL, 2 mL)
INFeD (2 mL)
o Goal hemoglobin: usually 14.8 g/dL (adults)
o Administer 0.5-mL test dose over 30 seconds to 5 minutes
Beware that negative reaction to test dose does not mean a negative
reaction to bolus/infusion!
Need crash cart to be accessible (negative reaction still dont know)
Iron dextran complex (continued)
o IV bolus: give at maximum of 50 mg/min
o IV infusion: administer in 250-1000 mL NS over 1 to 6 hours
Give 1st 25 mL of infusion slowly and observe reaction
Do not use D5W more local pain/phlebitis
o Should limit daily doses to 100 mg of iron (2 mL)
o Monitoring: H/H, reticulocyte count, TIBC, serum ferritin, serum iron
(3) Ferric carboxymaltose (newer, non-infusion option)
o Injectafer 750 mg/15 mL single-use vial (6 hours infusion!)
High-dose, non-dextran
o Indicated for adults who cannot tolerate or do not respond well to oral iron therapy
o Randomized, open label, controlled trial
Average patient: age 43, 94 % female, Caucasian
50 % were 65 years+, 25 % were 75 years+
Statistically significant results versus PO and IV iron
o Mean change in Hgb from baseline - modified intent-to-treat population
Injactefer superior to IV iron and oral iron in obtaining highest Hgb value and
highest change from baseline
Ferric carboxymaltose (continued)
o IV push at rate of 100 mg/min for 1 dose (MUST KNOW PTS WT)
Maximum single dose of 750 mg
Patients < 50 kg: give in two doses separated by at least 7 days as 15 mg/kg
body weight per dose
Patients > 50 kg: give in two doses of 750 mg separated by at least 7 days
with max cumulative dose of 1500 mg per treatment course
o IV infusion with up to 750 mg iron in 250 mL NS over at least 15 minutes
Ferric carboxymaltose (continued)
o Administration: beware of extravasation!
Leakage of fluid from vein into extravascular space DC infusion if
occurs
Results in pain, burning, erythema, tissue necrosis,
thrombophlebitis, brown discoloration of site
o Monitoring
o Adverse efects: hypertension, hypersensitivity, nausea, flushing, dizziness,
headache
o Labs: serum iron and transferrin bound iron may be falsely elevated within 24
hours
Transfusion
o No standard Hgb threshold for transfusion
o Consider patients condition and symptoms
o May give 2 units of PRBCs and reevaluate

Pregnancy: recommended if Hgb < 6 g/dL

Consequences: abnormal fetal oxygenation fetal heart tracings, low
amniotic fluid volumes, fetal cerebral vasodilation, fetal death
Functional iron deficiency (FID)
o Adequate iron stores BUT insufficient use of iron into erythroid precursors
o Normal serum ferritin present
o Detected via reticulocyte assessment
Number (%HRC), volume (MCV), hemoglobin content (MCH)
o May afect patients with infection, inflammatory and malignant disorders, and
anemia of chronic disease
Often see with erythropoietin therapy
o Intravenous iron often used as source of active iron*
o The iron is essentially metabolically inactive
o Precursors: i.e. proerythroblast, polychromatic erythroblast
o MCH mean cell hemoglobin, MCV mean cell volume, %HRC percentage of
hypochromic red cells
o *unless ferritin > 800 mcg/L can result in iron overload
Tolerable Daily Upper Intake Levels for Iron (U.S. DHHS, NIH)
o w/o IDA postmenopausal women and elderly men have higher risk for iron overload
o 40 mg 7 months to 13 years
o 45mg for older
Signs & symptoms of iron overload
o Early signs
Fatigue
Weakness
Weight loss
Abdominal pain
Joint pain
Arrhythmia
o Late signs
Arthritis
Missed menstrual cycle
Early menopause
Decreased libido
Impotence
Dyspnea
Arrhythmia
Chest pain
o TOO LATE signs
Arthritis
Liver disease
Pancreatitis
Chronic abdominal pain
Severe fatigue
Heart failure
Jaundice
o Iron overload (continued)
Why should we treat?: iron may accumulate in liver and heart
Treatment: iron chelation or blood donation
Many signs and symptoms improve after excess iron removal, except arthritis
Deferoxamine (Desferal). Deferasirox (Exjade).
o Iron poisoning
o

Highest risk: hemochromatosis (absorb iron more easily), pediatrics

Iron supplements should be stored out of reach of children and persons with
cognitive impairment
If poisoning suspected, call poison control center 1-800-222-1222
o 2. Folic acid (vitamin B9) deficiency
o Folic acid deficiency
Megaloblastic, macrocytic anemia
Associated with:
Pregnancy (hyperutilization)
Excessive alcohol intake (poor absorption)
Poor dietary intake
Inadequate intake or utilization, decreased absorption, or hyperutilization of
folic acid
Screen for vitamin B12 deficiency first
Screen for vitamin B12 deficiency as est. 60 % of patients with
pernicious anemia have falsely low RBC folate levels
Drug-induced folic acid deficiency
o Methotrexate
o Azathioprine
o 6-mercaptopurine
o 5-fluorouracil
o Hydroxyurea
o Zidovudine
o o Trimethoprim
o Pentamidine
o Primidone
o Phenobarbital
o Phenytoin (interacts when supplementing folic acid)
o Triamterene
o Drugs in first column (except MTX) directly inhibit DNA synthesis of folic acid
o Usually supplement with folic acid if these medications cannot be changed (as is
usually the case). Can give low-dose folic acid (500 mcg) with anticonvulsants but
beware that 1 mg of folic acid would be too much with phenytoin (would decrease
phenytoin concentrations)
Dietary sources of folic acid
o Leafy green vegetables
o Citrus fruits
o Dried beans
o Fortified breads, pastas, cereals
o Mushrooms and yeast
o Dairy products
o Animal meats such as liver and kidney
o Most folate in food is broken down in small intestine then converted to active form
o 1997: US govt mandates addition of folic acid into grain products to increase
dietary intake to 100 mcg daily per person goal was to reduce incidence of neural
tube defects without masking occult vitamin B12 deficiency
o Correct diet and decrease alcohol intake
Daily requirements & treatment
o Minimum daily requirements of folic acid
50-100 mcg in general population
400 mcg in non-pregnant women

600 mcg in pregnant women prevent neural tube defects

500 mcg for women who are breastfeeding
o Treatment doses
1 milligram daily of oral folic acid
1-5 mg daily may be needed if due to malabsorption
Oral folic acid absorbed well by GI tract
Continue therapy for about four months after dx
Assessment of folic acid treatment
o Evaluate for early symptomatic improvement
o Reticulocytosis 2-3 days
o Increase in hematocrit 2 weeks
o Increase in mean corpuscular volume early in tx then normalizes
Vitamin B12 deficiency
o Megaloblastic, macrocytic anemia
o Lack of intrinsic factor decreased vitamin B12 absorption pernicious anemia
o If caused by medication, chronic long-term afect
o Causes: inadequate intake or utilization, decreased absorption (more common)
o Signs and symptoms: peripheral neuropathy, gait abnormalities, memory loss,
poor vision, thrombocytopenia, irritability, glossitis
What puts you at risk?
o Overgrowth of bacteria in small bowel
o Excessive alcohol use
o Zollinger-Ellison syndrome
o Whipple disease
o Tropical sprue
o Intestinal resections
o Crohns disease
o Chronic PPI or metformin use!
Pernicious anemia
o Pernicious: causing great harm or damage 0ften in a way that is not easily seen or
noticed
o Megaloblastic anemia
o Hematologic values:
o Decreased vitamin B12 and reticulocyte count
o Neurologic symptoms may be irreversible
Daily requirements and dietary sources of vitamin B12
o Recommended daily allowance
2 mcg in adults
2.6 mcg in pregnant or breastfeeding women
o Absorb 1 to 5 mcg daily from Western diet
o Dietary sources include: meat, fish, poultry, dairy products, fortified cereals,
bivalves
Treatment of vitamin B12 or pernicious anemia
o Goals of therapy:
Reverse hematologic abnormalities
Replace body stores of B12
Prevent or resolve neurologic abnormalities
o Use of 1 to 2 mg oral B12 daily as effective as IM injection
Use larger doses if ileal resection
Avoid delayed release formulations
Point of giving 1000 mcg daily saturate stores in body and resolve clinical
abnormalities quickly

Treatment of vitamin B12 or pernicious anemia

o Avoid oral form if physical inability or N/V
Give daily injections of 1000 mcg of cyanocobalamin x 1 week then weekly x
1 month then monthly thereafter
o Nasal spray for patients in remission without neurologic abnormalities
Efficacy not well studied; dont recommend
Avoid food and beverage 1 hour before or after administration of nasal
spray
Assessment of vitamin B12 treatment (not everything will change after just 24hrs)
o After start of treatment:
Monitor CBC 1-2 months
Monitor MMA levels every 2-3 months

Signs and symptoms

Time frame

Resolution of glossitis

24 hours

Normoblastic bone marrow*

24 hours

Reticulocytosis

2 to 5 days

Increase in hemoglobin

7 days

Normalization of leukocytes,
platelets

7 days

Persisting hypersegmented
neutrophils

2 weeks

Monitor MMA levels every 2-3 months* not sure how many clinicians actually
monitor this frequently
o MMA = methylmalonic acid, uses B12 as a cofactor and is a sensitive indicator of
B12 deficiency
4. Anemia of chronic disease (ACD)
Anemia of chronic disease (ACD)
o Diagnosis of exclusion
o Causes: chronic inflammatory, infectious, and malignant disorders
HF, CKD, RA
May present 1 to 2 months after onset of disorders
Can significantly increase mortality with 1-g/dL decrease in Hgb
o Hematologic values
Decreased serum iron
Normal or decreased TIBC
Normal or increased serum ferritin
Treatment of ACD
o RBC transfusion should be limited
Threshold to transfuse is hemoglobin 8 to 10 g/dL
Goal hemoglobin is 11 to 12 g/dL
Consider risks of transfusion (discussed later)
o Erythropoiesis-stimulating agents (ESAs)
o

Sometimes used, but not currently approved

Response can depend on dose and cause of ACD
o Iron supplementation
Oral therapy warranted for transferrin sat < 20 % OR serum ferritin < 100
ng/mL
4a. Anemia of chronic kidney disease (CKD)
o Normochromic, normocytic anemia
Concomitant IDA - microcytic
Concomitant FA or B12 deficiency - macrocytic
o Decrease in production of EPO in the kidney
o Also decreased RBC life span possible due to:
Presence of uremia
Iron deficiency
Blood loss due to venipuncture and/or hemodialysis
o Kidney produces 90 % of EPO
o Decrease in RBC life span may be due to presence of uremia (from 120 to 60 days in
ESRD), iron deficiency, blood loss due to venipuncture labs and/or hemodialysis
o Erythropoietic stimulating agents (ESAs)
Anemia of CKD (continued)
o In patients with normal renal function, EPO increases significantly if Hgb/Hct
declines
This compensation does not occur in ESRD
o Monitoring for anemia in CKD
Hgb at least annually
Check Hgb more often if severe CKD or ESRD
Gradual Hgb decrease expected as CKD worsens
Remember that the kidney is the primary site for producing EPO cant do
this in renal failure
Target Parameters for Anemia Management in CKD (Dipiro 2008)

Parameter

CKD Stage IV and

Peritoneal
Dialysis

Hemodial
ysis

Hemoglobin (Hgb)

11-12 g/dL

11-12 g/dL

Transferrin saturation (TSat)

> 20 %

> 20 %

Content of hemoglobin in
reticulocytes (CHr)

-----

> 29
pg/cell

Serum ferritin

> 100 ng/mL

> 200
ng/mL

Anemia of CKD (continued)

o Goals of therapy:
Increase O2-carrying capacity of blood
Decrease dyspnea, orthopnea, fatigue
Prevent left ventricular hypertrophy and cardiovascular mortality
o Treatment

Address primary cause of CKD

Erythropoietin stimulating agents (ESAs)
Iron supplement prior to ESA if IDA is present
Supplement with folic acid or vitamin B12 if deficient
o Primary causes of CKD may include diabetes, HTN, glomerulonephritis
o Try to delay progression
o Iron supplement prior to ESA if IDA is present otherwise, resistance to therapy
o IDA present if TSat and serum ferritin levels are below range
o Not all patients receive ESAs even though it is indicated and not even iron
IV iron for anemia of CKD
Ferric carboxymaltose (Injectafer)
o Can be administered to patients with non-dialysis dependent CKD
o Refer to slides under Iron-deficiency anemia for dosing, administration, and side
efects
Iron sucrose (Venofer)
o Indicated for adults and children with dialysis-dependent and non-dialysis
dependent CKD
o Product labeling does not suggest test dose
o Safety: monitor for hypersensitivity, hypotension, nausea, headache, muscle
cramps, upper respiratory infection
o Bolded efects are higher in HD patients
Iron sucrose in adults
o Dosing depends on type of dialysis
HD: 100 mg given during consecutive dialysis sessions with cumulative total
dose of 1000 mg (10 doses); give early in HD session
Non-dialysis dependent: 200 mg given on 5 diferent occasions within 14day period with cumulative total dose of 1000 mg
Peritoneal dialysis: 2 infusions of 300 mg given 14 days apart, followed by
single 400 mg infusion 14 days later with cumulative total dose of 1000 mg
o Administration
Slow IV injection of 200 mg or less undiluted over 2-5 min
Infuse diluted doses of (inc. dose increases infusion time)
200 mg or less over at least 15 min
300 mg over 1.5 hours
400 mg over 2.5 hours
500 mg over 3.5-4 hours (limited data)
Mean change in Hgb from baseline modified intent-to-treat population
o Equal to each other both valid options
o Injectafer vs. Venofer
Ferumoxytol (Feraheme)
o Product labeling does not suggest test dose
o Adult dosing and administration
Give 510 mg (17 mL) as single dose followed by another dose of 510 mg in 38 days
Administer as undiluted injection at rate of 1 mL or less per second (30 mg
elemental iron per 1 second)
Give injection at least 1 hour after HD complete and blood pressure stable
o Monitor for response at least 30 days after 2nd dose
o Possible side efects: hypersensitivity, hypotension, dizziness, GI efects
o May readminister if needed
o Hypotension is less than with iron sucrose (at least thus far, since newer drug)

Do NOT administer if solution has particulate or is discolored (should be black to

reddish-brown)
Sodium ferric gluconate (Ferrlecit )
o Test dose no longer suggested in product labeling; can be given during dialysis
session
o Adults
125 mg elemental iron IV per dialysis session
May need cumulative dose of 1000 mg elemental iron over 8 consecutive
dialysis sessions for response
Administer diluted in 100 mL NS over 1 hour OR
Administer undiluted and infused slowly at rate of 12.5 mg/min
o Monitor for hypersensitivity, hypotension, hypertension, tachycardia, headache,
dizziness, GI efects, injection site reactions
o High incidence of side efects versus other formsespecially for cardiovascular
effects
ESAs for treatment of anemia of CKD
o Synthetic recombinant human erythropoietin
Stimulate erythropoiesis in patients w/low levels
o Epoetin alfa (Epogen, Procrit)
o Darbepoetin alfa (Aranesp)
Albumin free
Longer t , can be administered less frequently
o ESAs have NOT been shown to improve fatigue, quality of life, or patient well-being
o Peginesatide (Omontys) was recalled due to post marketing reports of serious
hypersensitivity reactions 2/2013
Initiation of ESAs
o Adults on dialysis
Initiate when Hgb < 10 g/dL and reduce or stop dose if Hgb approaches or
exceeds 11 g/dL
o Adults not on dialysis
Only use if rate of Hgb decline would result in RBC transfusion(s)
Consider initiating when Hgb < 10 g/dL and reduce or stop if Hgb exceeds 10
g/dL
E.g. 10 8
Epoetin alfa dosing & administration 3x a week (units)
o Adults on dialysis
50-100 units/kg IV 3 times/week
o Adults not on dialysis
50-100 units/kg IV or SubQ 3 times/week
Darbepoetin alfa dosing & administration (mcg/kg)
o Adults on dialysis
0.45 mcg/kg once weekly or 0.75 mcg/kg IV every 2 weeks OR convert from
epoetin alfa as above
o Adults not on dialysis
0.45 mcg/kg IV or SubQ every 4 weeks
Safety of ESAs
o CHOIR study (2006)
Open-label trial of 1432 patients with CKD receiving epoetin alfa
Primary endpoint: composite of death, MI, hospitalization for CHF, and stroke
Increased CVD events with target Hgb of 13.5 g/dL versus 11.3 g/dL
NNTH: 25 patients over median of 16 months
o CREATE study (2006)
o

Randomized trial of 603 patients with estimated GFR of 15 to 35

mL/min/1.73m2 and mild-moderate anemia
Epoetin beta was given at randomization and targeted to Hgb 13.0 to 15.0
g/dL OR when Hgb < 10.5 and targeted to 10.5 to 11.5 g/dL
Primary endpoint: composite of cardiovascular outcomes
Early complete correction of anemia did not reduce CVD events
o CHOIR study from 2006 increased ADEs with target of 13.5 g/dL
o CREATE study from 2006 early complete correction of anemia not helpful
ESAs & Risk Evaluation and Mitigation Strategies (REMS)
o REMS program in place for ESAs due to:
Increased risk of cardiovascular events such as stroke, myocardial infarction,
thromboembolism, and death
Events occurred in controlled trials of patients with target Hgb levels of > 11
g/dL
o Current labeling recommends starting ESA treatment when Hgb < 10 g/dL
Target Hgb should be individualized
Use lowest doses possible to avoid RBC transfusions
o Obtain informed consent before use and monitor hematologic labs
5. Aplastic anemia
Aplastic anemia
o Body stops making enough blood cells (pancytopenia)
Fewer WBCs infection
Fewer platelets impaired clotting
Fewer RBCs anemia
o Causes
Chemotherapy or radiation
Exposure to chemical toxins
Certain medications
Autoimmune disease
Viral infection
Genetic disorders
Drug-induced aplastic anemia
o Acetazolamide
o Aspirin
o Chloramphenicol
o Chlorpromazine
o Dapson
o Felbamate
o Interferon alfa
o Lisinopril, captopril
o Lithium
o Nizatidine
o Pentoxifylline
o Quinidine
o Sulindac
o Ticlopidine
Aplastic anemia (continued)
o Associated with higher mortality than other blood dyscrasias
Bacterial or fungal infections, bleeding
o Signs and symptoms: pallor, fatigue, weakness, fever, chills, pharyngitis,
bruising, bleeding, petechiae
Treatment of aplastic anemia

Early withdrawal of medication if drug-induced

Supportive care
Antibiotics if infection
Transfusion support
o Allogeneic hematopoietic stem cell transplant (HSCT)
If appropriate donor identified
o Immunosuppressive therapy
First line for older patients and non candidates of HSCT
May use antithymocyte globulin or cyclosporine
Both have 60-80 % response rate and similar 5-year survival to HSCT
Corticosteroids may be adjunct therapy
5a. Cancer- and chemotherapy-induced anemia (CIA) Anemia is prevalent in 30 to 90 % of
patients with cancer
National Cancer Institute Anemia Scale (NCCN 3.2014)
o
o

Treatment of CIA with IV iron

o Efficacious for treating absolute or functional iron deficiency in pts with cancer
receiving ESAs
Do not give if patient has active infection
o Iron dextran complex (unlabeled use)
INFeD recommended over Dexferrum due to risk of adverse events
o Use of ferric gluconate (Ferrlecit) or iron sucrose (Venofer) do not require test
doses
But should perform if prior reaction to iron dextran or history of multiple drug
allergies
Recommendations for administering IV iron (NCCN 3.2014) Dont memorize

Use of transfusion in CIA

o Goal of transfusion
Treat or prevent deficit of O2-carrying capacity in blood
o Benefits
1 unit (300 cc) of PRBCs may rapidly increase Hgb by 1 g/dL or Hct by 3 % in
average adult
Rapid improvement of fatigue
Possible survival benefit
o Risks
Transfusion-related reactions
Congestive heart failure
Bacterial contamination has decreased
Viral infections
Iron overload
o Survival benefit: study of 56 consecutive patients with unresectable esophageal
cancer receiving chemotherapy blood transfusion was associated with increase in
overall survival (HR 0.26; 95 % CI 0.09-0.75, P=0.01).
Goals of transfusion (NCCN 3.2014)

Transfusion thresholds
Help w/ s/x and maintain Hgb
Stable, hospitalized patients: Hgb 7 to 8 g/dL
Hospitalized patients with pre-existing cardiovascular disease + symptoms and Hgb
</= 8
Use of ESAs in CIA
o Efficacy in patients with cancer
One study demonstrated Hgb increase of >/= 1 g/dL in 65 %
Recommended if concomitant moderate to severe CKD
IV iron should be added to ESA if functional iron deficiency
o Benefits
Avoid transfusion (NNTT vs. placebo = 4 pts over 3 months)
Gradual improvement in fatigue
o Risks
Increased thrombotic events
Possible decrease in survival and time to tumor progression
BBW: use lowest dose of ESA possible and only for concurrent use of
chemotherapy discontinue once completed
Dosing & administration in CIA (NCCN 3.2014) be careful w/ units!
o Epoetin alfa and darbepoetin considered equal by NCCN for CIA
o
o
o
o

Monitoring of ESAs in CIA

o Takes approx. 2 weeks before increase in number of RBCs

Measure Hgb weekly until stable

Dose changes
Reduce dose by 25-40 % if Hgb increases by 1 g/dL or more in 2-week period
OR if Hgb reaches level sufficient to avoid transfusion
Increase dose if no response (i.e. < 1 g/dL in Hgb) after 4 weeks of epoetin or
6 weeks of darbepoetin
o Consider transfusion if no response after 8-9 weeks and addition of iron
supplementation
o Remember to monitor for ADEs as discussed in ACD section!
6. Inherited anemias
o Sludge in capillaries which decreases blood flow and O2 tension even further
o If Hemoglobin AS trait, not as likely to occur
Sickle cell disease (SCD)
o Patients have either sickle cell trait (SCT) (one gene) or SCD (both genes)
o Signs and s/xs include anemia, pain crisis, hepatosplenomegaly, pulmonary
diseases
o Complications include:
Infection
Neurologic complications that may lead to stroke
Acute chest syndrome (ACS) leading cause of death
Priapism and impotence
Ocular problems including proliferative retinopathy
Cholelithiasis
Depression
Renal complications including hematuria
o One defective gene = trait
o Two defective genes = disease
o Neurologic problems arise from vasoocclusion
o Cholelithiasis gallstones
Preventive Care of SCD
o Annual retinal examinations
o Immunization with PCV7 and PPSV23 depending on age and vaccination history
o Prophylaxis with penicillin until at least 5 years of age regardless of immunization
history
Penicillin V K 125 mg orally twice daily until age 3 THEN 250 mg twice daily
until age 5
May also use alternate regimen with IM penicillin
If PCN allergy: erythromycin 20 mg/kg/day twice daily
o Supplement with folic acid and check B vitamin levels
o This Pen VK regimen has been shown to reduce risk of pneumococcal infections by
84 %. Alternative regimen available using IM form of benzathine penicillin.
Hydroxyurea in SCD
o Stimulates hemoglobin F production
May reduce episodes of painful crises, hospitalization, ACS, blood
transfusions in adults
Does NOT prevent stroke, neurologic problems
o Side efects: bone marrow suppression, teratogenicity (Category D)
o Starting dose: 10 to 15 mg/kg/day as single dose
May increase dose after 8 to 12 weeks
o Monitor MCV, CBC every 2 weeks during titration & every 4-6 weeks after
o STOP therapy if any of the following occur:
Absolute neutrophil count < 2,000 cells/mm3
o
o

Platelet count < 80,000 cells/mm3

Hemoglobin < 5 g/dL
Reticulocytes < 80,000 cells/mm3 while hemoglobin is < 9 g/dL
o Hydroxyurea has been used in some children, but not FDA-approved
o Takes about 3-6 months to see an efect
Chronic transfusions for SCD
o For secondary prevention of stroke in children
o Can reduce risk of vasoocclusive pain, ACS (main cause of death w/ SCD)
o May prevent/delay progression of organ damage
o Goal: achieve and maintain concentration of hemoglobin S to < 30 % of total
hemoglobin
o Optimal duration is unclear (over 4 years)
o Risks: infection, sickle cell hemolytic transfusion reaction syndrome*
Looks like pain crisis but is specific
Steroids and IV immunoglobulins
Allogeneic HSCT
o Only curative therapy for SCD
Small study demonstrated 94 % survival rate and 84 % event-free survival for
patients < age 16, symptomatic, and with HLA-identical sibling donor
o Best candidates for HSCT
< 16 years old
Severe complications such as refractory pain, stroke, or recurrent ACS
HLA-matched donor
o Risks
Transplant related mortality
Graft rejection
Chronic graft v. host disease
Secondary malignancy
Management of acute complications in SCD
o Maintain O2 saturation of at least 92 %
o Pain during crisis: opioids, NSAIDS, acetaminophen
Refer to table in Dipiro for more details regarding regimens and doses
o Infection: consider antibiotics if fever > 101.3 F
o Episodic transfusions for severe vasoocculsive episodes, aplastic crisis, preparation
for procedures
o ACS: incentive spirometry, fluids, broad-spectrum antibiotics, oxygen,
corticosteroids (cover +, negs, and atypicals; staph vanco)
o Priapism: hydration and pain control; both vasodilators and vasoconstrictors have
been used
Thalassemias
o Result from genetic defects in alpha- and beta-globulin chains
Thalassemia major: 3-4 defects, often results in death from cardiovascular
causes by age 30
Thalassemia minor (trait) 1-2 defects, more common; normal life expectancy
o Anemia is due to hemolysis and inefective erythropoiesis
o Often asymptomatic
Treatment of thalassemias
o Bone marrow transplant
May be curative for children with beta thalassemia major
o Transfusion therapy
Allows for normal growth and suppresses inefective erythropoiesis
May lead to iron overload

Iron supplementation
Only use if patient has excessive blood loss and confirmed IDA
Iron overload = M&M in thalassemias (worry more about overload)
o Management of other comorbid conditions
Often folic acid deficient use 1 mg daily to supplement
Splenectomy if transfusion requirements significant increase
Psychosocial: educate patient and family regarding disease and prognosis
7. Hemolytic anemia
Hemolytic anemia
o Normocytic, normochromic anemia
o RBCs are destroyed in spleen or circulation
RBC lifespan decreased to < 120 days
o Due to membrane, Hgb, or metabolic defect
o Abnormalities: increased reticulocyte count, lactate dehydrogenase, indirect
bilirubin; hemoglobinuria
o Example of hemoglobin defects: sickle cell anemia, thalessemia syndrome
o Example of metabolic defect: G6PD deficiency
Treatment of hemolytic anemia
o Control underlying disorder
o Avoid precipitating factors if G6PD deficiency
Medications such as antimalarial drugs, aspirin and NSAIDS, nitrofurantoin,
sulfa drugs, quinidine, quinine
Severe stress
Certain foods (i.e. fava beans)
Mothballs
o Other possible treatments
Steroids and immunosuppressants
Antibiotics
Transfusion
Splenectomy
General patient education about anemia
o Get screened for anemia if at risk
Risk factors: e.g. vegetarian, women, lower socioeconomic class
o Eat a diet with adequate sources of iron, folic acid, and vitamin B12
o Report any signs and symptoms of bleeding
o Keep iron supplements out of the reach of children and adults with impaired
cognition
o Report any missed doses of medication to a healthcare professional
Recap
o Untreated anemia is associated with morbidity and mortality
o Appropriate treatment choices vary based on type of anemia and concomitant
diseases
Not all agents were used for each anemia
o Red blood cell indices are helpful for determining response to therapy
o Patients should be counseled regarding side efects, compliance, and interactions
o

Lymphoma therapeutics

The Lymph System

o Network of lymph nodes throughout body
o Lymph flow takes place in a low pressure system
o Protein-enriched fluid filtered
o Major lymph vessels empty into general circulation

Malignancy of cells near lymph nodes

Hodgkins Disease (HD) (Hodgkins Lymphoma)
Big Picture
o Progressive adenopathy
o Usually presents in the neck, mediastinum (chest area)
o Associated with symptoms: night sweats (have to get up 2-3x a night b/c of full
body sweat), fevers (cyclical ex. 102-103), weight loss (unintentional; 10-20% of
TBW)
o Pel-Ebstein fevers = periodic high fevers
o Pruritis (itching)
o EtOH intolerance: pain at site of disease
o Typically slow, orderly growth (months, years)
HD
o Demographics
bimodal distribution - 15 to 40 yo; > 55 yo
Caucasians account for 90% all cases
male predominance in children and > 50 yo
female predominance 10 - 40 yo
median age at diagnosis 20 - 29 years old
Etiology
o Unknown
o Epstein Barr virus - 20-80% of tumors contain EBV genome
o HIV
o Cytogenetics - bcl-2 rearrangement in 40%
Pathophysiology
o Reed-Sternberg cell - large, bi-nucleated cells
o derived from monocyte/macrophage cell line
o 4 diferent histological subtypes (dont know)
nodular sclerosing* (most common)
mixed cellularity
lymphocyte rich
lymphocyte depleted
Clinical Presentation
o Painless adenopathy - contiguous spread (one LN chain to another; progresses
through chain and doesnt skip)
supradiaphragmatic - 90% above the diaphragm
cervical, axilllary, mediastinal
subdiaphragmatic - 10% below the diaphragm
inguinal
o B symptoms - weight loss, night sweats, fever
Diagnosis
o History/physical
o Lymph node biopsy - remove entire node
o Lab studies - CBC, LDH (surrogate marker)
o Radiologic - PET-CT, gallium scan
o Bone marrow biopsy (imp)
o Staging laparotomy? wayside b/c of advent of radiologic interventions
Prognostic indicators
o B symptoms - presence (worse prognosis) or absence
o Staging
o Age (younger does better w/ dz)
o Bulky disease (large tumor)

Staging
o A absence of constitutional symptoms
o B constitutional symptoms
Unexplained fever, night sweats, weight loss
o M bulky mediastinal mass
> 1/3 thoracic diameter or > 10cm
o E extranodal involvement (e.g. spleen or liver; visceral involvement)
Treatment goals
o Classical HD is an aggressive, life-threatening
o Treatment aimed at cure
o Start as soon as possible
o Stratify patients based on bulky vs non-bulky disease
o Radiation and chemotherapy mainstay of treatment
Treatment
o Limited stage (I/II, non-bulky)
XRT alone (radiation)
E.g. above diaphragm alone
Can still cure with chemo if relapse
Short course chemo + involved field radiation
Chemotherapy alone
o Extensive stage (III, IV)
Chemotherapy
Treatment
o Early Stage, favorable disease
Stage I and II (A): 80-90% cure rate
Extended field radiation
2-4 cycles of chemo followed by involved field XRT
4-6 cycles of chemo
The treatment of early stage, favorable prognosis (none of the risk factors
from the last slide) HL can be XRT alone with extended fields (ie mantle, etc),
abbreviated chemotherapy followed by XRT just to the site of involvement (no
additional nodal areas), or chemotherapy alone. In younger patients, the
long term risks of XRT make the first two choices less attractive. In an elderly
patient, XRT alone may prove curative and involves only one month of
treatment as opposed to up to six months with chemotherapy regimens.
o Early Stage, unfavorable disease
Stage I and II (B): 80-90% cure rate
4 cycles of chemo followed by involved field XRT
4-6 cycles of chemo
Early stage, unfavorable risk disease has probably already spread beyond the
defined limits of limited stage disease and therefore local therapies are likely
to fail. Abbreviated chemotherapy + involved field XRT or chemotherapy
alone are viable options.
o Advanced Stage, favorable disease
Stage III and IVA: 75+% cure rate
6-8 cycles of chemo
6-8 cycles of chemo followed by involved field XRT to bulky disease
Following this scheme, advance disease patients (stage III or IV) with low risk
IPS should receive 6-8 cycles of chemotherapy followed by consolidating XRT
to site(s) of bulky disease.
o Advanced Stage, unfavorable disease
Stage III and IV: 50-65% cure rate

6-8 cycles of ABVD

Escalating dose chemotherapy (BEACOPP)
Unfavorable risk disease has a lower expected cure rate. These patients
should be considered for inclusion in clinical trials. Standard therapy would
involve 6-8 cycles of chemotherapy basically 2 cycles beyond best
response. More intense regimens may be considered.
ABVD superior to MOPP for toxicity (MOPP caused sterility)
o Alternating ABVD and MOPP non-significant increase in CR and 5yr OS
Chemotherapy for HD
o MOPP had been considered gold standard
o Infertility
mechlorethamine causes gonadal damage
o Secondary leukemias
more common with MOPP (RR 9.5%)
secondary tumors
Chemotherapy MOPP (Can be used as salvage therapy or if something intolerant w/
ABVD)
o Mechlorethamine
N/V
sterility
myelosuppression
o Vincristine (Oncovin)
vesicant
CNS toxicity (peripheral fingers/toes e.g. stocking neuropathy)
Autonomic neuropathy (constipation)
Laxative and stool softener
o Procarbazine
myelosuppression
MAO inhibitor
Alkylating agents
Oral capsule
o Prednisone
To tx lymphomas
50-100 mg
Lympholytic at high doses
Very high doses
ABVD
o Administered for 4-8 cycles depending on stage/subtype HD
Adriamycin (doxorubicin)
Bleomycin
Vinblastine
Dacarbazine
ABVD
o Adriamycin (doxorubicin) 450 m2 (be careful at 300 m2)
myelosuppression, cardiotoxicity (idiosyncratic cardiac toxicity changes in
EKG CANT GIVE IT EVER; there is also a toxicity manifests w/ CHF monitor EF
w/ echo), vesicant, alopecia
o Bleomycin
Irreversible pulmonary toxicity (baseline PFTs- follow DLCO; presents w/
cough), hypersensitivity reactions, skin reactions
Use test dose
o Vinblastine (bone marrow toxicity)

 myelosuppression, vesicant
Dacarbazine
myelosuppression, N/V, flu-like syndrome (w/ infusion and couple hours after
infusion), photosensitivity
ABVD vs BEACOPP
o A recent randomized trial published in the New England Journal of Medicine
compared ABVD to dose-escalated BEACOPP with a planned autologous transplant
for those that did not achieve a remission (refractory disease) for advanced stage
disease.
o PFS makes diference in psych of dz
o But OS no diference
o PFS realize dz has come back
Other regimens
o Stanford V
patients with locally extensive/advanced HD
Stanford V + XRT
o Median follow up - 5.4 years
5 year FFP 89%
OS 96%
42 pregnancies after treatment
Other regimens
o Stanford V - combination chemo; 3 cycles (12 weeks)
o mechlorethamine
o doxorubicin
o Etoposide*
o vincristine
o vinblastine
o bleomycin
o prednisone
Long term efects of treatment
o Hypothyroidism (b/c of radiation to cervical area monitor thyroid fxn)
o CAD (radiation to left side of mediastinum; e.g. 30-40 y/o w/ advanced CAD)
o Infertility (less so w/ ABVD)
o Secondary malignancies (<10%)
10-15 years
Relapsed disease changing times
o Depends on how long remission lasted
o Initial CR lasted > 12 months
use original chemo; dependent on organ fxn e.g. cardiac/pulmonary toxicity
o Initial CR lasted < 12 months
Non cross-resistant chemo
ICE, DHAP, ESHAP (salvage regimen)
o Induction failure - ? BMT
Dont go to remission w/ initial chemotherapy regimen
Primary refractory bone marrow transplant (autologous: pt themselves are
donors of their stem cells)
Relapsed/refractory disease
o Brentuximab (SGN-35) monoclonal antibody targeting CD30 (marker of HD)
newest therapy thus far approved
o Conjugated to toxin monomethyl auristatin E (MMAE afects microtubule
formation)
o Approved August 2011
o

o Brentuximab in primary refractory patients amazing response rate

o Complete remission 1/3
o 102 patients
o Primary refractory /non responders
o ORR 75%
o CR
34%
o Relapse refractory patients
o Brentuximab - pulmonary toxicity
o MOPP more secondary tumors
Non- Hodgkins Lymphoma (NHL)
Epidemiology/demographics
o New cases 56,200; deaths 26,300
o B cell origin (90-95% of NHL)
o Median age at diagnosis 55 years old
o More common in Caucasians
o Rate rising at 3-4% per year
Etiology
o Congenital/inherited immunodeficiency states (Down syndrome)
o Acquired immunodeficiency states (e.g. HIV)
o Autoimmune diseases
o Radiation exposure
o Drugs phenytoin (long-term tx)
Clinical presentation
o Incidental
o Generalized adenopathy
o B symptoms (fever, wt loss)
o Waxing/waning symptoms
Diagnosis
o History/physical
o Lymph node biopsy - **entire node**
o Lab studies - CBC, LDH (marker of dz; not diagnostic), uric acid (as cells are broken
down, uric acid increases)
o Radiographic studies
o Bilateral bone marrow biopsy (has dz infiltrated bone marrow?)
Pathophysiology
o Cytogenetic abnormalities
o Bcl associated w/ apoptosis
o t(14:18) increased expression bcl-2
o t(11:14) increased expression bcl-1
o c-myc overexpression (oncogene)
o B cell origin (85%)
Staging
o Multiple staging systems
Ann Arbor
Working formulation*
low, intermediate, high grade
REAL classification
TNM
WHO
Staging

T-cell lymphoma NHL are harder to treat because they dont follow the rules; dont
respond to chemotherapy as well
Prognostic factors
o IPI index
o Determines aggressiveness of disease
o

Figure 2. Survival among the 1274 Younger Patients (<= 60 Years) According to Risk
Group Defined by the Age-Adjusted International Index. The left panel shows the
Kaplan-Meier curves for this age group, and the right panel the death rates during
the study period. L denotes low risk, LI low intermediate risk, HI high intermediate
risk, and H high risk. Only 1274 of the 1931 patients 60 or younger had enough
relevant information for classification according to the international index.
Treatment approach
o Indolent
Slow growing, asymptomatic
Respond to chemo but recur
Cant get rid of all the dz
Goal of treatment is to maintain quality of life
o Aggressive
Quick growing, cause symptoms
Respond to chemo, curable
Goal of treatment is to cure
NHL Limited Stage
o

Stage I
Single lymph node group
o Stage II
> 2 lymph node groups on same side of diaphragm
Bulky adenopathy (>10cm or > 1/3 thoracic diameter)
o Low grade - incurable
o Intermediate grade in between
o High grade curable
o Limited vs. extensive
Treatment - Limited stage/low grade
o Watch and wait e.g. 80 y/o low grade lymphoma w/o s/x
o Combination chemotherapy
CHOP, CVP (CHOP w/o the H; non-anthracycline containing regimen for e.g.
elderly pts w/ CV dz), ProMACE/MOPP
CHOP NHL
o Single agent chemotherapy
purine analogues; pentostatin, fludarabine, cladribine
o Biologics - rituximab
o BMT e.g. 50 y/o w/ low grade lymphoma
Watchful waiting vs chemotherapy
o Patients with low grade lymphoma
o Indications to treat
massive bulk, cytopenias, recurrent infections, symptomatic disease,
progression
Symptomatic dz and progression
Heavy bulky dz
Chemotherapy - low grade
o Anthracycline containing regimen
CHOP vs CVP
H hydroxydoxirubinol (metabolite of doxorubicin)
O vincristine
P prednisone
If pt has low EJ, no anthracycline
Purine analogues
o Cladribine, fludarabine, pentostatin
inhibit adenosine deaminase inhibits nucleic acid synthesis
o Response rates 20 - 40% range
o Very immunosuppressive (opportunistic infxn, pneumonia)
o Used in combination
FND (fludarabine, mitoxantrone, dexamethasone)
PCR (pentostatin, cyclophosphamide, rituximab)
Purine analogues toxicities
o Immunosuppressive
prophylactic coverage for PCP, antivirals, antifungals
HSV, CMV, pneumocystitis pneumonia
Aspergillus, candida etc.
o Neurotoxicity
Not normal doses but w/ elderly pts w/ renal dysfxn!
Biologic therapy
o Rituximab
monoclonal antibody against CD20 (b-cell marker)
Single agent or combination of other chemotherapy
o

Campath
humanized rat monoclonal Ab against CD52 (lymphoid marker)
special dosing (lots of reactions)
o Radioisotopes (monoclonal antibody linked to radio-nucleotide)
Zevalin
Bexxar
Monoclonal antibodies
o

Mechanism of
complement
cytotoxicity
Mechanism of
apoptosis
Mechanism of
antibody
cellular
cytotoxicity
Mechanism of
radiolabeled
Rituximab
o Chimeric
MoAb
o Duck tape in CD20+ dz
o IgG1
o Relapsed/refractory low grade, follicular CD 20+ lymphoma
Low grade lymphoma MAINTENANCE W/ RITUXAN
o ASH 2005 abstract # 350
o R-CVP vs CVP in follicular NHL
o
CR
Overall RR
o CVP*
10%
57%
o R-CVP
41%
81%
o *cyclophosphamide, vincristine, prednisone
Rituximab toxicities
o Infusion -related reactions - premedicate
o Tumor lysis syndrome prophylaxis required
o Infectious complications
reactivation of hepatitis
o Nausea/vomiting
o HAMA; HACA
M mouse
C chimeric

action
mediated
action
action
dependent

action
antibody
anti-CD 20

Antibody against antibody

Campath-1H
o MoAb against CD52
o Phase II study
o All patients had failed fludarabine
Campath-1H toxicities
o Infusion related reactions severe rxns b/c from rat
o Immunosuppression
Prophylaxis for opportunistic infections
CMV reactivation (~90%)
Radiolabeled MoAb
o 131I-tositumomab (Bexxar)

IgG2a, murine MoAb against CD20

g, b emitter
o 90 Y-ibritumomab (Zevalin)

IgG1, murine MoAb against CD20

b emitter
o I gamma and beta emitter (need heavy shield)
o Y weak beta (just need a sheet of paper)
Radiolabeled MoAb
o Dosimetric dose
cold dose
evaluate biodistribution of MoAb
Make sure dose isnt concentrating into an organ
o Therapeutic dose
cold dose
individualized
o Precautions
No sexual activity
Double flush
Radiation safety - Zevalin
o Plastic sheilding
o Physical contact
o No sexual contact/ kissing for 24 hours
Radiation safety - Bexxar
o Lead shielding
o No physical contact for 3-4 days
o Separate utensils
o Double flushing
NHL Extensive Stage
o Stage III
o > two LN groups, on both sides of diaphragm
o Stage IV
o extramedulary disease (includes bone marrow)
Moderate /High grade NHL
o Localized disease
CHOP x 3 cycles then XRT
o Advanced disease
CHOP gold standard
addition of Rituximab if CD20+
Why CHOP?

o All equally effective, CHOP least toxic

CHOP
o Cyclophosphamide - hemorrhagic cystitis (hydration), myelosuppression,
cardiotoxicity (seen with high doses; not the doses to tx lymphoma), SIADH
o Doxorubicin cardiotoxicity (baseline EF), alopecia, myelosuppression, vesicant
o Vincristine - vesicant, neurotoxicity (autonomic results in constipation laxative and
stool softener)
o Prednisone - glucose intolerance, immunosuppression
Rituximab
o Study that prompted rituximab added to all CD20+ dz
o Less events and increased CR
o Increases survival for every stage
o R-CHOP
Bone Marrow Transplant
o Younger patients < 60 years old
o Increased morbidity/mortality
o Curative?
Maintenance therapy
o Prolonged therapy to keep lymphoma in check
Rituximab
o Two schedules
every 6 months
every other month
Salvage chemotherapy
o EPOCH, DHAP, ESHAP, HyperCVAD
o Radioisotopes
Bexxar, Zevalin
Bone Marrow Transplant
o Sources of hematopoietic stem cells
Patient
Unrelated donor
Umbilical cord
o Types of BMT
Autologous
Allogeneic
Cord blood
o NOTHING ON TRANSPLANT

Leukemias Therapeutics

Leukemias
o Hematologic malignancy

proliferation
accumulation
Pathogenesis
o Normal hematopoiesis
Hematopoietic pluripotent stem cell gives rise to all blood cells
o Stop in diferentiation at a certain point that is immature and non-functional
o For the most part myeloid and lymphoid changes tx
Leukemia
o Arise from single cell
o Proliferate
o Impaired apoptosis
o crowd out bone marrow
o No diferentiation immature and serves no fxn
Etiology
o Benzene
o Alkylating agents
o Cigarrette smoking
o Ionizing radiation
o Viruses
o Genetic e.g. down syndrome, Fanconi anemia
Diagnosis
o bone marrow biopsy
aspirate
core biopsy
o flow cytometry what are the markers on cell surface
o cytogenetic profile genes associated w/ leukemia
o Myeloid can cause more problems
o Lymphoblast much smaller cell; a lot floating around ok
Prognosis
o good prognosis
younger
histologic type
o poor prognosis
extramedullary disease
chromosome abnormalitites
2 leukemias
inc. LDH, WBC
long time to CR
Preparation
o insertion of central access
o treat infections
o What drugs can go together and what drug can go into what line.
o Permanent central catheter port (tunneled and goes into the vein); double ports
can give into two separate ports
o Hickmans tunneled into skin and line is outside the body
Categories
o Acute
Myeloid
Lymphoid
o Chronic
Myeloid
Lymphoid

Acute leukemias
o acute myeloid (AML)
33% WBC
Decrease plts
gingival hyperplasia
constitutional sxs
1/3 normal
1/3 elevated
1/3 low
o acute lymphoid (ALL)
85% WBC
lymphadenopathy
Splenomegaly (other organs compensate for hematopoietic fxn)
ALL
o Most common in children < 5yo
o L1 (kids)
o L2 (adults)
o L3 w/e
o T-cell prognosis worse
ALL Cytogenetics
o Philadelphia chromosome (Ph+)
t(9;22)
o POOR prognosis
Presentation
o Bone marrow failure
Infection, fatigue, coagulopathies
o Metabolic abnormalities
o Extramedullary
Splenomegaly, lymphadenopathy
Staging
o WHO (World Health Organization)
> 20% blasts in bone marrow
o Molecular/cellular studies
Cytogenetics
Flow cytometry
Treatment
o Induction
CNS prophylaxis
o Consolidation (micrometastatic dz)
o Maintenance low dose chemo
o If there are a lot of blast cells in peripheral blood, can introduce leukemia into blood
WAIT TILL 0
o KNOW
Chemotherapy
o Multi-drug regimens
o Cyclophosphamide, l-asparaginase (only used in ALL), doxorubicin, vincristine,
prednisone. 6-mercaptopurine
o Tyrosine kinase inhibitor for Ph+ (Philadelphia chromosome)
o Intrathecal medications***
Ara-C, methotrexate, thiotepa
l-asparaginase

Tumor cells lack asparagine synthetase therefore require exogenous asparagine; lasparaginase decreases asparagine therefore cells die
o Essential amino acid that tumor cell cant make kills leukemia cells
l-asp - toxicity
o Anaphylaxis
test dose 2 unit ID
o Liver
transaminases, decreased fibrinogen
o Pancreatitis
o Neurologic
confusion, lethargy, agitation
l-asp - drug interactions
o Methotrexate
rescues cells from MTX toxicity
Prevents cell from going to S phase so avoid MTX
24h window b/w doses
o Vincristine
inhibits VCR clearance therefore increases toxicity
l-asparaginase
o Administration
IM, IV
o Formulations
regular
pegylated - q2week dosing, may be given IV
Ommaya reservoir
o If leukemia cells in CSF, then have to tx a pt w/ lumbar punctures but also can put a
port into the head
o Tx 2x after a negative finding for good luck
Relapse
o Sanctuary sites
CNS
Testes radiation for tx
Isolated relapses in these areas
Relapsed ALL
o New agents
Liposomal vincristine
o Bone marrow transplantation
o Investigational protocols
AML
o WBC
o Gingival hyperplasia
o CNS involvement (a lot less, only if pt is symptomatic)
o DIC (subtype 3 that presents with this)
Pts bleed for the most part; clotting also occurs
o Skin involvement
WHO classification Promyelocytic
o AML with characteristic genetic abnormalities
AML with 15;17 translocation
o AML with multilineage dysplasia
o AML & MDS, therapy related
o AML not otherwise characterized
o Acute leukemias of ambiguous lineage
o

Staging
o WHO (World Health Organization)
> 20% blasts in bone marrow
o Molecular/cellular studies
Cytogenetics
Flow cytometry
Presentation
o Bone marrow failure
Infection, fatigue, coagulopathies
o Metabolic abnormalities
Treatment
o Induction
o Consolidation
o ? BMT
o First 2 steps the same compared to ALL
o Must give consolidation or pt relapses
o Maintenance therapy and AML not efective; transplant depends on high risk (high
risk go ahead)
o Allogeneic must have a donor
Treatment
o 7&3
7 days continuous infusion cytarabine
3 days of anthracycline (donorubicin and iburobicin)
o CNS prophylaxis only w/ s/x
o One round will result in CR in 60-80% patients
o 3 cycles consolidation
Neutropenia and infection
Monitoring
o Bone marrow biopsy 7 days out from end of treatment
Day 14 - look for aplastic marrow (any more leukemia around?)
No more leukemia aplastic bone marrow
Let pt recover
o Bone marrow biopsy when counts recover
look for normal marrow
Cytarabine
o Low dose (20-200 mg/m2/day) - induction
mild nausea/vomiting
myelosuppression
rash
mucositis
o High dose (2-3 gm/m2/dose) consolidation
Conjunctivitis high dose excreted in tears
Give eye drops artificial tears, prednisone eye drops 24h after
cerebellar toxicity (micrographia)
nausea /vomiting
Anthracyclines
o Daunorubicin (induction), idarubicin (induction some data suggesting
better in younger pts < 60 y/o), epirubicin
cardiotoxicity
nausea/vomiting (delayed)
neutropenia
vesicant

BMT
o
o
o
o
APL
o
o
o
o
o
o

alopecia

Bad cytogenetics
Multiple cytogenetic abnormalities
? donor
Age of patient
5-10% of AML cases
Important to recognize because the treatment is diferent
Patients are younger, often ages 30-40
Usually present with leukopenia (WBC >10K higher risk of relapse)
DIC due to granules with proteolytic enzymes
Presence of t(15;17) or detection of the PML/RAR fusion product confirms the
diagnosis

APML
o Tretinoin (all-trans retinoic acid) binds to PML-RAR fusion protein
CIS is for acne
o Restores transcription of genes that allow diferentiation
o Does not kill cells
o Side efects
APL diferentation syndrome: hyperleukocytosis, fever, pulmonary infiltrates
overwhelms body b/c all of immature cells become mature
can be fatal if not recognized and treated with steroids
o Addition of an anthracycline decreases APL syndrome from 25% to 5%
Tretinoin (Vesanoid)
o Retinoic acid syndrome fever, cough, pulmonary infiltrate
o Hyperleukocytosis
o headache
o Dry skin/mucous membranes
o Hypertriglyceridemia
o Teratogenic
APML
o Arsenic Trioxide (ATO) for relapsed after failure w/ tretinoin
o Induces apoptosis in the APL cells
o Retinoic acid syndrome steroids + chemo
o Cardiac toxicities: prolongation of the QTc interval, toursades de points, Atrioventricular block (check EKG weekly and check magnesium and potassium)
o Can also cause APL Diferentiation Syndrome
o Standard treatment: ATRA and anthracycline for induction Complete remission
>90%
o Maintenance therapy with ATRA and oral anti-metabolite equals long term
remission in 70%
Tx
o Arsenic + tretinoin
o Arsenic + idarubicin
o
Newly diagnosed APML patients
o
Randomized to 2 arms
o
Non- inferior
APML future
o Position arsenic trioxide
o Elimination of conventional chemo
Chronic leukemias

o
o
o
o
CML
o
o
o

CML
CLL
Overall may be less aggressive
Death in months to years

Benzene, ionizing radiation

Median age = 65 years old
Ph+ in 90-95% cases
used to follow response
o Translocation t(9;22)
o Results in bcr/abl hybrid
Presentation
o B symptoms
o Fatigue
o Infection
o Splenomegaly
o Hepatomegaly
Staging

Treatment
o BMT
keep in chronic phase
Imatinib, dasatinib nilotinib
avoid alkylators
allo BMT
o non- BMT
keep in chronic phase
Imatinib, dasatinib, nilotinib
hydroxyurea
Splenectomy
Keep in chronic phase
o Drug first and then if they fail - transplant
Imatinib mesylate (Gleevec)
o First in class
o Tyrosine kinase inhibitor
inhibits bcr-abl tyrosine kinase
o Indicated for interferon failures
o dosing 200-800mg per day
Toxicities
o Superficial edema around orbits/cardiac efusions
o Nausea higher doses
o Muscle cramps

o Neutropenia, thrombocytopenia
o Hepatotoxicity
o Cardiotoxicity
Dasatinib (Sprycel)
o Approved June 2006
o Tyrosine kinase inhibitor
src, abl
o Ph+ chronic or accelerated phase CML, CML blast crisis ; Ph+ ALL
Dasatinib
o Well tolerated
neutropenia & thrombocytopenia
pleural efusions (18%)
diarrhea
peripheral edema
Nilotinib (Tasigna)
o Inhibits TKIs associated with bcr/abl
o Similar side efect profile to toher TKIs
o Not active against T315I mutation
o Resistance
Point mutations
T315I (threonine to isoleucine)
Frame shift
Ponatinib
o Active in T315I translocation only one that works with this mutation
o Approved withdrawn- approved
o Side efect
Thrombotic events (arterial thrombosis)
Bosutinib (Bosulif)
o GI side efects
TKI Failures
o Bone Marrow Transplant
Curative
Must have donor
CLL
o Unknown etiology
o Second most common leukemia
o Median age = 60 years old
o Proliferation of malfunctioning lymphocytes
Presentation
o Indolent disease
o B symptoms
o LAD, splenomegaly, hepatomegaly
o Anemia, thrombocytopenia, neutropenia
Staging
o RAI classification
o Stage 0, I, II, III, IV
o Depends on degree of adenopathy, and other cell lines afected
o Richters transformation
Therapeutic Options for CLL LOW GRADE
o Symptom management (palliation)
o Oral chemotherapy (C&P)
o Single agent infusional chemotherapy

Combination chemo-immunotherapy
High dose chemotherapy (auto SCT)
Allogeneic transplant
The options for treatment of CLL run the gamut of treatments for all hematologic
malignancies from symptom management to allogeneic transplant. With so many
choices, how do we decide which approach is best for which patient?
Treatment
o No cures (? BMT)
o Treatment for late stage or pts with symptoms
o Oral alkylating agents
o Chemotherapy fludarabine based regimens, cladribine, bendamustine
Fludarabine vs. Chlorambucil
Purine antimetabolites
o Fludarabine
immunosuppressive
opportunistic infections
myelosuppression
CNS toxicity
o Cladribine
immunosuppressive
neutropenia
opportunistic infections
rash
Treatment
o Radiation
o IVIg - for passive immunity
New agents
o Rituximab
monoclonal antibody directed against CD20
Rituximab in CLL
Bendamustine
o Alkylator and induces apoptosis
o Replacing chlorambucil as front line therapy
o Well tolerated in elderly
o Drawback IV only
Ibrutinib
o Approved January 2014 (oral drug)
o Overall response rate 58%
o Duration of response 5.6 24.4 months
o Minimal side efects
Myelodysplastic syndromes
o Old classification
RA - < 5% blasts
RARS - < 5% blasts
RAEB - 5-20% blasts
CMML - 5-20% blasts
o WHO classification
RA
RARS
refractory cytopenia
with multilineage
dysplasia
o
o
o
o

RAEB I and II,

del (5q) syndrome
MDS unclassifiable

MDS
o Occurs in older patients
o Can develop into leukemia
o Difficult to treat
Guidelines for Treatment in MDS
o Control of symptoms due to cytopenias
o Improving quality of life
o Improving overall survival
o Decreasing progression to AML
Treatment of MDS
o Transfusion with iron chelation therapy
o Growth factors (G-CSF, erythropoietin, ?IL-11)
o Low dose chemotherapy (cytarabine, mitoxantrone)
o High intensity (anti-leukemic) chemotherapy
o Hematopoietic stem cell transplantation
o Demethylating agents: azacitidine, decitabine
o Immunomodulatory agents (lenalidomide) in 5q-