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1/21/2010
Goals of this presentation
Clinical Trials: Adverse Events,
Toxicity Criteria & Reporting, and
Managing Symptoms
Willis Navarro, MD
Medical Director, Transplant Services
National Marrow Donor Program
Form 2100
• Questions 497-528
• Review the “Other Organ Impairment/
Disorder” section of Form 2100
• Review AEs, “incidents” associated with stem
cell infusion on Form 2006
• Discuss the context of each item in the
marrow transplant realm
• Review the management of the
symptoms/complications
• Liver, lung AEs not covered because of
previous presentations
Avascular Necrosis
• Synonyms: osteonecrosis, bone necrosis,
ischemic bone necrosis
• Pathophysiology: Results from ischemia of
the end of the bone (usually femur at the hip
hip,
but also the knee, shoulder joints)
• Risks: Underlying risk is often steroid use,
but includes alcoholism, vasculitis, radiation
injury, hemoglobinopathies (sickle cell, etc)
• Symptoms include pain, decreased range of
motion of the affected joint
Avascular Necrosis
Cataracts
• DDx: osteomyelitis, fracture due to
osteoporosis
• Diagnosis: radiographic
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• Treatment:
• Synonyms: traumatic cataract (the trauma is usually
radiation or drug effect in the case of HCT)
• Pathophysiology: Results most likely from oxidative
stress to the lens with age, but accelerated especially
by radiation injury; proteins become opaque, water
content falls
• Risks: Underlying risk is often radiation injury but
also includes steroid use, possibly alcohol, smoking,
age, diabetes,
• Symptoms include decreased visual acuity, glare
– symptomatic treatment
– decreased weight bearing
– joint replacement
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Cataracts
Congestive Heart Failure
• DDx: eye injury, other eye problems
• Diagnosis: physical exam (slit lamp)
• Treatment/Management:
– Observation/monitoring
– Surgical lens extraction
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• Intracapsular cataract extraction (ICCE)
• Extracapsular cataract extraction (ECCE)
• Phacoemulsification
Congestive Heart Failure
•
•
•
DDx: volume overload, sepsis,
“diastolic” dysfunction,
Diagnosis: echocardiography,
increased b-natriuretic protein
((BNP),
), CXR,, physical
p y
exam,,
MUGA scan, cardiac
catheterization
Treatment/Management:
Diabetes Mellitus/Hyperglycemia
• Caveat (again): discussion here will be limited in scope to
transplant-associated issues or we would be here for hours…
• Synonyms: none, really
• Pathophysiology: where do I begin? Diabetes is a syndrome of
either decreased insulin production (Type 1-often
1 often autoimmune)
or insulin resistance (Type 2, “adult onset”), often with endorgan damage as a result of long-standing hyperglycemia.
Hyperglycemia is simply blood glucose above the upper limit of
normal (and isn’t necessarily diabetes).
• Risks: pregnancy, steroids, certain chemo drugs (but ones not
used in transplant), sepsis (for hyperglycemia)
• Signs and Symptoms include increased serum glucose,
elevated Hgb A1C, end organ damage-related (peripheral
neuropathy, renal failure, CVD, PVD)
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– Diuretics, ACE inhibitors,
vasodilators
– Correct underlying issue (stop
EtOH, fix valve, etc)
– Inotropic agents, beta blockers
– Heart transplant
Diabetes Mellitus/Hyperglycemia
• DDx: glucose intolerance
• Diagnosis: serum glucose, microalbuminuria,
elevated Hgb A1C
• Treatment/Management:
T
t
t/M
t
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–
• Caveat: discussion here will be limited in scope to transplantassociated issues or we would be here for hours…
• Synonyms: left-sided heart failure, left ventricular systolic
dysfunction, CHF
• Pathophysiology: where do I begin? Anything that affects the
function of myocytes directly (toxins, Chagas’, inherited
syndromes), or which causes a persistent excessive load on the
heart(MI, HTN, valvular disorders); note that CHF is the result
of a pathologic process in the circulatory system
• Risks: certain chemotherapeutics (anthracyclines in particular),
myocardial infarction, inherited disorders, long-standing
hypertension, alcoholism, valvular disorders; rarely, infections
like Chagas’; certain viral infections (Coxsackie, etc)
• Signs and Symptoms include poor exercise tolerance, rales,
dyspnea, pleural effusions, pulmonary edema, lower extremity
edema, cardiac dysrhythmias (especially a fib); cardiomegaly
Anti-hyperglycemics, insulin
Treat underlying cause of hyperglycemia
Weight loss, exercise
Pancreas transplant for Type I in some cases
Gonadal Dysfunction Requiring
Hormone Replacement/Infertility
• Note that I changed the “requiring hormone replacement”
to associate with gonadal dysfunction, though Form 2100
has in the opposite order
• Synonyms: hypogonadism, sterility, early menopause,
yp
, hypoestrogenism
yp
g
hypotestosteronism,
• Pathophysiology: damage from chemotherapy and/or radiation
can lead to gonadal failure; more likely to occur in women,
increased risk with age; prepubescent children will manifest
delayed or arrested sexual development; indirect failure can
result from primary pituitary failure
• Risks: radiotherapy; alkylating chemo agents
(cyclophosphamide, busulfan, BCNU, CCNU, melphalan,
nitrogen mustard, and many others)
• Signs and Symptoms include low measured testosterone or
estrogen levels, menopause symptoms, decreased libido,
impotence, dysparuria, muscle wasting in men
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Gonadal Dysfunction Requiring
Hormone Replacement/Infertility
Growth Hormone
Deficiency/Growth Disturbance
• DDx: hormone replacement for reasons other than
gonadal failure (i.e. testosterone for muscle wasting,
or for red cell production); infertility of the partner of
the patient
• Diagnosis: symptoms consistent with decreased sex
hormone levels, confirmation by estrogen or
testosterone levels (caution: hormone levels must be
interpreted in context)
• Treatment/Management:
• Synonyms/Related Disorders: panhypopituitarism, short
stature, psychosocial dwarfism, achondroplasia, Noonan
syndrome, hypothyroidism, constitutional growth delay
• CAVEAT: keep in mind that reporting is required only for those
p p
issues which occurred “after the start of the preparative
regimen” so one issue in this category is to sort out any growth
issue that was ongoing prior to transplant (growth disturbance)
• Pathophysiology: Growth hormone (GH) production is
stimulated by GHRH; pituitary damage (radiation, tumor,
surgery), or congenital defects can impair GH production;
damage to the hypothalamus can prevent adequate GHRH
production
• Risks: radiotherapy, especially to the CNS as with ALL therapy;
• Signs and Symptoms include short stature but normal
appearance/proportions
– Hormone replacement therapy
– Infertility care (hormones, in vitro fertilization, surrogacy)
Growth Hormone
Deficiency/Growth Disturbance
Hemorrhagic Cystitis/Hematuria
Requiring Medical Intervention
• DDx: short stature but normal variant, other inherited
disorders of growth (IGF-1 insensitivity, Prader-Willi
and Noonan syndromes, etc)
• Diagnosis: evaluation of levels of IGF-1, IGFBP-3
(GH dependent); karyotype; TFTs, MRI; GH is tough
to measure (must be stimulated)
• Treatment/Management:
• Synonyms: blood in urine
• Pathophysiology: injury to bladder epithelium,
usually by radiation or the chemo drugs
cyclophosphamide or ifosphamide, or due to viral
infections, esp. BK virus but also CMV, adenovirus;
may also be related to trauma (urinary catheters), or
• Risks: as above; infectious causes enhanced in HCT
settings with slow immune recovery
• Signs and Symptoms include hematuria, sometimes
with significant bleeding, urinary obstruction due to
gross clotting is seen
– Growth hormone replacement
– Monitoring for failure of other pituitary
hormones (thyroid, sex hormones)
axis
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Hemorrhagic Cystitis/Hematuria
Requiring Medical Intervention
• DDx: bleeding from another site (vaginal in women)
• Diagnosis: urinalysis, cystoscopy
• Treatment/Management:
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–
–
–
Transfusion support
Bladder irrigation
Urology consult
Cytoscopic fulguration of bleeding areas
Surgery
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Hypothyroidism
• Synonyms: none
• Pathophysiology: Usually due to primary thyroid
failure due to toxic effects of chemo and/or radiation
or but can be secondary due to failure of TSH
secretion
• Risks: chemotherapy and/or radiation, autoimmunity,
effects of GVHD
• Signs and Symptoms include fatigue, weight gain,
cold intolerance, but also many other non-specific
symptoms
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Hypothyroidism
Myocardial Infarction
• DDx: lots of symptoms of hypothyroidism can
be attributed to other disorders
• Diagnosis: elevated TSH (primary thyroid
failure) or low TSH with low T3 and T4
hormone levels
• Treatment/Management:
• Synonyms: heart attack,
• Pathophysiology: severe and persistent ischemia to
the cardiac muscle leads to myocyte cell death and
then scarring with repair
• Risks: atherosclerosis, history of radiotherapy
including the heart in the treatment window, cardiac
risk factors
• Signs and Symptoms include chest pain, nausea,
fatigue, dyspnea, sudden death
– Replacement
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Myocardial Infarction
• DDx: aortic dissection, GERD, pericarditis,
esophagitis/esophageal spasm, pneumothorax
• Diagnosis: increased troponin, CPK-MB fraction,
EKG with characteristic changes, echocardiography
showing focal wall motion abnormalities, cardiac
catheterization
• Treatment/Management:
– Vessel unblocking (via stent/angioplasty, coronary artery
bypass)
– Beta blockers, nitrates, ASA, antiplatelet agents, ACEI
– Risk factor reduction maneuvers
Pancreatitis
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• Synonyms: none
• Pathophysiology: problem with the control
mechanisms that keep pancreatic enzymes under
control, usually associated with pancreatic cellular
injury (toxins like EtOH, chemo drugs, radiation);
gallstone blockage of duct is most common cause; in
heme malig setting: L-asparaginase, GVHD
• Risks: as above
• Signs and Symptoms include fever, tachycardia,
abdominal pain, less commonly jaundice
Pancreatitis
TTP/HUS
• DDx: gall bladder disease, pancreatic cancer,
myocardial infarction, pneumonia
• Diagnosis: amylase, lipase serum levels, abdominal
imaging
• Treatment/Management:
• Synonyms: none
• Pathophysiology: the lack of the enzyme required to
break down large multimers of vWF leads to TTP;
fibrin microvascular clots develop and shear RBCs;
renal failure, CNS symptoms result. Can be
autoimmune or drug-based
• Risks: calcineurin inhibitors, exposure to O157:H7 E.
Coli, other drugs
• Signs and Symptoms include thrombocytopenia,
schistocytes on the peripheral smear, renal failure,
fever, CNS symptoms, elevated LDH
–
–
–
–
Bowel rest
Pain medications
Fluid support
Surgical intervention if there is a mechanical issue that can
be dealt with
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TTP/HUS
Renal Failure Warranting Dialysis
• DDx: DIC, malignant hypertension
• Diagnosis: having the pentad (required:
increased LDH, schistocytes; often seen:
fever renal and CNS manifestations); should
fever,
have a negative w/u for DIC
• Treatment/Management:
– Plasma exchange
– Stop offending drug
– Rituximab for autoimmune form
• Synonyms: kidney failure, ESRD, ARF, acute tubular necrosis
(ATN), azotemia
• Pathophysiology: often multifactorial but associated with
nephrotoxic drugs, particularly calcineurin inhibitors, some
g
antibiotics,, cidofovir,, manyy others;; severe stressors during
transplant (sepsis) can lead to temporary renal failure requiring
dialysis or hemofiltration (usually done in the ICU; continuous so
reduced fluid shifts, but equivalent to dialysis)
• Risks: multiple
• Signs and Symptoms include uremic symptoms (confusion,
nausea and vomiting, tremor, coma), reduced or absent urine
output
Renal Failure Warranting Dialysis
• DDx: pre-renal vs infrarenal vs post-renal
causes
• Diagnosis: abnl urinalysis, rapidly rising
creatinine calcium and acid
creatinine,
acid-base
base
disturbances, symptoms of uremia, anemia if
chronic
• Treatment/Management:
– Dialysis or hemofiltration
– Supportive measures, reduce/eliminate
nephrotoxic drugs
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Stroke/Seizure
Stroke/Seizure
• Synonyms:
– Stroke: CVA, brain ischemia
– Seizure: epilepsy
• Pathophysiology:
– Stroke: due to embolic or thrombotic clot,
clot ischemia,
ischemia and loss of
function. Because of neuronal crossover, loss is on the opposite
side from the stroke; handedness matters for speech centers
– Seizure: due to uncontrolled electrical activity
• Risks: stroke: similar to MI risk factors; seizure: prior head
injury, some medications, brain tumor, inherited disorders
• Signs and Symptoms
– Stroke: hemiplegia, visual disturbance, dizziness, headache,
balance disturbance
– Seizure: physical exam, post-ictal state
Form 2100: Other Adverse
Events
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• DDx:
– Stroke: CNS hemorrhage; seizure; migraine, TIA (stroke-like
but temporary); CNS infection
– Seizure:
• Diagnosis:
Di
i
– Stroke: physical exam, brain MRI (more sensitive early on);
head CT
– Seizure: physical exam, EEG
• Treatment/Management:
– Stroke: thrombolytics, ASA, control hypertension if present
– Seizure: antiseizure drugs (lots of different drugs)
• Report events that were serious
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–
Life-threatening
Led to initial or prolonged hospitalization
Resulted in death
Resulted in a birth defect
Resulted in disability
Required medical intervention to prevent
permanent impairment or damage
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The Problems with Question
528: “Other”
• Stuff here that should go elsewhere
– PTLD (Question 549-lymphoma or
lymphoproliferative disease)
– Seizures (Q
(Q. 524-stroke/seizures)
524 stroke/seizures)
– Low testosterone (Q. 506-gonadal dysfxn)
– Elevated LFTs (Q. 490-elevated liver enzymes)
– BK virus cystitis, typhilitis, gangrenous gallbladder
(Q. 389-site and infectious agent)
The Problems with Question
528: “Other”
• Examples of items not covered elsewhere
that do go here:
–
–
–
–
–
–
–
–
The Problems with Question
528: “Other”
• Stuff that doesn’t fit “any clinically significant organ
impairment or disorder after the start of the prep
regimen to last contact”
–
–
–
–
white discoloration of tongue (too vague)
redman syndrome (not clinically significant)
occasional dysuria (not clinically significant)
leukemia cutis (relapse or secondary malig, not an organ
impairment)
– osteoporosis (almost certainly pre-existing give the 100 day
timeframe)
– death (not an organ impairment, report elsewhere)
– renal failure (if not requiring dialysis, not significant)
Form 2006: InfusionAssociated AEs/Incidents
• Questions 202-263
DVT
Steroid myopathy
DIC
CNS hemorrhage
Hearing loss
TRALI
Leukoencephalopathy
Etc…
Terms
• Bradycardia: simply defined as a measured
heart rate less than 60 bpm
• Chest tightness/pain
• Chill att titime off iinfusion
f i
• Fever ≤103°F or >103°F (39.4°C) within 24
hrs of infusion
• Gross hemoglobinuria: as opposed to
microscopic; urine should have been visibly
pink to red; gross hematuria is equivalent
More Terms
• Headache: as reported and documented
• Hives: may also be reported as urticaria or
wheal and flare reaction
• Hypertension:
H
t
i
SBP≥140 or DBP≥90
• Hypotension: SBP<90 and/or DBP<60 (but
this is sketchier)
• Hypoxia requiring O2 support (nl O2 saturation
can vary even with altitude)
• Nausea: as reported and documented
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Even More Terms
• Rigors, Mild: resolving without pharmacologic
intervention
• Rigors, Severe: requiring pharmacologic
treatment
• Shortness of breath (dyspnea): as reported
and documented
• Tachycardia: heart rate >100 bpm
• Vomiting
Other Expected AEs
• Infusional reactions related to DMSO
– Abdominal pain/cramping
– Flushing
– Cough
– Malaise
Questions?
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