Transcript Hematology (Board Review)

Hematology
Board Review Workshop
Daniel Martin MD
The road to success is always
under construction.
Di$clo$ure$
None
Overview
• Anemia
• VTE
• Lymphoma
– NHL
– Hodgkin Lymphoma
• MGUS
• Myeloma
• CML
What is a heme work up?
• CBC (with Differential and MCV)
• Smear Evaluation
• Reticulocyte count – (residual RNA precipitates in
clumps- reticulum Latin for net)
Anemia
MCV Guides the workup in
underproduction anemia (low retic)
Normal MCV (81-98) Low MCV (IRON)
Elevated MCV (DNA)
Chronic renal failure
Iron deficiency
B12 deficiency
Aplastic Anemia
Inflammatory disease
Folate deficiency
Myelophthistic process
(marrow replacement
with tumor, granuloma,
fibrosis)
Thalassemia
Chemotherapy or related
drugs (AZT)
Endocrine disease
Sideroblastic anemia
(EtOH, lead poisoning,
copper deficiency)
Myelodysplasia
*I suggest you always prefix anemia with normo-, macro- or
microcytic and/or hemolytic or underproduction.
High retic count implies
Peripheral destruction or blood loss
Intravascular Hemolysis
Extravascular Hemolysis
(Slow/spleen)
Immunohemolytic anemia (IgM
mediated)
Immunohemolytic anemia (IgG
mediated)
Fragmentation (DIC, TTP, mechanical,
burns, prosthetic valve, clostridium
toxin)
RBC membrane and enzyme defects
(hereditary spherocytosis and G6PD,
pyruvate kinase, or hexokinase
deficiency)
PHN
Hemoglobinopathies (Hb S, Hb C,
unstable hemoglobin)
Hemolysis workup
Haptoglobin, bilirubin, LDH, DAT, Plasma
hemoglobin
Patient presentation #1
• 65-year old retired male airline pilot, in for “annual”
• 1 mo: chest pressure 2-3/week, while walking relieved
by rest
– Now at a progressively earlier spot on the hill in his route
• Last colonoscopy 14 years ago. Doesn’t like the prep
CBC results
•
•
•
•
WBC 5.4
HCT 29%
MCV 74
Platelets 554,000/μl
• Reticulocyte count = 1.0%
• Corrected retic count:
– 1.0 % x 26/45 = 0.58%
Our patient’s Iron study results
Test
Iron
Result
38 L
Normal Range
(40-155)
TIBC
Transferrin Sat
Ferritin
410
9% L
9L
(250-460)
(15 – 50)
(20 – 230)
Causes of Iron Deficiency
• Blood Loss
– Gastrointestinal Tract
– Menstrual Blood Loss
– Blood donation (not so uncommon in Seattle)
• Malabsorption
– Tropical Sprue
– Gastrectomy
– Chronic atrophic gastritis
“They gave me a pin
when I was there last
month”
IRON DEFICIENCY
Symptoms
•
•
•
•
•
•
Fatigue - Sometimes out of proportion to anemia
Atrophic glossitis
Pica-burning in the mouth-ice chewing
Koilonychia (Nail spooning)
Esophageal Webs
Restless leg
“Crushed ice tastes the
best. In the summer my
refrigerator can’t keep up”
Iron therapy
• 325 mg tablet FeSO4, ~65 mg of Fe
– I recommend 1 tab/day with OJ
– 3 x day usually NOT tolerated due to GI Sx
– Do NOT assume your patient is taking iron as instructed
•
•
•
•
Initial response takes 7-14 days
Correction of anemia requires 2-3 months
6 months of therapy is reasonable
Tannins in black tea impair absorption of iron
Patient presentation #2
•
•
•
•
51 yo woman with rheumatoid arthritis
Recent arthritic flare (increased pain, swelling)
Blood: + rheumatoid factor, increased ESR & CRP
On non-steroidal anti-inflammatory medications
Physical exam
•
•
•
•
Appears weak & pale
Conjunctival pallor
PIP & MCP joints are swollen, red, & warm
Abdomen is soft & non-tender
What is a heme work up?
• CBC (+diff)
• Smear Eval
• Reticulocyte count
Hematology work up
• WBC = 11.4  103/μl
• Hct 30.5
• MCV 79
• Reticulocyte count = 1.5%
• Corrected retic count:
•
1.5  30/40% = 1.1
• Serum Fe 45, TIBC 270
• Ferritin 800
MCV Guides the workup in
underproduction anemia (low retic)
Normal MCV (81-98)
Low MCV (IRON)
Elevated MCV (DNA)
Chronic renal failure
Iron deficiency
B12 deficiency
Aplastic Anemia
Inflammatory disease
Folate deficiency
Myelophthistic process
(marrow replacement with
tumor, granuloma, fibrosis)
Thalassemia
Chemotherapy or related
drugs (AZT)
Endocrine disease
Sideroblastic anemia (EtOH, Myelodysplasia
lead poisoning, copper
deficiency)
Anemia of chronic inflammation
• Hct usually ~25-35%; normal to low MCV
• Fe cannot be utilized
– It is stuck in marrow macrophages
• Iron absorption is blocked
• “Inflammatory block” is a protective sequestration of
iron.
– upregulated hepcidin blocks ferroportin mediated Fe export
• Improves with treatment of underlying cause
• Why? Generalized anti-infective response
Hepcidin Blocks Ferroportin Fe export
Patient presentation #3
• 67 yo man. His wife died 6 mo ago, drinking heavily
since, poor diet
• Previously a house painter
• Drank “about 6 beers a day” for years
Physical exam
•
•
•
•
•
WBC 3.2
Hct 27%
MCV 108
platelets 118,000/μl
Reticulocyte count = 2.1%
• Corrected reticulocyte count
•
2.1% x 27/45 = 1.3%
• B12
• Folate
308 pg/ml
0.2 ng/ml
MCV Guides the workup in
underproduction anemia (low retic)
Normal MCV (81-98)
Low MCV (IRON)
Elevated MCV (DNA)
Chronic renal failure
Iron deficiency
B12 deficiency
Aplastic Anemia
Inflammatory disease
Folate deficiency
Myelophthistic process
(marrow replacement with
tumor, granuloma, fibrosis)
Thalassemia
Chemotherapy or related
drugs (AZT)
Endocrine disease
Sideroblastic anemia (EtOH, Myelodysplasia
lead poisoning, copper
deficiency)
*I suggest you always prefix anemia with normo-, macro- or
microcytic and/or hemolytic or underproduction.
Patient presentation #3
• An 19 year old college sophomore complains of right
thigh fullness and pain. She also notes some swelling
in her lower leg.
• She is a soccer player and recently had ACL repair two
weeks ago and postoperative immobilization
• She has no past medical history.
• On physical exam her left leg is swollen and tender to
the mid thigh. Vitals and oxygen sat are normal
• She uses a NuvaRing for contraception.
Case continued
• Her Wells score is 7.5
• A lower extremity vascular study shows a DVT in the
common femoral vein.
• She has no family history of DVT
• CBC, coags, and CMP is normal
• She has a provoked DVT
• She gets 3 months of anticoagulation
• DOACs are now preferred 1st line therapy
Choosing wisely with VTE management
Chosing Wisely
Hematologic Malignancy
• Lymphoma
– NHL
– Hodgkin Lymphoma
• Myeloma
• More Leukemia (if time allows)
Relative frequencies of different lymphomas
Hodgkin
Lymphoma
11% ~9000
cases/yr
Non-Hodgkin Lymphomas 89%
~72,000 cases/yr
Diffuse large Bcell
Follicular and
CLL/SLL
NHL
Other NHL
~90% of NHL are B-lineage
Lymphoma in HIV-Positive People*
• ~100-fold increased incidence of aggressive NHL (in
comparison to HIV-negative people)
• ~10-fold increased incidence of Hodgkin lymphoma
• Primary CNS lymphoma – CD4 cells < 50/mL (and
often < 10/mL)
Lymphoma breakdown
Lymphoma Type
Survival
without
treatment
Curability
Non-Hodgkin
Lymphoma
Indolent
(Follicular)
Years
Not curable Treat when
symptomatic
Aggressive
(DLBCL)
Months
Curable in
50-60%
Treat
immediately
All types
Months to
years
Curable in
most
Treat
immediately
Hodgkin
Lymphoma
Treatment
urgency
Non-hodgkin Lymphoma
Non-Hodgkin Lymphoma
• Exam:
– Rubbery adenopathy
– Splenomegaly
– Hepatomegaly
• Labs:
– CBC often normal
– LDH often elevated
Non-Hodgkin Lymphoma
• Diagnosis:
– Excisional biopsy of a lymph node to evaluate node
histology and architecture
– Flow cytometry for B and T cell markers, FISH for
molecular abnormalities
• Pathology and stage determine prognosis and
treatment
Case 1
• A healthy 57 year-old presents with a one month
history of a mass in his right axilla. The mass was
increasing rapidly in size. He had lost 17 lbs. He had
night sweats.
• Exam: large right firm mass in the right axilla. Several
enlarged rubbery right cervical nodes, the largest 5x5
cm.
AggressiveDLBCL
R-CHOP Chemotherapy
• Rituximab (anti-CD20)
• Cyclophosphamide
• Hydroxydaunorubicin (DoxorubicinAdriamycin*)
• Oncovin (vincristine)
• Prednisone
Outcomes in the Rituximab Era
BLOOD, 6 FEBRUARY 2014 x VOLUME 123, NUMBER 6
Case 2
• 42 y/o female presents with persistent abdominal
pain over the last 12 months that became acute
over the last 3 days.
• CT shows diffuse bulky retroperitoneal and
mesenteric lymphadenopathy. She also has
palpable right axillary and cervical adenopathy.
IndolentFollicular lymphoma
Follicular Lymphoma Therapy
Whac-A-Mole
Treatment of Follicular Lymphoma
• Stage I-II
– Radiation therapy if contiguous
• Stage III-IV
– Watchful waiting (of asymptomatic patients)
– Rituximab alone for frail patients
– R-Bendamustine or R-CHOP
Treatment of Follicular Lymphoma
at Relapse
• Watchful waiting (of asymptomatic patients)
• Rituximab, especially for frail patients
• R-Bendamustine or R-CHOP
• Stem Cell transplant
• Protocol-New drugs are coming along
Survival in Follicular Lymphoma in Era of
Rituximab by FLIPI
Ann Oncol (2013) 24 (2): 441-448
Case 5
•
A 62 year-old man with neuropathy is found to
have a monoclonal spike on his SPEP (IgGl 1.0
g/dL). He is asymptomatic.
Causes of Monoclonal Spike
n=945 (Mayo Clinic)
• MGUS
• Multiple
Myeloma
• Amyloid AL
• Non-Hodgkin
Lymphoma
• CLL
63%
13%
10%
6%
2%
Monoclonal Gammopathy of
Undetermined Significance (MGUS)
• No CRAB
– C: Elevated Calcium
– R: Renal insufficiency
– A: Anemia
– B: Lytic Bone lesions/severe
osteopenia/fracture
Monoclonal Gammopathy of
Undetermined Significance (MGUS)
•
•
•
•
•
No CRAB
Small monoclonal spike (< 3 g/dl)
Less than 10% plasma cells in bone marrow
Seen in 5% of people older than 70 years
25% risk of progression to multiple myeloma
during 20 years of follow-up
Survival of 241 Patients with MGUS
Case 6
•
A 62 year-old man with anemia is found to have
a monoclonal spike on his SPEP (IgGl 4.0 g/dL).
He complains of back pain. He is constipated.
Multiple Myeloma
• A monoclonal expansion of B cells with mature plasma cell
morphology with end organ (CRAB) damage:
• Mnemonic
–
–
–
–
C: Elevated Calcium
R: Renal insufficiency
A: Anemia
B: Lytic Bone lesions/severe
osteopenia/fracture
• SPEP with monoclonal spike IgG, IgA, etc.
• Light chains only (check serum free light chains)
• Non secretory (no monoclonal spike)
Multiple Myeloma
• Second most common hematologic malignancy
after NHL
• Roughly 27,000 cases in the US annually
• More common in men
• Twice as common in African Americans as
Caucasians.
• Median Survival is improving, currently around 5
years or more.
Lytic lesions
Rouleaux
• The skeletal series shows multiple lytic lesions. His
bone marrow shows 22% plasma cells. His
creatinine is 2.1. His calcium is 13.5. You diagnose
multiple myeloma.
• He needs therapy
• Front line therapy is typically bortezomib,
lenalidomide, and dexamethasone
Treatment of Multiple Myeloma Has Evolved
• Pre-2003: Chemotherapy Only:
– Median Survival increased with auto transplant
• 2003: Bortezomib approved-binds the catalytic
site of the 26S proteasome
• 2006: Thalidomide approved-soon followed by
lenalidomide
• Current survival trends improved
Case 7
• A 55 year-old healthy man presents for a routine CBC
prior to elective surgery. His spleen is palpable 2 cm
below the left costal margin
• CBC: WBC 38,000/mL, Hct 45%, Platelets 500,000/mL.
Differential: Neutrophils 30,000, Bands 5,000, and a
moderate number of metamyelocytes, myelocytes,
and promyelocytes. An occasional blast is seen
Chronic Myelogenous Leukemia
• Median age at diagnosis 60 years
• Symptoms – asymptomatic, fatigue, sweats,
fever, LUQ pain (splenic infarct)
• Exam – splenomegaly
• Labs – high WBC with a little bit of everything on
the smear
Neutrophils > bands > metamyelocytes > myelocytes > promyelocytes > blasts
Chronic Myelogenous Leukemia
• Diagnosis – RT-PCR to look for Bcr-Abl mRNA in the
blood, or cytogenetics to look for t(9;22) in the
marrow
• Natural history of untreated CML
– Chronic phase lasts ~ 4 years
– Accelerated phase lasts ~ 6 months
– Blast crisis (AML or ALL) lasts ~ 3 months
• A longitudinal study of patients who achieved
complete cytogenetic remission within two years
demonstrated an age-adjusted mortality rate
similar to the general population
J Natl Cancer Inst. 2011;103(7):553
Chronic Myelogenous Leukemia
Treatment
• Imatinib inhibits Bcr-Abl tyrosine kinase activity
ATP
ATP
Bcr-Abl
tyrosine
kinase
ATP
CML
PO4
TYR
Bcr-Abl
tyrosine
kinase
Substrate
CML
Imatinib
TYR
Substrate
Thank you
If you don't know where you are going, you
might wind up someplace else.
Appendix
Case 4
• A 75 year-old man presents because of “swollen
glands” in his neck for 2 years. Exam confirms
diffuse rubbery adenopathy, 2 cm in diameter. His
CBC shows WBC 45,000/mL, Hct 35%, platelets
142,000/mL
Chronic Lymphocytic Leukemia
•
•
•
•
•
Most common form of leukemia (15,000/yr)
Median age at diagnosis - 72 years
“B” symptoms - night sweats, fever, weight loss
Exam - diffuse rubbery non-tender adenopathy
Labs - high WBC, with lots of small mature-appearing
lymphocytes, “smudge cells”
Chronic Lymphocytic Leukemia
• Diagnosis – flow cytometry on blood showing
monoclonal (k or l) lymphocytes with a
characteristic immunophenotype
• Prognosis – Stage 0 CLL ~ 14 years
• Treatment – Not curable, so treat for symptoms
e.g. sweats/fever/weight loss, larg lymph nodes,
cytopenias
• Whac-A-Mole with chemoimmunotherapy
Case 8
• 29 y/o F presents to the hospital with progressive
SOB, fatigue, H/A, and petechial rash over legs
• CBC shows WBC 128K (126K blasts), Hgb 5.3, plt 12
Peripheral smear (with Auer rods)
AML
• Characterized by clonal accumulation of abnormal
immature myeloid cells with impaired production or
normal blood cells
• Most common acute leukemia in adults
• Approximately 15000 cases/yr in US
• Increases in frequency with age
AML epidemiology
Early considerations in
diagnosis/treatment
• First, rule out APL! (start ATRA if unsure)
• Hyperleukocytosis
–
–
–
–
Common symptoms include H/A or SOB
Aggressively cytoreduce (Hydrea and/or leukapheresis)
Do NOT transfuse PRBCs because of hyperviscosity
Start definitive treatment quickly
Treatment of AML
• In younger/fit patients (calculate TRM score),
intensive induction chemotherapy (7+3, GCLAM, etc.)
at UWMC
• In older/less fit patients, azacitidine/decitabine vs.
clinical trial vs. supportive care
Management of AML
Good
Induction
Chemotherapy
Risk Stratification,
Availability of donor
Int
Consolidation
Chemotherapy
Consolidation
Chemotx or Allo
Younger/fit
Poor
Diagnosis
Allogeneic HCT
Older/less fit
Clinical Trial vs.
Supportive Care
Outcomes by Proposed ELN
Stratification
• 1557 patients treated in the
AML96 trial
Age 18-60
Age > 60
Rollig C et al. JCO 2011, 29(20): 2758-2765
Case 3
•
•
A 23 year-old man presents because of a persistent itch,
night sweats requiring him to change his sheets, and a
bump on his neck.
Exam shows right axillary and cervical adenopathy. CXR
shows a left mediastinal mass. His skin is excoriated in
places.
Classical Hodgkin Lymphoma
Images from the History of Medicine (NLM) Bramwell, Byrom Atlas of Clinical
Medicine v. I, pl. IX, p. 94 Edinburgh, Constable, 1892
HL-Reed Sternberg Cells
Hodgkin Lymphoma
• Epidemiology
–
–
–
–
11% of malignant lymphomas
approximately 9000 new cases/yr in US
approximately 1100 deaths/yr
over past 30 years
• age adjusted incidence rates declined
• mortality rates declined
Age distribution of new Hodgkin Lymphoma
cases
Hodgkin Lymphoma
• Symptoms: Painless adenopathy, fever, night
sweats, weight loss
• Exam: Rubbery adenopathy (particularly cervical)
• Labs: May have eosinophilia
• Diagnosis: Excisional biopsy of lymph node
Hodgkin Lymphoma
• Staging: Hodgkin lymphoma spreads in an orderly
way from lymph node to adjacent lymph node
– Palpate all lymph node areas
– PET/CT scan
– Bone marrow aspirate/biopsy
• Staging determines prognosis and treatment
Hodgkin Lymphoma
• Hodgkin lymphoma is among the most curable of
neoplasms – all patients should be treated with
the goal of cure
• Stage I-IIA
– ABVD chemotherapy x 2-4 cycles +/- RT
– ~90% cured
• Stage IIB, III, IV
– ABVD x 6 cycles, +/- RT for bulky nodes
– ~65% cured
ABVD
• ABVD
–
–
–
–
Adriamycin*
Bleomycin*
Vinblastine
Dacarbazine
Hodgkin’s Lymphoma
Progress in the Treatment of Advanced HL Since 1940
1.0
BEACOPP escalated
(1993–2004)
Probability
0.8
ABVD
COPP/ABVD
(1988–1993)
0.6
Only alkylating agents
(1965)
0.4
No
treatment
(1940)
0.2
0.0
0
1
2
3
4
5
6
Overall Survival (y)
7
8
9
10
Long-Term Complications of Hodgkin
Lymphoma Treatment
• Radiation therapy
– Hypothyroidism
– Breast cancer (young women)
– Early onset coronary artery disease
– Pulmonary fibrosis
– Lung cancer, sarcoma
• Chemotherapy
– Sterility (MOPP)
– Secondary AML (MOPP)
– Cardiomyopathy (ABVD)
– Pulmonary fibrosis (ABVD)