Question 1 (MKSAP Q4)

Board Review
Malignant a g a Hematology e a o ogy
Nitin Jain
Fellow Fellow, HemOnc
April 18, 18 2011

Question 1 (MKSAP Q4)
A 67-year-old man comes for a routine physical examination. The patient has
hypertension treated with hydrochlorothiazide. On examination, temperature
is normal normal, blood pressure is 140/85 mm Hg Hg, pulse rate is 88/min 88/min, and
respiration rate is 16/min. The patient has a ruddy complexion. There is no
jugular venous distention. Cardiopulmonary examination is normal. The
spleen tip is palpable just below the left costal margin.
Laboratory studies
Hematocrit 61% Leukocyte count 11.2 K
Platelet count 405 K Erythropoietin 10 mU/mL
Arterial oxygen saturation 96%
C Cytogenetic ( (correct is Molecular) ) studies show a JAK2 mutation
Which of the following is the most appropriate treatment?
A Therapeutic phlebotomy
A. Therapeutic phlebotomy
B. Therapeutic phlebotomy plus anagrelide
C. Therapeutic phlebotomy plus aspirin
D. Therapeutic phlebotomy plus hydroxyurea

Myeloproliferative neoplasms (MPN)
2008 WHO classification: MPD (Myeloproliferative disorder) renamed as MPN
Chronic myelogenous leukemia
Polycythemia vera
Essential thrombocythemia
Primary myelofibrosis
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia
Hypereosinophilic syndrome
Mast cell disease
MPNs, unclassifiable
.
Classic C ass c MPN

Polycythemia vera
Overproduction of erythrocytes (ONLY myeloproliferative disorder
with increased Hb)
WBC cells and platelets can also be increased
Signs and symptoms
Headache
Pruritus (especially with hot bath)
Erythromelalgia (burning pain in feet/hands with warmth and
erythema) y )
Thrombotic disorders most serious issue (TIA, MI ,Stroke, DVT)
Budd-Chiari syndrome: 50% have underlying PV
Diagnosis: Rule out secondary causes
Smoking, COPD, Sleep Apnea, morbid obesity, high altitude
Renal cell carcinoma, carcinoma Hepatocellualr carcinoma carcinoma, uterine fibroids

Osler (1903) PVSG (1967) WHO (2001) WHO (2008)
Erythrocytosis
Cyanosis
Splenomegaly


Major
A-criteria
Major criteria
TABLE # 4: Increased Diagnostic red criteria cell mass for polycythemia # Elevated vera over red different cell mass time or periods # Hb >18.5 (men) or
# Normal oxygen saturation Hb >18.5 (men) or >16.5 Hb >16.5 (women)
# Splenomegaly
(women)
# No cause of secondary # Presence of JAK2
Minor
erythrocytosis
mutation
# Platelet count > 400 K # Splenomegaly
# WBC > 12 K
# clonal genetic
Minor criteria
# LAP score
# Vitamin B12
abnormality
# Endogenous g erythroid y
colony formation
# Bone marrow biopsy
showing gp panmyelosis y with
erythroid, granulocytic
and megakaryocytic
Diagnosis: All 3 major or first B-criteria
proliferation
2 major and any 2 minor # Platelet count > 400 K # Low serum epo
# WBC > 12 K
# Endogenous erythroid
# Bone B marrow biopsy bi
showing panmyelosis with
colony l formation f ti i in vitro it
erythroid and
Diagnosis: Both major
megakaryocytic
criteria with 1 minor or
proliferation
first major with any 2
# Low serum erythropoietin minor criteria
Diagnosis: First 2 A-criteria
with either any other Acriteria
or 2 B-criteria

First described in 2005
~ 100% ofPV of PV
JAK2 mutation
50% ET (essential thrombocythemia)
50% PMF (primary myelofibrosis)
Presence of JAK2 mutation
establishes Dx of MPN
could be PV / ET / PMF
Negative JAK2
rules out PV
could be ET/PMF or anything else

PV treatment
Phlebotomy all patients
Goal Hct

Question 1 (MKSAP Q4)
A 67-year-old man comes for a routine physical examination. The patient has
hypertension treated with hydrochlorothiazide. On examination, temperature
is normal normal, blood pressure is 140/85 mm Hg Hg, pulse rate is 88/min 88/min, and
respiration rate is 16/min. The patient has a ruddy complexion. There is no
jugular venous distention. Cardiopulmonary examination is normal. The
spleen tip is palpable just below the left costal margin.
Laboratory studies
Hematocrit 61% Leukocyte count 11.2 K
Platelet count 405 K Erythropoietin 10 mU/mL
Arterial oxygen saturation 96%
C Cytogenetic ( (correct is Molecular) ) studies show a JAK2 mutation
Which of the following is the most appropriate treatment?
A Therapeutic phlebotomy
A. Therapeutic phlebotomy
B. Therapeutic phlebotomy plus anagrelide
C. Therapeutic phlebotomy plus aspirin
D. Therapeutic phlebotomy plus hydroxyurea

Question 2 (MKSAP Q32)
A 55-year-old man has a 1-year history of fatigue, daytime hypersomnolence,
and frequent nighttime awakenings. The patient has hypertension and a 48pack-year
smoking history. His only medication is lisinopril.
On physical examination, temperature is normal, blood pressure is 135/85 mm
Hg, pulse rate is 88/min, and respiration rate is 28/min. BMI is 35. Examination
is otherwise unremarkable.
Laboratory studies: Hematocrit 59%, WBC 5.7 K, Platelet count 345 K, Epo 30
mU/mL
Arterial oxygen saturation (on ambient air) 95%
Hematocrit measurements prior to 5 years ago were all normal
Cytogenetic (correct is Molecular) studies are negative for the JAK2 gene
mutation
Which of the following g is the most likely y cause of the patient’s elevated
hematocrit?
A. Relative polycythemia
B. High-oxygen–affinity hemoglobin
CC. PPolycythemia l th i vera
D. Secondary polycythemia
Needs pulse ox with exertion, sleep study

Question 3 (MKSAP Q18)
A 54-year-old man is evaluated for increased lethargy and vague abdominal
symptoms of 2 weeks weeks’ duration duration. His medical and family histories are
noncontributory. He does not smoke and takes no medications. Vitals stable.
Arterial oxygen saturation is 99% on ambient air. There is no clubbing or
evidence of cyanosis. y Cardiopulmonary y examination is normal. The abdomen
is soft, and there is no hepatosplenomegaly.
Lab studies: Hemoglobin 20.2 g/dL, Platelet count 312, WBC 8.2 k/µL
Erythropoietin 35 mU/mL
Which of the following is the most appropriate next diagnostic test?
A. Ultrasound of the abdomen
B. Echocardiogram
C. JAK2 mutation analysis
DD. Erythrocyte mass study

Question 4 (MKSAP Q21)
A 42-year-old woman who is scheduled to undergo a hysterectomy for
endometrial carcinoma comes for a preoperative evaluation. At the time of
her initial evaluation, , she was also discovered to have thrombocytosis. y In
addition to menorrhagia, the patient recently developed epistaxis and easy
bruising. Her only medications are an oral contraceptive agent and an iron
supplement.
EExamination i ti iis normal. l NNo petechiae, t hi ecchymoses, h or splenomegaly.
l l
Laboratory studies: Hemoglobin 11.3, WBC 4.6, platelet count 1,500 K
Platelet function studies: Abnormal platelet aggregation
Cytogenetic (correct is Molecular) studies reveal a JAK2 mutation
Bone marrow examination: Hypercellular marrow with increased
megakaryocytes in clusters.
Which of the following is the most appropriate treatment?
Anagrelide beginning 2 days preoperatively
Hydroxyurea beginning the night after surgery
Low-dose aspirin postoperatively
Platelet apheresis p ppreoperatively p y and hydroxyurea y y ppostoperatively p y

Essential thrombocythemia
2008 WHO criteria for diagnosis g
Sustained platelet count ≥ 450 K
Bone marrow biopsy showing proliferation of megakaryocytes
Not meeting criteria for others MPNs
Demonstration of JAK2 mutation or other clonal markers (no evidence
for reactive thrombocytosis)
Diagnosis of ET requires meeting all 4 criteria
Important to rule out secondary causes:
Iron deficiency deficiency, post post-op op state, state acute inflammatory states
DOES NOT increase thrombosis risk irrespective of degree of elevation

Essential thrombocythemia
Thrombosis main risk
Paradoxical bleeding when platelets >1 million
(some say >1.5 million)
Acquired vWF deficiency
Treatment:
ASA ffor all ll unless l bl bleeding di or platelets l l >1.5 1 5 M
Hydroxyurea vs. anagrelide
UUsed d if age >60 60 / previous i th thrombosis b i
Hydroxyurea preferred over anagrelide (NEJM 2006)
IInterferon t f for f pregnant t patients
ti t

Question 5 (MKSAP Q27)
A 77-year-old man has a 1-year history of increasing fatigue. He has not seen
a physician p y for at least 3 yyears. Medical and family y histories are
unremarkable, and he takes no medications.
Vitals stable. Cardiopulmonary examination is normal. The spleen is palpable
6 cm below the left costal margin.
Laboratory studies: Hemoglobin 77.6 6 g/dL g/dL, WBC 11 11.2 2 KK, Platelet 104 K
Haptoglobin Elevated, Direct Coombs Negative
A bone marrow aspiration p reveals a “dry y tap.” p
A peripheral blood smear and bone marrow
biopsy are shown
CCytogenetics: t ti NNegative ti Phil Philadelphia d l hi chromosome
h
Which of the following is the most likely diagnosis?
A. Aplastic anemia
B. Chronic myeloid leukemia
C. Myelofibrosis
D. Pure red cell aplasia

Normal megakaryocyte
Myelofibrosis
Normal megakaryocyte

Myelofibrosis
Clonal proliferation of abnormal stromal cells that release fibrosispromoting
p g cytokines y in the bone marrow.
Peripheral blood smear: classic leukoerythroblastic picture of
immature granulocytes, nucleated RBCs, dysmorphic
erythrocytes th t (tear-drop (t d cells) ll )
Prefibrotic stage: Leukocytosis, thrombocytosis
Fibrotic stage: pancytopenia
Splenomegaly and hepatomegaly
Bone marrow: Hypercellularity with dysmorphic megakaryocytes
and fibrosis
Main risk: transformation to AML
Median survival is 3 to 5 years

2008 WHO criteria for diagnosis of PMF

No real good treatment
Myelofibrosis
Conservative management: Epo, G-CSF, PRBC and
platelet p transfusion
Allogeneic stem cell transplant: only curative approach
50% JAK2 mutation positive
• Many y
JAK2 inhibitors in clinical trials

Blood counts in different MPNs
Hb WBC Plt JAK2
PV 100% patients
ET
50% patients
Normal
Pre-fibrotic Pre fibrotic
50% patients
myelofibrosis Normal
CML
Normal
JAK2 negative,
BCR-ABL
positive

Question 6 (MKSAP Q15)
A 78-year-old woman has a 3-month history of increasing fatigue. She has no
other medical problems and does not take any medications. Vitals normal. The
patient appears pale pale. Examination is unremarkable
unremarkable.
Laboratory studies:
Hemoglobin 7.8 g/dL, Leukocyte count 2.8, ANC 1.2, Platelet count 560
Erythropoietin 600 mU/mL
Bone marrow examination shows hypercellular marrow with erythroid hyperplasia
and dysplasia of the erythroid and granulocyte series. Megakaryocytes are
increased with many hypolobulated cells cells. Iron stores are normal normal. Cytogenetic
studies show deletion of the long arm of chromosome 5 [del(5q-)].
Which of the following is the most appropriate treatment?
AA. AAzacitidine itidi
B. Danazol
C. Lenalidomide
D. Granulocyte colony colony-stimulating stimulating factor and recombinant erythropoietin

5q- 5q MDS
Subtype of MDS with interstitial deletion of 5q
Classically seen in older women
Anemia and thromobocytosis: hallmark
Neutropenia less common
Better prognosis (median ssurvival r i al in one st study d 66.5 5 yrs rs
compared to 2 yrs for other chromosomal abnormalities)
Rx – lenalidomide (Revlimid) – 2 nd generation thalidomide

Question 7 (MKSAP Q28)
A 25-year-old man is evaluated for the recent onset of fever, fatigue, dyspnea, easy
bruising, and bleeding gums. On physical examination, temperature is 38.8 °C
(101 (101.8 8 °F) °F), BP is 105/60 mm Hg Hg, pulse 120/min 120/min, and RR is 24/min 24/min. Cervical and
axillary lymphadenopathy is noted. Cardiopulmonary examination is normal. The
liver edge and spleen tip are palpable. Laboratory studies: Hemoglobin 8.5 g/dL,
WBC 104 K, ANC 0.6, platelet 17 K, LDH 2200, Uric acid 11.5 mg/dL
CXR: mediastinal mass. Bone marrow: Hypercellular marrow that is replaced with
large blasts containing prominent nucleoli and abundant basophilic cytoplasm. The
blasts do not contain Auer rods. Sudan black and myeloperoxidase y p stains are
negative; periodic acid-Schiff stain is positive. Blasts are also positive for terminal
deoxynucleotidyl transferase (TdT). Immunophenotyping shows CD2, CD3, CD7,
and CD38. BCR/ABL translocation is absent.
Which of the following is the most likely diagnosis?
A. Acute lymphoblastic leukemia
B. Acute myeloid leukemia
CC. Chronic lymphocytic leukemia
D. Hodgkin lymphoma

Acute lymphoblastic leukemia (ALL)
Proliferation of immature lymphoblasts
Constitutes 20% of acute leukemias in adults
Present with lymphocytosis, y p y , neutropenia, p , anemia, , and
thrombocytopenia
Lymphadenopathy and hepatosplenomegaly common
Central nervous system involvement seen (need for LP)
Bone marrow: increased lymphoblasts (Flow cytometry
important)

Treatment
Acute lymphoblastic leukemia (ALL)
Induction: prednisone, vincristine, anthracyclines,
L-asparaginase, 6-mercaptopurine, and high-
dose cytarabine
Consolidation: Variety of drugs similar to Induction
Maintenance: 6-mercaptopurine and methotrexate
Central nervous system prophylaxis: Intrathecal chemotherapy
Philadelphia chromosome positive ALL
Add imatinib/dasatinib to above chemo

Question 8 (MKSAP Q40)
A 57-year-old woman is brought to the emergency department because of
fever and shaking chills of 8 hours’ duration. The patient has a 1-year history
of myelodysplastic syndrome treated with azacitidine azacitidine. On physical
examination, temperature is 39.2 °C (102.6 °F), BP 100/70 mm Hg, pulse
110/min, and respiration rate is 20/min. Examination is unremarkable. There is
no rash, lymphadenopathy, costovertebral angle tenderness, abdominal
tenderness, or splenomegaly.
Laboratory studies: Hemoglobin 10.6 g/dL
WBC 33.6K, 33 6K Platelet 88
Chest radiograph is normal.
A peripheral blood smear is shown.
Wh What t is i the th likely lik l di diagnosis? i ?
A. Acute lymphoblastic leukemia
B. Acute myeloid leukemia
C. Acute promyelocytic leukemia
D. Chronic myeloid leukemia

Acute myelogenous leukemia
Proliferation of immature myeloblasts
By definition: ≥ 20% blasts in bone marrow
Auer rods clinches the Dx
NOTE NOTE:

Treatment of AML
Acute myelogenous leukemia
Induction: Classically 7+3
7 days of cytarabine and 3 days of idarubicin
At UofC: High dose cytarabine+ Mitoxantrone
Consolidation: high dose cytarabine or many other
regimens i
Unlike ALL, maintenance treatment is not standard
(though many trials underway)

Question 9 (MKSAP Q34)
An asymptomatic 35-year-old man comes for a routine annual examination.
Medical and family y histories are unremarkable. Vitals and pphysical y examination
normal.
Laboratory studies: Hemoglobin 9.1 g/dL, WBC 2.1, Platelet count 135
LDH 890 U/L U/L, Uric acid 11 11.6 6 mg/dL
Peripheral blood smear: Circulating blasts and promyelocytes
Bone marrow: Hypercellular marrow with 80% myeloblasts and promyelocytes.
Cytogenetic y g studies reveal translocation of chromosomes 15 and 17 [ [t(15;17)]. ( ; )]
In addition to hydration and allopurinol, which of the following is the most
appropriate management at this time?
AA. BBroad-spectrum d t antibiotics tibi ti
B. Chemotherapy
C. Chemotherapy plus all-trans-retinoic acid
DD. HLA typing

Acute promyelocytic leukemia
AML M3 by FAB
Increased number of myeloblasts and promyelocytes
Presence of t(15;17) leading to PML/RARα fusion gene
Besides pancytopenia, DIC main feature (watch bleeding, DIC
panel)
Treatment: all-trans-retinoic acid (ATRA) ( )
Arsenic trioxide
Standard chemotherapy
Some protocols use only ATRA and arsenic (no chemotherapy at all)
ATRA syndrome (Differentiation syndrome)
develops while on ATRA or arsenic
DDyspnea, spnea pulmonary p lmonar infiltrates, infiltrates fe fever er
Stop drug, start steroids

Question 10 (MKSAP Q8)
A 58-year-old man is evaluated for increasing fatigue of 2 months’
duration duration. Vitals stable stable. There is no lymphadenopathy lymphadenopathy. The spleen is
palpable 4 cm below the left costal margin.
Laboratory studies: Hemoglobin 12.1 g/dL, WBC 55.2 K, Platelet 105 K
A peripheral blood smear shows an increased number of granulocytic cells
in all phases of development but no Auer rods in the blasts.
Bone marrow examination shows hypercellular marrow (80% cellularity)
with marked granulocytic hyperplasia, a left shift in the granulocytes, and
3% myeloblasts myeloblasts. Cytogenetic testing reveals a BCR/ABL translocation
translocation.
Which of the following is the most appropriate next step in managing this
patient?
A. Administration of imatinib
B. HLA typing of the patient and his sister
C. Leukapheresis
DD. Observation with monthly follow-up follow up office visits

Chronic myelogenous leukemia
Characterized by translocation 9;22
Leads to juxtaposition of BCR on chr 22 to ABL on chr 9
(BCR-ABL)
RRx – tyrosine i ki kinase iinhibitors hibi
• First line: Imatinib
First line: Imatinib
• Second line: Dasatinib, Nilotinib

Question 11 (MKSAP Q91)
A 75-year-old woman with chronic lymphocytic leukemia who was previously
asymptomatic on no therapy undergoes follow-up evaluation for community-acquired
pneumonia for which she was hospitalized hospitalized. The patient completed a course of antibiotic
therapy and currently feels well. She reports no fevers, chills, night sweats, weight loss,
abdominal pain, or new lymphadenopathy, and her pulmonary symptoms have resolved.
Medical history is significant for a previous episode of pneumonia for which she was
hospitalized within the past year year.
Exam is normal other than splenomegaly
Laboratory studies: Hemoglobin 11 g/dL, WBC 24 K, with 80% mature-appearing
lymphocytes, y p y , Platelet count 120 K
IgG: 500 mg/dL
Which of the following is the most appropriate next step in management?
A. Intravenous immune globulin
B. Prophylactic trimethoprim-sulfamethoxazole
CC. Splenectomy
D. Repeat blood counts in 1 month

Question 12 (MKSAP Q49 CVS)
A 31-year-old woman is evaluated for painless, bilateral lower extremity edema of 4
weeks’ duration. She denies chest pain, dyspnea, orthopnea, and paroxysmal
nocturnal dyspnea dyspnea. She has hypertension hypertension, which has been treated for 2 years with
hydrochlorothiazide. At age 5 years, she had acute lymphoblastic leukemia, which was
treated with vincristine, doxorubicin, and dexamethasone. She is currently on no
medications other than hydrochlorothiazide.
Her blood pressure p is 138/92 mm Hg, g ppulse is 90/min, and respiration p rate is 18/min.
Her BMI is 27. Her estimated central venous pressure is 10 cm H2O. Cardiac
examination reveals a nondisplaced apical impulse, normal heart sounds, and no
murmurs or extracardiac sounds. Pulmonary examination is normal. There is bilateral
lower extremity edema to the knees. Laboratory results include normal levels of
sodium, potassium, p blood urea nitrogen, g and creatinine. Urinalysis y is normal and there
is no evidence of proteinuria.
Electrocardiogram demonstrates sinus rhythm (88/min) and left bundle branch block.
Which of the following is the most appropriate management for this patient?
Which of the following is the most appropriate management for this patient?
A. Adenosine nuclear perfusion imaging study
B. Bilateral lower extremity venous duplex ultrasound
C. Change hydrochlorothiazide to furosemide
D. Transthoracic echocardiography

Hyperleukocytosis and leukostasis
Hyperleukocytosis: Total leukemic cell count > 50K or
100K.
• Seen in AML, ALL, CML, CLL
Leukostasis: seen only in AML
• Need myeloid blasts to clog the arteries
Patient with CLL with WBC count 150K
• no concern for leukostasis
• llymphocytes h t are small ll and d easily il pass th through h th the
blood vessels

Thank you!
And
All the Best