Myeloproliferative Diseases 2020

Myeloproliferative Diseases
February 14, 2020

Case Presentation
• 59-year-old African American woman
• 6 months fatigue, increased abdominal
girth, and a 25 lb weight loss despite a good
appetite over the preceding year.
• Physical examination a palpable spleen tip.
• A complete blood cell count (CBC) white
blood cell count- 57.8 k/ul, hemoglobin
(Hgb)- 11.8 g/dl, hematocrit (Hct)- 36.1%,
MCV 91 fl
platelets- 400k/ul.
• Chemistry - lactate dehydrogenase (LDH)-
397 U/L, and U.A.- 5.3 mg/dl.
Figure 2. CML
Maslak, P. ASH Image Bank 2001;2001:100202

Peripheral smear detected predominantly neutrophils and bands, myelocytes, metamyelocytes,
and rare basophils. The differential revealed 50% neutrophils, 21% band forms, 11% myelocytes,
7% metamyelocytes, 1% blasts, 6% lymphocytes, 1% basophils, and 3% eosinophils
Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

Figure 1. Low power view reveals increased mature myeloid elements as well as
hypolobulated megakaryocytes

Figure 5. CML

The bone marrow aspirate and biopsy revealed a hypercellular bone marrow with an
increased M:E ratio. Maturation was preserved in the myeloid series although there was
a left shift.
Figure 6. CML

Figure 10. CML

Figure 1. A pair of pseudo-Gaucher cells are seen in this bone marrow aspirate from a patient
with CML

Chronic Myelogenous
Leukemia
Figure 14. CML

Figure 16.24a The Biology of Cancer (© Garland Science 2007)
Blood, Vol 92, No 10
(November 15),
1998: pp 3780-3792
Curr Hematol Malig Rep. 2012 Jun; 7(2): 125–132.
Published online 2012 Mar 31. doi: 10.1007/s11899-012-0121-6
Signaling pathways impacted by BCR-ABL expression.
Brian J. Druker Blood 2008;112:4808-4817
©2008 by American Society of Hematology

Historical Perspective on CML
Presented By Brian Druker at 2017 ASCO Annual Meeting

Tyrosine Phosphorylation
www.univ-angers.fr
BCR-ABL As a Therapeutic Target for CML

The inspiration for targeting bcr abl came
from
• A) the development of bone marrow transplantation as a treatment
for CML
• B) sequencing of the Abelson gene
• C) treatments for herpetic infections
• D) treatments for HIV
Kinases are Not a Viable Target

How Can BCR-ABL be Targeted?

Figure 16.10b The Biology of Cancer (© Garland Science 2007)
BCR-ABL As a Therapeutic Target for CML

Overall Survival
Druker NEJM 2006;355:2408

IRIS: Significantly Higher Rates of Complete Hematologic Response With Imatinib
Mesylate According to Kaplan-Meier Analysis
100 96% 97%

93%
87%
90
80 P<0.001
70
% responding
60 69%
67%
50
58%
40
30 38%
20 Imatinib mesylate
10 IFN- + ara-C
0
0 3 6 9 12 15 18 21 24
Months since randomization
Larson R, on behalf of the IRIS study group. Blood. 2002;100:4a. Abstract 2.
Survival According to Molecular Response

Imatinib is also effective in patients whose
tumors harbor
• A) EGFR mutations
• B) c kit mutations
• C) PDGFR mutations
• D) p53 mutations
Tyrosine kinase inhibitors
• Imatinib
• Dasatinib,
• nilotinib,
• bosutinib, and
• ponatinib (T315I)
The CP CML patients’ journey through TKI therapy for 5 years.
Tessa L. Holyoake, and David Vetrie Blood 2017;129:1595-

1606

Match a TKI with a side effect
TKI Side effect

• Imatinib • Renal decreased GFR, phosphate
• Dasatinib • Pleural effusions
• Nilotinib • Pancreatitis
• Bosutinib • GI symptoms
• Ponatinib • Arterial events
TKI Side Effects
• Specific side effects for different TKI.
• Nilotinib has very little incidence of fluid retention and has the least
hematologic toxicity compared to the other agents, but it has more rash,
headache, pancreatitis, and cardiovascular effects than imatinib.
• Dasatinib has less peripheral edema but more GI toxicity and pleural
effusions than imatinib.
• Bosutinib has had more diarrhea, vomiting and abdominal pain but less
edema and bone and muscle pain.
• Ponatinib had more rash, abdominal pain, headache, and pancreatitis but
less reported nausea, muscle pain, and diarrhea than imatinib.
Cardiovascular toxicity – arterial events
Caldemeyer L, Dugan M, Edwards J, Akard L. Long-Term Side Effects of
Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia. Curr Hematol Malig
Rep. 2016 Apr;11(2):71-9. doi: 10.1007/s11899-016-0309-2
Figure 16.10b The Biology of Cancer (© Garland Science 2007)
Figure 16.28 The Biology of Cancer (© Garland Science 2007)
Stem cell transplantation
• Graft versus leukemia effect important in CML
• Donor lymphocyte infusions
Polycythemia vera
• 65 yo man with a red face, left arm
weakness
CBC WBC 12,500/ul
Hgb 21 g/dl (14-17)
Plt 455,000/ul
Vignette
A 47-year-old dentist presented with a routine blood test
showing hemoglobin (Hb) 23.3 g/dL; hematocrit (Hct),
68.9%; mean corpuscular volume, 81 fL; leukocytes, 4300/ul
; platelets, 145,000 /uL; hyperuricemia, and subnormal
ferritin levels.
He said he felt “perfectly well,” “I am working 10 hours a
day,” but acknowledged occasional scotoma and tinnitus in
the last weeks
Physical examination was unremarkable except for mild
hypertension
Which ONE of the following would you recommend
A) Initiate hydroxyurea
B) Order sleep study
C) Perform bone marrow biopsy
D) Perform phlebotomy
Blood. 2014;124(22): 3212-3220
Vignette
A 65 yo man is referred for hemoglobin of 17.5 g/dl. There
is a 2 year history of daytime somnolence and loud snoring.
The patient has hypertension for which he takes lisinopril
and atenolol.
On examination, blood pressure is 170/98 mm Hg,
respiration 18/min, oxygen saturation 95%. BMI is 44. The
patient’s face is erythematous and his neck is thick. There is
no splenomegaly or adenopathy.
Lab studies hemoglobin 17.5 g/dl, leukocyte count 5000/ul,
platelet count 225,000/ul, erythropoietin 35 mU/ml.
Which ONE of the following is the most appropriate
management?
A) Initiate hydroxyurea
B) Order sleep study
C) Perform bone marrow biopsy
D) Perform phlebotomy
MKSAP 16 25
Vignette
A 35 yo woman is seen in the ED for a 2 week history of abdominal
pain, increased abdominal girth, and peripheral edema.
On exam, temperature is normal, blood pressure is 120/65 mm Hg,
pulse rate is 55/min, and respiration rate is 22/min. marked scleral and
mucosal icterus is present. She has hepatomegaly and ascites, and 3+
pitting edema of the lower extremities
MKSAP 16 48
Vignette (continued)
Laboratory studies
Hematocrit 37%
Hemoglobin 12.5 g/dl
Leukocyte count 10,000/ul
MCV 72 fl
Platelet count 1,095,000/ul
Albumin 1.5 g/dl
Total bilirubin 6.0 mg/dl
Alkaline phosphatase 300 units/L
ALT 550 U/L
AST 600 U/L
Urinalysis normal
Doppler ultrasound of the abdomen shows occlusion of the hepatic veins
MSKAP 16 48
Which ONE of the following is the most appropriate next step in the
evaluation of this patient
A) Antiphospholipid antibody assay
B) Antithrombin activity assay
C) Flow cytometry for paroxysmal nocturnal hemoglobinuria
D) JAK2 V617F mutational analysis
E) Protein C activity assay
MKSAP 16 48
Figure 2.8c The Biology of Cancer (© Garland Science 2007)
A simplified flowchart for a diagnostic approach to PV for the investigation of erythrocytosis.
Alessandro M. Vannucchi Blood 2014;124:3212-3220

Question
• What is the JAK mutation?
Figure 4.14 The Biology of Cancer (© Garland Science 2007)
JAK2 mutation
NEJM
Figure 2. A proposed structure of JAK2
Kaushansky, K. Blood 2005;105:4187-4190

Disorders Associated with Mutations of JAKs and STATs.
O'Shea JJ et al. N Engl J Med 2013;368:161-170.

The prothrombotic effect of an elevated HCT in ET and PV patients.
Tiziano Barbui et al. Blood 2013;122:2176-2184

Pathogenesis of thrombophilia in MPN. The pathogenesis of the acquired thrombophilic state
in ET and PV is multifaceted.

Essential Thrombocythemia
73 yo man with ecchymoses
CBC WBC10,000/ul
Hgb 15.4 g/dl
Plt 1,400,000/ul
Figure 1. Platelet clumps are noted in the peripheral blood smear of this patient with essential
thrombocythemia

Figure 1. Giant platelet circulating in the peripheral blood of a patient with a
myeloproliferative disorder

Figure 3. A clustering of megakaryocytes is often noted in essential thrombocythemia

Vignette
A 34 yo man is evaluated for a 3 month history of fatigue, early satiety, and
10 kg (22 pound) weight loss.
Physical exam shows pulse rate of 114/min, an a spleen palpable 10 cm
below the costal margin. There is no adenopathy. Lab studies show Hgb 8.4
g/dl, leukocyte 314,000/ul, and Plt 622,000/ul.
Which of the following is the most likely genetic mutation to explain this
patient’s findings?
A) BCR ABL
B) IGH/CD1
C) JAK2 V617F
D) PML-RAR
MKSAP 17 50
Vignette
• A 67 yo man is evaluated after an incidental diagnosis of essential
thrombocythemia is made. Physical exam is unremarkable. Lab
studies show Hgb of 15 g/dl, leukocyte 5000/ul, platelet count
770,000/ul. Which of the following is the most appropriate treatment
a) Anagrelide and low dose aspirin
b) Hydroxyurea and low dose aspirin
c) Ruxolitinib
d) Warfarin
e) Observation
MKSAP 17 26
A 42 year old previously healthy mailman
presents with progressively worsening redness and
intense burning pain of the feet and hands. On exam,
a palpable spleen tip is present, as are erythematous
toes and fingers, mottling of the skin on the feet, and
normal arterial pulses.
Laboratory studies:
Hemoglobin 16.0 g/dL Hct 48%
Red cell mass study Normal
Leukocyte count 10,500/ul
Leuk Alk Phosphatase Normal
Platelets 842,000/ul
Platelet aggregation Absent response to epinephrine
Serum K 7.5 mEq/L
Peripheral smear Occasional megathrombocytes
What is the most appropriate immediate
treatment for this patient?
A) Kayexalate enemas
B) Acetylsalicylic acid, 600 mg
C) Heparin bolus, followed by continuous
infusion
D) Platelet pheresis
E) Hydroxyurea
from MKSAP Subspecialty Hematology
A 32 year old man is referred to you with a platelet
count of 1.2 million/ul. He had been well until 2 weeks earlier
when he was in a motor vehicle accident and sustained neck
trauma. He then required cervical surgery and required
transfusions of packed red blood cells intraoperatively and
postoperatively. His recovery has been unremarkable except
that his platelet count has been steadily rising and today you
are asked to see the patient. He is asymptomatic, and
physical exam shows no splenomegaly.
Which ONE of the following approaches would you
recommend?
A) Hydroxyurea and aspirin
B) Plateletpheresis
C) Allogeneic bone marrow transplantation
D) Splenectomy
E) Observation
Figure 1. Platelet clumps are noted in the peripheral blood smear of this patient with essential
thrombocythemia

Figure 3. A clustering of megakaryocytes is often noted in essential thrombocythemia

An approach to the differential diagnosis of thrombocytosis.
Elisa Rumi, and Mario Cazzola Blood 2016;128:2403-2414

Question
Patients with platelet counts greater than 1.5 million/ul are at
increased risk of
a) Bleeding
b) Clotting
c) Both
d) Neither
Flow chart of the recommended treatment for patients with PV.

Flow chart of the recommended treatment for patients with ET.

Essential Thrombocythemia
Clinical Features:
•Hemorrhagic or thrombotic phenomena in 80% patients
•May occur in young patients with more benign course
•Five year survival 80%
Laboratory diagnosis:
•Platelet count greater than 750,000/ul
•Splenomegaly
•Bone marrow displays megakaryocytic hyperplasia
Treatment
•Plateletpheresis, hydroxyurea, observation, anagrelide
Question
• What is the CALR mutation?
Role of cytokine receptors in the oncogenic properties of JAK2V617F and CALR mutants.
William Vainchenker, and Robert Kralovics Blood

2017;129:667-679

The CALR mutants bind and activate MPL. (A) WT CALR binds to MPL in the ER by
interaction of its lectin domain with MPL N-glycosylation, controls the quality of the proteins,
and then comes away from the receptor, which traffics to the cell surface mainly b...
William Vainchenker, and Robert Kralovics Blood

2017;129:667-679
Clinical presentation in chronic phase and relationship to phenotypic driver mutation.
Jyoti Nangalia, and Anthony R. Green Blood

2017;130:2475-2483

Myelofibrosis
79 yo man
20 years agodiagnosis of P vera
phlebotomy
3 years ago stopped phlebotomy
6 months ago onset splenomegaly
Vignette
A 62 yo man presents with 8 months of fatigue. Physical exam shows a
spleen palpable 3 finger breadths below the left costal margin.
Laboratory studies indicate hemoglobin of 12.5 g/dl, leukocyte
14,400/ul, platelets 148,000/ul.
Peripheral blood smear shows teardrop cells, a nucleated red cell,
metamyelocyte, and giant platelets.
MKSAP 16 1
Bone marrow is not aspirable and the biopsy shows a hypercellular marrow
with extensive fibrosis and abnormal appearing megakaryocytes.
Cytogenetics are normal. JAK2 assay is positive, and FISH for t(9;22) is
negative.
Which of the following is the most appropriate management of this patient
now?
a) Allogeneic hematopoietic stem cell transplantation
b) Danazol
c) Hydroxyurea
d) Imatinib
e) Observation
MKSAP 16 1
Distinctive Clinical Features
• Splenomegaly
• Leukoerythroblastic peripheral blood smear
• Extramedullary hematopoiesis
• Fibrosis
• Anemia
• Cachexia
Splenomegaly
Splenomegaly
Photomicrograph showing reticulin (silver) stain in a specimen from a patient with
myelofibrosis.
Abdallah Abou Zahr et al. Haematologica 2016;101:660-671
©2016 by Ferrata Storti Foundation

Representative bone marrow biopsies from patients with MPNs. (A) ET: Normocellular
marrow, proliferation of giant megakaryocytes with hyperlobulated nuclei, scattered or in
loose clusters (hematoxylin and eosin [H&E], original magnification ×40).

Original Article
JAK Inhibition with Ruxolitinib versus Best
Available Therapy for Myelofibrosis
Claire Harrison, D.M., Jean-Jacques Kiladjian, M.D., Ph.D., Haifa Kathrin Al-Ali, M.D.,
Heinz Gisslinger, M.D., Roger Waltzman, M.D., M.B.A., Viktoriya Stalbovskaya, Ph.D.,
Mari McQuitty, R.N., M.P.H., Deborah S. Hunter, Ph.D., Richard Levy, M.D., Laurent
Knoops, M.D., Ph.D., Francisco Cervantes, M.D., Ph.D., Alessandro M.
Vannucchi, M.D., Tiziano Barbui, M.D., and Giovanni Barosi, M.D.
N Engl J Med
Volume 366(9):787-798
March 1, 2012
Changes in Spleen Volume and Spleen Length, According to Treatment Group.
Harrison C et al. N Engl J Med 2012;366:787-798

Changes in Quality-of-Life and Symptom-Assessment Scores, According to Treatment Group.
Harrison C et al. N Engl J Med

2012;366:787-798
Kaplan-Meier analysis of survival of PMF patients stratified according to their driver mutation
or a clinical-molecular prognostic model that includes IPSS variables and driver mutation.

Systemic Mastocytosis
• Basophils in the blood are mast cells in tissue
• Increased number of mast cells in skin, bone, liver, spleen, and other
organs
• Rare disease
• Some patients (30%) have a kit mutation (D816V)
• A proportion of patients (50%) will respond to a trial of imatinib
Figure 1. Basophil with characteristic purple granules circulating in the peripheral blood from
this patient with a chronic myeloproliferative disorder (unclassifiable)

Eosinophilic Syndrome
• Patients with a proliferation of eosinophils
• Some of these patients have a mutation of the platelet derived
growth factor alpha or beta receptor gene, fused with another gene.
• The tyrosine kinase in these patients is sensitive to imatinib.
Figure 4. Etiology of this disorder is unknown

Figure 1. The bone marrow is hypercellular

Conventional and molecular risk factors for patients with MPNs. Information is from studies
discussed in the “Risk stratification” section.

Blast Crisis of MPD
55 yo man
15 years diagnosis of p vera
1 year onset of splenomegaly,
increasing WBC
2nd opinion WBC 41.3
4 days 70.9
8 days 122.6
Figure 4. Immature myeloid cells circulating in the peripheral blood

Current concept regarding clonal origination and evolution in BCR-ABL1–negative
myeloproliferative neoplasms: polycythemia vera (PV), essential thrombocythemia (ET), and
primary myelofibrosis (PMF).
Tefferi A , and Vainchenker W JCO 2011;29:573-582
©2011 by American Society of Clinical Oncology

Thrombosis and Chronic MPD
• Budd Chiari syndrome
• Splanchnic vein thrombosis
• Myocardial infarction
Pathogenesis of thrombophilia in MPN. The pathogenesis of the acquired thrombophilic state
in ET and PV is multifaceted.

Natural history of chronic myeloproliferative
leukemias
• Can progress to myelofibrosis
• Can progress to acute myeloid leukemia
Key steps during MPN development from normal hematopoiesis following acquisition of an
MPN-initiating mutation in a single HSC. The mutant HSC acquires a selective advantage over
normal HSC and also promotes myeloid differentiation, eventually leading to a ...
Adam J. Mead, and Ann Mullally Blood 2017;129:1607-1616

The leukemic stem cell
model
Cell Death Differ. 2015 Feb;22(2):187-98.

Role of megakaryocytes in the pathophysiology of myeloproliferative neoplasms, and
patterns of clonal evolution and phenotypic switch in these disorders.
Mario Cazzola, and Robert Kralovics Blood 2014;123:3714-

3719

The 2008 WHO classification system for myeloid neoplasms: acute myeloid leukemia (AML),
myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN, and MPN
eosinophilia (eos), platelet-derived growth factor receptor (PDGFR), or fibroblast ...
Tefferi A , and Vainchenker W JCO 2011;29:573-582
©2011 by American Society of Clinical Oncology

Key somatic mutations and growth factor receptors important for MPN development.
Adam J. Mead, and Ann Mullally Blood 2017;129:1607-1616

Role of BM blood vessels in myeloid malignancies.
Claudia Korn, and Simón Méndez-Ferrer Blood

2017;129:811-822

JAK2 or CALR mutation status defines subtypes of
essential thrombocythemia with substantially
different clinical course and outcomes
by Elisa Rumi, Daniela Pietra, Virginia Ferretti, Thorsten Klampfl, Ashot S.
Harutyunyan, Jelena D. Milosevic, Nicole C. C. Them, Tiina Berg, Chiara Elena, Ilaria
C. Casetti, Chiara Milanesi, Emanuela Sant’Antonio, Marta Bellini, Elena Fugazza,
Maria C. Renna, Emanuela Boveri, Cesare Astori, Cristiana Pascutto, Robert
Kralovics, and Mario Cazzola
Blood
Volume 123(10):1544-1551
March 6, 2014

A fundamental limitation for imatinib and
other TKI in treating CML is:
• A) the cost of the medications
• B) the side effects of the medications
• C) the taste of the medications
• D) these medications are not effective on CML stem cells
EBMT Allo-HSCT Risk Score
• Donor type
• HLA id sib 0 • Time interval between diagnosis &
• MUD 1 transplant
• Stage of disease • < 12 mos 0
• CP 0 • > 12 mos 1
• AP 1
• BC 2
• Age EBMT TRM OS
• <20 0 score
• 20-40 1 0-1 20% 75%
• >40 2
2 25% 70%
• Donor-recipient gender combination
• Other 0 3 37% 50%
• Female to male 1
4 45% 40%
5-7 70% 25%

Myeloproliferative Diseases 2020

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Myeloproliferative Diseases

February 14, 2020

Maslak, P. ASH Image Bank 2001;2001:100202

Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2004;2004:100990

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2001;2001:100202

Maslak, P. ASH Image Bank 2001;2001:100202

Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2001;2001:100202

Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2002;2002:100469

Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2001;2001:100202

Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

Brian J. Druker Blood 2008;112:4808-4817

©2008 by American Society of Hematology

Presented By Brian Druker at 2017 ASCO Annual Meeting

Presented By Brian Druker at 2017 ASCO Annual Meeting

Presented By Brian Druker at 2017 ASCO Annual Meeting

Presented By Brian Druker at 2017 ASCO Annual Meeting

Presented By Brian Druker at 2017 ASCO Annual Meeting

Druker NEJM 2006;355:2408

100 96% 97%

Presented By Brian Druker at 2017 ASCO Annual Meeting

Tessa L. Holyoake, and David Vetrie Blood 2017;129:1595-

©2017 by American Society of Hematology

TKI Side effect

Doppler ultrasound of the abdomen shows occlusion of the hepatic veins

Alessandro M. Vannucchi Blood 2014;124:3212-3220

Kaushansky, K. Blood 2005;105:4187-4190

Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

O'Shea JJ et al. N Engl J Med 2013;368:161-170.

Tiziano Barbui et al. Blood 2013;122:2176-2184

©2013 by American Society of Hematology

Tiziano Barbui et al. Blood 2013;122:2176-2184

©2013 by American Society of Hematology

Maslak, P. ASH Image Bank 2004;2004:101118

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2003;2003:100727

Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2003;2003:100634

Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2004;2004:101118

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2003;2003:100634

Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.

Elisa Rumi, and Mario Cazzola Blood 2016;128:2403-2414

©2016 by American Society of Hematology

Tiziano Barbui et al. Blood 2013;122:2176-2184

©2013 by American Society of Hematology

Tiziano Barbui et al. Blood 2013;122:2176-2184

©2013 by American Society of Hematology

William Vainchenker, and Robert Kralovics Blood

©2017 by American Society of Hematology

William Vainchenker, and Robert Kralovics Blood

Jyoti Nangalia, and Anthony R. Green Blood

©2017 by American Society of Hematology

Abdallah Abou Zahr et al. Haematologica 2016;101:660-671

©2016 by Ferrata Storti Foundation

Elisa Rumi, and Mario Cazzola Blood 2017;129:680-692

Harrison C et al. N Engl J Med 2012;366:787-798

Harrison C et al. N Engl J Med

Elisa Rumi, and Mario Cazzola Blood 2017;129:680-692