Myeloprleftative disorders slides6953685.ppt

Medical slides

1. Dr.Mahmoodzadeh
Hemathologist-Oncologist

2. The Chronic Myeloproliferative Disorders

3. MYELOPROLIFERATIVE NEOPLASMS
•Chronic myeloid leukemia, BCR-ABL1-positive
•Chronic neutrophilic leukemia
•Polycythemia vera
•Essential thrombocytosis
•Primary myelofibrosis
•Chronic eosinophilic leukemia, not otherwise specified
•Mastocytosis
•Myeloproliferative neoplasms, unclassifiable
The Revised WHO Classification of the
Chronic MPDs

4. •These 3 disorders share in common mutations in
the JAK2and MPLgenes
•There is an inherent (germline) patient proclivity
to JAK2and MPLmutations
•Constitutive signal transduction in these disorders
occurs through normalsignaling pathways
•Phenotypic mimicry and clinical overlap occur
between these 3 disorders but not between them
and the other MPNs
•Targeted therapy has been developed for PV, ET,
and PMF
Rationale for Classifying PV, ET, and PMF
Separately From the Myeloproliferative
Neoplasms

5. The Phenotypic Mimicry of the Chronic
Myeloproliferative Disorders
“All pathways lead to polycythemia vera”
Essential
Thrombocytosis
Primary
Myelofibrosis
Polycythemia
Vera
Acute
Leukemia
“Isolated
Thrombocytosis”

6. .
Cytokine Receptors Utilizing Janus Family Kinases

7. Pluripotent
Hematopoietic
Stem Cell
T Lymphocytes
Common
Hematopoietic
Stem Cell
B Lymphocytes
Granulocyte-Monocyte
Progenitors
Erythroid Progenitors
Megakaryocytic
Progenitors
JAK2V617F
Polycythemia vera is the ultimate
consequence of the JAK2V617F mutation
Hematopoietic Stem Cell Hierarchy

8. PV PMF ET
JAK2V617F
+
92% 42% 45%
JAK2V617F
–
8%* 58% 55%
*Some of these patients have JAK2exon 12
mutations
JAK2V617F Expression in the Chronic
Myeloproliferative Disorders

9. PV ET PMF
Age - Older Older
HemoglobinHigher (+/+)Higher
Fewer
transfusions
Leukocyte
count
- Higher Higher
Thrombosis -
More
(venous)
Pruritus More (+/+) - +
TransformationFibrosis (+/+)PV -
Survival - - Longer(?)
Effect of JAK2V617F Expression on Clinical
Phenotype

10. JAK2V617F Is Not the Initiating
Mutation in the 3 MPDs
Hematopoietic stem cells do not require JAK2for their
survival or proliferation
JAK2V617F is not present in some patients with familial
polycythemia vera
JAK2V617F can arise as a secondary event in clones
expressing a cytogenetic abnormality or another mutation
Leukemic transformation in patients with JAK2V617F-
positive MPD can occur in a JAK2V617F-negative type cell
BUT: JAK2 is the major final common signaling pathway
in all chronic MPDs and, therefore, whether mutated or
not, is an appropriate therapeutic target

11. •Polycythemia vera is a chronic
myeloproliferative disorder in which there
is overproduction of morphologically
normal red blood cells, white blood cells,
and platelets in the absence of a definable
stimulus
•Erythrocytosis is the feature that
distinguishes polycythemia vera from the
other 2 chronic myeloproliferative
disorders
•There is currently no specific clonal
diagnostic marker for polycythemia vera
Polycythemia Vera

12. Causes of Absolute
Erythrocytosis
Hypoxia
Carbon monoxide intoxication (tobacco
abuse, environmental)
High-affinity hemoglobins
High altitude
Pulmonary disease
Right-to-left shunts
Sleep apnea syndrome
Neurologic disease
Renal
Disease
Renal artery stenosis
Focal sclerosing or membranous
glomerulonephritis
Renal transplantation
Tumors
Hypernephroma
Hepatoma
Cerebellar hemangioblastoma
Uterine fibromyoma
Adrenal tumors
Meningioma
Pheochromocytoma
Drugs
Androgenic steroids
Recombinant erythropoietin
Familial(with normal hemoglobin function; Chuvash;
EPO receptor mutations;2,3 BPG deficiency)
Polycythemia vera
JAK2V617F
JAK2exon 12 mutations
Causes of Relative
Erythrocytosis
Loss of Fluid
From the
Vascular
Space
Emesis
Diarrhea
Diuretics
Sweating
Polyuria
Hypodipsia
Hypoalbuminemia
Capillary leak syndromes,
burns
Peritonitis
Chronic
Plasma
Volume
Contraction
Hypoxia from any cause
Androgen therapy
Recombinant erythropoietin therapy
Hypertension
Tobacco use
Pheochromocytoma
Ethanol abuse
Sleep apnea
Only ~5 % of patients with
absolute erythrocytosis are
likely to have polycythemia
vera

13. Major
criteria
1. Hemoglobin > 18.5 g/dL in men, 16.5 g/dL in women or other
evidence of increased red bloodcell volume*
2. Presence of JAK2617V > F or other functionally similar
mutation such as JAK2exon 12 mutation
Minor
criteria
1. Bone marrow biopsy showing hypercellularity for age with
trilineage growth (panmyelosis) with prominent erythroid,
granulocytic, and megakaryocytic proliferation
2. Serum erythropoietin level below the reference range for
normal
3. Endogenous erythroid colony formation in vitro
Diagnosis requires the presence of both major criteria and 1 minor criterion or the presence of the first
major criterion together with 2 minor criteria.
*Hemoglobin or hematocrit greater than 99th percentile of method-specific reference range for age,
sex, altitude of residence or hemoglobin greater than 17 g/dL in men, 15 g/dL in women if associated
with a documented and sustained increase of at least 2 g/dL from an individual’s baseline value that
cannot be attributed to correction of iron deficiency, or elevated red blood cell mass greater than 25%
above mean normal predicted value.
.
Proposed Revised WHO Criteria for
Polycythemia Vera

14. A1Raised red cell mass
A2Normal O2 sats and EPO
A3Palpable spleen
A4No BCR-ABL fusion
B1Thrombocytosis >400 x 109/L
B2Neutrophilia >10 x 109/L
B3Radiological splenomegaly
B4Endogenous erythroid colonies
A1+A2+either another A or two B
establishes PV

15. Red cell mass and
plasma volume
measurements
Elevated red cell mass
Tobacco use
Androgens
Diuretics
Pheochromocytoma
Hypoxic erythrocytosis
JAK2V617
F
Polycythemia
vera
–
Serum
erythropoietin level
Normal or low
Polycythemia vera
EPO-receptor mutation
Renal disease
Tumors
High-affinity hemoglobins
Elevated
Renal disease
Tumors
VHL mutation
High-affinity hemoglobins
Elevated hemoglobin or hematocrit
Both
normal
..
+
O
2
saturation
Normal red cell mass
Decreased plasma volume> 93% < 93%
Algorithm for the Diagnosis of Polycythemia
Vera

16. •Also known as essential thrombocythemia,
hemorrhagic thrombocytosis, idiopathic
thrombocytosis,or primary thrombocytosis
•Disorder of unknown etiology
•Principal clinical feature is the overproduction of
platelets in the absence of a definable cause
•No specific diagnostic marker
Essential Thrombocytosis

17. •Tissue inflammation
–Collagen vascular disease, inflammatory bowel disease
•Malignancy
•Infection
•Myeloproliferative disorders
–Polycythemia vera, primary myelofibrosis, essential thrombocytosis,
chronic myelogenous leukemia
•Myelodysplastic disorders
–5q-syndrome, idiopathic refractory sideroblastic anemia
•Postsplenectomy or hyposplenism
•Hemorrhage
•Iron deficiency anemia
•Surgery
•Rebound
–Correction of vitamin B12 or folate deficiency, post-ethanol abuse
•Hemolysis
•Familial
–Thrombopoietin overproduction, constitutive Mpl activation, K39N
Causes of Thrombocytosis

18. Platelet count >600 x 109/L for at least 2 months
Megakaryocytic hyperplasia on bone marrow
aspiration and biopsy
No cause for reactive thrombocytosis
Absence of the Philadelphia chromosome
Normal red blood cell (RBC) mass or a HCT <0.48
Presence of stainable iron in a bone marrow
aspiration
No evidence of myelofibrosis
No evidence of MDS

23. Diagnostic Criteria for Essential
Thrombocytosis
Persistent thrombocytosis more than 400 x 10
9
/L in the absence of a
reactive cause*
Absence of iron deficiency (normal serum ferritin for sex)
JAK2V617F assay (peripheral blood; expression establishes the
presence of an MPD but not its type; absence does not exclude an MPD)
Hemoglobin less than 16 g/dL in a man or less than 14 g/dL in a woman
(hematocrit < 47% in a man or < 44% in a woman) in the absence of
splenomegaly; otherwise, red blood cell mass and plasma volume
determinations are mandatory if a JAK2V617F assay is positive
Negative Bcr-Abl FISH (peripheral blood) if a JAK2V617F assay is
negative
If there is anemia, macrocytosis, or leukopenia, or evidence of
extramedullary hematopoiesis (ie, circulating nucleated erythrocytes,
immature myelocytes, or splenomegaly), a bone marrow examination
(including flow cytometry and cytogenetics) is mandatory regardless of
JAK2V617F expression status

24. Primary Myelofibrosis

25. Malignant
Acute leukemia (lymphocytic,
myelogenous,
megakaryocytic)
Chronic myelogenous
leukemia
Hairy cell leukemia
Hodgkin disease
Primary myelofibrosis
Lymphoma
Multiple myeloma
Myelodysplasia
Metastatic carcinoma
Polycythemia vera
Systemic mastocytosis
Causes of Myelofibrosis
Non-Malignant
HIV infection
Hyperparathyroidism
Renal osteodystrophy
Systemic lupus
erythematosus
Tuberculosis
Vitamin D deficiency
Thorium dioxide exposure
Gray platelet syndrome
Thrombopoietin receptor
agonists

26. Diagnostic Criteria for Primary
Myelofibrosis
Leukoerythroblastic blood picture
Increased marrow reticulin in the absence of an infiltrative or
granulomatous process
Splenomegaly
JAK2V617F assay (peripheral blood; expression establishes
the presence of an MPD but not its type; PV is always a
consideration; absence does not exclude an MPD)
Increased circulating CD34+ cells (> 15 x 10
6
/L) and no
increase in marrow CD34+ cells by in situ
immunohistochemistry
Characteristic cytogenetic abnormalities (peripheral blood:
del(13q), 9p, del(20q), del(12p), partial trisomy 1q, trisomy 8,
and trisomy 9)
Absence of Bcr-Abl, AML, or MDS cytogenetic abnormalities
by FISH (peripheral blood)

27. The Consequences of Polycythemia Vera
Consequence Cause
Thrombosis, systemic
hypertension, hemorrhage
Elevated red blood cell mass, decreased
von Willebrand factor multimers
Organomegaly, pulmonary
hypertension
Extramedullary hematopoiesis or elevated red
blood cell mass
Pruritus, acid-peptic
disease
Inflammatory mediators
Erythromelalgia Thrombocytosis
Hyperuricemia, gout, renal
stones
Increased cell turnover
Myelofibrosis Reaction to the neoplastic clone
Acute leukemia
Therapy-induced or clonal evolution
(“Richter syndrome”)

28. •In a study of 1213 patients with PV, cancer-free survival and
survival analyses for death or major thrombosis were better
among patients who did not receive chemotherapy
[a]
•In a prospective, controlled clinical trial of 292 patients with
PV, hydroxyurea did not prevent thrombosis or myelofibrosis
[b]
•Hydroxyurea therapy was associated with a late (> 10 years)
risk for transformation to acute leukemia
[b,c]
•In a study of 40 patients with PV, pegylated interferon alfa-1a
induced complete hematologic and molecular responses with
low toxicity
[d]
The Challenges of Treating Polycythemia
Vera

29. The Complications of Polycythemia Vera
and Their Management

30. •97% achieved durable hematocrit control in the absence of
phlebotomy
•59% achieved a durable reduction in splenomegaly of at
least 50%
•88% achieved a reduction in leukocytosis to ≤ 15x 10
9
/L
•92% achieved a reduction in platelet count to ≤ 600 x
10
9
/L
•59% achieved a complete phenotypic remission
•92% had durable relief from pruritus in 1 month
•The reduction in JAK2V617F allele burden was modest
•There were 3 grade 3 adverse events: 2 thrombocytopenia
and 1 neutropenia
•The nonresponder rate was 3%
Effect of a JAK2 Inhibitor in 34
Patients With Established PV (Phase 2
trial data)

31. Complications of Essential
Thrombocytosis
Microvascular
ischemia
•migraine
•erythromelalgia
•transient ischemic attacks
Macrovascular
thrombosis
•stroke
•acute coronary syndrome
•peripheral arterial occlusion
•digital gangrene
•deep venous thrombosis
Hemorrhage due to acquired von Willebrand
disease
Transformation to acute leukemia

33. •Asymptomatic thrombocytosis requires no therapy in the absence of
a thrombotic (prior thrombosis, tobacco use) or significant
hemorrhagic diathesis
•Platelet counts ≥ 1000 x 10
9
/L can be associated with reduced von
Willebrand factor, high molecular-weight multimers, and ristocetin
cofactor activity
•Hemorrhage associated with thrombocytosis can be controlled with
epsilon aminocaproic acid
•Aspirin is the treatment of choice for erythromelalgia unless
ristocetin cofactor activity is reduced
•For platelet count reduction, particularly in patients under age 60,
anagrelide or interferon, if tolerated, are preferable to hydroxyurea.
The new JAK2 inhibitors may prove preferable to the above drugs
•It is not necessary to lower the platelet count to normal but only to a
level that alleviates symptoms
Management of Thrombocytosis in
Essential Thrombocytosis

34. •49% normalized their platelet count within 2 weeks
•82% maintained a platelet count ≤ 600 x 10
9
/L for 9.8
months
•93% with a platelet count ≥ 1000 x 10
9
/L achieved a >
50% reduction
•75% had complete resolution of splenomegaly
•49% had a complete phenotypic remission
•Reduction in the JAK2V617F allele burden was modest
•There were 2 grade 3 adverse events involving leukopenia
•The nonresponder rate was 8%
Effects of a JAK2 Inhibitor in 39 Patients
With Established Thrombocytosis (Phase 2
trial data)

35. Complications of Primary
Myelofibrosis
Anemia •Hypoproliferative due to folate or iron deficiency,
inflammation, autoimmune hemolysis,
hemodilution, or impaired stem cell function
Thrombocytopeni
a
•Splenic sequestration, impaired stem cell function
Incapacitating splenomegaly and splenic infarction
Portal hypertension
Pulmonary hypertension
Organ
compromise due
to extramedullary
hematopoiesis
•Obstructive uropathy
•Intestinal obstruction
•Ascites
•Pleural effusions
•Hepatic failure
•Fibrous tumors
•Spinal or cranial compression
•Bone pain due to periostitis or increased
intramedullary vascularity
Bone marrow failure with pancytopenia

36. Management of Primary Myelofibrosis
a. Rondelli D, et al. Blood. 2005;105:4115.
b. Mesa RA, et al. Blood. 2003;101:2534.
c. Verstovsek S, et al. N Engl J Med. 2010;363:1117.

37. Summary
•The chronic MPDs —PV, ET, and PMF —are distinct disease entities that
sharemany clinical features (phenotypic mimicry) due to unregulated
JAK2 signaling or a similar signaling abnormality
•Because these disorders differ with respect to their natural history and
survival, diagnosis must be accurate to ensure that therapy is
appropriate
•Treatment of these 3 disorders should be tailored to fit their clinical
manifestations
•PV is the most common of the 3 MPDs because it is the ultimate
expression of the JAK2V617F mutation
•All chemotherapeutic agents are leukemogenic in the MPDs and should
be avoided whenever possible, which may now be possible with the new
JAK2 inhibitors
•JAK2 inhibitors will be very useful for safely reducing splenomegaly,
controlling blood counts, and alleviating constitutional symptoms, but
will not eradicate these disorders
•Pegylated interferon or reduced-intensity conditioning bone marrow
transplantation offer the possibility of complete molecular remission