Transcript 20131121110001540

HongzhiXu
Shandong Provincial Hospital
CONTENTS
 Pathogenesis and management of
essential thrombocythemia
 Idiopathic erythrocytosis: a
disappearing entity
 Therapeutic potential of JAK2 inhibitors
Pathogenesis and management
of essential thrombocythemia
Pathogenesis
 Relationship of ET to PV and PMF
The level of JAK2-STAT5 signaling
provides a rheostat that determines
whether the disease phenotype is
predominantly erythroid or
megakaryocytic.
Several lines of evidence suggest a
blurring of the distinction between these
disorders. A proporation of patients
diagnosed with ET (see Table 1 for
criteria) harbor increased levels of bone
marrow reticulin in the absence of other
features suggesting a diagnosis of PMF
The variable degree of reticulin
accumulation reflects the combined
effects of genetic background, disease
duration, therapy, clonal burden and the
acquisition of additional genetic lesions.
Table 1.Suggested diagnostic criteria for
essential thrombocythemia(ET)
Diagnosis requires A1-A3 OR A1+A3-A5
 A1 Sustained platelet count >450X109/L.
 A2 Presence of an acquired pathogenetic mutation(eg, in JAK2 or
MPL).
 A3 No other myeloid malignancy, especially polycythemia
vera(PV), primary myelofibrosis(PMF), chronic myeloid
leukemia(CML) or myelodysplastic syndrome(MDS).
 A4 No reactive cause for thrombocytosis and normal iron stores.
 A5 Bone marrow trephine histology showing increased
megakaryocytes with prominent large hyperlobated forms; reticulin
is generally not increased(≤2 on a 0-4 scale).
Familial Predisposition to ET and Other
Myeloproliferative Neoplasms
A relative risk of 7.4 for developing ET
in those with an affected first-degree
relative.
Are Mutations in JAK2 Disease-initiating Events?
The acquisition of a JAK2 mutation was
preceded by either a deletion of chromosome
20q24 or a mutation in TET2.
Direct evidence now exists demonstrating
that JAK2 mutations are not the diseaseinitiating event in some patients, although the
frequency of this scenario remains unclear.
Progression to Acute Myeloid Leukemia
Progression to acute myeloid
leukemia(AML) occurs in a small minority
of ET patients and involves the accrual of
further genetic events.
 Diagnosis and Management
Diagnostic Criteria
Mutations in JAK2 exon 12 are not thought
to occur in patients with ET.
The combination of an isolated
thrombocytosis with a pathogenetic mutation,
in the absence of iron deficiency or features of
PMF, is usually sufficient to make a diagnosis
of ET.
Therapy
 Low-dose aspirin
 Cytoreductive therapy

Hydroxyurea

Anagrelide
 JAK2 inhibitors
Idiopathic erythrocytosis : a
disappearing entity

Classification of Erythrocytoses
An erythrocytosis can be classified depending on
the identified cause. The main division is on the basis
of primary causes, where an intrinsic defect in the
erythroid progenitor cell is associated with an
enhanced response to cytokines; or secondary, where
the increased red cell production is driven by factors
external to the erythroid compartment, such as
increased erythropoietin(EPO) production for any
reason. Primary and secondary causes can be
classified further as either congenital or
acquired(Table2).
Table 2.Causes of an erythrocytosis
 Primary Erythrocytosis
 Secondary erythrocytosis
 Idiopathic erythrocytosis
Table 2.Causes of an erythrocytosis
Primary Erythrocytosis
Congenital
Erythropoietin(EPO) receptor
mutations
Acquired
Polycythemia vera (including
JAK2 exon 12 mutations)
 Secondary erythrocytosis
Congenital
Defects of the oxygen sensing pathway
VHL gene mutation (Chuvash erythrocytosis)
PHD2 mutations
HIF-2a mutations
Other congenital defects
High oxygen-affinity hemoglobin
Bisphosphoglycerate mutase deficiency
Acquired
EPO-mediated
Central hypoxia
Chronic lung disease
Right-to-left cardiopulmonary vascular shunts
Carbon monoxide poisoning
Smoker′s erythrocytosis
Hypoventilation syndromes including obstructive sleep apnea
High-altitude
Local hypoxia
Renal artery stenosis
End-stage renal disease
Hydronephrosis
Renal cysts (polycystic kidney disease)
Post-renal transplant erythrocytosis
Pathologic EPO production
Tumors
Cerebellar hemangioblastoma
Meningioma
Parathyriod carcinoma/adenomas
Hepatocellular carcinoma
Renal cell cancer
Pheochromocytoma
Uterine leiomyomas
Drug associated
Erythropoietin administration
Androgen administration

Investigation of an Erythrocytosis
Once an erythrocytosis has been established identification of the cause is
the next focus.

Clinical Consequences
A raised red cell count will increase the viscosity and thus may have clinical
consequences.

Management of an Erythrocytosis
Reducing the Hct by phlebotomy/venesection reduces the blood viscosity
and maybe of benefit.

Cytoreductive

Low-dose aspirin
Therapeutic potential of
JAK2 inhibitors
The V617F mutation is localized in a region
outside the adenosine triphosphate(ATP)binding pocket of JAK2 enzyme, ATPcompetitive inhibitors of JAK2 kinase are not
likely to discriminate between wild-type and
mutant JAK2 enzymes. Therefore, JAK2
inhibitors, by virtue of their near equipotent
activity against wild-type JAK2 that is important
for normal hematopoiesis, may have adverse
myelosuppression as an expected side effect,
if administered at doses that aim to completely
inhibit the mutant JAK2 enzyme.
While they may prove to be effective in
controlling hyperproliferation of
hematopoietic cells in PV and ET, they
may not be able to eliminate mutant
clones.
Most importantly, patients with and
without the JAK2 V617F mutation appear
to benefit to the same extent.
Preliminary clinical observations in selected JAK2
inhibitor trials.
Agent
Company Target(s) JAK IC50(nM) Curre
nt
phase
INCB0
18424
Incyte
Preliminary clinical
obserbations in myelofibrosis
studies
JAK1,
JAK2
JAK1=2.7*
JAK2=4.5*
JAK3=322*
III
Decreased spleen size irrespective
of JAK2 mutational status;
improved quality of life, weight
and performance; decreased
inflammatory cytokine levels.
Myelosuppression
TG101 TargeGE
384
N
JAK2
JAK1=105
JAK2=3
JAK3=996
II
Decreased spleen
size;decrease in
WBC.Myelosuppression;
gastrointestinal disturbance
XL019
JAK2
JAK1=132
JAK2=2
JAK3=250
discon
tinued
Decreased spleensize only in
patients with JAK2 V617F or MPL
mutation; decreased pruritis and
improved fatigue.
Neurotoxicity
JAK2,F
LT3
JAK2=1
I/II
Decreased spleen size,
improvement in blood cell
count.Myelosuppression;gastroint
estinal disturbance
Exelixis
CEP701( Cephalon
lestaurtin
ib)