Hongzhixu shandong provincial hospital
This presentation is the property of its rightful owner.
Sponsored Links
1 / 26

HongzhiXu Shandong Provincial Hospital PowerPoint PPT Presentation


  • 68 Views
  • Uploaded on
  • Presentation posted in: General

Myeloproliferative Disorders. HongzhiXu Shandong Provincial Hospital. CONTENTS. Pathogenesis and management of essential thrombocythemia Idiopathic erythrocytosis: a disappearing entity Therapeutic potential of JAK2 inhibitors.

Download Presentation

HongzhiXu Shandong Provincial Hospital

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Hongzhixu shandong provincial hospital

Myeloproliferative Disorders

HongzhiXuShandong Provincial Hospital


Contents

CONTENTS

  • Pathogenesis and management of essential thrombocythemia

  • Idiopathic erythrocytosis: a disappearing entity

  • Therapeutic potential of JAK2 inhibitors


Pathogenesis and management of essential thrombocythemia

Pathogenesis and management of essential thrombocythemia


Pathogenesis

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.


Hongzhixu shandong provincial hospital

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


Hongzhixu shandong provincial hospital

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

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).


Hongzhixu shandong provincial hospital

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.


Hongzhixu shandong provincial hospital

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 disease-initiating event in some patients, although the frequency of this scenario remains unclear.


Hongzhixu shandong provincial hospital

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.


Hongzhixu shandong provincial hospital

  • 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.


Hongzhixu shandong provincial hospital

Therapy

  • Low-dose aspirin

  • Cytoreductive therapy

  • Hydroxyurea

  • Anagrelide

  • JAK2 inhibitors


Idiopathic erythrocytosis a disappearing entity

Idiopathic erythrocytosis : a disappearing entity


Hongzhixu shandong provincial hospital

  • 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

Table 2.Causes of an erythrocytosis

  • Primary Erythrocytosis

  • Secondary erythrocytosis

  • Idiopathic erythrocytosis


Table 2 causes of an erythrocytosis1

Table 2.Causes of an erythrocytosis

  • Primary Erythrocytosis

    Congenital

    Erythropoietin(EPO) receptor mutations

    Acquired

    Polycythemia vera (including JAK2 exon 12 mutations)


Hongzhixu shandong provincial hospital

  • 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


Hongzhixu shandong provincial hospital

Acquired

EPO-mediated

Central hypoxia

Chronic lung disease

Right-to-left cardiopulmonary vascular shunts

Carbon monoxide poisoning

Smoker′s erythrocytosis

Hypoventilation syndromes including obstru-

ctive sleep apnea

High-altitude


Hongzhixu shandong provincial hospital

Local hypoxia

Renal artery stenosis

End-stage renal disease

Hydronephrosis

Renal cysts (polycystic kidney disease)

Post-renal transplant erythrocytosis


Hongzhixu shandong provincial hospital

Pathologic EPO production

Tumors

Cerebellar hemangioblastoma

Meningioma

Parathyriod carcinoma/adenomas

Hepatocellular carcinoma

Renal cell cancer

Pheochromocytoma

Uterine leiomyomas

Drug associated

Erythropoietin administration

Androgen administration


Hongzhixu shandong provincial hospital

  • 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

Therapeutic potential of JAK2 inhibitors


Hongzhixu shandong provincial hospital

The V617F mutation is localized in a region outside the adenosine triphosphate(ATP)-binding pocket of JAK2 enzyme, ATP-competitive 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.


Hongzhixu shandong provincial hospital

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

Preliminary clinical observations in selected JAK2 inhibitor trials.


Hongzhixu shandong provincial hospital

THANK YOU !


  • Login