myeloproliferative disorder pdf - ali m

MEDICINE

haematology

Lec.55

Dr.Ali M. Jawad

Myeloproliferative Disorders

Lec . 7

23/3/2017

Done by : Taher Ali Taher

2016-2017

مكتب اشور لالستنساخ

Dr.

Ali M. Jawad

Myeloproliferative Disorders

23/3/2017

By : taher ali taher

Objectives

By the end of this lecture, the student should be able to:
1-classify myeloproliferative disorders.
2-list the clinical features of myeloproliferative disorders.
3-discuss briefly the diagnosis and treatment of polycythemia rubra vera,
myelofibrosis and essential thrombocythemia.

Case Scenario



A 60 year old male presented with 4 months history of progressive
pallor , weight loss and heaviness in the abdomen. He bled after tooth
extraction.



An US of abdomen revealed a hugely enlarged spleen.



His Hemoglobin was 9 gm/dl.



What is your differential diagnosis?

Myeloproliferative Disorders

o  Neoplastic (clonal) disorders of hemopoietic stem cells
o  Over-production of all cell lines, with usually one line in particular
o  Fibrosis is a secondary event
o  Transformation to Acute Myeloid Leukemia may occur

MPD

–Classification

1. Polycythemia (Rubra) Vera (PRV, PV)
2. Myelofibrosis (with Myeloid Metaplasia)
3. Essential (Primary) Thrombocythemia

Bone marrow stem cell

Clonal abnormality

Granulocyte

precursors

Red cell

precursors

Megakaryocytes

Reactive

fibrosis

Essential

thrombocytosis

(ET)

Polycythaemia

rubra vera

(PRV)

Myelofibrosis

AML

Chronic myeloid

leukemia

70%

10%

30%

Dr.

Ali M. Jawad

Myeloproliferative Disorders

23/3/2017

By : taher ali taher

Polycythemia

  True / Absolute
  Primary Polycythemia
  Secondary Polycythemia

1-  Epo dependent
-  Hypoxia dependent
-  Hypoxia independent
2-  Epo independent

 Apparent / Relative

- Reduction in plasma volume

Causes of secondary polycythemia :-

ERYTHROPOIETIN (EPO)-MEDIATED
- Hypoxia-Driven

  Chronic lung disease
  Right-to-left cardiopulmonary vascular shunts
  High-altitude habitat
  Chronic carbon monoxide exposure (e.g., smoking)
  Hypoventilation syndromes including sleep apnea
  Renal artery stenosis or an equivalent renal pathology

- Hypoxia-Independent (Pathologic EPO Production)

Malignant tumors

  Hepatocellular carcinoma
  Renal cell cancer
  Cerebellar hemangioblastoma

Nonmalignant conditions



Uterine leiomyomas



Renal cysts



Postrenal transplantation



Adrenal tumors

POLYCYTHEMIA VERA

o Chronic, clonal myeloproliferative disorder characterized by an

absolute increase in number of RBCs.

o  Incidence:2-3 / 100000.
o  Median age at presentation: 55-60 y.
o  M/F: 0.8:1.2 .
o  The hallmark is JAK2 mutation.

Dr.

Ali M. Jawad

Myeloproliferative Disorders

23/3/2017

By : taher ali taher

Clinical features

  Plethora and Headaches
  Splenomegaly
  Generalized pruritus (after bathing)
  Vascular occlusion

- Venous thrombosis
- TIA, stroke, MI

 Erythromelalgia (acral dysesthesia and erythema)
 Gouty attacks due to hyperuricemia

Lab Investigations

1-CBP: erythrocytosis, increased Hb> 17gm/dl, may find basophilia and
eosinophilia and thrombocytosis.
2-BM study: hypercellular marrow with increased fibrous tissue and
megakaryocytes.
3-Hyperuricemia, increased serum vit B12.
4-US of abdomen usually reveals Splenomegaly.
5-Decreased serum erythropoietin.
6-+ve JAK2 mutation by PCR study.

Diagnostic Criteria
Major Criteria

1- Hemoglobin >18.5 g/dL in men, >16.5 g/dL in women, or other evidence of

increased red blood cell volume.

2- Presence of JAK2 V617F.

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 one minor criterion
or the presence of the first major criterion together with two minor criteria

Dr.

Ali M. Jawad

Myeloproliferative Disorders

23/3/2017

By : taher ali taher

Treatment

 The mainstay of therapy in PV remains phlebotomy to keep the PCV

below 45 percent in men and 42 percent in women

 hydroxyurea in high-risk patients for thrombosis (age over 70, prior

thrombosis, platelet count >1,000,000/microL, presence of
cardiovascular risk factors)

  Aspirin (75-100 mg/d) .
  Interferon alfa in patients with refractory pruritus, and for pregnants.
  Anagrelide is used mainly to manage thrombocytosis in patients

refractory to other treatments.

 Allopurinol
 JAK2 inhibitors like ruxolitinib for refractory cases.

Prognosis:

After many years progression to myelofibrosis and few will go to AML.

Causes of Death:

1-Thromotic episodes.
2-Bleeding.
3-Transformation into AML.

Student Activity

o Take 3 minutes to discuss why some cases of polycyhema vera develop

anemia after a time.

o Try to give 3 explanations for that.

Primary Myelofibrosis (MF)

  Clonal hemopoietic stem cell disorder.
  Ending in bone marrow failure.
  There is myeloid metaplasia (extra-medullary hemopoiesis)
  JAK 2 mutation in around 50% of cases.
  Tendency to transformation to AML.

Dr.

Ali M. Jawad

Myeloproliferative Disorders

23/3/2017

By : taher ali taher

Clinical Features

  Fatigue, weight loss, nocturnal sweating, pruritus.
  Splenomegaly .
  Anemia .
  Portal hypertension due to huge splenomegaly .
  Splenic infarction and hypersplenism.
  GI bleeding (melena or hematochezia).
  Hypertrophic osteoarthropathy.
  Bone and musculoskeletal pain.
  Thrombotic and bleeding  episodes.

Laboratory Investigations

1-CBP: anemia, WBC count increased or normal or decreased, Platelet
increased and later decreased.
Blood film: tear drop cells with leuco-erythroblastic blood picture(immature
RBC+WBC).
2-BM Biopsy: megakaryocyte proliferation +Fibrosis and later sclerosis.
3-Increased S.uric acid and LDH.
4-Splenomegaly by US of Abdmen.
5- 50% have JAK 2 mutation.

Tear Drop Cells (or Tear
Drop Poikilocytes)

Blood Film of MF

Dr.

Ali M. Jawad

Myeloproliferative Disorders

23/3/2017

By : taher ali taher

Bone Marrow biopsy of MF

fibrosis

new bone (arrows)

Treatment

1-correction of anemia .
2-prevention of thrombotic events by aspirin.
3-allopurinol.
4-hydroxyurea or alfa interferone to control systemic symptoms ,
thrombocytosis and to decrease size of spleen.
5-JAK 2 inhibitors in resistant splenomegaly.
5-Allogeneic BMT for refractory cases and on AML transformation.

Essential Thrombocythemia (ET)

o ET is the second-most-common MPN .
o The median age at diagnosis is approximately 60 years, although the

diagnosis increasingly is made in younger adults.

o Women with ET outnumber men 1.5- to 2-fold, particularly among ETs

diagnosed in the third

o  to fifth decade of life.
o  Morbidity and mortality from ET predominantly
o  related to thrombo-embolic and less commonly, hemorrhagic

complications.

o 40% have JAK2/MPL mutation

Dr.

Ali M. Jawad

Myeloproliferative Disorders

23/3/2017

By : taher ali taher

Clinical Features

1-  Vasomotor:
A.  “Vascular” headaches, visual disturbances, dizziness, burning
B.  dysesthesia of the palms and soles (erythromelalgia),
C.  acrocyanosis, paresthesias, cutaneous ulcers.
D.  cognitive or psychiatric deficits, seizures.
2-  Thrombotic:

Arterial: cerebral (TIA, CVA), coronary, ophthalmic, distal/
extremities

II.

Venous: deep extremities, pelvic, mesenteric, hepatic, portal.

3- Hemorrhagic:

- Gastrointestinal, mucosal, epistaxis, urogenital, deep hematoma.

4- Obstetric:

- First-trimester spontaneous abortion

5- Splenomegaly occur in some cases.
6- AML transformation is rare.

Laboratory Investigations

1-CBP: persistant thrombocytosis with large size platelets.WBC count may be
increased.
2-+ve JAK 2/MPL mutation.
3-BM study: clusters of large megakaryocytes.
4-Need to exclude:

  Iron Deficiency
  CML
  Myelofibrosis

ET Blood Film

Dr.

Ali M. Jawad

Myeloproliferative Disorders

23/3/2017

By : taher ali taher

Risk stratification for ET

  Low risk (all of the following)
1-  Age <60 years old
2-  No history of thromboembolism
3-  No cardiovascular risk factors (smoking,hypercholesterolemia)
  Indeterminate risk

- Neither low nor high-risk disease

  High risk (one or both)
A.  Age ≥60 years old
B.  History of thromboembolism

Treatment

According to Risk categories:

  Low Risk:   Low-dose aspirin
  Intermediate Risk:   Low-dose aspirin
  High Risk :  Low-dose aspirin + hydroxyurea

Conclusion

1-Myeloproliferative neoplasms are chronic disorders arising from BM stem
cells .The hallmark is JAK 2 mutation and variable tendency for AML
transformation.
2-Polcythemia vera present with erythrocytosis, splenomegaly and thrombotic
tendency, control is by phlebotomy ,aspirin and hydroxyurea.
3-Primary myelofibrosis presents with anemia and huge splenomegaly. It is
treated with blood transfusion and hydroxyurea.
4-Essential thrombocythemia presents with thrombotic tendency and in high
risk patients it is treated with aspirin and hydroxyurea.

…the end…