Heme - Chronic Myeloproliferative Disorders

Front 1

Myeloproliferative disorders affect which line of stem cells?

Back 1

Myeloid precursor line (giving rise to platelets, monos, PMNs, RBCs)

Front 2

General char of Myeloproliferative disorders

Back 2

Hepatosplenomegaly (extramedullary hematopoeisis)

Clonal marrow expansion (from single cell that got a key mutation

Hypercatabolism (fevers, sweats, weight loss)

Predisp to evolve into acute myeloid leuk

Loss of control of normal prolif.

Front 3

CML other sx and findings
(chronic myeloid leukemia)

Back 3

Early satiety, abdom pain.

Labs - elev WBC, Hgb, platelets. Later will get anemia and thrombocytopenia.

Periph smear - immature myeloid cells but few blasts.

Leukocyte alkaline phophatase score is low. (normal/high in reactive leukocytosis)

BM biopsy - hypercell marrow with inc myeloid/erth ratio. Also more eosinophils. THIS IS THE MAIN WAY TO TELL.

t(9;22) must be present.

Front 4

Diff in cells in CML and AML

Back 4

CML - increase prolif at each step so there are more cells than normal.

AML - More prolif and a block to differentiation. So there is a build up of blasts with very few of the downstream cells.

Front 5

CML WBC differential characteristics

Back 5

Total WBC increased.

WBC have full range of immature myeloid cells.
Baso/eosinophils are increased
Blasts are usualyl more prominent in AML.

Front 6

CML - Pathogenesis

Back 6

The Philadelphia Chromosome (t9;22). bcr-abl transfusion.

Dx by FISH

Makes a tyrosine kinase constitutively active (Gleevec targets this). The signal that it sends is very complex

Front 7

CML stages
Chronic

Back 7

1.

High counts, splenomegaly. Easily controlled with hydroxyurea (slow down DNA synth).

Best results of HSC transplant is in this phase.

Median duration is 3 years

Front 8

CML Stages
Accelerated

Back 8

2.

Elev WBC more difficult to control.

Higher doses of hydroxyurea needed to suppres RBCs and platelets.

Spleen begins to increase in size and constitutional symptoms return.

Median duration - 1 year

Front 9

CML stages
Blast

Back 9

3.

Equiv to acute leukemia. Blast cells may have AML or ALL phenotypes.

Unresponsive to typical leukemia therapies and allogeneic HSCTransplant.

Survival - 3-6 months.

Front 10

CML tx strategy

Back 10

Start gleevec immediately.
monitor resp with FISH for the translocation and RT-PCR and cytogenetics (karyotyping).

If response is poor, consider HSCT (but SE and GVHD can be very bad)

Front 11

Polycythemia vera

Back 11

Median age 60.

Visual disturbances, thrombosis, puritis, erythromelalgia (itchy?)

Plethora-face looks red.

Labs - elev Hgb/Hct with or without elev WBC and platelets.
Later in disease - anemia and thrombocytopenia.

Periph blood smear shows normal cells and erythropoetin is below normal.

Molec dx - V617F JAK2 mutation. This is part of the epo signaling pathway and when mutated, it is constitutively active.

Front 12

Dx of polycythemia vera

Back 12

No diseases causing secondary erythrocytosis (incl hypoxia, polycythemic disorders, high-affin hemoglobins, tumor causing EPO production).

Incr hemoglobin

Low EPO concentration. This is key for polycythemia!!!

Presenve of JAK2 mutation

BM biopsy will be hypercellular. Prominent erythroid, granulocytic, and megakaryocytic proliferation.

Front 13

Tx of polycythemia vera

Back 13

Untreated - 6-9 month (stroke, PE, MI)

Phlebotomy is very useful.
Gradually only have to do it 2-4 times a year.

Long-term prognosis - Can develop myelofibrosis, secondary AML/MDS. These patients respond poorly to therapy.

JAK2 kinase inhibitors may also be helpful in future.

THIS IS FAIRLY CURABLE!

Front 14

Essential thrombocythemia - general features

Back 14

HA, syncope, visual changes.

Complc - thrombosis, abnormal bleeding

Platelet counts high, incr and abn megakaryocytes in BM, no chronic inflammation (i.e. a cause of reactive thrombocytosis), normal iron stores.

Note that almost 50% have the V617F JAK2 mutation.

Front 15

CML - Philly chromosome translocation goes away with gleevec?

Back 15

yes

Front 16

Essential thrombocytopenia therapy and prognosis

Back 16

Low risk - No tx neccessary (if <60 y.o., no hisotry of thrombosis and platelets < 1,000,000)

High risk - all others - hydroxyurea (and aspirin and anagrelide is used sometimes)

Prognosis - Normal life span with therapy as outlined as above. Small % continue to AML, MDS or myelofibrosis.

SO THIS IS FAIRLY TREATABLE.

Front 17

Essential thrombocythemia appearance in BM

Back 17

Increased and clustered megakaryocytes in the marrow

Front 18

Primary myelofibrosis

Back 18

Splenomegaly is the hallmark of this disease (but you see it in lots of other things too)

Labs - Anemia (50% have hgb<10%), teardrop RBCs
platelets and wbcs are elevated or decreased
megakaryocytes in BM are increased and abnormal
Fibrosis due to deposition of collagen in the bone marrow.
50% will have V617F JAK2 mutation (same as polucythemia vera and essential thrombocytosis)

Front 19

Prognosis and therapy of primary myelofibrosis

Back 19

Prognosis - based on a point system from cell counts.

Therapy - Allogeneic HSCT can be curative.
hydroxyurea can shrink the spleen, transfusions for anemia, splenectomy or splenic irradiation for enlarged spleen.

JAK2 kinase inhibitors are showing good results.

Causes of death - transformation into MDS or AML, bleeding from low platelets, infection from low WBC.

reiterate - it often presents with anemia and has high prob of turning into AML.

Front 20

Tx strategy in general for chronic myeloproliferative disorders

Back 20

Always check for CML (t(9;22) because it is very easily and uniquely treatable!!!