Chronic myelocytic leukemia (CML), polycythemia vera (PV), 1' myelofibrosis (MF) and essential thrombocythemia (ET) are malignant clonal proliferations of multipotent stem cells. While all three cell lines (myeloid, erythroid and megakaryocytic) are involved in each disorder, each has specific genetic abnormalities. As a result the dominant cell differs in each allowing for the subclassification of the chronic myeloproliferative disorders. For instance, in PV the proliferation is predominately erythroid, yet white cell and megakaryocytic lines are also part of the malignant proliferation.

Chronic myeloproliferative disorders are:

1) acquired, malignant clonal disorders

2) characterized by expansion of pluripotent stem cells showing

3) deranged production of one or more myeloid lines and having

4) a variable predisposition to transform to leukemia.

Leukemia: Chronic Myeloid Leukemia

Definition: Chronic myeloid leukemia (CML), (15% of all leukemia), is a malignant disorder of multipotent stem cells with predominance of mature granulocytes and their precursors accumulating in excess in the marrow and blood.

Clinical Course: The initial phase of CML is stable or indolent (usually lasting 2-4 years), but is followed by an acclerated stage (6-12 months), and finally an acute phase or blast crisis (2-4 months) similar to acute leukemia.

Molecular Genetics: CML is associated with perhaps the best known chromosome translocation, the Philadelphia chromosome (Ph') or t(9;22)(q34;q11) in which the c-abl gene from 9 is juxtaposed with the bcr sequence on 22. This leads to a chimeric gene (bcr-abl) the product of which is an aberrant 210kD tyrosine kinase (thought to be involved in cell regulation). Mature myeloid cells appear to live longer and thus accumulate.

Blood Cell Count: The peripheral blood WBC count of stable CML is typically elevated from 20 x 10⁹/L, and is often >100 x10⁹/L. Segmented neutrophils, myelocytes, and metamyelocytes predominate, but eosinophilia and basophilia are characteristic PB findings in CML. Less than 2% peripheral blasts or myelodysplasia accompany CML. Anemia is usually only moderate. Platelet numbers may be normal or elevated (50%) in most patients.

LAP (leukocyte alkaline phosphatase) activity in leukocytes of CML is abnormally low or absent. [LAP: +Control (blue stain); CML]

Bone Marrow: The bone marrow is hypercellular (100%) with a great increase in the M:E ratio; a left shifted myeloid series, and increased eosinophils. Megakaryocytes may be normal or elevated and are often smaller (as in this case) than normal.

Progression of Disease: During the accelerated phase eosinophilia and basophilia increase, and immature cells and blasts increase in number. The blast phase is reached when the number of blasts exceeds 30% in either the peripheral blood or marrow. The blasts are usually myeloid (>60%), but may be lymphoid (30%) reflecting the stem cell origin of the disorder.

CML must be differentiated from leukemoid reactions in which there is a marked increase in myeloid elements secondary to infection, chronic inflammation and other causes. Occasionally CML will present in blast crisis and should be distinguished from acute leukemia.

Genetics: When CML enters an accelerated or blast phase a double Ph' or other chromosomes abnormality, ie. trisomy 8, may be encountered.

Clinical Characteristics: The average age at presentation is 45 yrs (rare in children). The incidence is ≈1/100,000/year with equal numbers of men and women.

Death is usually secondary to blast crisis, marrow failure or marrow fibrosis.

Leukemia: Polycythemia vera

Definition: Polycythemia vera is a malignant stem cell disorder manifest primarily as erythroid hyperplasia and an absolute increase of the red cell mass. Myeloid and megakaryocytic elements are part of the neoplastic proliferation.

Proposed Pathophysiology: The etiology and nature of PV are in large part unknown. One theory is that malignant stem cells respond to unusually low levels of erythropoietin. This results in an increased red cell mass and suppresses erythropoietin production, such that normal erythroid stem cells are not stimulated at the same low erythropoietin levels. Myeloid and megakaryocytic cells also fail to respond to regulatory mechanisms.

Bone Marrow: The bone marrow of P vera is hypercellular with proliferation of all three major cell lines, although erythroid elements predominate resulting in M:E ratios of 1:1 or lower.

Features of the Blood Cell Count: Peripheral blood abnormalities include increased hematocrit, hemoglobin and RBC mass, but the RBCs are morphologically normal. About half of the patients have a mild - moderate leukocytosis and thrombocytosis. Basophils are frequently increased.

Differential Diagnosis: 1) Relative increases in red cell concentration (hemoconcentration,ie. dehydration) and 2) secondary forms of absolute increases in red cell number (increased erythropoietin, ie. smoking & sleep apnea).

The menu below is helpful in securing a valid diagnosis of PV.

Clinical Picture: Polycythemia vera presents at an average age of 40-60 years with symptoms secondary to the increased blood volume and viscosity - including plethora, hypertension, headache, dizziness and hematemesis. Pruritis is a frequent symptom. Why?

Some patients become cyanotic. Why?

Splenomegaly is a frequent finding.

Disease Course: About 25-30% of patients present with a thrombotic event (CVA, MI, DVT, portal vein thrombosis) and 30-40% of all PV patients eventually die from a thrombotic or hemorrhagic event.

The initial disease period is the "proliferative" phase. Untreated, most patients with polycythemia vera die within months of vascular complications, but maintainence of the red cell mass at or near normal by phelbotomy or chemotherapy allows for long term survival (7-10 years).

End stage P vera is referred to as the "spent" phase, usually with splenomegaly and hypercellular marrow fibrosis and myeloid metaplasia. This is sometimes called postpolycythemic myeloid metaplasia. About 5% die of PPMM.

A number of P vera patients eventually develop an acute leukemia: 2% after phelbotomy and ≈15% after chemotherapy. In most a period of myelodysplasia precedes the acute leukemia and have the chromosome abnormalities associated with acute leukemia secondary to therapy.

Do you remember which chromosome abnormalities are associated with chemotherapy?

Interestingly, 15% of P vera patients die of other neoplasms.

Leukemia: Primary Myelofibrosis

Definition: Primary myelofibrosis or myelosclerosis with myeloid metaplasia (MMM) also know as agnogenic (idiopathic) myeloid metaplasia or myeloid metaplasia with myelofibrosis is a hematopoietic stem cell malignancy of red, white and megakaryocytic cells - a panmyelosis. Marrow fibrosis with either increased or decreased cellularity is a constant feature of this disorder. The fibrosis is secondary probably due to the production of PDGF (platelet derived growth factor) by malignant megakaryocytes. PDGF is a known mitogenic stimulus of fibroblasts.

Bone Marrow: The typical 1'MF bone marrow is hypocellular due to extensive fibrosis (best demonstrated by a silver reticulin stain) replacing the myeloid and erythroid elements. Megakaryocytes, although not always increased in number, appear morphologically abnormal. Osteosclerosis is a common finding.

As the marrow fibrosis progresses the amount of extramedullary myeloid metaplasia increases. Although the spleen is the primary site of myeloid metaplasia, almost any site can be involved especially the liver, lymph nodes, and kidneys.

Clinical Presentation: Primary myelofibrosis is about one-third less common than CML and is seen primarily in people >50 years of age (peak 60-70yrs). Splenomegaly (early satiety, abdominal discomfort and weight loss) or increasing anemia (fatigue and weakness) are the usual presenting findings (symptoms). Bone pain, fever and night sweats are also common.

Peripheral Blood Findings: Moderate to severe anemia with anisocytosis and pronounced poikilocytosis characterized by teardrop shapes (dacryocytes). Nucleated red cells are usually present. There is a leukocytosis with immature forms. The LAP score is usually normal or high. Abnormally large platelets and sometimes megakaryocyte nuclei are found. Of course, not all of these findings are present in early disease.

Differential Diagnosis: Metastatic neoplasia and inflammation must be considered in the differential as both may cause fibrosis of the marrow and many of the symptoms listed above.

Disease Course: The average survival of patients with MF is about 5 years (range 1-16 years) following an estimated two year period of asymptomatic disease. Death is may be secondary to infection, hemorrhagic episodes or acute leukemia.

Treatment: Treatment consists of chemotherapy (to lower the platelet and white cell count) or packed red cells or platelets as needed.

Leukemia: Essential Thrombocythemia

Definition: Essential thrombocythemia (ET) is also a hematopoietic stem cell neoplasm the etiology and pathogenesis of which is unknown.

Peripheral Blood: The platelet count often exceeds one million/mL, but must be carefully differentiated from reactive thrombocytoses seen with various malignancies, iron deficiency anemia, etc.

Diagnosis: The other chronic myeloproliferative disorders CML, PV and 1'MF must be ruled out before a diagnosis of ET can be made. The most striking peripheral blood abnormality is the increased number of platelets which may be functionally abnormal.

Bone Marrow: The bone marrow in ET is hypercellular with excessive numbers of megakaryocytes and can be difficult to distinguish from polycythemia vera.

Clinical Picture: Patients with ET present with thrombosis or hemorrhage often involving the microvasculature with resultant neurologic symptoms. The platelet dysfunction may lead to bleeding and bruising. About one-half of patients have splenomegaly at presentation. Myelosuppressive chemotherapy, platelet pheresis or platelet inhibitors are used to control the platelet count.

Diagnostic Criteria:

1. platelets >600 x10 /L
2. hemoglobin <130g/L
3. marrow iron stores or failed Fe trial
4. Philadelphia chromosome negative
5. no collagenous fibrosis of marrow or fibrosis <1/3 examined area with no splenomegaly and no leukoerythroblastic reaction
6. no known cause of reactive thrombocytosis

Leukemia: Chronic Myeloproliferative Disorders

Although the incidence of the myeloproliferative disorders is low (<1 to 2 cases /100,000 people) they remain an intriguing group of closely related disorders. The role of unique chromosomal abnormalities involving growth signaling and/or growth factors is only now beginning to be explored.

High serum uric acid and elevated LDH are often seen in the myeloproliferative disorders, especially MF. Why?

B12 and B12 binding levels are often elevated in the chronic myeloproliferative disorders. Why?

A 54-year-old woman complains of gradual weight loss and increasing lethragy. She notes early satiety.

A chest roentgenogram appears normal. There is no lymphadenopathy. A CBC revealed a WBC of 85.0 x10⁹/L with a differential of 2 blasts, 3 pros, 22 myelos, 30 segs, 12 eos, 6 basos, 5 monos and 20 lymphocytes. The LAP was "0".

With the results of this information you make the following diagnosis:

A. Acute myelocytic leukemia, NOS (not otherwise specified)

B. Chronic myelocytic leukemia, stable

C. Chronic myelocytic leukemia, accelerated phase

D. Chronic myelocytic leukemia, blast phase

E. Leukemoid reaction

A 57-year-old woman complains of weakness, fatigue and increasing lethragy. She notes early satiety.

A chest roentgenogram appears normal. The spleen is palpable 13cm below the LCM and the liver at 6cm below the RCM. There is no lymphadenopathy.

The Hct is .36L/L and the Hgb is 130g/L. A CBC revealed a WBC of 26.0 x10⁹/L with a differential of 3 blasts, 3 pros, 9 myelos, 59 segs, 4 eos, 3 basos, 6 monos and 13 lymphocytes. Five NRBCs/100 WBCs and numerous tear drop RBCs were seen on the peripheral smear. Platelets were 325.0 x10⁹/L. The LAP was "160" (normal40-150).

With the results of this information you make the following diagnosis:

A. Acute myelocytic leukemia, NOS (not otherwise specified)

B. Chronic myelocytic leukemia, stable

C. Chronic myelocytic leukemia, accelerated phase

D. Agnogenic myeloid metaplasia (1' myelofibrosis)

E. Leukemoid reaction

Although AML must be considered as there are a small number of blasts, AML is unlikely as there seems to be full myeloid maturation, normal platelet numbers and minimal anemia.

A leukemoid reaction although possibly having a similar WBC count and differential would not have the teardrop RBCs. The NRBCs would also be unlikely.", "Answer")'>

A 61-year-old man has a persistent platelet count of > 100 x10 /L. You should make the diagnosis of ET (essential thrombocythemia) if the patient also has:

A. bcr-c-abl juxtaposition by a t(9;22)

B. Post splenectomy, recent

C. Diffuse marrow fibrosis

D. Absent bone marrow iron stores

E. None of the above