CHRONIC MYELOPROLIFERATIVE

NEOPLASMS (MPN)

ByDr MONKEZ M YOUSIF

Professor of Internal MedicineZagazig university

2016

Definition

MPNs are clonal diseases Originating in multipotential

hematopoietic progenitor cell

Characterized by independence of numerous cytokines.

Resulting in increased and abnormal

myelopoiesis and

Classified according to the predominant phenotypic

expression of the myeloproliverative disease

Myeloproliferative disease can develop in any one of these cell types

Normal development of blood cells

TK

Growth Factors And Tyrosine Kinase Signaling Pathways

TK

StatStat

StatStat Proliferation and survivalP P

Cell Membrane

Cell nucleus

Growth Factors

PP

ErythropoietinThrombopoietinGM-CSF

Systemic mastocytosis

Polycythemia vera

Essential thrombocythemia

Hypereosinophilic syndrome

Myeloproliferative Neoplasms

Chronic myeloid leukemia

Myelomonocytic leukemia

Myelofibrosis

Epidemiology Incidence: 2–3 cases/100,000

population/yearmale: female = 1:1

Classification of Myeloproliferative Neoplasms

A. Classic Disorders - Philadelphia +ve :

Chronic myeloid leukemia (CML) - Philadelphia –ve :

Polycythemia vera (PV) Essential thrombocythemia (ET)

Chronic idiopathic myelofibrosis (CIMF)B. Atypical Disorders - Chronic neutrophilic leukemia - Chronic eosinophilic leukemia - Chronic mast cell leukemia

MYELOPROLIFERATIVE NEOPLASMS

• CML, polycythemia, and essential thrombocythemia may evolve into chronic myelofibrosis.

• All myeloproliferative disorders carry an increased risk of transformation to acute myeloid leukemia (AML).

MPN have been caused by mutations in tyrosine kinases

Molecular Genetic Abnormalities

A. CML: Philadelphia chromosome: t(9;22), BCR / ABL oncogene

B. PV, ET, CIMF: point mutation (V617F) of the tyrosine kinase JAK-2 (Janus kinase 2) on the short arm of chromosome 9 (9p), present in patients with PV (99%), ET (50%), and CIMF (50%).

C. Chromosomal aberrations are detectable in 10–60% of cases.

JAK2

JAK2 V617F is always on!!!

What does JAK2 normally do?It is a switch that tells blood cells to grow

JAK2

StatStat

StatStat Proliferation and survivalP P

Cell Membrane

Cell nucleus

Erythropoietin independence

Valine 617 Phenylalanine

JAK2V617F prevalence in MPN

PV 99%

ET ~50%

MF ~50%

Common CharacteristicsOverproduction of one or several blood

elements with dominance of a transformed clone.

Hypercellular marrow/marrow fibrosis. Cytogenetic abnormalities. Thrombotic and/or hemorrhagic

diatheses. Increased cell turnover →

hyperuricemiaExtramedullary hematopoiesis

(liver/spleen). Transformation to acute leukemia. Overlapping clinical features.

Characterization of individual MPNs

V617F JAK-2

PhChrom

Marrow Fibrosis

LAPIndex

Splenomegaly

Thromocytes

Leukocytes

Hct Disease

- +++

n/+ ↓ +++

↑/n/↓

↑↑↑

n/↓ CML

+++

- + ↑↑ + ↑ ↑ ↑↑↑

PV

+ - ± n/↑ + ↑↑↑

n/↑ n ET

+ - ↑↑↑

↑ +++

↑/n/↓

↑/n/↓

↓ CIMF

Therapy

Curative treatment options for patients up to 75 years of age consist of adequate conditioning protocols with subsequent allogenic bone marrow or peripheral blood stem cell transplantation.

Molecular inhibitors (targeted therapies), such as tyrosine kinase inhibitors) (imatinib) .

Palliative treatment includes supportive care, conventional chemotherapy (incl. hydroxyurea), radiotherapy, and use of cytokines (interferon α)

Polycythemia Rubra Vera (PRV)

Definition

A neoplastic stem cell disorder possessing a JAK-2 mutation, which leads to excessive production of all myeloid cell lines, but predominantly red cells.

Pathology

A. Bone Marrow

Initially hypercellular bone marrow with distinct proliferation of all three cell lineages with emphasis on erythropoiesis .

Further disease progression fibrosis

Pathology

B. Peripheral Blood

Normochromic normocytic erythrocytosis, hematocrit ↑↑.

Thrombocytosis in > 50% of cases.

Neutrophilia and basophilia.

Clinical Picture

The clinical course is characterized by two phases:

Initial proliferative phase with increased erythrocyte count

“Spent phase” with increasing cytopenia, bone marrow fibrosis, extramedullary hematopoiesis and progressive splenomegaly

Symptoms & signs

Symptoms are due to

A.Increased blood viscosity, B.Pathologic microcirculation, C.Hypertension, and D.The underlying malignancy

Clinical Picture Erythema (plethora), lip cyanosis Dizziness, headache, tinnitus, impaired

vision Manifestations of malignancy: Fatigue,

weakness, reduced performance: Fever, night sweats, weight loss

Vascular symptoms: TIA, intermittent claudication, Raynaud’s syndrome

Bleeding from duodenal / stomach ulcers,esophageal varices, epistaxis

Splenomegaly, hepatomegaly Pruritus Erythromelalgia “burning feet syndrome”

Laboratory Tests

CBC: hematocrit ↑↑, erythrocytes ↑↑, platelets ↑, granulocytes ↑.

Routine laboratory tests Uric acid ↑ LDH ↑ vitamin B12 ↑ serum iron ↓, ferritin ↓

Leukocyte alkaline phosphatase ↑↑

Erythropoietin level ↓↓Analysis of JAK-2 mutation status

(V617F)

Revised WHO criteria for PV

Major criteria

1 .Hemoglobin ≥18.5 g/dL in men, 16.5 g/dL in women

2 .Presence of JAK2 V 617F

Minor criteria 1. Hypercellular BM with panmyelosis and prominent erythroid

2. Serum erythropoietin level

3. Endogenous erythroid colony formation in vitro Diagnosis = 2 major + 1 minor or first major + 2 minor

Differential Diagnosis

A.Secondary Polycythemia Dehydration, pulmonary / cardiac disease Sleep apnea syndrome, smoking Height adaptation (stay at heights of >

2,000 m) Hemoglobinopathies, methemoglobinemia

B. Erythropoietin ↑↑ Renal disorder Paraneoplastic syndromes (renal cell

carcinoma cerebellar hemangioblastoma, lung cancer, pheochromocytoma

Complications

HypertensionHypervolemia with

hyperviscosity and pathologic microcirculation (pulmonary / cerebral / renal)

Thromboembolic events / hemorrhage (platelet dysfunction)

Development of osteomyelo-fibrosis

Transformation to Acute Leukemia

Treatment

1. Phlebotomy: One unit of blood (approximately 500 mL) is removed weekly until the hematocrit is < 45%; the hematocrit is maintained at < 45% by repeated phlebotomy as necessary.

2. Chemotherapy: Patients for whom phlebotomy is problematic (because of poor venous access) may be managed primarily with hydroxyurea

Therapy

3. Allogeneic bone marrow or stem cell transplantation in patients < 70–75 years with severe polycythemia

4. Inhibitors of mutated JAK2 (investigational)

Symptomatic Treatment

Pruritus: antihistamines, H2 receptor inhibitors, cholestyramine, serotonin re-uptake inhibitors

Hyperuricemia: allopurinol 100–300 mg/day p.o.

Thrombocytosis: acetylsalicylic acid 100 mg/daily p.o., anagrelide 0.5–1 mg/day p.o.

Erythromelalgia: acetylsalicylic acid 100 mg/daily p.o., reduction of platelet count

Prognosis •Ten-year survival: 40–50% of

patients • Median survival: 9–12 years

Essential Thrombocythemia

Definition

Hematopoietic stem cell disease with clonal

expansion of thrombocytopoiesis and

thrombocytosis > 450,000/μl.

Epidemiology

Median age at presentation 60–70 years Male: female = 3:4 Incidence 1–2 cases/1,000,000/year

Pathology

A. Bone Marrow Pronounced proliferation of large mature

megakarocytes. No signs of leukoerythroblastosis.

B. Peripheral Blood Thrombocytosis > 450,000/μl, “giant platelets,” platelet aggregates

Clinical PictureA.Initially usually asymptomatic, often

accidental diagnosis.

B.Symptoms due to thrombocytic complications:

Weight loss, mild fever, sweating, pruritus Cerebral, cardiac, or peripheral arterial

thrombosis Deep vein thrombosis of the leg, pulmonary

emboli Hemorrhage Splenomegaly Skin symptoms: erythromelalgia (“burning

feet syndrome”), ischemic acrocyanosis, and even gangrene

Laboratory Tests

CBC: thrombocytosis > 450,000/μlRoutine laboratory tests :

LDH ↑ serum K+ often ↑↑ (pseudohyperkalemia

due to K+ release from platelets).Leukocyte alkaline phosphatase:

normal / ↑ .Platelet function test, bleeding timeAnalysis of JAK-2 mutation status

(V617F)

WHO criteria for diagnosis of essential thrombocythemia

(ET)A. Sustained platelet count ≥ 450 χ 109/L

B. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes

C. Not meeting WHO criteria for PV, PMF, CML, MDS, or other myeloid neoplasm

D. Demonstration of JAK2 V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis

Diagnosis requires meeting all 4 criteria.

D.DA. Other myeloproliferative

neoplasms (CML, CIMF, PV)

B. Myelodysplastic syndromes (MDS)

C. Secondary thrombocytosis − Following splenectomy

− Chronic iron deficiency, hemolytic anemia, blood loss

− Acute-phase reaction to infection / tumors / vasculitis / allergic reactions, etc.

Treatment

1. Observation2. ASA: 100 mg od3. Chemotherapy : hydroxyurea

0.5–1.5 g/day4. Anagrelide (dipyridamole analog)

Action: inhibits the phosphodiesterase and phospholipase A2 leading to inhibition of megakaryopoiesis and the thrombopoiesis5. Interferon-α 3–5 × 106 IU s.c. 3

times weekly, pegylated interferon-α 50–100/μg weekly.

Prognosis

Essential thrombocythemia patients have an almost normal life expectancy.

Chronic Idiopathic Myelofibrosis (CIMF)

Definition

Malignant stem cell disease with BM fibrosis and successive suppression of hematopoietic active bone marrow.

Epidemiology

Incidence 3–15/1,000,000/year. Median age at presentation 50–70

years:greater incidence in men

Pathogenesis

Clonal myeloproliferation, atypical megakaryocytic hyperplasia

→ Stimulation of normal fibroblasts, collagen synthesis, angiogenesis in response to increased PDGF.

→Increasing reactive bone marrow fibrosis (transition of prefibrotic to fibrotic stage)

→ Suppression of normal hematopoiesis and anemia

→Extramedullary hematopoiesis in spleen, liver, and other organs

Symptoms &signs

A) Initially asymptomatic, often diagnosed accidentally.

B) As bone marrow fibrosis increases and

normal hematopoiesis decreases: General symptoms (reduced performance

status, anorexia, weight loss, fever, possibly night sweats)

Anemia, weakness, fatigue, decreased performance, pallor

leukopenia: susceptibility to infection, mucositis Thrombocytopenia: tendency to bleed

(gastrointestinal bleeding), petechiae Splenomegaly, hepatomegaly (extramedullary

hematopoiesis)

Laboratory Findings

Patients are almost invariably anemic at presentation. The white blood count is variable—either low, normal,

or elevated). The platelet count is variable. The peripheral blood smear is dramatic, with

significant poikilocytosis and numerous teardrop forms in the red cell line. Nucleated red blood cells are present and the myeloid series is shifted, with immature forms including a

small percentage of promyelocytes or myeloblasts. Platelet morphology may be bizarre, and giant degranulated

platelet forms (megakaryocyte fragments) may be seen. The triad of teardrop poikilocytosis, leukoerythroblastic

blood, and giant abnormal platelets is highly suggestive of myelofibrosis.

The bone marrow usually cannot be aspirated (dry tap), though early in the course of the disease it is hypercellular, with a marked increase in megakaryocytes. Fibrosis at this stage is detected by a silver stain demonstrating increased reticulin fibers.

Later, biopsy reveals more severe fibrosis, with eventual replacement of hematopoietic precursors by collagen.

There is no characteristic chromosomal abnormality. JAK2 is mutated in ~65% of cases.

D.D

A. Other myeloproliferative syndromes (CML, essential thrombocythemia, polycythemia vera)

B. Aplastic anemia, bone marrow metastases

C. Chronic infections (miliary tuberculosis, histoplasmosis)

Treatment Anemic patients are supported with transfusion.

Anemia can also be controlled with androgens, prednisone, thalidomide, or lenalidomide.

First-line therapy for myelofibrosis-associated splenomegaly is hydroxyurea, which is effective in reducing spleen size by half in approximately 40% of patients.

Radiation therapy has a role for painful sites of extramedullary hematopoiesis, pulmonary hypertension, or severe bone pain.

Transjugular intrahepatic portosystemic shunt might also be considered to alleviate symptoms of portal hypertension.

The immunomodulatory medications, lenalidomide and pomalidomide, result in control of anemia in 25% and thrombocytopenia in ~58% of cases, without significant reduction in splenic size.

There are several JAK2 inhibitors in development. Ruxolitinib, a JAK2 inhibitor, has been approved by the US Food

and Drug Administration for myelofibrosis. Even though treatment with ruxolitinib can exacerbate cytopenias, it results in reduction of spleen size, improvement of constitutional symptoms, and may lead to an overall survival benefit in patients with an intermediateor high-risk disease.

The only potentially curative option for this disease is allogeneic stem cell transplantation in selected patients.

CHRONIC MYELOID LEUKEMIA

Definition

CML is a myeloproliferative disorder characterized by overproduction of myeloid cells. These myeloid cells continue to differentiate and circulate in increased numbers in the peripheral blood.

General Considerations

CML is characterized by a specific chromosomal abnormality and specific molecular abnormality. The Philadelphia chromosome is a reciprocal translocation between the long arms of chromosomes 9 and 22. The portion of 9q that is translocated contains abl, a protooncogene that is the cellular homolog of the Ableson murine leukemia virus.

The abl gene is received at a specific site on 22q, the break point cluster (bcr). The fusion gene bcr/abl produces a novel protein that differs from the normal transcript of the abl gene in that it possesses tyrosine kinase activity. This disorder is the first example of tyrosine kinase “addiction” by cancer cells.

Early CML (“chronic phase”) does not behave like a malignant disease. Normal bone marrow function is

retained, white blood cells differentiate and, despite some qualitative abnormalities, the neutrophils combat infection normally.

However, untreated CML is inherently unstable, and without treatment the disease progresses to an accelerated and then acute blast phase, which is morphologically indistinguishable from acute leukemia.

bcr

abl

fusion 9abl/bcr

fusion 22bcr/abl

Clinical FindingsSymptoms and Signs CML is a disorder of middle age (median age at

presentation is 55 years).

Patients usually complain of fatigue, night sweats, and low-grade fevers related to the hypermetabolic state caused by overproduction of white blood cells.

Patients may also complain of abdominal fullness related to splenomegaly.

Rarely, the patient will present with a clinical syndrome related to leukostasis with blurred vision, respiratory distress, or priapism. The white blood count in these cases is usually < 500,000/mcL (500 × 109/L).

Physical Examination

On examination, the spleen is enlarged (often markedly so), and sternal tenderness may be present as a sign of marrow overexpansion.

Acceleration of the disease is often associated with fever in the absence of infection, bone pain, and splenomegaly.

Laboratory Findings

CML is characterized by an elevated white blood count; the median white blood count at diagnosis is 150,000/mcL (150 × 109/L) .

The peripheral blood is characteristic. The myeloid series is left shifted, with mature forms dominating and

with cells usually present in proportion to their degree of maturation. Blasts are usually < 5%. Basophilia and eosinophilia of granulocytes may be present. At presentation, the patient is usually not anemic. Red blood cell morphology is normal, and nucleated red blood cells

are rarely seen. The platelet count may be normal or elevated (sometimes to strikingly high levels).

The bone marrow is hypercellular, with left-shifted myelopoiesis. Myeloblasts comprise < 5% of marrow cells.

The hallmark of the disease is that the bcr/abl gene is detected by the PCR test in the peripheral blood.

A bone marrow examination is not necessary for diagnosis, although it is useful for prognosis and for detecting other chromosomal abnormalities in addition to the Philadelphia chromosome.

With progression to the accelerated and blast phases, progressive anemia and thrombocytopenia occur, and the percentage of blasts in the blood and bone marrow

increases.

Blast phase CML is diagnosed when blasts comprise more than 20% of bone marrow cells.

Differential Diagnosis Early CML must be differentiated from the reactive

leukocytosis associated with infection. In such cases, the white blood count is usually < 50,000/mcL (< 50 × 109/L), splenomegaly is absent, and the bcr/abl gene is not present.

CML must be distinguished from other myeloproliferative disease . The hematocrit should not be elevated, the red blood cell morphology is normal, and nucleated red blood cells are rare or absent. Definitive diagnosis is made by finding the bcr/abl gene.

Treatment

Goals of Treatment Normalization of the hematologic

abnormalities

Suppression of the malignant, bcr/abl-expressing clone.

The treatment of choice consists of a tyrosine kinase inhibitor targeting the aberrantly active abl kinase.

It is expected that a hematologic complete remission, with normalization of blood counts and splenomegaly will occur within 3 months of treatment initiation.

Second, a major cytogenetic response should be achieved, ideally within 3 months but certainly within 6 months.

Lastly, a major molecular response is desired within 12 months and is defined as a 3-log reduction of the bcr/abl transcript as measured by quantitative PCR.

Patients who achieve this level of molecular response have an excellent prognosis, with 100% of such patients remaining free of progression at 8 years.

Imatinib mesylate was the first tyrosine kinase inhibitor to be approved and it results in nearly universal (98%) hematologic control of chronic phase disease at a dose of 400 mg/d.

The second-generation tyrosine kinase inhibitors, dasatinib and nilotinib, have also been approved for use as front-line therapy and have been shown to significantly increase the rate of achievement of a major molecular response compared to imatinib .

A dual bcr/abl tyrosine kinase inhibitor, bosutinib, was approved in 2012 for patients who are resistant or intolerant to the other tyrosine kinase inhibitors.

Patients who cannot achieve a good molecular response to any of these agents or progress following therapy should be considered for treatment with allogeneic transplantation.

Patients with advanced-stage disease (accelerated phase or myeloid/lymphoid blast crisis) should be treated with a tyrosine kinase inhibitor alone or in combination with myelosuppressive chemotherapy.

The doses of tyrosine kinase inhibitors in that setting

are usually higher than those appropriate for chronic-phase disease.

Since the duration of response to tyrosine kinase inhibitors in this setting is limited, these patients should ultimately be considered for allogeneic stem cell transplantation.

Course & Prognosis

Patients with good molecular responses to tyrosine kinase inhibitor therapy have an excellent prognosis, with essentially 100% survival at 9 years, and it is likely that some fraction of these patients will be cured.

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Monkez M Yousif