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By
Dr MONKEZ MYOUSIF
Professor of Internal Medicine
Zagazig university
2016
MPNs are clonal diseases
Originating in multipotential hematopoietic progenitor cell
Characterized by independence of nume...
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 survival
P P
Cell Membrane...
Systemic mastocytosis
Polycythemia vera
Essential thrombocythemia
Hypereosinophilic syndrome
Myeloproliferative Neoplasms
...
 Incidence: 2–3 cases/100,000 population/year
 male: female = 1:1
A. Classic Disorders
- Philadelphia +ve :
Chronic myeloid leukemia (CML)
- Philadelphia –ve :
Polycythemia vera (PV)
Essen...
• CML, polycythemia, and essential thrombocythemia may
evolve into chronic myelofibrosis.
• All myeloproliferative disorde...
MPN have been caused by mutations
in tyrosine kinases
A. CML: Philadelphia chromosome: t(9;22),
BCR / ABL oncogene
B. PV, ET, CIMF: point mutation (V617F) of the
tyrosine kinas...
JAK2
JAK2 V617F is always on!!!
What does JAK2 normally do?
It is a switch that tells blood cells to grow
JAK2
StatStat
St...
JAK2V617F prevalence in MPN
PV 99%
ET ~50%
MF ~50%
 Overproduction of one or several blood
elements with dominance of a transformed
clone.
 Hypercellular marrow/marrow fib...
V617F
JAK-2
Ph
Chrom
Marrow
Fibrosis
LAP
Index
Spleno
megaly
Throm
ocytes
Leuko
cytes
HctDisease
-+++n/+↓+++↑/n/↓↑↑↑n/↓CML...
 Curative treatment options for patients up to 75 years
of age consist of adequate conditioning protocols with
subsequent...
A neoplastic stem cell disorder possessing
a JAK-2 mutation, which leads to
excessive production of all myeloid cell
lines...
A. Bone Marrow
 Initially hypercellular bone marrow with
distinct proliferation of all three cell lineages
with emphasis ...
B. Peripheral Blood
 Normochromic normocytic erythrocytosis,
hematocrit ↑↑.
 Thrombocytosis in > 50% of cases.
 Neutrop...
The clinical course is characterized by two phases:
 Initial proliferative phase with increased
erythrocyte count
 “Spen...
Symptoms are due to
A.Increased blood viscosity,
B.Pathologic microcirculation,
C.Hypertension, and
D.The underlying malig...
 Erythema (plethora), lip cyanosis
 Dizziness, headache, tinnitus, impaired vision
 Manifestations of malignancy: Fatig...
 CBC: hematocrit ↑↑, erythrocytes ↑↑,
platelets ↑, granulocytes ↑.
 Routine laboratory tests
 Uric acid ↑
 LDH ↑
 vit...
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. Hypercellu...
A. Secondary Polycythemia
 Dehydration, pulmonary / cardiac disease
 Sleep apnea syndrome, smoking
 Height adaptation (...
 Hypertension
 Hypervolemia with hyperviscosity and
pathologic microcirculation (pulmonary /
cerebral / renal)
 Thrombo...
1. Phlebotomy: One unit of blood (approximately
500 mL) is removed weekly until the hematocrit is
< 45%; the hematocrit is...
3. Allogeneic bone marrow or stem cell
transplantation in patients < 70–75 years
with severe polycythemia
4. Inhibitors of...
 Pruritus: antihistamines, H2 receptor inhibitors,
cholestyramine, serotonin re-uptake inhibitors
 Hyperuricemia: allopu...
 Prognosis
•Ten-year survival: 40–50% of patients
• Median survival: 9–12 years
Hematopoietic stem cell disease with clonal
expansion of thrombocytopoiesis and
thrombocytosis > 450,000/μl.
 Median age at presentation 60–70 years
 Male: female = 3:4
 Incidence 1–2 cases/1,000,000/year
A. Bone Marrow
 Pronounced proliferation of large mature
megakarocytes.
 No signs of leukoerythroblastosis.
B. Periphera...
A. Initially usually asymptomatic, often accidental diagnosis.
B. Symptoms due to thrombocytic complications:
 Weight los...
 CBC: thrombocytosis > 450,000/μl
 Routine laboratory tests :
 LDH ↑
 serum K+ often ↑↑ (pseudohyperkalemia due to K+
...
A. Sustained platelet count ≥ 450 χ 109/L
B. Bone marrow biopsy specimen showing proliferation
mainly of the megakaryocyti...
A. Other myeloproliferative neoplasms (CML,
CIMF, PV)
B. Myelodysplastic syndromes (MDS)
C. Secondary thrombocytosis
− Fol...
1. Observation
2. ASA: 100 mg od
3. Chemotherapy : hydroxyurea 0.5–1.5 g/day
4. Anagrelide (dipyridamole analog)
Action: i...
Essential thrombocythemia patients have
an almost normal life expectancy.
Malignant stem cell disease with BM fibrosis
and successive suppression of hematopoietic
active bone marrow.
 Incidence 3–15/1,000,000/year.
 Median age at presentation 50–70 years:
 greater incidence in men
Clonal myeloproliferation, atypical megakaryocytic hyperplasia
→ Stimulation of normal fibroblasts, collagen synthesis,
an...
A) Initially asymptomatic, often diagnosed accidentally.
B) As bone marrow fibrosis increases and normal
hematopoiesis dec...
 Patients are almost invariably anemic at presentation.
 The white blood count is variable—either low, normal, or
elevat...
 The bone marrow usually cannot be aspirated (dry
tap), though early in the course of the disease it is
hypercellular, wi...
A. Other myeloproliferative syndromes (CML,
essential thrombocythemia, polycythemia vera)
B. Aplastic anemia, bone marrow ...
 Anemic patients are supported with transfusion. Anemia can
also be controlled with androgens, prednisone, thalidomide, o...
 The immunomodulatory medications, lenalidomide and
pomalidomide, result in control of anemia in 25% and
thrombocytopenia...
 CML is a myeloproliferative disorder
characterized by overproduction of myeloid
cells. These myeloid cells continue to
d...
 CML is characterized by a specific chromosomal abnormality
and specific molecular abnormality. The Philadelphia
chromoso...
 Early CML (“chronic phase”) does not behave like a
malignant disease.
 Normal bone marrow function is retained, white
b...
bcr
abl
fusion 9
abl/bcr
fusion 22
bcr/abl
Symptoms and Signs
 CML is a disorder of middle age (median age at presentation is 55
years).
 Patients usually complain...
 On examination, the spleen is enlarged
(often markedly so), and sternal tenderness
may be present as a sign of marrow
ov...
 CML is characterized by an elevated white blood count; the
median white blood count at diagnosis is 150,000/mcL (150 × 1...
 The hallmark of the disease is that the bcr/abl gene is
detected by the PCR test in the peripheral blood.
 A bone marro...
 Early CML must be differentiated from the reactive
leukocytosis associated with infection. In such cases,
 the white bl...
 Goals ofTreatment
 Normalization of the hematologic abnormalities
 Suppression of the malignant, bcr/abl-expressing
cl...
 The treatment of choice consists of a tyrosine kinase
inhibitor targeting the aberrantly active abl kinase.
 It is expe...
 Imatinib mesylate was the first tyrosine kinase inhibitor
to be approved and it results in nearly universal (98%)
hemato...
 Patients who cannot achieve a good
molecular response to any of these agents or
progress following therapy should be
con...
 Patients with advanced-stage disease (accelerated
phase or myeloid/lymphoid blast crisis) should be
treated with a tyros...
 Patients with good molecular responses to
tyrosine kinase inhibitor therapy have an
excellent prognosis, with essentiall...
69
Monkez M Yousif
Myeloproliferative neoplasms for students
Myeloproliferative neoplasms for students
Myeloproliferative neoplasms for students
Myeloproliferative neoplasms for students
Myeloproliferative neoplasms for students
Myeloproliferative neoplasms for students
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Myeloproliferative neoplasms for students

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This presentation is prepared for undergraduate students about the various myeloproliferative neoplasms with updated information.

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Myeloproliferative neoplasms for students

  1. 1. By Dr MONKEZ MYOUSIF Professor of Internal Medicine Zagazig university 2016
  2. 2. 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
  3. 3. Myeloproliferative disease can develop in any one of these cell types Normal development of blood cells
  4. 4. TK Growth Factors And Tyrosine Kinase Signaling Pathways TK StatStat StatStat Proliferation and survival P P Cell Membrane Cell nucleus Growth Factors PP Erythropoietin Thrombopoietin GM-CSF
  5. 5. Systemic mastocytosis Polycythemia vera Essential thrombocythemia Hypereosinophilic syndrome Myeloproliferative Neoplasms Chronic myeloid leukemia Myelomonocytic leukemia Myelofibrosis
  6. 6.  Incidence: 2–3 cases/100,000 population/year  male: female = 1:1
  7. 7. 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
  8. 8. • CML, polycythemia, and essential thrombocythemia may evolve into chronic myelofibrosis. • All myeloproliferative disorders carry an increased risk of transformation to acute myeloid leukemia (AML).
  9. 9. MPN have been caused by mutations in tyrosine kinases
  10. 10. 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.
  11. 11. 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 survival P P Cell Membrane Cell nucleus Erythropoietin independence Valine 617 Phenylalanine
  12. 12. JAK2V617F prevalence in MPN PV 99% ET ~50% MF ~50%
  13. 13.  Overproduction 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 → hyperuricemia  Extramedullary hematopoiesis (liver/spleen).  Transformation to acute leukemia.  Overlapping clinical features.
  14. 14. V617F JAK-2 Ph Chrom Marrow Fibrosis LAP Index Spleno megaly Throm ocytes Leuko cytes HctDisease -+++n/+↓+++↑/n/↓↑↑↑n/↓CML +++-+↑↑+↑↑↑↑↑PV +-±n/↑+↑↑↑n/↑nET +-↑↑↑↑+++↑/n/↓↑/n/↓↓CIMF
  15. 15.  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)
  16. 16. A neoplastic stem cell disorder possessing a JAK-2 mutation, which leads to excessive production of all myeloid cell lines, but predominantly red cells.
  17. 17. A. Bone Marrow  Initially hypercellular bone marrow with distinct proliferation of all three cell lineages with emphasis on erythropoiesis .  Further disease progression fibrosis
  18. 18. B. Peripheral Blood  Normochromic normocytic erythrocytosis, hematocrit ↑↑.  Thrombocytosis in > 50% of cases.  Neutrophilia and basophilia.
  19. 19. 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
  20. 20. Symptoms are due to A.Increased blood viscosity, B.Pathologic microcirculation, C.Hypertension, and D.The underlying malignancy
  21. 21.  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”
  22. 22.  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)
  23. 23. 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
  24. 24. 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
  25. 25.  Hypertension  Hypervolemia with hyperviscosity and pathologic microcirculation (pulmonary / cerebral / renal)  Thromboembolic events / hemorrhage (platelet dysfunction)  Development of osteomyelo-fibrosis  Transformation to Acute Leukemia
  26. 26. 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
  27. 27. 3. Allogeneic bone marrow or stem cell transplantation in patients < 70–75 years with severe polycythemia 4. Inhibitors of mutated JAK2 (investigational)
  28. 28.  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
  29. 29.  Prognosis •Ten-year survival: 40–50% of patients • Median survival: 9–12 years
  30. 30. Hematopoietic stem cell disease with clonal expansion of thrombocytopoiesis and thrombocytosis > 450,000/μl.
  31. 31.  Median age at presentation 60–70 years  Male: female = 3:4  Incidence 1–2 cases/1,000,000/year
  32. 32. A. Bone Marrow  Pronounced proliferation of large mature megakarocytes.  No signs of leukoerythroblastosis. B. Peripheral Blood  Thrombocytosis > 450,000/μl,  “giant platelets,”  platelet aggregates
  33. 33. A. 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
  34. 34.  CBC: thrombocytosis > 450,000/μl  Routine laboratory tests :  LDH ↑  serum K+ often ↑↑ (pseudohyperkalemia due to K+ release from platelets).  Leukocyte alkaline phosphatase: normal / ↑ .  Platelet function test, bleeding time  Analysis of JAK-2 mutation status (V617F)
  35. 35. 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 meetingWHO criteria for PV, PMF, CML, MDS, or other myeloid neoplasm D. Demonstration of JAK2V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis Diagnosis requires meeting all 4 criteria.
  36. 36. A. 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.
  37. 37. 1. Observation 2. ASA: 100 mg od 3. Chemotherapy : hydroxyurea 0.5–1.5 g/day 4. Anagrelide (dipyridamole analog) Action: inhibits the phosphodiesterase and phospholipase A2 leading to inhibition of megakaryopoiesis and the thrombopoiesis 5. Interferon-α 3–5 × 106 IU s.c. 3 times weekly, pegylated interferon-α 50–100/μg weekly.
  38. 38. Essential thrombocythemia patients have an almost normal life expectancy.
  39. 39. Malignant stem cell disease with BM fibrosis and successive suppression of hematopoietic active bone marrow.
  40. 40.  Incidence 3–15/1,000,000/year.  Median age at presentation 50–70 years:  greater incidence in men
  41. 41. 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
  42. 42. 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)
  43. 43.  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.
  44. 44.  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.
  45. 45. A. Other myeloproliferative syndromes (CML, essential thrombocythemia, polycythemia vera) B. Aplastic anemia, bone marrow metastases C. Chronic infections (miliary tuberculosis, histoplasmosis)
  46. 46.  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.
  47. 47.  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.
  48. 48.  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.
  49. 49.  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.
  50. 50.  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.
  51. 51. bcr abl fusion 9 abl/bcr fusion 22 bcr/abl
  52. 52. Symptoms 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).
  53. 53.  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.
  54. 54.  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.
  55. 55.  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.
  56. 56.  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.
  57. 57.  Goals ofTreatment  Normalization of the hematologic abnormalities  Suppression of the malignant, bcr/abl-expressing clone.
  58. 58.  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.
  59. 59.  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.
  60. 60.  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.
  61. 61.  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.
  62. 62.  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.
  63. 63. 69 Monkez M Yousif

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