CHRONIC
MYELOGENOUS
LEUKEMIA
Definition, History & Epidemiology
Etiology and Pathogenesis
Clinical Features
Diagnosis
Course and special clinical situa...
The 2008 World Health Organization Classification
System for Myeloproliferative Neoplasms
DEFINITION
• Chronic myelogenous leukemia (CML) - pluripotential
stem cell disease characterized by
• Anemia
• Extreme blo...
HISTORY
• In 1845, Bennett in Scotland and Virchow in Germany
described splenic enlargement, severe anemia, and
leukocytos...
EPIDEMIOLOGY
• CML - 15 %of all cases of Leukemia
• US Incidence ~ 2 per lakh persons for men and 1.1 per
lakh persons for...
EPIDEMIOLOGY
7
ETIOPATHOGENESIS
1. Environmental Leukemogens
• Very high doses of ionizing radiation*
• Chemical leukemogens - benzene an...
Etiopathogenesis
9
2. The stem cell
2. The stem cell
Etiopathogenesis
10
CML Stem Cell
2. The stem cell
• Acquisition of the BCR-ABL fusion gene in a single
multipotential hematopoietic cell  CML stem cell
• ...
2. The stem cell
• The CML stem cells
have no regulation of
proliferation
• Mediated by IL3 –
GCSF autocrine loop
• Immatu...
3. BCR-ABL protein (Tyrosine Kinase)
• BCR (breakpoint cluster region) gene on chromosome
22 fused to the ABL (Ableson leu...
3. BCR-ABL (Tyrosine Kinase)
Etiopathogenesis
14
Altered
adhesion
•No adhesion to
marrow stroma
•Reduced
regulation by
mar...
CLINICAL FEATURES
A. Symptoms
• At diagnosis – 70% symptomatic
• Easy fatigability
• Loss of sense of well-being
• Decreas...
A. Symptoms
• Uncommon symptoms
• Night sweats
• Heat intolerance
• Gouty arthitis
• Left upper-quadrant and left shoulder...
Clinical features
17
Acute febrile neutrophilic
dermatosis (Sweet syndrome)
A. Symptoms
B. Signs
• Pallor
• Splenomegaly
• Sternal tenderness
• Rarely hepatomegaly,
lymphadenopathy – Poor
prognostic indicators
...
DIAGNOSIS
A. Laboratory studies
Blood counts and blood smear
• Hemoglobin concentration is decreased
• Nucleated red cells...
A. Laboratory studies
Diagnosis
20
Peripheral smear
A. Laboratory studies
Diagnosis
21
Bone marrow
Hypercellular
Replacement of fat
Granulopoiesis
Megakaryocytopoiesis
Erythr...
A. Laboratory studies
Bone Marrow studies
• Mitotic figures are increased
• Macrophages that mimic
Gaucher cells *
• Macro...
A. Laboratory studies
Other lab features :
• Neutrophil Alkaline Phosphatase reduced
• Serum B12 and transcobalamin increa...
B. Cytogenetics
• Study of the number and structure of chromosomes
• Samples from bone marrow myeloid cells
• The presence...
B. Cytogenetics
Diagnosis
25
90%
C. Molecular Probes
i. FISH (Fluorescence In Situ Hybridization)
• Detect the BCR-ABL fusion gene on chromosome 22
• Quali...
C. Molecular Probes
ii. PCR (Polymerase Chain Reaction)
• Most sensitive test to identify and measure the BCR-ABL
gene (Qu...
COURSE OF THE DISEASE
• CML has 3 phases
28
I. Chronic Phase
• Most patients are asymptomatic
• Incidental leukocytosis/sp...
II. Accelerated phase
defined by
• 10%–19% blasts in blood or bone marrow
• >20% basophils in blood or bone marrow
• Throm...
III. Blast Crisis
defined by
• ≥20% blasts in blood or bone marrow
• Extramedullary blastic infiltration (Chloroma)
• Rese...
Special Clinical situations
Neutrophilic CML
• A rare variant of BCR-ABL–positive CML with elevated
white cell count princ...
Special Clinical situations
Hyperleukocytosis (15% of cases)
• Intravascular flow-impeding effects of white cell counts
gr...
Special Clinical situations
Concurrence of Lymphoid Malignancies
1. CML years after irradiation of non-Hodgkin or Hodgkin
...
DIFFERENTIAL DIAGNOSIS
• Polycythemia vera
• Essential thrombocythemia
• Primary myelofibrosis
• Leukemoid reactions
34
TREATMENT
1. Initial Cytoreduction Therapy
2. Tyrosine Kinase Inhibitor Therapy
3. Interferon therapy
4. Chemotherapy
5. A...
1. Initial therapy
• Allopurinol 300 mg/day orally with adequate hydration 
Rasburicase 0.2 mg/kg i.v (one doses) for Hyp...
2. Tyrosine Kinase inhibitor therapy
Treatment
37
First generation Second generation
Imatinib
Dasatinib
Nilotinib
Bosutini...
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
• Approved for use in Ph+ CML in 2001
• Preliminary studies showed ...
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
39
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
• Dosage –400 mg/day orally  400 mg BD
• Well tolerated
• Myelosup...
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
41
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
42
90-96%
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
43
~63%
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
44
National Comprehensive Cancer Network
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
45
European Leukemia Net
2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Four mechanisms of resistance
(1) Gene amplification
(2) Mutations ...
2. Tyrosine Kinase inhibitor therapy
2nd Generation TKI
1. Dasatinib
• Used in imatinib resistance or intolerance
• 325-fo...
2. Tyrosine Kinase inhibitor therapy
2nd Generation TKI
2. Nilotinib
• Used in imatinib resistance or intolerance
• 30 tim...
3. Interferon α
• IFNα was the initial therapy before TKI therapy
• Complete cytogenetic response – uncommon (13%)
• 50% r...
4. Chemotherapeutic Agents and other modalities
i. Cytarabine
• IFNα combined with cytarabine (20 mg/m2/day -10
days per m...
4. Chemotherapeutic Agents and other modalities
iii. Splenectomy*
• Delay the onset of the accelerated phase
• Enhance sen...
4. Chemotherapeutic Agents and other modalities
v. Omacetaxine (formerly Homoharringtonine)
• Protein translation inhibito...
5. Allogeneic Stem Cell Transplantation
• Allogeneic HSCT - complicated by mortality owing to the
procedure
(1) The patien...
6. Treatment of accelerated/blast phases
• Goal  achieve remission
• Else aim to reduce to chronic phase
• TKI – bridging...
7. Treatment of CML in pregnancy
• Untreated CML  placental insufficiency (leukostasis)
• Risk of teratogenicity with Ima...
8. Treatment cessation
• Despite achieving deep and lasting remissions
• CML is not curable
• Patients with remissions sti...
57
Treatment
CONCLUSION
• Imatinib has revolutionized the management of CML
• Long term survival is a reality now
• TKI therapy is stil...
Chronic Myeloid Leukemia
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Chronic Myeloid Leukemia

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Chronic myelogenous leukemia (CML) - pluripotential stem cell disease
A malignancy the treatment of which has been revolutionised over the last decade.
Here is a comprehensive discussion on the disease

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Chronic Myeloid Leukemia

  1. 1. CHRONIC MYELOGENOUS LEUKEMIA
  2. 2. Definition, History & Epidemiology Etiology and Pathogenesis Clinical Features Diagnosis Course and special clinical situations Differential Diagnosis Therapy 2
  3. 3. The 2008 World Health Organization Classification System for Myeloproliferative Neoplasms
  4. 4. DEFINITION • Chronic myelogenous leukemia (CML) - pluripotential stem cell disease characterized by • Anemia • Extreme blood granulocytosis and granulocytic immaturity • Basophilia • Thrombocytosis • Splenomegaly • Characteristic genetic change - Reciprocal translocation between chromosomes 9 and 22 (Philadelphia (Ph) chromosome) 4
  5. 5. HISTORY • In 1845, Bennett in Scotland and Virchow in Germany described splenic enlargement, severe anemia, and leukocytosis at autopsy • Virchow proposed the term leukämie • In 1878, Neumann proposed – marrow origin for leukemia – myelogene (myelogenus) • Nowell and Hungerford in 1960 identified the culprit gene at the Perelman School of Medicine, Philadelphia • Dr. Rowley identified the BCR-ABL translocation • 1998 – Discovery of targeted TKI therapy 5
  6. 6. EPIDEMIOLOGY • CML - 15 %of all cases of Leukemia • US Incidence ~ 2 per lakh persons for men and 1.1 per lakh persons for women • Sparse Indian data - 0.8–2.2/lakh in men and 0.6– 1.6/lakh in women • 50-70% of leukemias in India • Male predominance (1.4:1) • Average age at presentation – 50 yrs • Incidence is least in Swedes 6
  7. 7. EPIDEMIOLOGY 7
  8. 8. ETIOPATHOGENESIS 1. Environmental Leukemogens • Very high doses of ionizing radiation* • Chemical leukemogens - benzene and alkylating agents – are not causative – increased incidence of AML • No concordance of the disease between identical twins • Several large studies – no links with smoking/diet/lifestyle 8
  9. 9. Etiopathogenesis 9 2. The stem cell
  10. 10. 2. The stem cell Etiopathogenesis 10 CML Stem Cell
  11. 11. 2. The stem cell • Acquisition of the BCR-ABL fusion gene in a single multipotential hematopoietic cell  CML stem cell • Majority of these cells would be in G0 phase of the cell cycle • These BCR-ABL stem cells favor differentiation over self- renewal • Ph chromosome is found on myeloid, monocytic, erythroid, megakaryocytic, B-cells and sometimes T-cell proof that CML derived from pluripotent stem cell Etiopathogenesis 11
  12. 12. 2. The stem cell • The CML stem cells have no regulation of proliferation • Mediated by IL3 – GCSF autocrine loop • Immature granulocytes >> mature granulocytes Etiopathogenesis 12
  13. 13. 3. BCR-ABL protein (Tyrosine Kinase) • BCR (breakpoint cluster region) gene on chromosome 22 fused to the ABL (Ableson leukemia virus) gene on chromosome 9 • The fusion protein derived from the BCR-ABL gene is a tyrosine kinase enzyme • This particular protein is seen in small amounts normally* • The ABL gene  regulated tyrosine kinase • BCR-ABL  unregulated tyrosine kinase Etiopathogenesis 13
  14. 14. 3. BCR-ABL (Tyrosine Kinase) Etiopathogenesis 14 Altered adhesion •No adhesion to marrow stroma •Reduced regulation by marrow factors Mitogenic activation •Activation of various pathways  proliferation Inhibition of apoptosis •Upregulation of Bcl-2 •Uninhibited proliferation
  15. 15. CLINICAL FEATURES A. Symptoms • At diagnosis – 70% symptomatic • Easy fatigability • Loss of sense of well-being • Decreased tolerance to exertion • Anorexia • Abdominal discomfort • Early satiety * • Weight loss • Excessive sweating 15
  16. 16. A. Symptoms • Uncommon symptoms • Night sweats • Heat intolerance • Gouty arthitis • Left upper-quadrant and left shoulder pain* • Urticaria • Hyperleukocytic Syndrome —dyspnea, tachypnea, hypoxia, lethargy, slurred speech Clinical features 16 Mimics thyrotoxicosis
  17. 17. Clinical features 17 Acute febrile neutrophilic dermatosis (Sweet syndrome) A. Symptoms
  18. 18. B. Signs • Pallor • Splenomegaly • Sternal tenderness • Rarely hepatomegaly, lymphadenopathy – Poor prognostic indicators Clinical features 18
  19. 19. DIAGNOSIS A. Laboratory studies Blood counts and blood smear • Hemoglobin concentration is decreased • Nucleated red cells in blood film • The leukocyte count above 25,000/μl (even > 1,00,000/μl), • Hypersegmented neutrophils • The basophil and eosinophil counts are increased (Absolute) • The platelet count is normal or increased • Blast cells ~ 3 % (<10% in the chronic phase) 19
  20. 20. A. Laboratory studies Diagnosis 20 Peripheral smear
  21. 21. A. Laboratory studies Diagnosis 21 Bone marrow Hypercellular Replacement of fat Granulopoiesis Megakaryocytopoiesis Erythropoiesis
  22. 22. A. Laboratory studies Bone Marrow studies • Mitotic figures are increased • Macrophages that mimic Gaucher cells * • Macrophages - engorged with lipids - yield ceroid pigment - imparting a granular and bluish cast - sea-blue histiocytes • Increased reticulin fibrosis (Collagen type III) * • Angiogenesis Diagnosis 22
  23. 23. A. Laboratory studies Other lab features : • Neutrophil Alkaline Phosphatase reduced • Serum B12 and transcobalamin increased (>10 ULN) • Serum uric acid increased • Lactate dehydrogenase increased • Mean histamine levels increased Diagnosis 23
  24. 24. B. Cytogenetics • Study of the number and structure of chromosomes • Samples from bone marrow myeloid cells • The presence of the Philadelphia chromosome – shortened chromosome 22* • Cytogenetics cannot identify complex translocations Diagnosis 24
  25. 25. B. Cytogenetics Diagnosis 25 90%
  26. 26. C. Molecular Probes i. FISH (Fluorescence In Situ Hybridization) • Detect the BCR-ABL fusion gene on chromosome 22 • Qualitative Diagnosis 26
  27. 27. C. Molecular Probes ii. PCR (Polymerase Chain Reaction) • Most sensitive test to identify and measure the BCR-ABL gene (Quantitative) • Can be performed on blood/marrow cells • Amplifies the BCR-ABL derived abnormal mRNA • One abnormal cell in one million cells can be detected Diagnosis 27
  28. 28. COURSE OF THE DISEASE • CML has 3 phases 28 I. Chronic Phase • Most patients are asymptomatic • Incidental leukocytosis/splenomegaly • Bleeding and infectious complications are uncommon in the chronic phase
  29. 29. II. Accelerated phase defined by • 10%–19% blasts in blood or bone marrow • >20% basophils in blood or bone marrow • Thrombocytosis, thrombocytopenia unrelated to therapy (<1 lakh>) • New clonal chromosome abnormalities • Anemia progresses and cause fatigue, loss of sense of well-being • Splenomegaly • Ranges from 4-5 years before progressing Course of the disease 29
  30. 30. III. Blast Crisis defined by • ≥20% blasts in blood or bone marrow • Extramedullary blastic infiltration (Chloroma) • Resembles acute leukemia • 2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic phase • Infection and bleeding common • Abdominal pain, bone pain • Survival is 6-12 months (worse for myeloid phenotype) Course of the disease 30
  31. 31. Special Clinical situations Neutrophilic CML • A rare variant of BCR-ABL–positive CML with elevated white cell count principally of mature neutrophils • WBC count lower than that of classic CML • Basophilia, myeloid immaturity in the blood, prominent splenomegaly, or low leukocyte alkaline phosphatase scores – are all absent! • Larger fusion protein than in classic CML • Usually has an indolent course • Now classified separately Course of the disease 31
  32. 32. Special Clinical situations Hyperleukocytosis (15% of cases) • Intravascular flow-impeding effects of white cell counts greater than 3,00,000/µL (upto 8 lakh) • Impaired circulation of the lung, central nervous system, special sensory organs, and penis • resulting in some combination of • Tachypnea, dyspnea, cyanosis, • Dizziness, slurred speech, delirium, stupor, • Visual blurring, diplopia, retinal vein distention, retinal hemorrhages, papilledema, • Tinnitus, impaired hearing, • And priapism Course of the disease 32
  33. 33. Special Clinical situations Concurrence of Lymphoid Malignancies 1. CML years after irradiation of non-Hodgkin or Hodgkin lymphoma 2. Accelerated phase  dedifferentiation of the CML clone  acute lymphoblastic transformation 3. Plasmacytic malignancies – positive association 4. Patients may present with Ph+ ALL, after chemotherapy-induced remission, develop the features of typical CML Course of the disease 33
  34. 34. DIFFERENTIAL DIAGNOSIS • Polycythemia vera • Essential thrombocythemia • Primary myelofibrosis • Leukemoid reactions 34
  35. 35. TREATMENT 1. Initial Cytoreduction Therapy 2. Tyrosine Kinase Inhibitor Therapy 3. Interferon therapy 4. Chemotherapy 5. Allogeneic Stem Cell Transplantation 6. Treatment of accelerated/blast phases 7. Treatment of CML in pregnancy 8. Treatment cessation 35
  36. 36. 1. Initial therapy • Allopurinol 300 mg/day orally with adequate hydration  Rasburicase 0.2 mg/kg i.v (one doses) for Hyperuricemia* • Leukapheresis – helps reduce leucocyte burden, only in conjunction with definitive therapy • Hydroxyurea - Reversible suppression of hematopoiesis 1 to 6 g/day orally (titre based on counts) • Anagrelide – to reduce the platelet burden Treatment 36
  37. 37. 2. Tyrosine Kinase inhibitor therapy Treatment 37 First generation Second generation Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Bafetinib
  38. 38. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate • Approved for use in Ph+ CML in 2001 • Preliminary studies showed a remarkable cytogenic remission • Hematological remission was seen in 95% • Now the treatment of choice for CML Treatment 38
  39. 39. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 39
  40. 40. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate • Dosage –400 mg/day orally  400 mg BD • Well tolerated • Myelosuppression is common in CML patients • Elevated hepatic transaminases (Acute liver failure described) • Periorbital edema • Cutaneous reactions • Osteoporosis Treatment 40
  41. 41. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 41
  42. 42. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 42 90-96%
  43. 43. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 43 ~63%
  44. 44. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 44 National Comprehensive Cancer Network
  45. 45. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 45 European Leukemia Net
  46. 46. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Four mechanisms of resistance (1) Gene amplification (2) Mutations at the kinase site (3) Enhanced expression of multidrug exporter proteins (4) Alternative signaling pathways compensating imatinib-sensitive mechanisms. Treatment 46
  47. 47. 2. Tyrosine Kinase inhibitor therapy 2nd Generation TKI 1. Dasatinib • Used in imatinib resistance or intolerance • 325-fold more potent than imatinib • 100 mg/day, administered in chronic phase CML • Unlike imatinib, dasatinib penetrates the blood–brain barrier • Cytopenia, followed by fluid retention, diarrhea, and skin rash Treatment 47
  48. 48. 2. Tyrosine Kinase inhibitor therapy 2nd Generation TKI 2. Nilotinib • Used in imatinib resistance or intolerance • 30 times more potent than imatinib • ATP-competitive inhibitor of BCR-ABL • 400 mg every 12 hours • Neutropenia, hyperbilirubinemia, hypophosphatemia, QT interval prolongation • Imatinib and nilotinib in combination may have additive or synergistic effects Treatment 48
  49. 49. 3. Interferon α • IFNα was the initial therapy before TKI therapy • Complete cytogenetic response – uncommon (13%) • 50% responders – long term survival • 3-5 million units/m2 five times per week • Neurotoxicity, thrombocytopenia, fatigue, and liver dysfunction  dose limiting effects • Single dose of 450 µg pegylated IFNα – comparable • IFNα was combined with Cytarabine • Some patients intolerant to a Imatinib may be treated successfully with INFα Treatment 49
  50. 50. 4. Chemotherapeutic Agents and other modalities i. Cytarabine • IFNα combined with cytarabine (20 mg/m2/day -10 days per month  better than IFN alone • Replaced by TKI ii. Busulfan • Once the mainstay of treatment – now almost never used • Use limited to the preparative regimen for allografting or autografting Treatment 50
  51. 51. 4. Chemotherapeutic Agents and other modalities iii. Splenectomy* • Delay the onset of the accelerated phase • Enhance sensitivity to chemotherapy • Prolong survival of patients • But, does not prolong the chronic phase iv. Radiotherapy • Splenic irradiation - extreme splenomegaly with splenic pain, perisplenitis • may be useful for extramedullary tumors (bone/soft tissue) Treatment 51
  52. 52. 4. Chemotherapeutic Agents and other modalities v. Omacetaxine (formerly Homoharringtonine) • Protein translation inhibitor • Still in Phase 2 trials • Showed promise in TKI intolerant/resistant cases • 18% major cytogenetic response in TKI failed cases vi. Experimental • Lonafarnib and tipifarnib • Berbamine • Adaphostin • Third-generation TKIs Treatment 52
  53. 53. 5. Allogeneic Stem Cell Transplantation • Allogeneic HSCT - complicated by mortality owing to the procedure (1) The patient (2) The type of donor (3) The preparative regimen (myeloablative or reduced- intensity) (4) Graft versus Host Disease (5) Post-transplantation treatment Treatment 53
  54. 54. 6. Treatment of accelerated/blast phases • Goal  achieve remission • Else aim to reduce to chronic phase • TKI – bridging therapy to permit allogenic SCT • Dasatinib and nilotinib achieve better molecular remission in accelerated phase • Imatinib+mitoxantrone+etoposide • Imatinib+cytarabine • Ultimately – Stem cell transplant Treatment 54 Blast crisis
  55. 55. 7. Treatment of CML in pregnancy • Untreated CML  placental insufficiency (leukostasis) • Risk of teratogenicity with Imatinib • IFN is safe – can be used • Leukapheresis – 1st trimester • Hydroxyurea – 2nd and 3rd trimester • Restart TKI therapy soon after delivery Treatment 55
  56. 56. 8. Treatment cessation • Despite achieving deep and lasting remissions • CML is not curable • Patients with remissions still have residual CML cells (PCR) • Available evidence suggests that people who receive TKIs may remain in remission for very long periods • Research still underway Treatment 56
  57. 57. 57 Treatment
  58. 58. CONCLUSION • Imatinib has revolutionized the management of CML • Long term survival is a reality now • TKI therapy is still not curative • 3rd generation TKI and newer drugs in the pipeline show some promise at achieving a possible cure 58

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