cml. stem cell disorder characterized by myeloproliferation well-described clinical course 9 9q+...
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Chronic Myelogenous Leukemia
CML
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Philadelphia Chromosome
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Philadelphia Chromosome Translocation in CML Results in BCR-ABL Oncogene
Stem cell disorder
Characterized by myeloproliferation
Well-described clinical course
9 9q+
22Ph22q-
BCRABL
BCRABL
Translocation
Transcription and translation
Inhibition byTKI
BCR-ABL fusionprotein
CML
Constitutive tyrosine kinase
Phosphorylation of multiple substrates
Mitogenic signaling and genomic instability increased
Apoptosis and stromal regulation decreased
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*Clonal myeloproliferative disorder resulting from neoplastic transformation of pluripotent stem cells (affect myeloid, erythroid & megakaryocytic lineages)* proliferation, apoptosis*Cytogenetic hallmark: Ph chromosome positivity
Definition
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*7% to 15% of all adult leukemias (5th leukemia in USA)
*Median age at diagnosis: 55 years (20% to 30% of patients ≥ 60 years)
Epidemiology
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*Fatal disorder with poor prognosis*Median survival: 3-5 years (2 years without
treatment)
*Allogeneic SCT curative in 40% to 70% of patients (Associated with mortality and toxicity)
*Interferon alfa ± cytarabine: CCyR of 20% to 30%Median survival: 6-7 yearsAlso associated with adverse events
*Other options: hydroxyurea, busulfan
CML: Historical Context Until 2000
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* The exact cause is not found* Pathogenesis is well established with
consequences on treatment & prognosis*Possible association with ionizing radiation &
exposure to industrial benzene
Etiology
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Asymptomatic – accidentally discovered on routine CBC
Anemia – easy fatigability, malaise, shortness of breath, chest pain, palpitation
High metabolic rate - weight loss, feverLt hypochondrial discomfort, easy satietyBleeding- skin ecchymoses, bruises, petechiaeUGI ulceration & bleeding (↑ s histamine due to
basophilia)Thrombosis – thrombocytosis, leukocytosisHeadache, bone pain, gouty arthritis, leukostasis,
priapism
Clinical Manifestations
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Pallor, cutaneous bleeding, splenomegaly (one of the largest spleens)
No lymphadenopathyFeverWeight Loss Hepatomegaly – less common than splenomegaly
Physical Signs
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*85% of patients diagnosed with chronic-phase CML
*50% of patients asymptomatic Symptomatic patients exhibit
Constitutional symptomsLeft upper quadrant discomfortEarly satietypurpura ,Splenomegaly, hepatomegaly
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1- Benign Phase – in which the disease behavior & response is predictable(Stable phase)
2- Accelerated phase – tumor burden increases rapidly with more systemic symptoms & increasing difficulty in control of disease
3- Acute phase – Blastic crisis may be AML,ALL, AUL
Patient may present in accelerated or acute phase for the first time
Clinical Course
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CBC- Hb↓, PCV↓, WBC↑ > 10000/µlDifferential count – Neutrophilic leukocytosis
different stages seen (blasts, promyelocytes, myelocytes, metamyelocytes, stab or band forms), eosinophilia, basophilia
Thrombocytosis or thrombocytopeniaLAP score ↓ or absentSTC I, III ↑, SLDH↑, S histamine↑, S uric
acid↑
Diagnosis
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Bone Marrow Aspirate & Biopsy- hypercellular, devoid of fat, myeloid hyperplasia, ↑retculin or collagen fibers, M:E ratio 15-20:1
Cytogenetics- Philadelphia chromosome positivity 95% (Ph –ve 5%) shortened long arm of chromosome22
Molecular biology- BCR/ABL gene positive
Dx-cont
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CMLCP
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LAP score- CML
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LAP+2 CML
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* Balanced reciprocal translocation between chromosome 22 & chromosome 9 [t(9;22)] that brings BCR gene in juxtaposition with ABL gene forming a new hybrid gene BCR/ABL that codes for synthesis of a chimeric protein P210 that shows tyrosine kinase activity causing uncontrolled proliferation of the malignant clone
Pathogenesis
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1- Leukemoid reaction rarely WBC count exceeds 30000, not clonal, BM no blasts excess, seen in overwhelming sepsis & disseminated TB.
2- MDS – CMML stage.3- chronic corticosteroids use
(demargination).4- other MPD.
DD
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Parameter Historical Perspective (Until 2000)
Modern Perspective (Since 2000)
Course Fatal Indolent
Prognosis Poor Excellent
Median survival, yrs 3-6 ≥25*
Frontline treatment Allogeneic SCT, interferon alfa
Imatinib
Second-line treatment Not established Allogeneic SCT, novel TKIs
CML: Overview of Historical vs Modern PerspectiveTreatment
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Targeted Therapy- 1- Imatinib mesylate 400 mg/d - TKI targets the pathogenetic mechanism - revolutionized treatment causing CCyR &
CMRS/E skin rash, edema, myelosuppression,
hepatitis2- Dasatinib & Nilotinib 2nd line for imatinib
failure or hypersensitivity3- high dose imatinib 600-800 mg/d
Treatment Lines
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* BMT when enter accelerated phase prior to acute phase
* Interferon-α + cytosine arabinoside* Hydroxyurea orally* Busulfan (myleran) orally – no more used now
because of severe & protracted myelosuppression
Other ttt
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1- Allopurinol2- H-2 blockers3- PPI4- Blood transfusion5- platelet transfusion
Other ttt- supportive
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It was an inevitably fatal diseaseWith recent treatment became a curable
disease compatible with long survivalNewer agents are evolvingImproving BMT &SCT resultsOnce the patient enters the acute phase the
only hope remains in transplantation & TKI are used as bridging to that
Prognosis
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Poor Prognostic Factors in CML •Older age
•Splenomegaly •Anemia
•Thrombocytosis, thrombocytopenia • Blasts, promyelocytes, basophils
•Marrow fibrosis •Cytogenetic clonal evolution
(Euro ,)MDACC Prognostic Models: Sokal, Hasford
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