1 / 52

Chronic Myelogenous Leukemia

Chronic Myelogenous Leukemia. CML. Philadelphia Chromosome. Philadelphia Chromosome Translocation in CML Results in BCR-ABL Oncogene. 9. 9q+. Ph 22q-. Stem cell disorder Characterized by myeloproliferation Well-described clinical course. 22. Translocation. BCR ABL. BCR. ABL.

astro
Download Presentation

Chronic Myelogenous Leukemia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Chronic MyelogenousLeukemia CML

  2. Philadelphia Chromosome

  3. Philadelphia Chromosome Translocation in CML Results in BCR-ABL Oncogene 9 9q+ Ph22q- • Stem cell disorder • Characterized by myeloproliferation • Well-described clinical course 22 Translocation BCRABL BCR ABL Transcription and translation BCR-ABL fusionprotein Inhibition byTKI Constitutive tyrosine kinase Phosphorylation of multiple substrates Mitogenic signaling and genomic instability increased Apoptosis and stromal regulation decreased CML

  4. Definition *Clonalmyeloproliferative disorder resulting from neoplastic transformation of pluripotent stem cells (affect myeloid, erythroid & megakaryocytic lineages) * proliferation,  apoptosis *Cytogenetic hallmark: Ph chromosome positivity

  5. Epidemiology *7% to 15% of all adult leukemias (5th leukemia in USA) *Median age at diagnosis: 55 years (20% to 30% of patients ≥ 60 years)

  6. CML: Historical Context Until 2000 *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 years Also associated with adverse events *Other options: hydroxyurea, busulfan

  7. Etiology * The exact cause is not found * Pathogenesis is well established with consequences on treatment & prognosis *Possible association with ionizing radiation & exposure to industrial benzene

  8. Clinical Manifestations Asymptomatic – accidentally discovered on routine CBC Anemia – easy fatigability, malaise, shortness of breath, chest pain, palpitation High metabolic rate - weight loss, fever Lt hypochondrial discomfort, easy satiety Bleeding- skin ecchymoses, bruises, petechiae UGI ulceration & bleeding (↑ s histamine due to basophilia) Thrombosis – thrombocytosis, leukocytosis Headache, bone pain, gouty arthritis, leukostasis, priapism

  9. Physical Signs Pallor, cutaneous bleeding, splenomegaly (one of the largest spleens) No lymphadenopathy Fever Weight Loss Hepatomegaly – less common than splenomegaly

  10. *85% of patients diagnosed with chronic-phase CML *50% of patients asymptomatic Symptomatic patients exhibit Constitutional symptoms Left upper quadrant discomfort Early satiety purpura ,Splenomegaly, hepatomegaly

  11. Clinical Course 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

  12. Diagnosis CBC- Hb↓, PCV↓, WBC↑ > 10000/µl Differential count – Neutrophilic leukocytosis different stages seen (blasts, promyelocytes, myelocytes, metamyelocytes, stab or band forms), eosinophilia, basophilia Thrombocytosis or thrombocytopenia LAP score ↓ or absent STC I, III ↑, SLDH↑, S histamine↑, S uric acid↑

  13. Dx-cont 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

  14. CMLCP

  15. LAP score- CML

  16. LAP+2 CML

  17. Pathogenesis * 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

  18. DD 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.

  19. CML: Overview of Historical vs Modern PerspectiveTreatment

  20. Treatment Lines Targeted Therapy- 1- Imatinibmesylate 400 mg/d - TKI targets the pathogenetic mechanism - revolutionized treatment causing CCyR & CMR S/E skin rash, edema, myelosuppression, hepatitis 2- Dasatinib & Nilotinib 2nd line for imatinib failure or hypersensitivity 3- high dose imatinib 600-800 mg/d

  21. Other ttt * 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

  22. Other ttt- supportive 1- Allopurinol 2- H-2 blockers 3- PPI 4- Blood transfusion 5- platelet transfusion

  23. Prognosis It was an inevitably fatal disease With recent treatment became a curable disease compatible with long survival Newer agents are evolving Improving BMT &SCT results Once the patient enters the acute phase the only hope remains in transplantation & TKI are used as bridging to that

  24. 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

More Related