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chronicmyeloidleukemia-oncohoure-190601070621 (1).pdf

  1. 1. Chronic Myeloid Chronic Myeloid Leukemia Leukemia SHUMAYLA ASLAM-FAIZ, MD SHUMAYLA ASLAM-FAIZ, MD 3 3RD RD YEAR RESIDENT YEAR RESIDENT DEPARTMENT OF INTERNAL MEDICINE DEPARTMENT OF INTERNAL MEDICINE EACMCC EACMCC Source: Harrisons 20th Edition, Ch 101, Pg 746-757 MD Calc American Cancer Society dr.shumaylaaslam@gmail.com
  2. 2. CML CMLcan develop from any of these dr.shumaylaaslam@gmail.com
  3. 3. Development of myeloid and lymphoid leukemias within the context of hematopoietic cell hierarchy. Hematopoietic stem cells (HSCs; S) produce granulocytic (G) and lymphocytic (L) precursors, which then go on to generate smaller differentiated cells. Genetic and/or epigenetic aberrancies (striped) in stem or progenitor cells lead to a neoplastic accumulation of cells due to hyperproliferation and decreased apoptosis. dr.shumaylaaslam@gmail.com
  4. 4. WHAT’S WRONG • CML is defined by the presence of BCR-ABL1 fusion gene in a patient with a myeloproliferative neoplasm. •Philadelphia chromosome (Ph) • the BCR-ABL1 chimeric gene product, that codes for a constitutively active tyrosine kinase, resulting from a reciprocal balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34.1;q11.2) dr.shumaylaaslam@gmail.com
  5. 5. INCIDENCE AND EPIDEMIOLOGY • CML accounts for 15% of all cases of leukemia ∼ • The annual incidence of CML is 1.5 cases per 100,000 individuals • Male : female ratio 1.6:1 • The median age at diagnosis is 55–65 years. • It is uncommon in children; only 3% of patients with CML are younger than 20 years. • the median survival in CML was 3–7 years but, with introduction of TKI therapy (tyrosine kinase inhibitors) imatinib mesylate, the first BCR-ABL1 TKI approved, is 85%. • The annual mortality has been reduced from 10–20% to about 2%. dr.shumaylaaslam@gmail.com
  6. 6. ETIOLOGY • No familial associations in CML • Exposure to ionizing radiation (e.g., nuclear accidents, radiation treatment for ankylosing spondylitis or cervical cancer) has increased the risk of CML, which peaks at 5–10 years after exposure and is dose-related (larger dose) • Because of adequate protection, the risk of CML is not increased in individuals working in the nuclear industry or among radiologists in recent times. dr.shumaylaaslam@gmail.com
  7. 7. HEMATOPOI ETIC STEM CELLS hybrid oncogene, BCR-ABL1 kinase activity Excessive proliferation and reduced apoptosis EXPOSURE TO RADIATIONS PATHOPHYSIOLOGY OF CML dr.shumaylaaslam@gmail.com
  8. 8. Phases of chronic myeloid leukemia • The phases are based mainly on the number of immature WBC (blasts blasts) in the blood or bone marrow. 1. Chronic phase • less than 10% blasts in their blood or bone marrow. • fairly mild symptoms (if any) and usually respond to standard treatments. • Most patients are diagnosed in the chronic phase. 2. Blast phase (aka acute phase or blast crisis) • 20% or more blasts • Large clusters of blasts are seen in the bone marrow. • The blast cells have spread to tissues and organs beyond the bone marrow. These patients often have fever, poor appetite, and weight loss. In this phase, the CML acts a lot like an acute leukemia. dr.shumaylaaslam@gmail.com
  9. 9. 3. Accelerated phase Patients are considered to be in accelerated phase if any of the following are true: •15% or more, but less than 30% blasts •Basophils make up 20% or more of the blood •Blasts and promyelocytes combined make up 30% or more of the blood •Very low platelet counts (100 x 1,000/mm3 or less) that are not caused by treatment •New chromosome changes in the leukemia cells with the Philadelphia chromosome •symptoms such as fever, poor appetite, and weight loss. CML in the accelerated phase doesn't respond as well to treatment as CML in the chronic phase. dr.shumaylaaslam@gmail.com
  10. 10. dr.shumaylaaslam@gmail.com
  11. 11. CML in Accelarated Phase dr.shumaylaaslam@gmail.com
  12. 12. CLINICAL PRESENTATION • Healthcare available areas 50–60% of patients are diagnosed on routine blood tests and have minimal symptoms at presentation, such as fatigue. • locations where access to health care is more limited, patients often present with high CML burden including splenomegaly, anemia splenomegaly, anemia, and related symptoms (abdominal abdominal pain, weight loss, fatigue pain, weight loss, fatigue), which translate into a higher frequency of high-risk CML. dr.shumaylaaslam@gmail.com
  13. 13. • Less common presenting findings include thrombotic or hyperviscosity-related events (from severe leukocytosis or thrombocytosis) • cardiovascular complications, MI, VTE, visual disturbances, dyspnea and pulmonary insufficiency, drowsiness, loss of coordination, confusion, or cerebrovascular accidents. • Manifestations of bleeding diatheses include retinal hemorrhages, gastrointestinal bleeding, and others. • Patients who present with, or progress to, the accelerated or blastic phases frequently have additional symptoms including unexplained fever, significant weight loss, severe fatigue, bone and joint pain, bleeding and thrombotic events, and infections. dr.shumaylaaslam@gmail.com
  14. 14. dr.shumaylaaslam@gmail.com
  15. 15. Hematologic and Marrow Findings • CBC: • leukocytosis ranging from 10–500 × 109/L. • predominance of neutrophils and the presence of bands • Basophils and/or eosinophils are frequently increased • Thrombocytosis • but thrombocytopenia is rare and, when present, suggests a worse prognosis, disease acceleration, or an unrelated etiology • Anemia is present in one-third of patients. • PBS: • left-shifted hematopoiesis with predominance of neutrophils and the presence of bands, myelocytes, metamyelocytes, promyelocytes, and blasts (usually ≤5%). Anemia is present in one-third of patients. dr.shumaylaaslam@gmail.com
  16. 16. dr.shumaylaaslam@gmail.com
  17. 17. • Bone Marrow • hypercellular with marked myeloid hyperplasia and a high myeloid-to-erythroid ratio of 15–20:1. • Marrow blasts are <5%; when >15 they carry a worse prognosis or represent transformation to accelerated phase. • Increased reticulin fibrosis (by Snook’s silver stain) is common, with 30–40% of patients demonstrating grade 3–4 reticulin fibrosis. • With TKI therapy, reticulin fibrosis resolves in most patients and is not an indicator of poor prognosis • Biochemical abnormalities include a low leukocyte alkaline phosphatase score and high levels of vitamin B12, uric acid, lactic dehydrogenase, and lysozyme. dr.shumaylaaslam@gmail.com
  18. 18. CML CML dr.shumaylaaslam@gmail.com
  19. 19. Cytogenetic and Molecular Findings • The diagnosis of CML is straightforward and depends on documenting the t(9;22)(q34.1;q11.2), which is identified by G-banding in 90% of cases. • Techniques such as FISH and PCR are now used to aid in the diagnosis of CML. • Both FISH and PCR studies can be falsely positive because of technical issues. Therefore, a diagnosis of CML must always rely on a marrow analysis with routine cytogenetics. dr.shumaylaaslam@gmail.com
  20. 20. TREATMENT dr.shumaylaaslam@gmail.com
  21. 21. • Serious side effects occur in <5–10% of patients. • With imatinib therapy, common mild to moderate side effects include fluid retention, weight gain, nausea, diarrhea, skin rashes, periorbital edema, bone or muscle aches, fatigue, and others (rates of 10–20%). • In general, second-generation TKIs are associated with lower rates of these bothersome adverse events. dr.shumaylaaslam@gmail.com
  22. 22. ALLOGENEIC STEM CELL TRANSPLANT • Allogeneic SCT, a curative modality in CML, is associated with long-term survival rates of 40– 60% when implemented in the chronic phase. dr.shumaylaaslam@gmail.com
  23. 23. dr.shumaylaaslam@gmail.com
  24. 24. OTHER TREATMENTS AND SPECIAL THERAPEUTIC CONSIDERATIONS • Chemotherapeutic Agents • Hydroxyurea remains a safe and effective agent (at daily doses of 0.5–10 g) to reduce initial CML burden, as a temporary measure in between definitive therapies in combination with TKIs to sustain complete hematologic or cytogenetic responses. • Busulfan is often used in allogeneic SCT preparative regimens. Because of its side effects (delayed myelosuppression, Addison- like disease, pulmonary and cardiac fibrosis, myelofibrosis), it is now only rarely used in the chronic management of CML. dr.shumaylaaslam@gmail.com
  25. 25. • Interferon α: Interferon α is considered in combination with TKIs, sometimes after CML failure on TKIs, occasionally in patients during pregnancy, or as part of investigational strategies with TKIs to eradicate residual molecular disease. • Others Splenectomy is now seldom considered to alleviate symptoms of massive splenomegaly and/or hypersplenism. Splenic irradiation is rarely used, if at all, because of the postirradiation adhesions and complications. dr.shumaylaaslam@gmail.com
  26. 26. MONITORING THERAPY IN CML • Achievement of complete cytogenetic response by 12 months 12 months of imatinib therapy • Failure to achieve a complete cytogenetic response by 12 months or occurrence of later cytogenetic or hematologic relapse are considered as treatment failure and an indication to change therapy. • Patients on frontline imatinib therapy should be closely monitored until documentation of complete cytogenetic response, every 6 months with peripheral blood FISH and PCR studies (to check for concordance of results), or more frequently (every 3 months) if there are concerns about changes in BCR-ABL1 transcripts dr.shumaylaaslam@gmail.com
  27. 27. Discontinuation of TKIs and Treatment-Free Remissions or “Molecular Cures” • Several studies have confirmed that TKI discontinuation among patients who achieve undetectable BCR-ABL1 transcripts for longer than 2–3 years can result in treatment-free remission rates of 40– 60% • low Sokal-risk CML in first chronic phase (no evidence of transformation) dr.shumaylaaslam@gmail.com
  28. 28. Sokal Index for Chronic Myelogenous Leukemia (CML) survival • Sokal Score = exp[0.0116 × (age in years – 43.4)] + [0.0345 × (spleen size in cm – 7.51)] + [0.188 x ((platelets in 109 /L / 700)2 – 0.563)] + [0.0887 × (blasts in % – 2.10)] dr.shumaylaaslam@gmail.com
  29. 29. PROGNOSIS AND CML COURSE • Before the TKI therapy, imatinib era, the annual mortality in CML was 10% in the first 2 years and 15–20% thereafter. The median survival time in CML was 3–7 years (with hydroxyurea-busulfan and interferon α). • Without a curative option of allogeneic SCT, the course of CML was toward transformation to, and death from, accelerated or blastic phases. dr.shumaylaaslam@gmail.com
  30. 30. Adverse prognostic factors: • Accelerated phase or blast phase • Enlarged spleen • Areas of bone damage from growth of leukemia • Increased number of basophils and eosinophils (certain types of granulocytes) in blood samples • Very high or very low platelet counts • Age 60 years or older • Multiple chromosome changes in the CML cells dr.shumaylaaslam@gmail.com
  31. 31. Thank You Thank You dr.shumaylaaslam@gmail.com

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