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  1. 1. Dr. Dharam Pal Bansal, M.D, D.M Dr. Mohd Viquas Uddin Saim DNB Medicine resident Medwin Hospital CHRONIC MYELOID LEUKEMIA (CML)
  2. 2. CML  Is a myeloproliferative disorder with a characteristic cytogenteic abnormality and propensity to evolve from a chronic phase into a blast phase  incidence of chronic myeloid leukemia (CML) is 1.5 per 100,000  higher in men than in women  incidence of CML increases slowly with age until the middle forties, when it starts to rise rapidly.  Median age at onset is in mid-50’s
  3. 3. DEFINITION  The diagnosis of CML is established by identifying a clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22.  This translocation results in the head-to-tail fusion of the (BCR) gene on chromosome 22q11 with the ABL1 (gene located on chromosome 9q34.  Untreated, the disease inevitably transforms from a chronic phase to an accelerated phase and on to blast crisis in a median time of 4 years.
  4. 4. ETIOLOGY  cigarette smoking accelerated the progression to blast crisis and therefore adversely affected survival in CML.  Atomic bomb survivors had an increased incidence; the development of a CML cell mass of 10,000/L took 6.3 years.  No increase in CML incidence was found in the survivors of the Chernobyl accident, suggesting that only large doses of radiation can induce CML.
  5. 5. Pathophysiology : clonality  CML is a clonal disease of an abnormal stem cell  Myeloid, erythroid, megakaryocytic and B lymphoid cells are involved in the malignant clone.
  6. 6. Philadelphia chromosome
  7. 7. Pathophysiology : philadelphia chromosome  It is the diminutive chromosome produced by an unbalanced translocation between chromosomes 9 and 22.  This translocation t(9:22) fuses the 3’ portion of the c-ABL gene on the long arm of chr 9 to 5’ end of BCR gene on long arm of chr 22.  The resultant fusion gene encodes a chimeric protein with constitutive tyrosine kinase activity.  The BCR-ABL protein stimulates the proliferation and enhances the survival of CML hematopoietic progenitor cells.
  8. 8. Clinical Presentation  Asymptomatic in 20 % patients , discovered on routine blood exams.  Onset : insidious  The excessive number of metabolically active myeloid cells can cause fevers and sweats.  fatigue, malaise, and weight loss  symptoms from splenic enlargement, like early satiety and left upper quadrant pain or mass.  Bone pain and tenderness from expanding leukemic mass  Less common are features related to granulocyte or platelet dysfunction, such as infections, thrombosis, or bleeding.
  9. 9. Clinical presnetation  Occasionally, patients present with leukostatic manifestations due to severe leukocytosis or thrombosis such as :  1. vasoocclusive disease, 2. cerebrovascular accidents, 3. myocardial infarction, 4. venous thrombosis, 5. priapism, 6. visual disturbances, and 7. pulmonary insufficiency.  Progression of CML is associated with worsening symptoms.  Unexplained fever, significant weight loss, increasing dose requirement of the drugs controlling the disease, bone and joint pain, bleeding, thrombosis, and infections suggest
  10. 10. Clinical features : Leukostasis  Marked leukocytosis > 1,00,000/microL can be associated with symptoms of leukostatsis  Manifestations may include  1. visual changes  2. seizures  3. Cerebral or myocardial infarctions
  11. 11. Physical findings  Minimal to moderate splenomegaly is the most common physical finding;  mild hepatomegaly is found occasionally.  Persistent splenomegaly despite continued therapy is a sign of disease acceleration.  Lymphadenopathy and myeloid sarcomas are unusual except late in the course of the disease; when they are present, the prognosis is poor.
  12. 12. Hematologic Findings  Elevated white blood (cell) counts (WBCs), with increases in both immature and mature granulocytes, are present at diagnosis.  WBC count usually exceeds > 30,000 and usually ranges from 1,00,000 to 3,00,000.  The peripheral blood smear often resembles a bone marrow aspirate due to presence of all stages of myeloid maturation.  myeloblasts constitute < 15 % of leukocytes and promyelocytes combined < 30 % in PBS  Platelet counts are almost always elevated at diagnosis, may exceed 1,000,000/UL and a mild degree of normocytic normochromic anemia is present.  Leukocyte alkaline phosphatase is low in CML cells.  Phagocytic functions are usually normal at diagnosis and remain normal during the chronic phase.  Histamine production secondary to basophilia is increased in later stages, causing pruritus, diarrhea, and flushing. Basophils < 20 %.
  13. 13. Bone marrow aspiration and biopsy  Should be performed on all patients as a part of diagnostic evaluation  In all cases marrow is markedly hypercellular due to massive myeloid hyperplasia  Markedly increased myeloid : erythroid ratio  Fibrosis may also be present
  14. 14. Disease acceleration  defined by the development of  1.increasing degrees of anemia unaccounted for by bleeding or therapy;  2. cytogenetic clonal evolution;  3. blood or marrow blasts between 10 and 20%, blood or marrow basophils 20%, or platelet count <100,000/L.  Hyposegmented neutrophils may appear (Pelger- Huët anomaly).
  15. 15. Blast crisis  WHO criteria :  Blasts > 20% of peripheral white blood cells or of nucleated bone marrow cells  Extramedullary blast proliferation  Large foci or clusters of blasts in the bone marrow biopsy
  16. 16. Blast crisis  International Bone Marrow Transplant Registry criteria  > 30% blasts in the blood, marrow, or both  Extramedullary infiltrates of leukemic cells
  17. 17. Cytogentic analysis  Should be performed at the time of bone marrow examination on all patients.  The cytogenetic hallmark of CML, found in 90–95% of patients, is the t(9;22)(q34;q11.2).  Infrequently complex translocations can occur which can mask BCR – ABL translocation.  In such situations FISH or PCR BCR-ABL can identify .  All patients should have evidence of the translocation molecularly or by cytogenetics or FISH to make a diagnosis of CML.  FISH is More sensitive than cytogenetics at detecting minimal residual disease during therapy.
  18. 18. Polymerase chain reaction  Is a molecular assay performed on peripheral blood that identifies the BCR-ABL, translocation.  The quantitative PCR or Q-PCR is the most sensitve method to follow residual disease during treatment of CML  A baseline Q-PCR should be obtained in all patients.  Can also detect complex translocations like FISH
  19. 19. Leukocyte alkaline phosphatase and uric acid levels in CML  LAP activity is decreased or absent in circulating granulocytes .  Helpful diagnostically.  Hyperuricemia and hyperuricosuria commonly present.
  20. 20. Diagnostic criteria and prognostic variables  WHO diagnostic criteria for chronic phase  1. leucocytosis  2. prominent dysgranulopoiesis  3. promyeloctyes, myelocytes and metamyelocytes > 10 % of WBC’s  4. basophils < 2 % of WBC’s  5. monocytes < 10 % of WBC’s  6. hypercellular bone marrow with granulocytic proliferation and dysplasia  7. < 20 % blasts in the blood or bone marrow
  21. 21. Diagnostic criteria and prognostic variables  WHO criteria for diagnosis of accelerated phase  1. blasts 10% to 19% in the blood or bone marrow  2. basophils > 20 % of peripheral blood WBC’s  3. platelets > 1,000,000/UL unresponsive to therapy or < 1,000,000/UL unrelated to therapy  4. increasing spleen size or WBC count unresponsive to therpy  5. cytogenetic evidence of clonal evolution
  22. 22. Diagnostic criteria and prognostic variables  WHO criteria for diagnosis of blast phase  1. Blasts > 20 % of bone marrow cells or peripheral WBC’s  2. extramedullary blast formation  3. large foci or clusters of blasts in bone marrow.
  23. 23. Prognostic factors  The clinical outcome of patients with CML is variable.   The Sokal index identified percentage of circulating blasts, spleen size, platelet count, age, and cytogenetic clonal evolution as the most important prognostic indicators.  The Hasford system was developed based on interferon (IFN) – treated patients. It identified percentage of circulating blasts, spleen size, platelet count, age, and percentage of eosinophils and basophils as the most important prognostic indicators.  Both of these scoring systems stratify patients into three risk groups (low, intermediate, and high) and have been used for the risk stratifications of patients in clinical trials evaluating tyrosine kinase inhibitors (TKIs). the Hasford system was better than the Sokal score for predicting survival time Ongoing assessment of response during therapy has emerged as a much more important predictor of progression free survival.
  24. 24. Treatment  The therapy of CML is a proven curative treatment (allogeneic transplantation) that has significant toxicity and a new targeted treatment (imatinib) with outstanding outcome.  Its recommended starting with TK inhibitors and reserving allogeneic transplantation for those who develop imatinib resistance.  At present, the goal of therapy in CML is to achieve prolonged, durable, nonneoplastic, nonclonal hematopoiesis, which entails the eradication of any residual cells containing the BCR-ABL1 transcript.  Hence, the goal is complete molecular remission and cure.
  25. 25. Imatinib Mesylate  Imatinib mesylate acts by competitive inhibition at the ATP-binding site of the Abl kinase, which leads to inhibition of tyrosine phosphorylation of proteins involved in Bcr-Abl signal transduction.  Treatment is currently recommended for life .  imatinib discontinuation after at least 2 years of complete molecular remission revealed molecular relapse in 6 of 12 patients.  Interestingly who were treated with IFN- before imatinib maintained molecular remission,
  26. 26. Imatinib mesylate  Standard dose is 400 mg / day  Can be increased to 600 mg/day if suboptimal response  800 mg/day in 2 divided doses also used.  People who cannot tolerate < 300 mg / day warrant a change in therapy.
  27. 27. Imatinib Mesylate  Imatinib is administered orally.  The main side effects are fluid retention, nausea, muscle cramps, diarrhea, and skin rashes.  Myelosuppression is the most common hematologic side effect. may require holding drug and/or growth factor support.  Doses <300 mg/d seem ineffective and may lead to development of resistance.
  28. 28. Acquired imatinib resistance  Is defined as a loss previous hematologic or cytogenetic response.  Best understood mechanism is development of point mutations in BCR-ABL.  CML with BCR-ABL mutation can be successfully treated with 2nd generation kinase inhibitors like dasatinib and nilotinib.  BCR-ABL harboring T315I is resistant to even these drugs.
  29. 29. Monitoring response to imatinib  Patients who do not achieve response end points within appropriate time frames should be treated by  1. dose escalation of Imatinib  2. therapy with alternate TK inhibitor  3. allogenic bone marrow transplantation
  30. 30. Response end points  Complete hematologic response (CHR)  Definition : CHR is defined as normalization of peripheral blood counts and can be expected in > 95% of chronic phase patients,  Failure to achieve this by 3 months warrants reassessment of treatment approach.
  31. 31. Response end points  Major cytogenetic response  Definition : its defined as reduction of the percentage of philadelphia chromosome to < 35% of bone marrow metaphases.  Complete cytogenetic response is defined as normalization of bone marrow cytogenetics.  Ideally MCR should be observed by 6 months and CCR by 1 yr.  Absence of any cytogenetic response at 6 months ,< MCR at 12 months, or < CCR at 18 months should prompt consideration of change in Rx.
  32. 32. Response end points  Major molecular response  Definition : at least a 3 log (1000 fold) reduction in the level of disease measured by Q-PCR.  Patients who achieve this end point by 1 yr have a zero percent risk of disease progression to AP or BP at 5 years.  Monitoring should also include Bone marrow aspiration and biopsy at baseline and every 6months, untill a complete cytogenetic response is achieved.  Q-PCR should be performed every 3 months.
  33. 33. Newer drugs for imatinib resistance  Mutations at the kinase domain occur in approximately half of imatinib-resistant chronic- phase cases.  These mutations are being targeted by novel TK inhibitors that have a different conformation than imatinib,  Nilotinib (Tasigma)  Dasatinib (Sprycel) .
  34. 34. Newer drugs for imatinib resistance  Dasatinib is approved by the FDA at a dose of 100 mg/day for the treatment of all stages of CML with resistance or intolerance to prior therapy, including imatinib.  Nilotinib is approved by the FDA at a dose of 400 mg twice daily for the treatment of chronic- and accelerated-phase CML with resistance or intolerance to prior therapy, including imatinib.  Both are oral agents, Dasatinib causes pleural effusions in 22% of patients.  Omacetaxine ,Sorafenib, Bosutinib ,Ponatinib
  35. 35. Allogeneic HSCT  Allogeneic HSCT is complicated by early mortality owing to the transplant procedure.  Outcome of HSCT depends on multiple factors, including  (1) the patient (e.g., age and phase of disease);  (2) the type of donor [e.g., syngeneic (monozygotic twins) or HLA-compatible allogeneic, related or unrelated];  (3) the preparative regimen (myeloablative or reduced-intensity);  (4) GVHD; and  (5) posttransplantation treatment.
  36. 36. chemotherapy  Initial management of patients with chemotherapy is currently reserved for rapid lowering of WBCs, reduction of symptoms, and reversal of symptomatic splenomegaly  . Hydroxyurea, a ribonucleotide reductase inhibitor, induces rapid disease control. The initial dose is 1–4 g/d; the dose should be halved with each 50% reduction of the leukocyte count  Busulphan, an alkylating agent that acts on early progenitor cells, has a more prolonged effect.  However, its not recommend its use because of its serious side effects, which include  unexpected, and occasionally fatal, myelosuppression in 5–10% of patients; pulmonary, endocardial, and marrow fibrosis; and an Addison-like wasting syndrome.
  37. 37. Leukapheresis and Splenectomy  Intensive leukapheresis may control the blood counts in chronic-phase CML;  It is useful in emergencies where leukostasis-related complications such as pulmonary failure or cerebrovascular accidents are likely.  It may also have a role in the treatment of pregnant women, in whom it is important to avoid potentially teratogenic drugs.  Splenectomy was used in CML in the past because of the suggestion that evolution to the acute phase might occur in the spleen.  splenectomy is now reserved for symptomatic relief of painful splenomegaly unresponsive to imatinib or chemotherapy, or for significant anemia or thrombocytopenia associated with hypersplenism.  Splenic radiation is used rarely to reduce the size of the spleen.
  38. 38. Treatment of Blast Crisis  Treatments for primary blast crisis, including imatinib, are generally ineffective.  Only 52% of patients treated with imatinib achieved hematologic remission and the median overall survival was 6.6 months.  Patients who achieve complete hematologic remission or whose disease returns to a second chronic phase should be considered for allogeneic HSCT.  Other approaches include induction chemotherapy tailored to the phenotype of the blast cell followed by TK inhibitors, with or without additional chemotherapy and HSCT.  Blast crisis following initial therapy with imatinib carries a dismal prognosis even if treated with
  39. 39. References  Harrison’s 18th edition  National comprehensive cancer network guidelines  Clinical manual of oncology
  40. 40. . thank you