Acute myeloid leukemia


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case discussion and topic review on acute myleoid leukemia

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Acute myeloid leukemia

  1. 1. Case discussion and topic review Moderator Dr. Naveen Pandey Presenter-Dr. Pradip katwal
  2. 2. • 35 years/ Female• Siraha• Housewife• Vegetarian – Presenting complains-• Easy fatigability 5 months• Fever 5 months
  3. 3. HOPI• Fever, intermittent in nature, associated with chills no rigors, no diurnal variation of fever,no h/o rashes• Easy fatigability which was progressive associated with shortness of breath, and now shortness of breath present on doing her daily activity.
  4. 4. Past history• h/o total abdominal hysterectomy 1 years back for menorrhagia• Tissue biopsy-showed granular tissue wih foreign body gaint cell• Has received ATT for genitourinany tuberculosis.
  5. 5. Family history• History of tuberculosis in family +
  6. 6. Examination• General condition- thin built• Pallor+• nails-leukonychia• no petichea/purpura• Pulse -88/min• Blood pressure -98/60 mmhg• Temperature -102 degree F• Respiratory rate -16/min
  7. 7. Systemic examinationChest – B/L equal air entry B/L normal vesicular breath soundsP/A-Soft, non tender -spleen not palpableCVS- S1 + S2 heard no murmurCNS- No neck rigidity WNL12/24/2011
  8. 8. Differential diagnosis• Megaloblastic anemia• Aplastic anemia• Acute leukemia• Tuberculosis• Systemic lupus erythematosus• Myelodysplastic disorder
  9. 9. Lab investigations• TLC- 2420 mm3• DLC-N 25% L45% M25% E 05%• HB- 2.74gm/dl• Platelates-2000 mm3• Urine RE/ME- WNL• Blood culture- sterile• Urine culture- sterile• Chest x-ray- wnl12/24/2011
  10. 10. • RK 39 –ve• HIV serology –ve• Ps cytology• ECG- sinus tachycardia• Fundoscopy-no evidence of retinal hemorrhage
  11. 11. Ps cytology- leukocytosis with presence of blastcells. Cells are large N:C ratio is highirregular nuclear membrane. Some of themshowing lobulated nuclei prominent 2-3nucleoli prominent 2-3 nuclei and moderateamount of cytoplasm.DLC- blast 40% premylocytes-12 %metamylocytes 2%
  12. 12. Management• Pt received three pints of fresh whole blood transfusion.• Personal hygeine• Dental hygeine
  13. 13. During her stay• After the reports, the nature of illness and treatment options was explained. Patient party wanted to take to bharatpur cancer hospital for further management and was referred.
  15. 15. Epidemiology• Incidence -3.5 per 100,000 people per year• Median age at diagnosis- 67 years• AML incidence increases with age
  16. 16. ALL naïve B-lymphocytes Plasma Lymphoid cells progenitor T-lymphocytes AMLHematopoietic Myeloid Neutrophilsstem cell progenitor Eosinophils Basophils Monocytes Platelets Red cells
  17. 17. Myeloid maturationmyeloblast promyelocyte myelocyte metamyelocyte band neutrophil MATURATION Adapted and modified from U Va website
  18. 18. Acute Leukemia• Blasts in the marrow
  19. 19. Two-hit model of leukemogenesisLoss of function of Gain of function mutations oftranscription factors tyrosine kinasesneeded for differentiation eg. FLT3, c-KIT mutationseg. AML1-ETO N- and K-RAS mutations CBFβ-SMMHC BCR-ABL PML-RARα TEL-PDGFβRdifferentiation enhanced Acute block + proliferation Leukemia
  20. 20. Etiology• Heredity – Down syndrome – Fanconi anemia – Bloom syndrome – ataxia-telangiectasia – Congenital neutropenia (Kostmann syndrome)• Radiation – High-dose radiation (atomic bombs survivors)
  21. 21. • chemical and occupational exposures – Benzene – petroleum products – Paint – embalming fluids – ethylene oxide – Herbicides – smoking
  22. 22. • Prospective data suggested an elevated risk of myeloid leukemia associated with cigarette smoking (relative risk, 1.4; 95% confidence interval, 1.2 to 1.6).• Population-attributable risk calculations suggested that approximately 14% of all US leukemia cases (including 17% of myeloid may be due to cigarette smoking.
  23. 23. • Drugs – Alkylating agent – Topoisomerase II inhibitor – Chloramphenicol – Phenylbutazone – Chloroquine – methoxypsoralen
  24. 24. ClassificationWorld Health Organization ClassificationAML with recurrent genetic abnormalitiesAML with t(8;21)(q22;q22);RUNX1-RUNX1T1bAML with inv(16)(pl3.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11bAcute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARAbAML with t(9;11)(p22;q23); MLLT3-MLLAML with t(6;9)(p23;q34); DEK-NUP214AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1Provisional entity: AML with mutated NPM1Provisional entity: AML with mutated CEBPAAML with myelodysplasia-related changes
  25. 25. Therapy-related myeloid neoplasmsAML not otherwise specifiedAML with minimal differentiationAML without maturationAML with maturationAcute myelomonocytic leukemiaAcute monoblastic and monocytic leukemiaAcute erythroid leukemiaAcute megakaryoblastic leukemiaAcute basophilic leukemiaAcute panmyelosis with myelofibrosis
  26. 26. Myeloid sarcomaMyeloid proliferations related to Down syndromeTransient abnormal myelopoiesisMyeloid leukemia associated with Down syndromeBlastic plasmacytoid dendritic cell neoplasmAcute leukemia of ambiguous lineageAcute undifferentiated leukemiaMixed phenotype acute leukemia with t(9;22)(q34;q11,20); BCR-ABL11Mixed phenotype acute leukemia with t(v;11q23); MLL rearrangedMixed phenotype acute leukemia, B/myeloid, NOSMixed phenotype acute leukemia, T/myeloid, NOSProvisional entity: Natural killer (NK)-cell lymphoblastic leukemia/lymphoma
  27. 27. Clinical Presentation• Nonspecific symptoms• Fatigue• Anorexia• Weight loss• Fever• Bleeding, easy bruising• Bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis
  28. 28. Physical Findings• Fever• Splenomegaly• Hepatomegaly• Lymphadenopathy• Sternal tenderness• Evidence of infection and hemorrhage
  29. 29. Gum hypertrophy
  30. 30. myeloid sarcoma• Myeloid sarcoma is a tumor mass consisting of myeloid blasts in which the tissue architecture is effaced, occurring at an anatomical site other than the bone marrow
  31. 31. Leukemia cutis
  32. 32. Hematologic Findings• Anemia =normocytic normochromic• The median presenting leukocyte count is about 15,000/L 25 and 40% of patients <5000/L 20% >100,000/L Fewer than 5% no detectable leukemic cells in the blood
  33. 33. Diagnostic procedure• Morphology• cytochemistry• Immunophenotyping• Cytogenetics• Molecular cytogenetics• Molecular genetics
  34. 34. • The morphology of the malignant cell varies in different subsets – the cytoplasm often contains primary (nonspecific) granules – the nucleus shows fine, lacy chromatin with one or more nucleoli – Abnormal rod-shaped granules called Auer rods are present – neutrophil -abnormal lobulation and deficient granulation.
  35. 35. Bone marrow in acute leukemia• Necessary for diagnosis• Useful for determining type• Useful for prognosis• Acute leukemias are defined by the presence of > 20% blasts in bone marrow (% of nucleated marrow cells)
  36. 36. AML
  37. 37. AML
  38. 38. Auer rods in AML
  39. 39. Pretreatment EvaluationInitial Diagnostic Evaluation and Management of Adult Patients with AMLHistoryIncreasing fatigue or decreased exercise tolerance (anemia)Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)Fevers or recurrent infections (granulocytopenia)Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia or bleed)Early satiety (splenomegaly)Family history of AML (Fanconi, Bloom, or Kostmann syndromes or ataxia-telangiectasia)History of cancer (exposure to alkylating agents, radiation, topoisomerase II inhibitors)Occupational exposures (radiation, benzene, petroleum products, paint, smoking,pesticides
  40. 40. Physical ExaminationPerformance status (prognostic factor)Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic leukemia)Fever and tachycardia (signs of infection)Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)Poor dentition, dental abscessesGum hypertrophy (leukemic infiltration, most common in monocytic leukemia)Skin infiltration or nodules (leukemia infiltration, most common in monocytic leukemia)Lymphadenopathy, splenomegaly, hepatomegalyBack pain, lower extremity weakness [spinal granulocytic sarcoma, most likely in t(8;21)patients]
  41. 41. Initial Diagnostic Evaluation and Management of Adult Patients with AMLLaboratory and Radiologic StudiesCBC with manual differential cell countChemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid, hepaticenzymes, bilirubin, LDH, amylase, lipase)Clotting studies (prothrombin time, partial thromboplastin time, fibrinogen, D-dimer)Viral serologies (CMV, HSV-1, varicella-zoster)RBC type and screenHLA typing for potential allogeneic HSCTBone marrow aspirate and biopsy (morphology, cytogenetics, flow cytometry, molecularstudies for NPM1 and CEBPA mutations and FLT3-ITD)Cryopreservation of viable leukemia cellsEchocardiogram or heart scanPA and lateral chest radiographPlacement of central venous access device
  42. 42. Initial Diagnostic Evaluation and Management of Adult Patients with AMLInterventions for Specific PatientsDental evaluation (for those with poor dentition)Lumbar puncture (for those with symptoms of CNS involvement)Screening spine MRI (for patients with back pain, lower extremity weakness,paresthesias)Social work referral for patient and family psychosocial supportCounseling for All PatientsProvide patient with information regarding their disease, financial counseling, andsupport group contacts.
  43. 43. Prognostic Factors• Age at diagnosis• Chronic and intercurrent diseases• Performance status• A prolonged symptomatic interval with cytopenias preceding diagnosis• A high presenting leukocyte count• Chromosome findings at diagnosis*• Achievement of CR• Secondary AML
  44. 44. Principles of treatment• Combination chemotherapy – First goal is complete remission – Further rx to prevent relapse• Supportive medical care – Transfusions, antibiotics, nutrition• Psychosocial support – Patient and family
  45. 45. Complete remissionCR is defined-•Blood neutrophil count -1000/L•Platelet count 100,000/L.•Circulating blasts - absent.•The bone marrow <5% blasts•Auer rods -absent.•Extramedullary leukemia -absent
  46. 46. Management: Acute Myeloid Leukemia
  47. 47. Dan Longo, Anthony Fauci, Dennis Kasper et al Harrisons Principles of InternalMedicine 18th Ed. 2011
  48. 48. Induction Chemotherapy• Cytarabine is usually administered as a continuous intravenous infusion for 7 days• Anthracycline therapy generally consists of daunorubicin intravenously on days 1, 2, and 3 (the 7 and 3 regimen).• Etoposide
  49. 49. Postremission Therapy• Postremission therapy is designed to eradicate residual leukemic cells to prevent relapse and prolong survival
  50. 50. • Intensive chemotherapy – High-dose cytarabine 4 cycles of HiDAC (3 g/m2 per q12h on days 1, 3, and 5)• Allogeneic or autologous HSCT
  51. 51. • Patients who fail to attain CR after two induction courses should be treated with an allogeneic hematopoietic stem cell transplant (HSCT)
  52. 52. Hematopoietic stem cell transplantation• Permits “rescue” from otherwise excessively toxic treatment• Additional advantage of graft-vs-leukemia effect in allogeneic transplants• Trade-off for allogeneic transplantation: greater anti-leukemic effect but more toxic
  53. 53. Molecularly targeted therapy• Gemtuzumab ozogamicin• Anti-cd33 antibody• Chemically linked to the cytotoxic agent calicheamicin• Inhibits DNA synthesis andinduces apoptosisZein N, Sinha AM, McGahren WJ, Ellestad GA. Calicheamicin gamma 1l:an antitumor antibiotic that cleaves double-stranded DNA site specifi-cally.Science.1988;240(4856):1198-1201.
  54. 54. Treatment of Promyelocytic Leukemia• Tretinoin – APL differentiation syndrome• anthracycline-based chemotherapy• Arsenic trioxide• Gemtuzumab ozogamicin
  55. 55. Management of special situations
  56. 56. Hyperleukocytosis• Hyperleukocytosis with leukostasis immediate medical treatment.• Leukapheresis• Hydroxyurea, given at dosages up – 50 to 60 mg/kg per day. – Until the wbc has been reduced.• Prevention of tumor lysis syndrome – Hydration, – Control of uric acid production using allopurinol or rasburicase – Control of urine ph
  57. 57. Cns involvement• Less than 5% of patient• Intrathecal cytarabine• Dexamethasone to prevent arachnoiditis
  58. 58. Supportive Care
  59. 59. Prophylactic anti-infectious treatment• Personal hygiene• Dental hygiene• Vigorous hand washing• Anti-fungal prophylaxis• Antibiotic prophylaxisLeibovici L, Paul M, Cullen M, et al. prophylaxis in neutropenic patients. Newevidence, practical decisions.Cancer.2006;107(8):1743-1751.
  60. 60. Growth factors• GM-CSF or G-CSF* – Accelerate neutrophil recovery by 2 to 5 days – Reduce antibiotic use – Reduce duration of fever – Number of days spent in hospital – Do not retard platelet recovery – Do not have a detrimental effect by stimulation of leukemic cell growth *Estey EH. Growth factors in acute myeloid leukaemia.Best Pract Res Clin Haematol. 2001;14(1):175-187
  61. 61. Transfusion support • Prophylactic platelet transfusions- • hemoglobin level above 8 g/dL • Prevent alloimmunization • Gamma irradiation (at least 25 Gy)Schiffer CA, Anderson KC, Bennett CL, et al. transfusion for patients with cancer:clini-cal practice guidelines of the American Clinical Oncology.J ClinOncol.2001;19(5):1519-1538.
  62. 62. Selected New Agents under Study for the Treatment ofAdults with AMLClass of Drugs Examples of Agents in ClassTyrosine kinase inhibitors PKC412, MLN518, SU11248, CHIR-258, imatinib (STI571, Gleevec), dasatinib, AMN107Demethylating agents Decitabine, 5-azacytidineHistone deacetylase inhibitors Suberoylanilide hydroxamic acid (SAHA), MS275, LBH589, valproic acidHeavy metals Arsenic trioxideFarnesyl transferase inhibitors R115777, SCH66336HSP-90 antagonists 17-allylaminogeldanamycin (17-AAG), DMAG, or derivativesCell cycle inhibitors Flavopiridol, CYC202 (R-Roscovitine), SNS-032Toxin-conjugated antibodies Gemtuzumab ozogamicinProteasome inhibitors BortezomibAurora inhibitors AZD1152, MLN-8237, AT9283Immunomodulatory Lenalidomide, IL-2, histamine dihydrochloride
  63. 63. Refrences• Dan Longo, Anthony Fauci, Dennis Kasper et al Harrisons Principles of Internal Medicine 18th Ed. 2011• Current Medical Diagnosis and Treatment 2012• Boblöwenberg et al, acute myeloid leukemia, review article,• Hartmut Döhner et. Al, recommendations from an international expert panel, on behalf of the Diagnosis and management of acute myeloid leukemia in adults:European LeukemiaNet
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