Acute myeloid leukemia

a summary of acute myeloid leukemia

1. AML ----WILLIAMS Hematology 9e ----HARRISON’s 19e

2. Acute Myelogenous Leukemia A clonal, malignant disease of hematopoietic tissues that is characterized by 1.Accumulation of abnormal (leukemic) blast cells, principally in the marrow and 2.Impaired production of normal blood cells Result of a sequence of somatic mutations in a primitive multipotential hematopoietic cell

3. Etiology Environmental factors : Radiation Benzene Alkylating agents T opoisomerase II inhibitors Tobacco smoke RR-1.5-2.0 Alpha emitter-Thorium Obesity-APL ? Leptin ,Adiponectin

4. Etiology Acquired diseases : Clonal myeloid diseases – CML Primary myelofibrosis ET PV PNH genomic instability and the acquisition of additional mutations

5. Etiology Sibling with AML 1.DNA Repair defects Congenital 2.Susceptible gene favouring 2 nd mutation Bloom syndrome 1 3.Tumour suppressor Congenital agranulocytosis ( Kostmann syndrome) defect Chronic thrombocytopenia with chromosome 21q 22.12 microdeletion Diamond- Blackfan syndrome Down syndrome Dyskeratosis congenita 3 Familial platelet disorder 2 Fanconi anemia 1 MonoMAC and Emberger syndromes (GATA2 mutations) Neurofibromatosis Werner syndrome (progeria)

6. MOLECULAR PATHOGENESIS The Leukemia Stem Cell S eries of somatic mutations in a primitive hematopoietic multipotential progenitor cell B ulk of AML cases arise from one of two predominant CD34+ cell populations: CD34+CD45RA+CD38–CD90– ( multipotential myeloid progenitor) or CD34+CD38+CD45RA+CD110+ (granulocyte-monocyte progenitor).

7. MOLECULAR PATHOGENESIS Preleukemic Stem Cells A ccumulation of genetic and epigenetic changes in normal pluripotential HSC AML progresses from such cells carrying founder mutations T hought to form a reservoir after therapy that can lead to relapse HSC with DNMT3A,TET2,IDH1&2 - promote self-renewal and block differentiation of stem and progenitor cells.

8. MOLECULAR PATHOGENESIS Somatic Mutations mutant protein product often is a transcription factor or an element in the transcription pathway-disrupts the regulatory sequences controlling growth rate or survival of blood cell progenitors & their differentiation and maturation core binding factor (CBF)- {CBF- β & RUNX1}-10% AML retinoic acid receptor- α ( RAR- α) HOX family mixed-lineage leukemia (MLL),

9. MOLECULAR PATHOGENESIS Somatic Mutations continued primary mutations are not sufficient to cause AML Additional activating mutations Fms -like tyrosine kinase (FLT)3 KIT N-RAS and K-RAS are required to induce a proliferative advantage in the affected primitive cell Other proto oncogene mutations that occur in leukemic cells involve FES, FOS, GATA-1, JUN B, MPL, MYC, p53, PU.1, RB, WT1, WNT, NPM1, CEPBA (CCAAT-enhancer binding protein A),

10. MOLECULAR PATHOGENESIS Somatic Mutations continued Significance PML- RARa or CEPBA double mutations-very favorable OS-83% RUNX1-RUNX1T1, CBFB-MYH11,NPM1 without FLT3-ITD OS-62.6%, MLL-PTD or RUNX1, or ASXL1 mutation OS-22% and very unfavorable TP53 mutation (OS at 3 years, 0%).

11. Classification

12. IHC

13. LAB Blood: Anemia with Retic count 0.5-2.0 TLC -< 5*10 9 in 50% at diagnosis ANC-<1*10 9 Platelets <50 *10 9 in 50% at diagnosis Auer Rods Faggot Cells Bone Marrow: Blast cells around 3-95% at diagnosis WHO criteria more >/= 20% blasts except APL

14. DIFFERENTIAL DIAGNOSIS In adults the term Pseudoleukemia has been applied to circumstances that mimic the marrow appearance of promyelocytic leukemia. Recovery from drug-induced or Pseudomonas aeruginosa–induced agranulocytosis is characterized by a striking cohort of promyelocytes in the marrow, which upon inspection of the marrow aspirate or biopsy mimics promyelocytic leukemia The promyelocytes in Pseudoleukemia contain a prominent paranuclear clear (Golgi) zone not covered with granules; and promyelocytes do not have Auer rods

15. TREATMENT-Preparation of patient Pretreatment laboratory examination blood cell counts cytochemistry analysis immunophenotyping of leukemic cells from blood or marrow, marrow examination including cytogenetic and molecular analyses to include FLT3 ITD, NPM-1, CEBP α, and KIT mutation status. Herpes simplex virus and cytomegalovirus serotyping may be helpful if transplantation is a consideration. HIV and hepatitis serology( sos ) patients should have a baseline cardiac scan to determine ejection fraction prior to administration of an anthracycline antibiotic.

16. TREATMENT-Preparation of patient A peripherally inserted central catheter or a tunneled central venous catheter should be placed. C irculation facilitates administration of chemotherapy, blood components, antibiotics, and other intravenous fluids and medications

17. TREATMENT-Preparation of patient Therapy for hyperuricemia is required the pretreatment uric acid level is greater than 7 mg/ dL , ( 2) the marrow is packed with blast cells or ( 3) the blood blast cell count is moderately or markedly elevated Allopurinol 300 mg/day orally discontinued after the risk of acute hyperuricosuria or tumor lysis has passed (usually 4 to 7 days ) Recombinant urate oxidase ( rasburicase ) can be used to prevent urate-induced nephropathy, recommended dose is 0.2 mg/kg daily for 5 to 7 days i.v. .

18. TREATMENT-INDUCTION Goal of induction therapy achievement of complete remission < 2 percent blasts in the marrow, a neutrophil count greater than 1000/ μL and a platelet count greater than 100,000/ μL

19. TREATMENT-INDUCTION Current standard induction treatment for non-APL AML involves drug regimens with two or more agents that include an anthracycline antibiotic or an anthraquinone and cytarabine Remission rates 55-90% Age Antecedant chemotherapy and clonal myeloid disorder

20. TREATMENT-INDUCTION standard induction Regimen the “7 plus 3” regimen Cytarabine -100 mg/m 2 daily by continuous infusion on days 1 through 7 and D aunorubicin at 45 to 90 mg/m 2 on days 1 through 3 Idarubicin 12 mg/m2 gives better complete remission rates in younger adults than does daunorubicin 45 mg/m 2 , each given for 3 days ----WILLIAMS Hematology 9e

21. TREATMENT-INDUCTION Age <60 years Cytarabine - 100 to 200 mg/m 2 daily by continuous infusion on days 1 through 7 or 2gm/m 2 i.v. q12h for 6 days and Daunorubicin at 60 to 90 mg/m 2 on days 1 through 3 High dose Cytarabine associated with higher remission rates.. Toxicity of High dose cytarabine-Pulmonary,Cerebellar ( ocassionally irreversible) ----HARRISON’s 19e

22. TREATMENT-INDUCTION Timed Sequential Therapy Mitoxantrone i.v. on days 1 to 3, Etoposide i.v. on days 8 to 10 along with C ytarabine i.v. on days 1 to 3 and 8 to 10 resulted in a complete remission in 60 percent of patients

23. TREATMENT-INDUCTION N ovel and Molecular Targeting agents For patients with FLT3ITD + trials with tyrosine kinase inhibitors are ongoing. Patients with CBF + may benefit from combination of Gemtuzumab ozogamicin , a monoclonal CD33 antibody linked to the cytotoxic agent calicheamicin , with induction and consolidation chemotherapies

24. TREATMENT Very old patients or patients with comorbid conditions who are unfit for intensive regimens single-agent therapies with clofarabine or H ypomethylating agents (i.e., 5-azacitidine or decitabine )

25. TREATMENT-INDUCTION Special Considerations during Induction Therapy : Hyperleukocytosis Patients with blast counts greater than 100 × 10 9 /L require prompt treatment to prevent serious complications of hyperleukocytosis : intracranial hemorrhage or pulmonary insufficiency. Hydration should be administered promptly to maintain urine flow greater than 100 mL/h/m 2 Cytoreduction therapy can be initiated with hydroxyurea 1.5 to 2.5 g orally every 6 hours (total dose 6 to 10 g/day) for approximately 36 hours

26. TREATMENT-INDUCTION Special Considerations during Induction Therapy : Antibiotic Therapy Pancytopenia is worsened or induced shortly after treatment is instituted. Absolute neutrophil counts less than 100/ μL (0.1 × 10 9 /L) are expected and are a sign of effective drug action. The patient usually becomes febrile (>38°C), often with associated rigors . Centers use prophylactic antibacterial, antifungal, and/or antiviral antibiotics

27. TREATMENT-INDUCTION Special Considerations during Induction Therapy : Component Transfusion Therapy Red cell transfusions should be used to keep the hemoglobin level greater than 7.0 g/ dL , or higher in special cases (e.g., symptomatic coronary artery disease) Platelet transfusions should be used for hemorrhagic manifestations related to thrombocytopenia and prophylactically if necessary to maintain the platelet count between 5 × 10 9 /L and 10 × 10 9 /L All red cell and platelet products should be depleted of leukocytes, and all products, including granulocytes for transfusions, should be irradiated to prevent transfusion-associated graft-versus-host disease (GVHD) in this immunosuppressed population

28. TREATMENT-INDUCTION Special Considerations during Induction Therapy : Management of Central Nervous System Disease Prophylactic therapy usually not indicated but examination of spinal fluid after remission should be considered in monocytic subtypes (2 ) cases with extramedullary disease (3 ) cases with inversion 16 and t(8;21) cytogenetics (4 ) CD7- and CD56-positive (neural-cell adhesion molecule) immunophenotypes and ( 5) patients who present with very high blood blast cell counts

29. TREATMENT-INDUCTION Special Considerations during Induction Therapy : Management of Central Nervous System Disease In these situations, the risk of meningeal leukemia or a brain myeloid sarcoma is more but prophylactic intrathecal chemotherapy is not recommended if high-dose cytarabine is used for consolidation Treatment of meningeal leukemia can include high-dose intravenous cytarabine (which penetrates the blood–brain barrier), intrathecal methotrexate, intrathecal cytarabine , cranial radiation, or chemotherapy and radiation in combination If CNS leukemia is present, intrathecal therapy is often given twice/week until blasts are cleared & then once/week for 4-6 weeks .

30. TREATMENT-INDUCTION Special Considerations during Induction Therapy : Management of Nonleukemic Myeloid Sarcoma: Myeloid sarcoma may be the presenting finding in approximately 1% of patients with AML. Such patients should receive intensive AML induction therapy Intensive therapy results in a longer nonleukemic period than patients who have undergone surgical resection or resection followed by local irradiation

31. TREATMENT POSTREMISSION THERAPY Postremission therapy is intended to prolong remission duration and overall survival but no consensus exists regarding the best approach Intensive consolidation therapy after remission results in a somewhat longer remission duration Currently transplantation is recommended for all but good-prognosis patients (CBF leukemias or those with NPM1 mutation without a FLT3 mutation).

32. TREATMENT POSTREMISSION THERAPY For patients who do not receive high-dose chemotherapy with autologous or allogeneic transplantation in first remission, consolidation chemotherapy regimens containing high-dose cytarabine provide better results RAS mutations are associated with benefit from high-dose cytarabine therapy.Patients with CBF leukemias such as t(8;21) also have particularly favorable responses to repetitive cycles of high-dose cytarabine Relapse Rate-19%

33. TREATMENT NOVEL CHEMOTHERAPY Epigenetic Modulation Methylation of DNA at critical sites cause transcriptional inactivation of genes or chromosomal instability. In AML aberrant methylation especially preferential methylation of chromosome 11 has been described. P resumptive demethylating agents such as 5-azacytidine or decitabine , silencing mediated by histone deacetylation is a target for histone deacetylases- Depsipeptide , vorinostat promote histone acetylation and gene transcription in RUNX1-positive leukemic

34. TREATMENT NOVEL CHEMOTHERAPY Antibodies to CD33 Gemtuzumab ozogamicin is a recombinant humanized anti-CD33 monoclonal IgG4 antibody conjugated to cytotoxin calicheamicin R apidly internalized causes subsequent cell apoptosis. Hyperbilirubinemia and transaminase elevations can occur .

35. TREATMENT NOVEL CHEMOTHERAPY Therapies Targeted to Signal Transduction Mediators: FLT3 Inhibitors:Crenolanib , Quizartinib , midostaurin Kit Tyrosine Kinase Inhibitors: Imatinib Mesylate , Dasatinib ( Kit+CBF ) Nuclear Factor-Kappa B Inhibitors:Bortezomib Prenylation Inhibitors:lovastatin , Simvastatin

36. TREATMENT-APL INDUCTION : ATRA combined with an anthracycline- I darubicin or with arsenic trioxide during induction treatment for most benefit and to prevent drug resistance Typical induction regimen ATRA 45 mg/m 2 daily in divided doses with idarubicin at standard induction doses (e.g., 12 mg/m 2 on days 1 to 3 ) MOA: ATRA overcome the recruitment of histone deacetylase activity by PMLRAR-α fusion gene through interference with a nuclear corepressor

37. TREATMENT-APL Arsenic Trioxide : T rigger apoptosis of APL cells at high concentrations & maturation at low concentrations. The presence of PML-RAR-α is important for the response. Apoptosis may occur through induction of activation of caspase-1 and caspase-3. also may function through NF- κB inhibition 0.06 to 0.12 mg/kg body weight per day until leukemic cells were eliminated from the marrow-induced remission within 12 to 89 days S.E: retinoic acid–like syndrome,Torsades pointes

38. TREATMENT-APL Maintenance Therapy : patients should be in a molecular remission i.e.,PCR - negative for PML-RAR-α. Best results were achieved when ATRA was combined with 6-mercaptopurine and methotrexate Maintenance is usually recommended for 2 years During maintenance, PCR monitoring on blood samples is recommended

39. TREATMENT-APL Differentiation Syndrome A rapid increase in the total blood leukocyte count to as high as 80 × 10 9 /L in the first several weeks of therapy median time of onset is 11 days Fever , weight gain, dependent edema, pleural or pericardial effusion Respiratory distress is the key feature Once respiratory distress is evident, the patient should receive dexamethasone 10 mg IV every 12 hours for several days

40. TREATMENT-APL Treatment of Coagulopathy : Requires use of fresh-frozen plasma, platelet replacement, and fibrinogen replacement Targeted levels platelet counts 30 to 50 × 10 9 , fibrinogen levels 1.5 g/L

41. AML PROGNOSIS CR & CR Platelets ( CRp ) Initial remission rates now approach 90 % in children 70 % in young adults 60 % in middle-aged patients and 40 % in older patients

42. AML PROGNOSIS