AML

----WILLIAMS Hematology 9e

----HARRISON’s 19e

Acute Myelogenous LeukemiaA 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

EtiologyEnvironmental factors :RadiationBenzeneAlkylating agentsTopoisomerase II inhibitorsTobacco smoke RR-1.5-2.0Alpha emitter-ThoriumObesity-APL ? Leptin ,Adiponectin

EtiologyAcquired diseases :Clonal myeloid diseases –CMLPrimary myelofibrosis ETPVPNH

genomic instability and the acquisition of additional mutations

Etiology Sibling with AML 1.DNA Repair defects

Congenital 2.Susceptible gene favouring 2 nd mutation

Bloom syndrome1 3.Tumour suppressor

Congenital agranulocytosis (Kostmann syndrome) defect

Chronic thrombocytopenia with chromosome 21q 22.12 microdeletion

Diamond-Blackfan syndrome

Down syndrome

Dyskeratosis congenita3

Familial platelet disorder2

Fanconi anemia1

MonoMAC and Emberger syndromes (GATA2 mutations)

Neurofibromatosis

Werner syndrome (progeria)

MOLECULAR PATHOGENESISThe Leukemia Stem CellSeries of somatic mutations in a primitive hematopoietic multipotential progenitor cell Bulk 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).

MOLECULAR PATHOGENESISPreleukemic Stem CellsAccumulation of genetic and epigenetic changes in normal pluripotential HSCAML progresses from such cells carrying founder mutationsThought 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.

MOLECULAR PATHOGENESISSomatic Mutationsmutant 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 maturationcore binding factor (CBF)- {CBF-β & RUNX1}-10% AMLretinoic acid receptor-α (RAR-α)HOX familymixed-lineage leukemia (MLL),

MOLECULAR PATHOGENESISSomatic Mutations continued

primary mutations are not sufficient to cause AMLAdditional activating mutationsFms-like tyrosine kinase (FLT)3KITN-RAS and K-RAS are required to induce a proliferative advantage in the affected primitive cellOther 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),

MOLECULAR PATHOGENESISSomatic Mutations continued

SignificancePML-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%).

Classification

IHC

LABBlood:Anemia with Retic count 0.5-2.0TLC -< 5*109 in 50% at diagnosisANC-<1*109

Platelets <50*109 in 50% at diagnosisAuer RodsFaggot CellsBone Marrow:Blast cells around 3-95% at diagnosis WHO criteria more >/= 20% blasts except APL

DIFFERENTIAL DIAGNOSISIn 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 leukemiaThe promyelocytes in Pseudoleukemia contain a prominent paranuclear clear (Golgi) zone not covered with granules; and promyelocytes do not have Auer rods

TREATMENT-Preparation of patientPretreatment laboratory examinationblood cell countscytochemistry analysisimmunophenotyping of leukemic cells from blood or marrow,marrow examination including cytogenetic and molecular analyses to include FLT3 ITD, NPM-1, CEBPα, 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.

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

TREATMENT-Preparation of patientTherapy for hyperuricemia is required (1) 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 elevatedAllopurinol 300 mg/day orallydiscontinued 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..

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

TREATMENT-INDUCTIONCurrent 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%AgeAntecedant chemotherapy and clonal myeloid disorder

TREATMENT-INDUCTIONstandard induction Regimen the “7 plus 3” regimenCytarabine -100 mg/m2 daily by continuous infusion on days 1 through 7 and Daunorubicin at 45 to 90 mg/m2 on days 1 through 3

Idarubicin 12 mg/m2 gives better complete remission rates in younger adults than does daunorubicin 45 mg/m2, each given for 3 days

----WILLIAMS Hematology 9e

TREATMENT-INDUCTIONAge <60 yearsCytarabine -100 to 200 mg/m2 daily by continuous infusion on days 1 through 7 or 2gm/m2 i.v. q12h for 6 days and Daunorubicin at 60 to 90 mg/m2 on days 1 through 3High dose Cytarabine associated with higher remission rates..Toxicity of High dose cytarabine-Pulmonary,Cerebellar(ocassionally irreversible)

----HARRISON’s 19e

TREATMENT-INDUCTIONTimed Sequential TherapyMitoxantrone i.v. on days 1 to 3, Etoposide i.v. on days 8 to 10 along withCytarabine i.v. on days 1 to 3 and 8 to 10 resulted in a complete remission in 60 percent of patients

TREATMENT-INDUCTIONNovel 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

TREATMENTVery old patients or patients with comorbid conditions who are unfit for intensive regimens

single-agent therapies with clofarabine or Hypomethylating agents (i.e., 5-azacitidine or decitabine)

TREATMENT-INDUCTIONSpecial Considerations during Induction Therapy :Hyperleukocytosis Patients with blast counts greater than 100 × 109/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/m2

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

TREATMENT-INDUCTIONSpecial 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 × 109/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

TREATMENT-INDUCTIONSpecial Considerations during Induction Therapy :Component Transfusion TherapyRed 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 × 109/L and 10 × 109/LAll 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

TREATMENT-INDUCTIONSpecial 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 (1) 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

TREATMENT-INDUCTIONSpecial 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 consolidationTreatment 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 combinationIf CNS leukemia is present, intrathecal therapy is often given twice/week until blasts are cleared & then once/week for 4-6 weeks.

TREATMENT-INDUCTIONSpecial 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

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

TREATMENTPOSTREMISSION 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%

TREATMENTNOVEL CHEMOTHERAPYEpigenetic 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.Presumptive 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

TREATMENTNOVEL CHEMOTHERAPYAntibodies to CD33 Gemtuzumab ozogamicin is a recombinant humanized anti-CD33 monoclonal IgG4 antibody conjugated to cytotoxin calicheamicinRapidly internalized causes subsequent cell apoptosis.Hyperbilirubinemia and transaminase elevations can occur.

TREATMENTNOVEL CHEMOTHERAPYTherapies 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

TREATMENT-APLINDUCTION:ATRA combined with an anthracycline-Idarubicin or with arsenic trioxide during induction treatment for most benefit and to prevent drug resistanceTypical induction regimen ATRA 45 mg/m2 daily in divided doses with idarubicin at standard induction doses (e.g., 12 mg/m2 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

TREATMENT-APLArsenic Trioxide :Trigger 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 daysS.E: retinoic acid–like syndrome,Torsades pointes

TREATMENT-APLMaintenance 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 methotrexateMaintenance is usually recommended for 2 yearsDuring maintenance, PCR monitoring on blood samples is recommended

TREATMENT-APLDifferentiation Syndrome A rapid increase in the total blood leukocyte count to as high as 80 × 109/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 featureOnce respiratory distress is evident, the patient should receive dexamethasone 10 mg IV every 12 hours for several days

TREATMENT-APLTreatment of Coagulopathy :Requires use of fresh-frozen plasma, platelet replacement, and fibrinogen replacementTargeted levels platelet counts 30 to 50 × 109 ,fibrinogen levels 1.5 g/L

AML PROGNOSISCR & CRPlatelets (CRp)Initial remission rates now approach 90 % in children70 % in young adults60 % in middle-aged patients and 40 % in older patients

AML PROGNOSIS