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Lecture 18

Acute Leukemias and Myelodysplasia

QuestionAnswer
What is the clinical criteria for leukemia? An increase in blasts in the bone marrow and/or blood of at least 20%
What is the level of blasts in normal human marrow? <5%
What is the morphologic characteristics of blast cells? High nuclear cytoplasmic ratios and fine nuclear chromatin
Compare the maturity of cells in acute leukemia vs. chronic leukemia Acute leukemais have immature or blasts cells whereas chronic leukemias have mature blood cells.
Compare the untreated clinical course of acute leukemias vs. chronic leukemias Acute leukemias: fatal in weeks to months vs. chronic leukemias: may survive for years
Compare the response of acute leukemias vs. chronic leukemias to chemotherapy Acute leukemias: highly sensitive vs. Chronic leukemias: relatively resistant
What are the cell types involved in AML? Precursors of granulocytes, monocytes, erytroid, and megakaryocytes.
What are the cell types involved in ALL? Precursors of B lymphocytes and T lymphocytes
What is the median age of onset of AML? It is a disease of adults with median age of 60 years.
What is the median age of onset of ALL? It is a disease of childrens with median age of 4 years of age.
What are morphologic hallmarks of AML? Auer rods and granules
What is the morphologic hallmarks of ALL? L1 type blasts
What are the flow cytometery markers of AML? MPO, CD13, CD33
What are the flow cytometery markers of ALL? TdT, CD19, CD3
What are the chromosomal abnormalities associated with AML? t(8;21), t(15;17), Inv16, 11q23, -5, -7, del5q, del7q
What are the chromosomal abnormalities associated with ALL? t(12;21), t(1;19), t(9;22), hyperdiploidy
What are the treatments of AML? ARa-C, Anthracycline, and Retinoic acid for t(15;17) type AML
What are the treatments of ALL? Prednisone, vincristine, L-asparaginase, anthracycline
What is the prognosis of ALL? Excellent in children
Clinical presenation of acute leukemia Pallor and fatigue due to decrease in red cell production; easy bruising, petechiae, and mucosal hemorrhage due to thrombocytopenia; fever secondary to bacterial and fungal infections due to decrease in neutrophil production
What are predisposing factors of AML? (1) Age (2) Marrow disease (myelodysplastic or myeloproliferative) (3) DNA damaging agents: chemotherapy, radiation, benzene (4) Congeital conditions:Down syndrome (5) Hereditary conditions:Faconi's anemia, Familial platelet disorder
Which cell lineage are CD13 and CD 33 flow cytometry markers for? Non-lymphoid cells
Which cell lineage is myeloperoxidase a flow cytometry marker for? Granulocytic cells
Which cell lineage are CD64 and CD14 a flow cytometry markers for? Monocytic cells
Which cell lineage is CD41a flow cytometry marker for? Megakaryocytic cells
Which cell lineage is Glycophorin A a flow cytometry marker for? Erythroid cells
Which flow cytometry markers are indicative a more mature cells? Myeloperoxidase, CD14, Glycophorin A
Which flow cytometry markers are indicative a more immature cells? CD 34, CD 117, HLA DR
Which cell lineage is CD 117 a flow cytometry marker for? Non-lymphoid cells
What cytogenetic finding is associated with promyelocytic AML (APL)? t(15;17)
What molecular defect is associated with APL? PML-RAR alpha fusion resulting in repression of target genes
What cytogenetic finding is associated with granulocytic differentiation type AML? t(8;21)
What cytogenetic finding is associated with myelomonocytic with marrow eosinophils type AML? Inv (16)
What cytogenetic finding is associated with post-therapy with topoisomerase II inhibitors type AML? translocation with 11q23
What cytogenetic finding is associated with post-therapy with alkylating agents type AML? del 7 or del 5
What is the molecular defect associated with granulocytic differntation type AML? AML1-ETO fusion resulting in repression of target genes responsible for myeloid maturation
What is the molecular defect associated with Inv(16)? CBFbeta-SMMHC resultin gin sequestration of AML1/RUNX1 transcription factor responsible for meyloid maturation
What is the molecular defect associated with translocation with 11q23 AML? MLL fusion proteins
What is the molecular defect associated with -7 or -5 type AML? Unknown
What are the cell signaling defects associated with AML? Aberrant activation of receptor tyrosine kinase (RTK) or ras signaling.
What is the theorem of Gilliland? Both transcriptional and signaling defects are necessary for full development of AML.
Describe how age is a prognostic factor in the survial of patients with AML? >55 year old tend to have more primitive, chemoresistant blasts. Also associated with unfavorable cytogenetics and higher rates of treatment complications.
What are the favorable prognostic genotypes of AML? t(15;17), t(8;21), and inv(16)
Which genotypes of AML have poor prognosis? 11q23 translocations, -5/-5q, -7/-7q, and complex.
What are the prognostic factors of AML? (1) age (2) genotype of AML (3) pre-existing myelodysplastic or myeloproliferative disorder (4) relaspe of previously treated AML
What is the convential chemotherapy regimen for AML? Ara-C + Anthracycline + others in 3 phases: induction, consolidation, and maintenance
What is the treatment for APL? All trans-retinoic acid (ATRA) + chemotherapy
What is the treatment for AML with poor prognosis or AML patients < 55 yo? Allogenic stem cell transplant
What are the predisposing factors of ALL? (1) congential conditions: Down syndrome (2) pre-existing maligancies: chronic myelogenous leukemia (3) hereditary conditions: ataxiz-telangiectasia (4) environment
(T or F) Majority of cases of ALL are B-cell precursor (BCP) malignancies. True
What is the morphologic appearance of L1 type blast cells? Small blast cells with virtually no cytoplasm
Which cell lineage are CD 19 and CD 20 flow cytometry markers for? B cells
Which cell lineage is surface Ig a flow cytometry markers for? B cells
Which cell lineage are CD 3, CD 2, CD 5, and CD 7flow cytometry markers for? T cells
Which cell lineage is TdT a flow cytometry markers for? Lymphoid cells
Which lymphoid flow cytometry markers are indicative of more mature cells? CD 20, surface IgG
Which lymphoid flow cytometry markers are indicative of immature cells? CD34 and TdT
What cytogentic finding is associated with B cell precursor type ALL? t(12;21) or hyper/hypo diploidy
What cytogentic finding is associated with pre B type ALL? t(1;19)
What cytogentic finding is associated with mature B (Burkitt's) type ALL? t(8;14)
What cytogentic finding is associated with Infantile (early BCP) type ALL? t(4;11)
What cytogentic finding is associated with Philadelphia chromosome type ALL? t(9;22)
What is the molecular defect associated with t(12;21)? TEL-AML1 fusion repressing target genes for B and T cell maturation
What is the molecular defect associated with pre B? E2A-PBX fusion blocking E2A function associated with B cell maturation
What is the molecular defect associated with Burkitt's ALL? c-MYC activation
What is the molecular defect associated with infantile ALL? AF4-MLL fusion resulting in upregulation of Hox genes
What is the molecular defect associated with Philadelphia chromosme ALL? BCR-ABL fusion resulting in aberrant tyrosine kinase activation
What age has the best prognostic factor in ALL? Age 1 to 15 years have excellent prognosis with 75% cure rate.
What cytogentic defects have the best prognosis in ALL? t(12;21) and hyperdiploidy (>50)
Which cytogenetic defects have the poorest prognosis in ALL? t(4;11) and t(9;22)
What type of ALL is most frequently found in adults (age>15 yo)? t(9;22) type ALL
What type of ALL is most frequently found in children < 1years of age? t(4;11) type ALL
What are the prognostic factors of ALL? (1) Age (2) cytogentic type (3) B-cell v T-cell precuros lineage (B cells have better prognosis) (4) WBC (>50,000 is indicative of poor prognosis) (5) CNS involvement (blasts in CSF is indicative of poor prognosis)
What is the convential treatment for ALL? Vincristine + Prednisone + L-asparaginase + anthracyclines (multiple phases: induction, intensification, and continuation)
What is the treatment for CNS involvement of ALL? Intrathecal methotrexate
What are the indications for allogeneic stem cell transplant for ALL? Multiple relapses, unfavorable cytogenetics, or adult patients
What is the percentage of blasts in myelodysplastic syndromes? Less than 20% blasts in bone marrow and/or blood
Compare the proliferative rate of cell in myelodysplastic syndromes vs. acute leukemias MDS: High proliferative rate but high levels of apoptosis vs. Acute leukemias: High proliferative rate with low rates of apoptosis
Compare the level of dysplasia in myelodysplastic syndromes vs. acute leukemias MDS: dysplasia in 75% of cases vs. Acute leukemia: dysplasis in 50% of cases
What grade classification would be given forMDS with refractory cytopenia with multilineage dysplasia? High grade Myelodysplasitc Syndrome
What grade classification would be given for MDS with refractory anemia with excess blasts (blasts <20% but >5%)? High grade Myelodysplasitc Syndrome
What grade classification would be given for MDS with refractory anemia with minimal dysplasia? Low grade Myelodysplastic Syndrome
What grade classification would be given for MDS with refractory anemia with ringed sideroblasts? Low grade Myelodysplastic syndrome
What grade classification would be given for MDS with 5q- syndrome? Low grade Myelodysplastic syndrome
What is the pathophysiology of most Low grade Myelodysplastic syndromes? Increased cellular proliferation accompanied by increased cell death. Such a finding suggests loss of normal cell cycle regulation leading to triggering of an apoptotic checkpoint.
What is the prognosis of low grade Low grade Myelodysplastic syndrome? Median survivial of at least 6 years.
What is the prognosis for high grade Myelodysplastic syndrome with refractory anemia with excess blasts? ~1 year
What is the prognosis for high grade Myelodysplastic syndrome with refractory anemia with multilineage dysplasia? ~2.5 years
What is the most common cause of death in high grade What is the prognosis for high grade Myelodysplastic syndrome? (1) 60% bone marrow failure (2) 40% progression to AML
What are the negative prognostic factors in What is the prognosis for Myelodysplastic syndrome? (1) Increased blasts (2) Unfavorable karyotype (complex, abnormalities of chromosome 7) (3) 2-3 lineages with cytopenia
What is the treatment for low grade myelodysplastic syndrome? Primarily supportive care including occasional red cell transfusions. There is a possible role for immunosuprression, and erythropoietin.
What are the treatments for high grade myelodysplastic syndromes? (1) Chemotherapy (2) allogeneic stem cell transplants for younger and healthier patients (3) G-CSF for neutropenia
Created by: UVAPATH4