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Lecture 18
Acute Leukemias and Myelodysplasia
| Question | Answer |
|---|---|
| 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 |
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UVAPATH4
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