8/13- MDS/AML Flashcards
What is MDS?
Myelodysplastic Syndrome
- Aka “refractory anemia”, “preleukemia”, or “smoldering leukemia”
Spectrum of clonal myeloid disorders characterized by:
- Ineffective hematopoiesis
- Cytopenias
- Qualitative disorders of blood cells
- Clonal chromosomal abnormalities
- Variable tendency to evolve into acute leukemia
Can divide/organize MDS how? (dkfjadj)
- “Clonal bicytopenia or tricytopenias”
- “Oligoblastic leukemia”
Epidemiology of MDS?
Most common clonal hematologic disorder
- 1-10/100,000 /year in Western countries
- 3,000-12,000 cases/year in US
Disease of the elderly – incidence increases logarithmically after the age of 20
Men affected more than women (1.5x)
Pathogenesis of MDS?
Clonal expansion of a multipotential hematopoietic cell
Chromosomal deletions or additions involving most frequently:
- Long arms (q) of chromsomes 5 and 7
- Del of 5 and 7
- Del of 11, 12, 13, 20
- Trisomy 8
Major mechanism is ineffective hematopoiesis: defective maturation and death of marrow precursor cells.
- Decreased production/sensitivity to hematopoietic growth factors
- Increased production of hematopoietic inhibitors (TNFa, Ifng) inducing apoptosis
- T-cell mediated immune dysregulation
Risk factors for MDS?
Radiation Drugs and toxins
- benzene and other solvents
- alkylating agents (-5, -7)
- topoisomerase II inhibitors (11q23)
- smoking
- hair dyes
- pesticides, herbicides, organic chemicals
Other hematologic disorders
- aplastic anemia, paroxysmal nocturnal hemoglobinuria, congenital neutropenia
Genetic disorders
- Down syndrome Fanconi’s anemia,
- Neurofibromatosis (von Recklinghausen’s disease)
Clinical Manifestations of MDS?
- Anemia: weakness, fatigue, palpitations, orthostasis
- Thrombocytopenia: bleeding, bruising
- Leukopenia: increased susceptibility to infection
- Other: Sweet disease, polyarthritis, neuropathy, acquired alpha thalassemia, splenomegaly
DDx of MDS?
- Drugs or toxic exposures
- Infections
- Rheumatic disorders
- Deficiencies of vitamins B12, B6, or folic acid
- Hypersplenism
- Metastatic cancer
- Acute leukemia
- Aplastic anemia
- Paroxysmal nocturnal hemoglobinuria
- Myelofibrosis
What are features of the PBS in MDS?
Red cells:
- Anisocytosis
- Normocytic or mildly macrocytic indices
- Low reticulocyte count
- Howell-Jolly bodies, Cabot rings, basophilic stippling
White cells:
- Small, poorly granulated neutrophils with hyper- or hypolobulated nuclei
- Increased monocytes
Platelets:
- Large, agranular
What is shown here?
Pseudo Pelger-Huet cell
What is shown here?
Stodtmeister cell
What is shown here?
A: Basophilic stippling
B: Howell-Jolly bodies
C: Cabot’s rings
Overview of bone marrow in MDS?
- Erythroid Dysplasia
- Myeloid Dysplasia
- Megakaryocytic Dysplasia
What is shown here?
MDS
What is shown here? Condition/features? Prognosis?
Refractory Anemia
- Dimorphic population
- Less than 5% blasts in marrow
- AML in 10% at 2 yrs
- Median survival 3-6 yrs
What is shown here? Conditions/features? Prognosis?
Refractory Anemia with Ringed Sideroblsats
- > 15% ringed sideroblasts
- Less than 5% blasts in marrow
- AML in 0% at 2 yrs
- Median survival: 3-6 yrs
MDS is associated with what genetically?
Isolated del(5q)
Epidemiology of MDS?
- Occurs primarily in middle-aged women
Characteristics of MDS?
- Characterized by macrocytic anemia and normal or increased platelet count
- Megakaryocytes with hypolobulated nuclei
- Favorable clinical course with absence of leukemic transformation
International Prognostic Index (IPI) for MDS?
Standard treatment of MDS?
Supportive care:
- Erythropoietin, G-CSF, GM-CSF, IL-11
- Blood transfusion
- Deferoxamine or Exjade (iron chelator)
- Pyridoxine, folic acid
- Danazol Immunomodulation
- Antithymocyte globulin
- Cyclosporine
- Steroids
AML-style chemotherapy
Newer agents affecting DNA methylation
Bone marrow transplantation
What are 5-zacytidine (Vdiaza) and Decitabine (Dacogen)?
Response?
Side effects?
- Vidaza is prodrug for Decitabine, which reduces DNA methylation at cytosine residues and allows reactivation of silenced tumor-suppressor genes (demethylating agents)
- Overall response rate 16-17% (CR 7%, PR 16%, improvement in 37%)
- Significant side effects including cytopenias, GI disturbances, fever, fatigue and various aches and pains
Organization/Division of the Leukemias?
Acute leukemias are a group of disorders characterized how?
- Neoplastic transformation of hematopoietic stem cell (Clonality)
- Malignant cells either do not differentiate or differentiate abnormally
- Abnormal cells accumulate in blood, marrow and tissues
- Normal hematopoiesis is inhibited
- Fatal if untreated
Relative frequency of leukemias?
CLL: 32%
AML: 30%
ALL: 13%
Other: 13%
CML: 125
TEST TEST TEST
What is shown here?
AML! Acute Myelogenous Leukemia
BE ABLE TO RECOGNIZE THIS
- Can see Auer rods!
Epidemiology of AML?
Percentage of acute leukemias in adults/children?
- 15-20% of acute leukemia in children
- 80% of acute leukemia in adults
- 12,000 new cases/yr in the US
- 8,000 deaths/yr in US
- Median age is 63 (Disease of the elderly!)
Risk factors for AML?
Genetics:
- Chromsomal abnormalities: Down’s, Klinefelters
- Chromsomal instability: Fanconi’s anemia, Bloom’s
Prior chemotherapy:
- Alkylating agents: Cyclophosphamide, Mechlorethamine
- Topoisomerase II inhibitors: Etoposide, Anthacyclines
Radiation exposure: Hiroshema survivors, Radiologists (before modern shielding)
Environmental exposure: benzene
Prior hematologic abnormalities: Myelodysplasia, MPNs
What is shown here?
WHO/FAB Classification of AML?
AML with genetic abnormalities
- t(8;21) or inv (16)
- 11q23 abnormalities
- APL with t(15;17) AML with multilineage dysplasia
- Evolution from MDS
- No MDS, but dysplasia in 2 or more cell lines AML secondary to therapy
- Radiation/alkylating agent
- Topoisomerase II inhibitor AML NOS (FAB classification)
FAB Classification of AML?
M2 (AML with maturation) is associated with what translocation?
t(8:21)
M3 (Acute promyelocytic leukemia) is associated with what translocation?
t(15:17)
M4 (Acute myelomonocytic leukemia) is associated with what translocation?
inv 16
Clinical Presentation of AML?
Cytopenias:
- Anemia (fatigue)
- Leukopenia (infection/fever)
- Thrombocytopenia (bleeding)
Hyperleukocytosis: increased risk of CNS involvement
- Leukostasis (blast count > 50-100K, limited flexibility of blasts, lungs/brain most affected)
Extramedullary disease:
- Gums with M4/M5
- Chloromas with M2
- CNS Coagulopathy
- DIC, especially with M3 (also M4 and M5)
Petechiae are usually indicative of what abnormality?
Low platelet count
What is shown here?
Hyperleukocytosis in pt with M4
- HUGE buffy coat!
Which form of AML is associated with gum infiltration?
M5
Which form of AML is associated with M3?
DIC Ex)
- Platelets 5,000
- Fibrinogen 25
CNS hemorrhage may occur in pt with what form of AML?
M3 (from DIC)
- Most feared complication (bleed before you can treat the leukemia)
CNS leukemia may cause what nerve complications?
CN VII palsy (Bell’s palsy)
Diagnosis of AML?
Bone marrow exam
- Wright-Giemsa stain
- Sudan/special stains
- Flow cytometry (aspirate)
- Cytogenetics (aspirate)
- Molecular rearrangements
Cytogenetics and prognosis in AML?
Good prognosis:
- t(8:21)
- inv(16)
- t(15:17)
Intermediate:
- Normal
Poor:
- del 5/5q or 7/7q
- Abnormalities of 11q23
- Multiple abnormalities
What is the most common subtype of AML?
- Genetics?
- Prognosis?
M2 AML (AML with maturation)
- 50% have t(8:21)
- Better prognosis than average
What demographic groups are most commonly affected by M3 AML?
- Genetics?
- Prognosis?
- Treatment?
M3 AML (Acute Promyelocytic Leukemia/APL)
- Seen in younger Hispanic pts
- May see Auer rods or big chunky granules in PBS (emergency!) 80-100% have t(15:17)
Risk of DIC: bleeding, thrombosis
Unique treatment: all-trans-retinoic acid
What is this?
M2 AML, t(8:21)
What is this?
M3 AML
- May see Auer rods or big chunky granules (emergency!)
What is shown here?
Abnormal cell with t(15:17) on FISH
- Indicative of M3 AML
Treatment of AML? Complications? Maintenance therapy?
Induction chemotherapy:
- Anthracycline plus
- Cytarabine
Complications:
- Prolonged neutropenia
- infection
- Prolonged thrombocytopenia
Consolidation chemotherapy
No maintenance except M3
Bone marrow transplantation
Treatment of APL (M3 AML)?
ATRA (all transretinoic acid) + Chemotherapy
or
ATRA + Arsenic
(ATRA can put pts into remission, but doesn’t keep them there; not enough)
Prognosis of AML for children? Adults?
Children:
- 90% complete remission
- 40% long-term cure rate
Adults:
- 65-70% complete remission
- 30% long-term cure
Adverse prognostic factors in AML?
- Age > 60 yo
- Poor risk cytogenetics
- Antecedent hematologic disorder
- WBC > 100K
- Presence of multidrug resistance gene 1 (MDR)
- Failure to achieve complete remission with first cycle
