Lecture 9 Acute Leukemia
what is the pathophysiology of ALL
unknown, but thought to be because of environmental exposures in conduction to genetic factors
what are the common cytogenetic findings associated with MDS
1) 5q deletion 2) monosomy 7 or monosomy 5 3) trisomy 8 4) 11q23 (therapy released to topoisomerase inhibitors)
what are the four categories that AML can be placed into based on genetic and clinical factors
1) AML with recurrent genetic aberrations 2) AML with MDS features (follows MDS) 3) AML that rises due to therapy 4) Not otherwise specified (NOS) (those remaining in the french-american-brutish categorization)
what are clinically favorable parameters for patients will ALL
1) Ages 2-9 2) caucasian female 3) low initial WBC 4) early cytoreduction of tumor 5) no relapse
diagnosis of MDS requires the combination of what tests
1) CBC 2) BM findings 3) Peripheral smear 4) cytogenetic studies
what steps must you take to make a MDS diagnosis
1) CBC 2) Review of peripheral smear 3) Rule out other causes of anemia 4) examine the bone marrow 5) bone marrow cytogenetic studies
what would be the typical immunophenotype in patients with burkitt ALL
1) CD10 2) Surface Ig 3) B cell related antigens (19, 20, 21, 22)
immunophenotypyping of AML blasts will show what positive markers
1) CD33 2) CD13 3) HLA-DR
what are the most common sites of relapse in a patient with ALL
1) CNS 2) Testes
what would be the typical hematologic findings (CBC and peripheral smear) of a patient with MDS
1) Decreased Hemoglobin and macrocytic anemia (refractory anemia) in all cases 2) Thrombocytopenia and neutropenia will also be seen in more sever cases 3) presence of macrocytes (enlarged nucleated RBCs) in smear 4) hyposegmented (less than 5 lobes) and hypogranular neutrophils 5) abnormal platelets
the CBC for a patient with MDS would show what, and what symptoms would these create
1) Decreased neutrophils: increased infection rate 2) Decreased RBCs: fatigue and weakness 3) Decreased Platelets: bleeding
genetic abnormalities that cause what systems to fail have been implicated in inducing AML and give example of each
1) Disruption of transcription factors necessary for normal hematopoiesis (T(8;21) and Inv 16 that block normal function of RUNX1 and CBF1-beta) 2) Disruption of tyrosine kinases that promote cell proliferation and survival (FLT3 mutation)
what are the typical hematological findings (both CBC and peripheral smear) of a patient with AML
1) Elevated WBC count (higher than infection) 2) >20% blasts in blood or BM 3) decreased hematocrit 4) decreased Hb (anemia) 5) decreases platelets (thrombocytopenic) 6) decreased neutrophils (neutropenic)
what will be the typical BM findings in a patient with ALL
1) Hypercellular 2) >20% blasts 3) few clusters of normal cells
list the common cytogenetic abnormalities associated with ALL and how these each affect prognosis of ALL and whether the mutation is B cell or T cell related
1) Hyperdiploidy (>50 chromosomes): favorable diagnosis, B cell type 2) Hypodiploidy (45 chromosomes): intermediate prognosis, B cell type 3) t(1;19) PBX/E2a: unfavorable prognosis, B cell type 4) t(12;21) TEL/AML-1 (detectable only by PCR): favorable prognosis. B cell type 5) t(9;22) BCR/ABL: unfavorable prognosis, B cell type 6) 14q11 (T cell receptor Gene): unfavorable prognosis, T cell type 7) t(x;11) (MLL gene): unfavorable prognosis, B cell type
what specific genetic mutations have been implicated in ALL
1) Notch1 (essential for T cell development) for T cell ALL 2) Pax 5 and E2A (essential for B cell development) for B cell ALL these mutations aid in growth and survival of ALL
what are the typical characteristics of Acute T cell Lymphoblastic Leukemia
1) Older median age then Pre-B cell type 2) High leukocyte count 3) Mediastinal mass in 50% of cases 4) morphologic features indistinguishable for B cell types 5) Express T cell antigens 6) TdT positive and express T cell antigens 7) earlier relapse and shorter disease free survival
name the common genetic abnormalities that are associated with AML
1) T(8;21) and inverted 16 creates abnormal fusion proteins of RUNX1 and CBF1-beta which are normally necessary for normal hemtopoeisis but the translocation blocks their normal function and maturation 2) FLT3 (tyrosine kinase) mutations promote proliferation and survival of several type of AML
what disorders increase the risk for ALL
1) Trisomy 21 2) Ataxia Telangiectasia
which syndromes are associated with increased risk of developing AML
1) Trisomy 21 2) Bloom syndrome (DNA breakage problems) 3) Fanconi's anemia (DNA repair problems) 4) Neurofibromatosis (nerve tissue tumors)
what common therapies are associated with therapy-related MDS
1) alkylating agents 2) type II topoisomerase inhibitors
what are the typical clinical findings in a patient with ALL
1) anemia 2) bleeding 3) infection 4) pallor 5) bone pain 6) petechiae 7) arthralgia (joint pain) 8) extramedullary involvement
what are the typical treatment options for AML
1) basic combination chemotherapy 2) BM transplant 3) CD33 and CD45 target therapies
what will be the typical hematological findings (smear and CBC) in a patient with ALL
1) decreased platelets 2) anemia (normocytic and normochromic) 3) WBC abnormal (could be high or low) 4) increased lymphoblasts
what are the typical BM findings in MDS
1) hypercelluar (even though hematopoiesis is ineffective) 2) Dysplasia in one two or all cell lines which includes a) mutinucleated or binucelategd erythroid precursors with nuclear bridging b) hypogranular granulocyte precursors with cytoplasmic blebbing c) micromegakaryocytes
what would you typically fine in a BM aspirate in a patient with AML
1) hyperceullar 2) >20% blasts 3) reduced normal bone marrow elements
what are the typical treatment options for someone with MDS
1) in elderly supportive care with transfusions and antibiotics 2) in children and young adults can do BM transplant to try to cure
what environmental factors are associated with AML
1) ionizing radiation 2) cytotoxic chemotherapy 3) benzene 4) cigarette smoking
how can you differentiate a blast from a mature cell
1) open/immature chromatin patters 2) high nuclear to cytoplasmic ratio 3) larger and paler cells 4) more prominent nucleoli
what are the typical morphological characteristics seen on a peripheral smear in a patient with PML
1) promyelocytes with red/purple cytoplasmic granules 2) numerous auer rods/bodies (crystal rod structure in cytoplasm) 3) nuclei that are reniform or bilobed
what are the major characteristics of myelodysplastic syndromes
1) qualitative and quantitative in one, two or all myeloid cells (RBC, neutrophils, platelets) 2) disorderly and ineffective hematopoiesis 3) risk of transformation to acute leukemia
describe the genetic pathogenesis that causes PML
1) t(15;17) occurs 2) this places the PML gene q22 on chromosome 15 and the retinoic acid receptor alpha (RAR-alpha) gene on chromosome 17 next to each other 3) this creates a new fusion gene which creates an abnormal retinoic acid receptor that blocks myeloid differentiation leading to clonal proliferation
what are the characteristics of acute promyelocytic leukemia (PML)
1) t(15;17) which can be targeted by therapy 2) abnormal multilobulate promyelocytes predominate 3) younger median age than AML (35-40 years) 4) high frequency of DIC
how does the extramedullary involvement in ALL typically manifest clinically
1) testicular enlargement or pain 2) headaceh 3) vomiting 4) lymphadenopathy 5) splenomegaly 6) mediastinal mass (if T cell ALL)
how common is hypodiploidy associated with ALL and what prognosis does it indicate
45 chromosomes is characterized as hypodiploidy and is found in 3-9% of patients with ALL and carries an intermediate to unfavorable prognosis
what percentage of ALL patients have karyotypic chromosome abnormalities
80-90%
how common is hyperdiploidy associated with ALL and what prognosis does it indicate
>50 chromosomes is characterized as hyperdiploidy and is found in precursor B cell type in 25% of childhood ALL. It carries a favorable prognosis
at what age does the peak incidence of AML occur
>60 years
what is the most common type of leukemia under the age of 17
ALL
how does the prognosis of AML that follows MDS compare to de novo AML
AML that follows MDS have a much poorer prognosis
presence of gingival hyperplasia is common in what type of acute leukemia
Acute Monocytic Leukemia (M5)
presence of t(15;17) is specific to which type of acute leukemia
Acute Promyelocytic Leukemia (PML)
presence of DIC is common in what type of Acute leukemia
Acute Promyelocytic Leukemia (PML, M3)
how common are chromosomal abnormalities. Compare the rate in idiopathic and therapy related MDS
Idiopathic (de-novo): 20-50% Therapy related: 80%
what is the typical treatment for PML/APL
All-trans retinoic acid (ATRA), a derivative of Vit A, is administered to overcome the fusion gene and is given in combination with conventional chemotherapy
hyperdiploidy is associated with T or B cell type ALL
B cell
are B or T cell ALLs more common an why
B cell ALL is more common because B cells tend to predominate throughout life with the peak mass occurring between ages 2-10 (hence why ALL is common in children)
describe the indicators associated with prognosis and response of AML to treatment
CLAPS 1) Cytogenetic findings ( inv(16), t(8;21), t(15;17) are better) 2) Leukocyte count (more leukocytosis is worse prognosis) 3) Age (infants and older patient >60 do worse) 4) preexisting MDS or prior treatment (patients do worse) 5) Speed to remission (faster is better, usually within 7-14 days)
what are favorable cytogenetic indicators and unfavorable cytogenetic indicators for AML
Favorable: 1) inv(16) 2) t(8;21) 3) t(15;17) Unfavorable: 1) -7 or 5 2) del7q 3) t(11q23)
what are good prognostic and poor prognostic indicators for MDS
GOOD: 1) Young age 2) moderate cytopenias 3) less blasts 4) ringed sideroblasts 5) normal karyotypes POOR: 1) Older age 2) sever cytopenias 3) high blast count 4) absent ringed sideroblasts 5) complex cytogenic abnormalities
what is the difference in prognosis between an ALL patient with hyperdiploidy and hypodiploidy
Hyper: favorable prognosis Hypo: intermediate to unfavorable prognosis
what is the difference between a leukemia and a lymphoma
Leukemia: a hematologic neoplasm that predominantly involves the BM and has circulating tumor cells and can be of myeloid or lymphoid origin Lymphoma: clonal proliferation of lymphocytes that arises in discrete tissue masses in lymph nodes or in extra nodal sites
differentiate the origin of myeloblasts vs normoblasts
Myeloblasts: from the granulocytic cell line Normoblasts: from the erythroid cell line
what would be the typical immunophenotype in patients with B and T cell ALLs respectively
Precursor B cells: 1) CD19 2) CD20 3) CD21 4) CD22 5) TdT Precursor T cells: 1) CD2 2) CD5 3) CD7 4) CD8 5) TdT
what immunophenotyping marker would be found in both B and T cell ALLs
Terminal deoxynucleotidyl transferase (TdT)
what is promyelocytic leukemia, what patient type is it common in, what are the genetics associated with it, what is the pathogenesis, what are the common symptoms, what are the CBC, Peripheral smear, and how is it treated
What: a type of AML with distinctive genetics and morphology Patient: young adults (35-40) genetics: t(15;17) creating the PML-RAR fusion gene pathogenesis: t(15;17) places the PML gene q22 on chromosome 15 and the retinoic acid receptor alpha (RAR-alpha) gene on chromosome 17 next to each other which creates a new fusion gene which creates an abnormal retinoic acid receptor that blocks myeloid differentiation leading to clonal proliferation clinical symptoms: DIC, Hemorrhage CBC 1) elevated WBC 2) decreased hematocrit 3) decreased hemoglobin 4) decreased platelets 5) decreased neutrophils PERIPHERAL SMEAR 1) promyelocytes characterized by red/purple granules, Auer rods, and bilobed nuclei Treatment: All-trans retinoic acid (ATRA) a derivation of vitamin A that targets t(15;17) fusion gene
what is acute myeloid leukemia, what patient type is it common in, what are the genetics associated with it, what is its immunephenotype, what is the pathogenesis, what are the common symptoms, what are the CBC, Peripheral smear, and BM aspirate associated with it, and how is it treated
What: tumor of hematopoietic progenitors caused by acquired oncogenic mutations that impede differentiation leading to the accumulation of immature myeloid blasts in the marrow patients: occur in adults over 60 and sometimes channel with bad cytogenetics pathogenesis: combination of genetics and environmental factors including: ionizing radiation, cytotoxic chemotherapy, benzene, cigarette smoking symptoms: fatigue, fever, infection, bleeding GENETICS 1) Favorable: Inv(16), t(8;21), t(15;17) 2) Unfavorable: -7 or 5, del7q, t(11q23) IMMUNOPHONTYPE 1) CD13 2) CD33 3) CD45 4) HLADR CBC: 1) elevated WBC (as the blasts are counted) 2) decreased hematocrit 3) decreased hemoglobin 4) decreased platelets 5) decreased neutrophils Peripheral Smear 1) immature myeloid precursors some with auer bodies BM: 1) hypercellular with >20% of blasts in BM TREATMENT 1) chemotherapy 2) BM transplant 3) CD33 and CD45 target therapy
which types of ALL can spread to the CNS
all types
what is primary MDS
an idiopathic MDS that has slower onset in older (>50) patients
what is Terminal deoxynucleotidyl transferase (TdT)
a DNA polymerase normally active during antigen receptor gene arrangement in primitive B and T cells and is useful for identifying lymphoblasts over myeloblasts
what is therapy-related MDS
a MDS that is secondary to toxic effects of alkylating agents or type II topoisomerase inhibitors and occurs 5 years after initiation of therapy
what is myelodysplastic syndrome (MDS)
a heterogenous group of clonal stem cell disorders characterized by disorderly and ineffective hematopoiesis that carries a high risk for transformation to acute leukemia
what is acute lymphoblastic leukemia (ALL)
a systemic, neoplastic proliferation of lymphoblasts within the bone marrow and/or the peripheral blood and is the most common leukemia in children under 17
what is Acute Myeloid Leukemia (AML)
a tumor of hematopoietic progenitors caused by acquired oncogenic mutations that impede differentiation leading to accumulation of immature myeloid blasts in the marrow
what is mixed lineage leukemia
a type of leukemia where tumors cells express both myeloid and lymphoid antigens and is caused by abnormalities of the MLL gene on chromosome 11 (t(x;11) mutation)
when dose bone marrow failure occur during progression of acute leukemia vs chronic leukemia
acute: early bone marrow failure chronic: late bone marrow failure
why can it be hard to diagnose MDS
because MDS can be asymptomatic and diagnosis would only be suspected by an abnormal CBC
why is the WBC count typically very high in acute leukemia's when looking at a CBC
because blasts are mistaken as WBC in the CBC and so the WBC counts will be high
why is the presence of t15;17 in acute leukemia consider a favorable cytogenetic abnormality
because this abnormality can be tarted by therapy
is ALL more common in males or females and whites or african americans
caucasian males most commonly get ALL
true or false: a mutation that blocks maturation is enough to cause acute leukemia
false: a second mutation that causes cell proliferation must often follow
true or false: MDS is commonly seen in women and children
false: it is more common in men and rarely seen in children with the average age being (60-75yo)
true or false: the karyotypic chromosome abnormalities associated with ALL is seen in both the neoplastic cells and normal cells
false: it is only in the DNA of cancer cells
what morphologic features distinguish B cell from T cell type ALL
indistinguishable for B cell types vs T cell type based on morphology
what is the prognosis of MDS and how does death normally occur
it is a progressive disorder that has a survival range of weeks-years with 30% progressing to acute leukemia. death normally comes from infection of bleeding
dose AML affect children or adults more
it is predominantly found in adults HOWEVER there is a higher incidence of AML in children during the first year of life
what could a CSF in an ALL patient show
leptomeningeal spread of leukemia which is clinically significant
what is bilineal leukemia
leukemia characterized by individual leukemic cells that express myeloid or lymphoid antigens but not both at the same lime
what is the general pathophysiology of MDS
most likely arises from an initial event that causes DNA damage and further mutations ("secondary hits") that enhance disease progression
what is the pathophysiology of AML
multifactorial: genetic + environmental and occupational factors that includes radiation, chemotherapy and smoking
what is the general cause of ALL
mutation in the DNA that causes a block in maturation and subsequent drive in proliferation
T cell ALL often occurs in what age
older children (teenagers)
what in general causes AML
primary oncogenic mutation that impede differentiation and second mutation that causes proliferation leading to accumulation of immature myeloid blasts in the marrow
which is the most common peripheral blood finding in MDS
refractory anemia that is normally macrocytic with hyposegment hypogranular neutrophils
what are the classic symptoms of AML
symptoms of BM failure 1) fatigue 2) fever 3) infection 4) bleeding with petechiae
which cytogenetic abnormality associate with ALL can only be detected by PCR
t(12;21)
Burkitt type Leukemia/Lymphoma carries which type of cytogenetic abnormality
t(8;14)
A mediastinal mass in a patient with ALL would indicate what
that T cells are the abnormal cells in this ALL and the thymus is involved
what is the hallmark findings of acute leukemia
the presence of >20% of blasts in the BM or peripheral blood
does idiopathic or therapy related MDS carry a worse prognosis
therapy related
what are ringed sideroblasts and how do they change the prognosis of MDS
these are immature nucleated erythroid precursors with a ring of iron around them that become present in the blood in early MDS because the iron can't be incorporated into the hemoglobin during maturation. The presence of them indicate early and mild forms of MDS which indicates a better prognosis
how will the immunopheontype of ALL cells change after relapse
they will typically have a preserved phenotype with 25% potentially becoming TdT- from TdT+
what is the goal of ALL treatment
to have undetectable disease in the bone marrow as demonstrated by morphology and molecular studies
what do you do a CSF analysis in patients with ALL
to see if there is any CNS spread of ALL
what is the remission rate of AML and how does this change if the AML formed from MDS and therapies
typical remission rate: 60-70% but this drops with MDS or therapy-related AML
what is myelodysplastic syndrome, what patient type is it common in, what are the genetics associated with it, what is the pathogenesis, what are the common symptoms, what are the CBC, Peripheral smear, and BM aspirate associated with it, and how is it treated
what: clonal stem cell disorder characterized by maturation defects associate with ineffective hematopoiesis patients: older men genetics: 1) 5q deletion 2) monosomy 7 or 5 3) trisomy 8 4) 11q23 pathogenesis: genetic abnormalities leading to defects in maturation and disorderly and ineffective hematopoiesis that leads to cytopenias and functional defects in myeloid cells symptoms: increased infection, fatigue and weakness, increased bleeding CBC 1) decreased Hb 2) high MCV 3) thrombocytopenia 4) neutropenia PERIPHERAL SMEAR 1) macrocytic RBCs 2) hyposegmented and hypogranular neutrophils 3) abnormal platelets 4) micromegakaryocytes BM 1) hypercellular 2) dysplasia in cells lines: multinucleate erythroid precursors, hypogranular granulocytes with cytoplasmic blebbing, micromegakaryocytes Treatment: supportive treatment and transplantation for cure
at what point during ALL treatment is remission considered to be reached
when normal hematopoiesis has returned as evidenced by normal blood cell measurements