Describe leukemic stem cells
- Potential for crazy amounts of self renewal
- Also differentiate into leukemic blasts cells
- THIS IS WHERE IT ALL BEGINS!
What are the risk factors for acute leukemia? — Remember, however, that majority of acute leukemias occur in absence of risk factors
1) Previous chemo (remember DNA damage from alkylating agents or topoisomerase II inhibitors)
2) Tobacco smoke
3) Ionizing radiation
4) Benzene exposure
5) Genetic syndromes (e.g. Down syndrome, Bloom syndrome, Fanconi anemia, ataxia-telangiectasia)
What are the common signs/symptoms exhibited by pts w/ acute leukemia at initial presentation?
Symptoms of anemia
1) Fatigue
2) Malaise
3) Dyspnea
4) Pallor
Symptoms of thrombocytopenia
1) Easy bruising
2) petechiae
3) Hemorrhage
Symptoms of neutropenia
1) Fever
2) Infections
Why are the signs and symptoms exhibited by pts w/ acute leukemia at initial presentation?
Decreased #s of normal peripheral blood cells — b/c of marrow infiltration by leukemic cells
Low platelets
Low RBCs
Low neutrophils
What are a few basic markers that would help to assign blasts to a precursor-B, precursor-T, or myeloid lineage?
Pre-B: CD19, CD22
Pre-T: CD3, CD7
Mye: CD34 (myeloblasts)
Lymph: TdT (lymphoblasts)
Constrast B-ALL and T-ALL in regards to pt age and sex, manner of manifestation, and prognosis
For T-ALL compared to B-ALL…
Age: adolescents, YA
Sex: favors males
M: presents w/ a component of T-LBL, or mediastinal mass (B-ALL no lymphoma, only leukemia)
- Have markedly elevated WBC count
What are 3 commonly observed cytogenetic abnormalities in B-ALL?
1) t(9;22)(q34;q11.2) — BCR-ABL1
2) t(11q23) — MLL
3) t(12;21)(p13;q22) — ETV6-RUNX1
What is the usual pt age group and prognosis associated with BCR-ABL1?
Philadelphia chromosome (Ph+ ALL)
A: adults, children
P: worst prognosis of any subtype of ALL
What is the usual pt age group and prognosis associated with MLL (ALL)?
A: neonates, young infants
P: poor
What is the usual pt age group and prognosis associated with ETV6-RUNX1?
A: children
P: very favorable!
25% of cases in childhood B-ALL
What are the 5 factors affecting prognosis in ALL? Worse prognosis in parentheses.
1) Age (less than 1yo, more than 10yo, adults)
2) WBC count (elevated @ diagnosis)
3) Slow response to therapy or small amounts of disease after therapy
4) # of chromosomes (<46 chromosomes)
5) B vs. T lineage (T has it bad)
What are 2 types of findings that would allow for diagnosis of AML?
Increased myeloblasts accounting to >20% of nucleated cells in…
1) BM or
2) peripheral blood
What is an Auer rod? What is its clinical significance?
- Fused azurophilic granules forming small stick-like structures in cytoplasm
- Only seen in abnormal myeloblasts
- Can be used in diagnosis of AML!
W/o Auer rods, you can’t differentiate btwn myeloblasts and lymphoblasts in a smear
What are the 5 recurrent cytogenetic abnormalities for AML?
1) t(8;21) — RUNX1-RUNX1T1
2) inv(16) or t(16;16) — CBFC-MYH11
3) t(15;17) — PML-RARA
4) t(1;22) — RBM15-MKL1
5) 11q23 —MLL
What is the usual pt age group and prognosis associated with RUNX1-RUNX1T1 — t(8;21)?
A: younger pts (20s, 30s, 40s)
P: Good prognosis
What is the usual pt age group and prognosis associated with CBFC-MYH11 — inv(16) or t(16;16)?
A: younger pts (20s, 30s, 40s)
P: Good prognosis
Associated w/ presence of abnormal eosinophilic percursors w/ abnormal basophilic granules and eos granules (BASOS EOS!!)
What is the usual pt age group and prognosis associated with RBM15-MKL1 — t(1;22)?
A: infants w/ Down syndrome
P: Good prognosis
Shows megakaryoblastic differentiation
What is the usual pt age group and prognosis associated with MLL (AML) — 11q23?
A: kids and adults
P: Poor prognosis
Explain 2 reasons why it is important to recognize at initial diagnosis that a case of AML is the AML w/ t(15;17) subtype of AML (aka: acute promyelocytic leukemia, APL)
1) Encodes alpha-subunit of retinoic acid — signaling required for a receptor to begin differentiation past the promyelocyte stage
- A mutation in this is a problem!
- Can be mitigated w/ retinoic acid therapy
2) Associated w/ DIC (crazy clotting and hemorrhage)
Contrast the 2 main categories of therapy-related AML. Talk about latency, cytogenetic abnormalities, and processes to AML through an MDS stage
1) Alkylating agents/radiation
2) Topoisomerase Inhibitors
AA/R vs TI
L: 2-8 y vs. 1-2 y
C: complex karyotype w/ whole/partial deletions in 5 or 7 vs. rearrangement of 11q23 (MLL)
MDS?: Usually yes vs. usually no
Compare the prognosis of the 2 main categories of therapy-related AML
Both BADDDDDD
What are the 3 molecular markers currently used to predict prognosis in pts w/ AML w/ normal karyotype?
1) FLT3 ITD
2) NPM1
3) CEBPA
Of the 3 molecular markers currently used to predict prognosis in pts w/ AML w/ normal karyotype, which of these trumps the other 2 as a driving prognostic factor?
FLT3 ITD!
You only check for NPM-1 or CERPA if you are negative for FLT3
What are the surface markers used to diagnose AML?
1) CD34 (lymphoblasts)
2) CD117 - C-Kit (myeloid marker)
3) Myeloperoxidase (myeloid marker)
