4- Introduction to WBC Disorders Reactive an Neoplastic Myeloid Processes Targeted Leukemia Therapy Flashcards
In order to make a diagnosis of acute leukemia, how many blasts (at a minimum) would you have to se in a peripheral blood (or bone marrow) smear?
over 20%
What cells are these?
Neutrophils! You rock!
What type of WBC would be elevated with a streptococcal tonsilitis infection? How about Mono? Whooping cough? Cutaneous larva migrans? G-CSF administration?
mono- lymphocytes
strep tonsilitis- neutrophils
whooping cough- lymphocytes
cutaneous larva migrans- eosinophils
G-CSF- neutrophils (but not as elevated as with a bacterial infection)
What would the following laboratory tests be used to confirm?
JAK2 mutational analysis
Throat culture
Monospot test
Cytogenetics for the philadelphia chromosome
flow cytometry for Tdt(+) cells
JAK2 mutational analysis- PV, ET, PMF
Throat culture: Strep tonsilitis (neutrocytoses)
Monospot test: Infectious mononucleosis
Cytogenetics for the philadelphia chromosome: CML
flow cytometry for Tdt(+) cells: ALL (notice this is not the word all, I was confused at first haha)
What is the significance of “toxic changes” in peripheral blood neutrophils?
indicates the presence of primary granules
What disease is associated with Disseminated Intravascular Coagulation (DIC) and has the following histology?
Acute Myeloid Leukemia
Which cytogenic abnormality is associated with the following histology slide?
t(15;17)
There are a LOT of Auer rods so it is probably APL
What is the funcional defect that is associated with the product of the PML-RARa fusion gene? Therefore what therapy is recommended?
A block in terminal differentiation due to retinoic acid receptor disruption
therapy is all trans retinoic acid
Which cytogenic/molecular abnormalities have a similar prognostic significance to t(15;17), in a patient with AML?
t(8;21)
inv(16) aka t(16;16)
Leukemias are about 5% of all cancers. (S/O to Miss Matter). WHat percentage of adult leukemias are Acute Myelogenous Leukemia? What percentage of their etiologies re therapy related?
AML is 30% of adult leukemias and 10% of them are due to therapy
What 3 things does the prognosis of AML depend on?
Age
cytogenetics
Molecular
What is the difference bewteen cytogenetics and Molecular?
Cytogenetics is BIG, like a peice of highway compeltely dropped off
MOlecular is SMALL, like a little pot hole in the road (usually point mutations)
WHat does induction mean? And what drugs are usually used furing the induction process for AML?
Induction is inducing the patient into remission!
“7+3” with Ara-C + Daunorubicin
+Midostaurin (with FLT3 mutation)
Mylotarg (with CBF mutation) (immunotherapy)
What is consolidation?
Consolidation is ensuring that the patient is in remission!
chemotherapy
or stem cell transplantation
WHat does this patent likely have and why?
Chronic myelogenous leukemia
- blasts are <20% so not acute
- leukocytoses
In MDS would you have leukocytoses or leukopenia?
Leukopenia
Hypercellular bone marrow with effective hematopoiesis is seen in what?
Myeloproliferative Neoplasms (PV, ET, PMF, CML)
What are the basic questions you should ask yourself to assess what disease a person has, and then also to assess its severity?
-
Are blasts>20%
- if yes, its acute= emergency
- AML or ALL
- if no, chronic= not emergency
- if yes, its acute= emergency
- What cells are elevated?
WHat is hypercellular bone marrow with ineffective hematopoiesis associated with?
MDS
What is Hypercellular bone mrrow with extensive fibrosis associated with?
PMF
Leukocytes positive for CD10 is associated with what?
ALL
Leukocytes positive for JAK2V617F mutation suggestive of?
MPN :PV, EET, PMF
Not CML bc that is tyrosine kinase
What protein does the Philadelphia result in and what is the translocation?
The philadelphia chromosome, which brings about the BCR-ABL fusion protein is the consequence of t(9;22)
WHat is the functional defect that is associated with the product of the BCR-ABL fusion gene? What therapy is often used?
A constitutively activated tyrsine kinase
A tyrosine kinase inhibitor is recommended for CML
What is Chronic Myelogenous Leukemia (CML)? What are 2 hallmarks? Etiologies?
- Clonal myeloproliferative disorder of pluripotent stem cells. Increased proliferation and decreased apoptosis
- Hallmarks:
- Cytogenetic- Philidephia chromosome
- Molecular-BCR/ABL
- Etiology: Irradiation <5%, Unkown 95%
What are the 3 phases of CML progression without treatment?
Chronic
Accelerated
Blast phase
without treatment people usually go through all the phases and die within 7 years
How does a tyrosine kinase inhibitor work? When do we use it?
Typically ATP binds to BCR ABL
A TKI blocks the ATP binding sit so ATP can’t bind
No proliferation, Cell dies
**Used for CML!
What are 5 TKIs? How effective are these?
Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib
The lifespan of people on this drug are about the same as a person without CML! Unfortunately the side effects are brutal so even though a person’s survival is preserved, their quality of life is not
A patient has elevated hemoglobin and platelets, and a JAK2 mutational analysis is homozygous for the V617F mutation. What lab finding is likely present?
Decreased EPO
This patient probably has PV
A patient has elevated hemoglobin and a spleen palpable 4cm at MCL presenting with fatigue, cachexia, bone pain, night sweats and the following histology. What lab test would be positive to confirm the diagnosis?
JAK2 mutational analysis. This is PMF!
What are the 4 MPNs? What mutations typically cause them?
Polycythemia vera (JAK2)
Essential thrombocythemia (JAK2)
Primary myelofibrosis (JAK2)
Chronic Myeologenois leukemia (Tyrosine kinase)
A patient presents with pancytopenia, hyperceullar bone marrow, and frequent hypogranular and hypolobated neutrophils, and small, hypolobated megakaryocytes. What is the most likely diagnosis?
Myelodysplastic syndrome
MDS- Pancytopenia (ineffective hematopeiesis) and hypercellular bone marrow
What is the most important diagnostic criterion in differentiating myelodysplastic syndrome from and acute myeloid leukemia with myelodysplasia-associated changes?
Bone marrow blast percentage! in AML blast>20%
What cytogenic abnormality is most likely to be found in a patient with MDS? What is the most likely treatment?
Monosomy 7
A hypomethylating agent
What are the therapies for myelodysplastic syndrome?
Stem cell transplantation (BM transplant)
Supportive care +/- growth factors
hypomethylating agents
lenalidomide
histone deacetylase inhibitors
What is the Molecular mechanism for MDS? How do the therapies interfere with this?
Hypermethylation of genes silences them blocking gene expression leading to a differentiation problem (MDS)
Hypomethylating agents work by preventing DNAmethytransferase from hypermethylating
How do hypomethylating agents help with lifespan of patients with MDS?
9.4 months
What are the 3 categories of leukemias? Which ones fall into each category?
- Problems with Differentiation
- MDS
- Problems with Proliferation
- CML and /CLL
- PV
- ET
- PMF
- Problems with BOTH DIfferentiation and proliferation
- AML and ALL
