myeloproliferative neoplasms Flashcards
MPNs is defined as unregulated cell proliferation and survival due to dysregulated _______ or its associated signal transduction
tyrosine kinase
two important tyrosine kinase mutations associated
- ________ and _________oncogene in CML
- _________ up-regulation in p. vera, ET and MF
- philadelphia chromosome and BCR-ABL1 oncogene in CML
2. JAK2 up-regulation in p. vera, ET and MF
positive philadelphia chromosome
chronic myleogenous leukemia
chronic myleogenous leukemia
slowly progressing blood and bone marrow disease that usually occurs during or after middle age and rarely occurs in children and with presence of philadelphia chromosome
CML:
- slightly higher in males or females
- risk factors
- what would be expected to find in lab?
- 50% are asymptomatic with suspicion based on labs but we could expect to see what symptoms?
- why do we see heapot-splenomegaly?
- slightly higher in males
- risk factors include ionizing radiation and maybe post chemo
- lab should show an increased WBC count (leukocytosis), mild anemia and either a normal or elevated platelet count
- excess cytokiness could lead to fatigue, malaise and bleeding dysfunction due to platelet dysfunction
- due to other organs starting to compensate for BM and generate cells called extramedullary hematopoiesis
CML clinical hallmark is uncontrolled production of __________ cells of the neutrophil lineage with disease progression in triphasic phases .
these phases are:
- chronic phase where there is an increase in committed myeloid progenitors leading to _____ and _____
- Accelerated phase there is increase ____cells in the peripheral blood smear with _____and an _______ WBC count. there is a need for more intensive myelosuppressive therapy
- Blast crisis- blasts cells are over 20% thus this phase resembles _____
CML clinical hallmark is uncontrolled production of maturing myeloid cells of the neutrophil lineage with disease progression in triphasic phases .
these phases are:
- chronic phase where there is an increase in committed myeloid progenitors leading to leukocytosis and thrombocytosis
- Accelerated phase there is increase blast cells in the peripheral blood smear with splenomegaly an increasing WBC count. there is a need for more intensive myelosuppressive therapy
- Blast crisis- blasts cells are over 20% thus this phase resembles AML
cytoplasmic constitutively active tyrosine kinase
BCT-ABL1
what is a non-diagnostic finding but a prognostic finding for CML
granulocytic hyperplasia from a BM aspiration in patients with CML in chronic phase
causes of Imatinib resistance :
- point mutation in the _____kinase domain
- amplification of _____gene
- medication non-compliance
- point mutation in the ABL1 kinase domain
- amplification of ABL1 gene
- medication non-compliance
role of allogenic stem cell transplantation
Pre-TKI it was the only known curative treatment but there were many cases of graft failure vs host that decreased overall survival
Now, it is done post- TKI where, TKI serve a a bridge
Ph-negative myeloproliferative neoplasms are (3)
and the cardinal feature is the dysregulated activation of _________signal transduction pathway
- polycythemia Vera
- essential thrombocytosis
- primary myelofribrosis
and the cardinal feature is the dysregulated activation of Jak-STAT signal transduction pathway
Important for cytokine and growth factor signaling
Transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell.
JAK-STAT pathway
which drug is active against T3151 mutation
posatinib
codes for a tyrosine kinase (JAK2) that is associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor receptors
Janus Kinase 2 Gene:
codes for thrombopoietin receptor
____Exon 10 mutation
Myeloproliverative leukemia virus oncogene (MPL
encodes for the protein, calreticulin, is a second messenger during signal transduction
_______exon 9 mutation: mainly activate MPL and at a low level the G-CSFR but not the EPOR,explaining the thrombocytosis associated with these mutants
CALR
a disease in which too many RBC are made in the Bone marrow
polycythemia Vera
polycythemia Vera:
- pathogenesis: autonomous – ?
- presentation- ?
- lab: includes____________ HCT/HGB/RBC# and RBC mass, platelets > 400k, WBC > 12,000, BM is ______ with __________ Fe storage and __________ serum Epo
- pathogenesis: autonomous – Epo or erythropoietin independent erythropoiesis
- presentation- hepatosplenomagly
- lab: includes elevated HCT/HGB/RBC# and RBC mass, platelets > 400k, WBC > 12,000, BM is hypercellular with absent Fe storage and decreased serum Epo
polycythemia Vera the EPO receptor is activated constitutively due to lack of auto-inhibition of the ______ enzyme probably due to the presence of an activating mutation involving an amino acid substitution of __________
polycythemia Vera the EPO receptor is activated constitutively due to lack of auto-inhibition of the JAK2 enzyme probably due to the presence of an activating mutation involving an amino acid substitution of valine to phenylalanine (V617F)
diagnosis of P. Vera requries 3 major criteria or the first 2 major criteria and the minor criterion:
a. major criteria
(1) Hgb is ?
(2) BM is _______ with proliferation of mature myeloid cell line
(3) presence of ______
b. Minor criteria
(1) serum Epo is ______
a. major criteria
(1) Hgb is > 16.5
(2) BM is hypercellular with proliferation of mature myeloid cell line
(3) presence of JAK-2
b. Minor criteria
(1) serum Epo is decreased
prognosis and treatment of P.Vera
- prognosis in untreated is _______and in treated it is ________
- adverse events include _________ due to hyperviscosity from increased counts and progression of disease to either ____ or _______
- treatment goal is to reduce Hct to ________. other treatments include a new inhibitor that blocks
_____ and _____that normalizes Hct and reduce JAK2 levels. Adding _________might be a good idea for elderly or refractory patients
- prognosis in untreated is months and in treated it is years
- adverse events include thrombosis due to hyperviscosity from increased counts and progression of disease to either myelofibrosis or AML
- treatment goal is to reduce Hct to <45%. other treatments include a new inhibitor that blocks JAK2 and IFN alpha that normalizes Hct and reduce JAK2 levels. Adding hydroxyurea might be a good idea for elderly or refractory patients
presence of an abnormal increase in the number of platelets made in the bone marrow and circulate in the blood
essential thrombocytopenia
essential thrombocytopenia requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion:
a. major criteria
1. _____ platelets count
2. BM showing proliferation of enlarged mature __________
3. not meeting any criteria of other________
4. mutation in either (3) mutation
b. minor criteria
1. presence of _______ marker
2. absence of evidence of reactive _____________
a. major criteria
1. elevated platelets count
2. BM showing proliferation of enlarged mature megakaryocytes
3. not meeting any criteria of other MPNs
4. mutation in either JAK2, CALR or MPL mutation
b. minor criteria
1. presence of clonal marker
2. absence of evidence of reactive thrombocytosis
cant confuse essential thrombocytosis from secondary thrombocytiosis conditions such as iron-deficiency anemia , hemolytic anemia, absence of spleen or from more acute causes like blood loss, infection, physical activity
yep
essential thrombocytosis treatments:
- low risk-
_________ - intermediate/high risk– (2)
- addition of ________ is beneficial for patients who are older in preventing thrombotic events
- low risk- no treatment
- intermediate/high risk– (1) hydroxurea (2)anagrelide
- addition of aspirin is beneficial for patients who are older in preventing thrombotic events
a disease in which abnormal blood cells and fibers build up inside the bone marrow
primary myelofibrosis
teardrop cells in peripheral blood smear
primary myelofibrosis
in primary myelofibrosis results of BM biopsy show megakaryocyte proliferation and atypia with evidence of
in primary myelofibrosis results of BM biopsy show megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
primary myelofibrosis:
- pathogenesis- ____________ secondary to secreted GF
- patients have the _______ mutation in about 30-50%
- some cases evolve from pre-existing _______ or ______
- pathogenesis- nonclonal BM fibroblast proliferation secondary to secreted GF
- patients have the JAK2 mutation in about 30-50%
- some cases evolve from pre-existing PV or ET
primary myelofibrosis: requires all three major criteria and one minor criterion:
a. major:
1. presence of _________ proliferation with __________ fibrosis
2. not meeting criteria for _________
3. mutations in either __________
b. minor:
1. leukocytosis
2. __________ serum level of lactate dehydrogenase
3. anemia
4. palpable splenomegaly
a. major:
1. presence of megakaryocyte proliferation with reticulin /collagen fibrosis
2. not meeting criteria for P. Vera, CML or other MPN’s
3. mutations in either JAK2, CALR or MPL
b. minor:
1. leukocytosis
2. increased serum level of lactate dehydrogenase
3. anemia
4. palpable splenomegaly
primary myelofibrosis:
- presentation- massive _________ due to extramdeullary hematopoiesis
- lab should show anemia and BM asp. that is dry ,meaning there is a lot of ________. about 30-50% should have a __________ abnl. such as 13q- and 20q-
- prognosis is_________with overall survival of 3 yr.
- which mutation is associated with a more indolent clinical course-
- only curative treatment is
- supportive therapy for _________such as Epo, ________ for constitutional symptoms, _________for pain and transfusion dependent anemia or _______ inhibitors for reduction in spleen
- presentation- massive spleenomegaly due to extramdeullary hematopoiesis
- lab should show anemia and BM asp. that is dry ,meaning there is a lot of fibrosis. aabout 30-50% should have a clonal cytogenetic abnl. such as 13q- and 20q-
- prognosis is poor with overall survival of 3 yr.
- which mutation is associated with a more indolent clinical course- calreticulin gene
- only curative treatment is allogeneic HSCT
- supportive therapy for anemia such as Epo, chemo for constitutional symptoms, splenectomy for pain and transfusion dependent anemia or JAK2 inhibitors for reduction in spleen
shrink spleen and improve constitutional symptoms and quality of life
JAK2 inhibitor
