SET9 Flashcards
What kind of “CML” is Ruxolitinib useful in and why?
CNL (Chronic Neutrophilic Leukemia) in which most have CSF3R mutations leading to preferential downstream kinase signalling though SRC family-TNK i.e. JAK kinases so Ruxolitinib useful here
What is the treatment for Indolent Mastocytosis?
Cromolyn, H1/H2 blockers and topical steroids
What kind of Essential thrombocytosis has the shortest survival? Longest?
ET w/ MLP515+; longest are those who have triple negative ET which is negative for JAK2, CALR, and MLP515
Low Risk MDS w/ 5q del can be treated with what?
Lenalidomide 10 mg PO daily
What are the 5 points used for a Prognostic Scoring system for Primary Myelofibrosis?
Age >65, presence of consitutional sx, Hgb less than 10, Leukocyte count >25k, and circulating blast count >1% (0 - low risk, 1 - intermediate1, 2 -intermediate2, 3 or more - high risk)
What lymphoma will often have cytoplasmic staining + for BCL-2?
Follicular Lymphoma because t(14;18) leads to BCL2 overexpression
What C-kit mutation in Systemic Mastocytosis precludes use of imatinib (usually DOC for C-kit mutations)
C-kit with D816V
In what type of MDS is lenalidomide used?
Transfusion dependent low or intermediate risk MDS w/ del 5q; if concomittant del7q that is a poor risk factor and probably would not give lenalidomide
What is the typical EPO level in patients with congenital erythrocytosis? Which one has the opposite?
Usually low except in Chuvash Polycythemia (which is normal to high and due to abnormalities of O2 signalling)
What is Pacritinib?
A newer JAK2 inhibitor that can be used regardless of platelet count as Ruxolitinib often only good if platelet count >50k and usually pts with PMF have cytopenias due to BM fibrosis
What was evaluated in the COMFORT-1 and COMFORT-2 trials?
That JAK2 inhibitors where useful for decreasing B symptoms of Primary Myelofibrosis as well as for treating painful splenomegaly (also increase PFS and OS)
FIP1L1/PDGFRA fusion protein is the most common mutation in _________ and is also commonly seen in __________
Hypereosinophilic Syndromes; Systemic Mastocytosis (however, in mastocytosis the most common gene is C-kit)
What are 4 features in Hypoplastic MDS that predict for good response to immunsuppressive tx (i.e. ATG and cyclosporine)?
Age <60, hypocellular marrow, HLA-DR15+ and PNH clone +
Patients with Myeloproliferative Neoplasms can have JAK2 or CALR positivity (there are others) but which is assoc with decreased risk of thrombosis and improved OS?
CALR (encodes Calreticulin) decreased risk of thrombosis
How would you tx a pt with ET if their platelet count was >1 million but pt was 50 and had no evidence of thrombosis or personal hx of thrombosis
Aspirin alone; High risk ET is based on age>60 and personal hx of clot alone regardless of platelet count
What is the optimal hematocrit in JAK2 Polycythemia Vera?
45 (~hgb 15)
What should you send for if there is concern for Polycythemia vera but JAK2 V617F is negative?
Send for JAK2 exon 12 mutation analysis
What is CALR and what is the significance in patients with Myeloproliferative Disorders?
CALR encodes Calreticulin and patients with this mutation have more favorable prognosis than those w/ JAK2 mutations (this is discussed more so in ET and PMF than PV)
What two mutations in Systemic Mastocytosis can have response to Imatinib?
C-kit mutation (MC) as well as FIP1L1-PDGFRA fusion protein; HOWEVER, if C-kit w/ D816V present imatinib not useful
What is the most common mutation seen in Hypereosinophilic Syndrome? What other one can be seen?
FIP1L1/PDGFRA (fusion protein) and Imatinib can be useful here; ALSO some have 5q33 translocation leading to PDGFRB and also respond to Imatinib just like CMML
How does WHO define RAEB-1 and RAEB-2?
RAEB-1 is MDS w/ 5-9% blasts; RAEB-2 is MDS w/ 10-19% blasts
Bone loss (on DEXA), diarrhea and flushing with elevated tryptase suggests what
Systemic Mastocytosis (often C-kit mutation sometimes FIP1L1/PDGFRA); BM flow CD117+ CD25+; responsive to Imatinib unless C-kit D816V
How does Follicular lymphoma usually present?
Multistation Lymphadenopathy, BM involvement (paratrabecular infiltrates) and splenomegaly- i.e. Ann Arbor Stage IV
Androgen creams may result in what finding on CBC?
Erythrocytosis as does being s/p renal xplant
When should you consider chelation therapy in patients with transfusion-dependent MDS?
If ferritin >1000
What defines a person as having high risk Essential Thrombocytosis? Tx?
Age >60 OR personal hx of blood clots; Hydroxyurea AND Aspirin
The underlying mutation in Systemic Mastocytosis is often C-kit but can also be _______. Also seen in?
FIP1L1/PDGFRA; Hypereosinophilic Syndromes
What are the 3 possible mutations for Essential Thrombocytosis that are typically though of? What is the deal with “Triple Negative ET”?
JAK2, CALR, and MLP515; triple negative ET has the longest survival and lowest incidence of recurrent thrombosis
Erythromelalgia and Aquatic Pruritis are common sx of this
Polycythemia Vera
CSF3R mutations underly 90% of this hematologic malignancy
Chronic Neutrophilic Leukemia (atypical CML)- sometimes called CNL
What is CNL?
Chronic Neutrophilic Leukemia (atypical CML); >90% have CSF3R mutation; this mutation leads to increased signaling through JAK and so Ruxolitinib useful
At what lifetime # of tranfusions should you suspect someone probably has some degree of iron overload?
20-40 transfusions; start monitoring ferritin at this point
What is the use of Ruxolitinib in Polycythemia vera?
Can be used for patients who either had inadequate reponse to or could not tolerate Hydroxyurea; has been shown to decrease splenomegaly and need for phlebotomy
What medication can help to resolve an erythrocytosis in a patient who is s/p renal transplant?
ACE-inhibitors due to the deregulated Renin-Angiotensin-Aldosterone axis
What is a potential issue in giving Ruxolitinib in patients with Primary Myelofibrosis?
It can cause thrombocytopenia and should not be given in patients with platelet count <50k which is common in PMF as it leads to cytopenia, use Pacritinib instead
How is the starting dose of Ruxolitinib decided?
20 mg PO bid if platelet count >200k, 15 mg BID if platelet count 100-200 and not used if <50k would then need Pacritinib instead
Hypoplastic MDS often has overexpression of what and is treated how?
HLA-DR2 and its serologic split HLA-DR15 and a study showed a statistical significance in pts with HLA-DR15 to anti-thymocyte globulin and cyclosporine
What mutations underly Chronic Neutrophilic Leukemia (atypical CML)?
CSF3R
T/F: Ruxolitinib (a JAK2 inhibitor) only works in primary myelofibrosis if there is JAK2 positivity
False can be given in PM whether there is JAK2 positivity or NOT; this is because the JAK-STAT pathway is STILL INVOLVED in cell division!
Explain the difference in using imatinib to tx CMML vs. CML
In CML imatinib has activity against BCR-ABL which is a tyrosine kinase; in CMML imatinib has activity against PDGFR-B which is also a tyr kinase; CMML has nothing to do with BCR-ABL
What does the data show with respect to interruption of hypomethylating agents in a patient who is responding w/ MDS?
Associated with relapse and poor prognosis
What are the two possible mutations for Polycythemia vera?
JAK2 V617F and JAK2 Exon 12
What happens with the V617F mutation in PV?
A phenylalanine is switched for valine at position 617 in the JAK2 gene
What is the IHC of follicular lymphoma?
CD19+, CD20+, and CD23+ often with cytoplasmic expression of BCL2
Bone Marrow flow cytometry of Systemic Mastocytosis often shows what
CD117+ and CD25+
What percent of Essential Thrombocytosis is JAK2+?
50%
MDS-RA (w/ ringed sideroblasts) is classically not very responsive to what?
ESA’s but can show some improvement with G-CSF
Patients who are s/p renal transplant may have what finding on CBC?
Erythrocytosis as do androgen creams
Explain the molecular similarity of CMML and Hypereosinophilic Syndrome
CMML often has activation of PDGFRB due to 5q33 translocation and is treated with Imatinib; Most Hypereosinophilic Syndromes have the fusion tyrosine kinase FIP1L1/PDGFRA and Imatinib can also be used here; however, they often ALSO have 5q33 translocation leading to PDGFRB just like CMML and imatinib also used here
What can you say, from a prognosis standpoint about MDS w/ 5q del and one with 7q del?
5q del is a good prognostic indicator and has robust response to lenalidomide 10 mg PO daily; 7q is a poor prognostic finding
What are the indications for JAK2 inhibitors (Ruxolitinib) in Primary Myelofibrosis
Consitutional B symptoms and in cases of painful splenomegaly or symptomatic splenomegaly (early satiety); it does also increase PFS and OS
What is the minimal platelet count for which you can give Ruxolitinib?
50,000 as it causes thrombocytopenia so should not be given if platelet count lower
Typically AML is defined by having greater than 20% blasts but what cytogenetic features also define it as AML even if blast count is lower?
t(8;21), t(15;17) and inv(16)
PDGFR-B activation in CMML is due to mutations on what gene?
5q33, esp t(5;12)- can be tx with imatinib as PDGFR-B is a tyrosine kinase
What are often the sx of Systemic Mastocytosis?
Bone loss, diarrhea and flushing with elevated tryptase
If a pt w/ low risk MDS w/ 5q del was on lenalidomide progresses to high risk what do you do?
DC the lenalidomide and treat as a normal high risk MDS w/ chemo or azacitadine (if elderly) w/ allo-HSCT or reduced-intensity allo-HSCT
What is Chuvash Polycythemia?
An Autosomal Recessive disorder of erythrocytosis due to abnormalities of oxygen signaling (has a normal to high EPO, most congenital erythrocytoses have low) and was first discovered in the Chuvash region of Russia
What kind of sx can Primary Myelofibrosis cause?
Cytopenias with B symptoms and JAK2 inhibitors are useful to treat BOTH the constitutional sx AND the splenomegaly
How do you make a diagnosis of Hypereosinophilic syndrome?
Needs to be Eosinophilia >1500 at least for 6 months and all other causes ruled out (allergy, parasite) and there should be organ involvement often neurologic or endomyocardial fibrosis are the fatal ones
What did the PERSIST trial show?
That Pacritinib which is a newer JAK2 inhibitor can be used in PMF w/ platelet count <50k
At what CrCl should Defirasirox not be given?
CrCl <40
What myeloproliferative disorder often has PDGFR-B activation and can look like CML?
CMML- it has activation of PDGFR-B which encodes a tyrosine kinase, the gene is on 5q33 and t(5;12) in particular leads to its activation and can be Tx w/ imatinib which also affects this tyr kinase
What is the definition of Systemic Mastocytosis?
Abnormal proliferation of Mast Cells in 1 or more organs (often C-kit +)
Neurologic involvement and Endomyocardial fibrosis are often seen in what hematologic disorder of granulocytes?
Hypereosinophilic Syndromes (eos are granulocytes)
