SET6 Flashcards
What is the most favorable cytogenetic abnormality in CLL?
Deletion of 13q
Veno-occlusive disease due to transplant was previously called ______
Sinusoidal Obstruction Syndrome; US will show reversal of portal venous flow
What is high dose Daunorubicin? Intermediate dose? What patients may benefit from high dose daunorubicin?
90 mg/m2 as opposed to 60 (this is the 7+3 dosing); patients with DNTM3A, mutant NPM1, and MLL translocations may benefit
From worst to best list 5 cytogenetic abnormalities in CLL
17p del (32 months), 11q del (79 months), Normal Cytogenetics (114 months), trisomy 12 (111 months), 13q del (133 months)
What effect can Ibrutinib initially have on CLL lymphocyte counts? Why?
It can actually cause an increase because it, in addition to other things, inhibits binding of the CLL cells to the stroma
Which source of HSCs has the best platelet recovery?
Cord blood
What is the deal with Isocitrate Dehydrogenase mutations in AML with respect to prognosis?
IDH2 mutations associated with better prognosis; IDH1 is not
Deletion of 17p implies loss of what gene?
TP53 which is located on 17p so you’ve lost the “guardian of the genome”
What is the flow cytometry for APML?
HLADR-, CD34- (they are promyelocytes not blasts), MPO+, and CD33+
Why do the vast majority of Hairy Cell patients have splenomegaly?
Due to extramedullary hematopoeisis
Patients who are determined to be high risk for veno-occlusive disease with allo-HSCT should receive prophylactic _______
Defibrotide
What does CEBPA stand for? What is the relationship with AML?
CCAAT Enhancer Binding Protein Alpha; BIALLELIC mutations are associated with a better prognosis
What imaging would be useful if you suspected that a person was suffering from veno-occlusive disease due to acute GVHD from transplant?
Doppler US of liver will show reversal of portal venous flow
What is a good way to manage patients under 60 who have a late relapse from their initial AML?
They should be reinduced with a salvage regimen and consolidate with alloHSCT
What is a bad choice of drug for CLL patients who have autoimmune hemolytic anemia?
Fludarabine because purine analogs can also cause AIHA
In what CLL patients is Ofatumumab indicated?
(Anti-CD20) it is indicated in patients who have either failed alemtuzumab + fludarabine or in patients who are not candidates for alemtuzumab tx
t(v;11) suggests a mutation in what gene?
MLL (Mixed Lineage Leukemia)
What are some signs of differentiation syndrome?
Fever, elevation of WBC count, dyspnea with increasing oxygen requirement and pleural + pericardial effusions; CXR often showing diffuse interstitial pulmonary infiltrates
What is the cure for CLL?
Allo-HSCT
What are the first line drugs for Hairy Cell Leukemia?
Cladribine and Pentostatin (both are antimetabolites)
What drug is a chimeric CD20 inhibitor?
Rituximab
If using lenalidomide in CLL, in addtion to hypercoagulability, what is a common AE?
Tumor Flare
Explain what the granules of promyelocytes have to do with differentiation syndrome
Promyelocytes have granules and when they differentiate w /ATRA based tx the granules stimulate pulmonary edema and lead to fluid retention
Name 2 drugs that have shown benefit in CLL with 17p del
Ibrutinib and Venetoclax
What is Passenger Lymphocyte Syndrome?
This is when the B-cells from the donor form antibodies against the recipients red cells and cause hemolysis. Tx = supportive as the donor RBCs will eventually engraft
Can you give 7+3 to pregnant patients?
Yes, however there is certainly a real risk to the fetus; choice of anthracycline is unclear
If you want to give Ibrutinib + Rituximab to a patient with CLL but note that pt is on plavix what might be a better option?
Idelalisib + Rituximab as Ibrutinib causes bleeding issues
What are the two types of cells seen in Large Granular Lyphoctye Leukemia?
Generally, either CD3+ cytotoxic T cells or CD3- NK cells with CD57 + being the most common of the NK cell variety
What can you say about the loss of 17p in CLL?
Predictive for lack of benefit from chemotherapeutics and monoclonal ab therapies; tx with Ibrutinib and Venetoclax have shown benefit
After what period of time can live vaccines be safely given to BMT patients?
2 years, the risk is highest up until 2 years
What is the characteristic immunophenotype of Hairy Cell Leukemia?
CD19+, CD20+, CD103+, CD11c+, CD25+, and CD123+
What are the Stage 0-IV of the Rai staging system for CLL?
Stage 0 = ALC >5000 only; Stage 1 = ALC >5,000 + LAD; Stage 2 = ALC >5000 + HSM; Stage 3 = ALC>5000 +anemia (not AIHA); Stage IV = ALC >5000 + thrombocytopenia (not ITP/Evans)
What is the mechanism of action of Defibrotide? Where does it come from?
It protects the endothelium of the small veins of the liver, used to tx VOD from acute GVHD (6.25 mg/kg IV qid); unknown MOA. Comes from intestinal mucosa of pigs
What kind of lymphocytes are NOT affected by Ibrutinib?
T lymphcytes; so you do not have same PCP risk as with other CLL drugs
What is the driver mutation in Hairy Cell Leukemia?
It is almost always BRAF V600E which activates the MEK-ERK pathway (vemurafenib has shown efficacy in some case reports but first line is cladribine)
What is FCR?
Fludarabine + Cyclophosphamide + Rituximab, used in CLL
Ibrutinib is approved for first line tx in CLL pts with _____
17p del
What drug is a humanized CD20 inhibitor?
Ofatumumab
What source of HSCs is not ideal in patients with a large BMI?
Cord blood due to the low volume; will lead to delayed hematopoeitic recovery
What is the caveat about CEBPA mutations in AML and favorable prognosis?
There must be biallelic CEBPA mutations, just one is NOT associated with good prognosis
What should you think if you have prolonged lymphocytosis on Ibrutinib?
It may be due to a quiescent clone but can be due to the ibrutinib itself
Mutations in what gene lead to ibrutinib resistance?
CXCR4 C481S mutations because Ibrutinib is a BTK inhibitor that binds to C481 of the kinase covalently at a sulfhydryl group resulting in irreversible inhibition of the kinase
What is the role of MLL gene in AML pathogenesis? What mutations associated with this? Drug?
MLL encodes a histone methyltransferase that maintains gene expression during hematopoeisis, MLL fusion proteins i.e. 11q23 amplifications lead to fusion proteins that directly bind DNA and cause transcription = more cell division; topoisomerase II inhibitors can cause these mutations
What conditioning regimen has been shown to increase risk of VOD?
Cyclophosphamide + Busulfan as well as Gemtuzumab ozogamicin
If the Rai staging system places a patient at either stage III or stage IV what needs to be ruled out?
Need to rule out AIHA or ITP (i.e. Evans syndrome) so it needs to be from true BM failure d/t CLL and not autoimmune phenomena
A CLL patient with bleeding issues should not receive ______
Ibrutinib
Ibrutinib is good for upfront tx in what specific cytogenetic risk CLL
17p del as this has been shown to predict for lack of responsiveness to traditional upfront chemo
What is the MOA of Ibrutinib?
It is a BTK inhibitor and causes apopotosis, downregulation of CD20 (target of Rituximab/Ofatumumab), and prevents cells from responding to survival stimuli of the bone marrow microenvironment
Which drug is used to treat veno-occlusive disese from acute GVHD?
Defibrotide 6.25 mg/kg IV qid. Comes from intestinal mucosa of pigs
A person just got an allo-HSCT and is now presenting with jaundice, ascites, and elevated liver enzymes
Veno-occlusive disease (VOD) which is injury to the small veins of the liver due to aGVHD
What should you do if you have a CLL patient with recurrent sinopulmonary infections?
Send for immunoglobulin levels; if hypogammaglobulinemic can then give IVIG
In patients with relapsed Hairy Cell Leukemia after cladribine induction what should be tried?
If relapse within 1 year can do pentostatin w/ or w/o rituximab and if >1 year can re-challenge with cladribine
A seminal study in 2013 showed that this conditioning regimen is best for AML _____ but this myeloablative regimen has less toxicity and similar survival ________
Cyclophosphamide + Busulfan; Fludarabine + Busulfan (Flu/Bu/TBI)
A mutation in IDH2 in AML is assoc with ______ prognosis
Good; IDH1 is not only IDH2
These are HLADR-, CD34-, MPO+, and CD33+
Acute Promyelocytic leukemia
Generally speaking, t(8;21) can be cured with 7+3 and HiDAC consolidation; what molecular mutation causes a worse prognosis in this group?
Mutant C-kit
What indolent leukemia is often associated with RA, splenomegaly, anemia, and neutropenia and is treated with MTX + Cyclosporine
t-LGL (t- large granular lyphocyte leukemia
What lymphocyte doubling time is an indication to start tx for CLL?
Doubling time of <6 months
What is a common AE of fludarabine that can also be caused by CLL itself?
AIHA
What can you say about deletion of 13q in CLL?
This is the most favorable cytogenetic change in CLL
When should you discontinue ATRA in the setting of differentiation syndrome?
Only if you have started dexamethasone 10 mg IV daily and it still continues
How do you manage differentiation syndrome?
Continue ATRA but give dexamethasone 10 mg IV daily x3-5 days. Consider stopping ATRA if progresses on steroids
Mutant C-kit causes a worse prognosis on what generally good prognostic group of AML?
t(8;21) so if you have this can generally do 7+3 followed by HiDAC but if mutant C-kit may need alloHSCT
Live vaccines can generally be given 2 years after HSCT but what are some caveats at this point
They should be without GVHD and not on ongoing immunosuppression prior to receiving vaccines
What is the MOA of Idelalisib?
It is an inhibitor of the PI3K (delta isoform) and inhibits the ATP catalyzing domain; causes apoptosis and inhibits signaling through BCR (B cell Receptor) as well as CXCR4 and CXCR5 signaling which affects homing to lymph nodes and BM
What is good upfront chemo for CLL patients that are frail or have significant comorbidity and cannot tolerate purine analogs?
Obinutuzumab + chlorambucil
