Term
| Aplastic Anemia: def, etiology of pancytopenia, AA classification |
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Definition
a peripheral blood pancytopenia with bone marrow hypocellularity (<25% cellular)
o Severe AA – very low cell counts, usually indicate a non-spontaneous regression of disease
o Bone marrow – required for Dx of AA
• Pancytopenia etiology – not just AA! Also MDS, neoplasm, toxins, nutritional, genetic, infection, HSM
• AA Classification – include idiopathic, secondary, & inherited
o Idiopathic AA – aplastic anemia is primary disease
o Secondary AA – AA 2o to radiation, chemotherapy, toxins (benzene), drugs, infection
o Inherited AA – such as Fanconi’s anemia, dyskeratosis congenital….Down’s, not really important… |
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Term
| Clinical presentation of AA |
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Definition
| • Px present with anemia, neutropenia, and TCP (all signs of BM failure) |
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Term
| Diagnosis by counts and Grading (Non-severe, severe, very severe) |
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Definition
• Diagnosis – blood counts, low reticulocyte count, bone marrow biopsy shows loss of cellularity, work-up to rule out other causes
• Grading
o Non-Severe – marrows cellularity <30%, absence of severe pancytopenia, depression of at least 2 blood elements
o Severe – marrow cellularity < 25% or <50% w/ fewer than 30% hematopoietic cells and 2 of the following: ANC < 0.5 X 10^9, platelets < 20 X 10^9, retic count < 40 X 10^9
o Very Severe – as above but ANC < 0.2 X 10^9 |
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Term
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Definition
• Pathophysiology – damage/destruction/suppression of HSC depletion of stem cell pool bone marrow failure AA
o Direct insult – toxicity of hematopoietic stem cell (HSC) to radiation, chemotherapy, benzene
o Immune-mediated injury – T cells inhibit HSC colony formation; cytotoxins released in marrow |
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Term
| Treatment options: - non-idiopathic, supportive care, transplant, immunosuppression...age matters! |
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Definition
• either matched sibling donor transplant (<20, 20-45 if healthy) or immunosuppression (otherwise):
o Non-idiopathic – treat underlying condition
o Supportive care
Tranfusions – may become refractory, or if multiple needed may need iron chelation
Antibiotics – to prevent neutropenic infection
Growth factor support – GCSF, EPO
Androgens – can stimulate hematopoiesis
o Transplant – allogenic HSC transplantation; cyclophosphamide + ATG immunosuppress, prophylax for GVHD with MTX/cyclosporine; 88% 4-yr survival; complications are graft failiure, GVHD, secondary malignancy
o Immunosuppression – give anti-thymocyte (T-cell) Ig’s + cyclosporine; stop T-cell inhibition 70% response; may take 3-4 months to see response, relapse is common but can respond to re-treatment; complications of serum sickness, renal failure (cyclosporine), HTN, late malignancies (MDS/AML)
o Over 45 yrs you want to give immunsuppression, but below you want to consider HSC-transplant or IS
o HSCT is potentially only curative tx for this… |
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Term
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Definition
• MDS – acquired bone marrow failure syndromes, due to production of dysfunctional dysplastic clonal blood cells
• Heterogenous – MDS has many varying subtypes with many varying prognoses
• Bone marrow – usually hypercellular, but producing dysfunctional blood cells |
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Term
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Definition
• Dx – made through a morphological review of blood & marrow smears
o Dyserythropoiesis – RBC anisopoikilocytosis, megaloblastic maturation and dysmorphic nuclei
o Dysgranulopoiesis – Pelger-Huet cells (2 lobed nuclei vs. 5/6 nl) and hypogranularity
o Dysplastic platelets – huge platelets
o Dysmegakaryopoiesis – multiple separate nuceli and unilobulate megakaryocytes |
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Term
| Clinical Presentation of MDS |
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Definition
| – cytopenia Sx (anemia symptoms, neutropenic infections, thrombocytopenic hemorrhage) |
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Term
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Definition
involves DNA changes acquired in bone marrow only; rarely inherited
o Abnormalities – various chromosomal abnormalities can be important for prognosis/Tx
o Deletion 5q Syndrome – F predominance, 68 yo median, macrocytic anemia, nl-high platelets, erythroid hyperplasia, hypolobulated megakaryocytes, blasts < 20%, good prognosis, if no other mutations
o Complex karyotypes – more than 3 abnormalities poor prognosis |
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Term
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Definition
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Term
| MDS classification: FAB, IPSS, WHO classification |
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Definition
o French-American-British – classify by amount of blasts in blood/marrow (more = worse)
o International Prognostic Scoring System – risk scores by blasts and karyotyping & cytopenias but this SS has many limitations!
o WHO Classification – newest classification system…most often used by pathologists |
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Term
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Definition
• Blast percentage – less blasts longer survival and decreased conversion to leukemia
• Age – older had lower survival rates even in low-risk IPSS classes |
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Term
| Treatment for MDS? what components? |
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Definition
• Chemotherapy – treatment for some marrow diseases, but has negative outcomes:
o Alkylating agents – include cyclophosphamide, can put patient at risk for MDS & AML
o Radiation exposure
o MDS Recurrence – can occur 4-5 years after treatment, has poor prognosis
o Genetics – deletion or loss of chromosome 5 and/or 7 and complex karyotypes are common; poor prognosis |
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Term
| Chronic Myelomonocytic Leukemia (CMML): |
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Definition
| Peripheral blood and bone marrow…can resemble MDS hypoprolif state or AA hyperprolif state. |
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Term
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Definition
| female more, normal elevated platelet counts, BM erythroid hyperplasia, hypolobulated megakaryocytes, BM blasts<20%, good prognosis with less AML transformation. |
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Term
| Is chemo a good therapy for MDS?! |
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Definition
No...
• Stem Cell Transplant – bone marrow transplant can help cure disease, more successful in young patients
o Eligibility – young, no existing co-morbidities, available donor
o Early low-risk MDS – delay transplant until disease progresses (still have good QOL now)
o Later high-risk MDS – proceed to transplant ASAP
• Erythropoietin Therapy – give EPO to low/int-1 risk pts that are tranfusion dependent, px must have good iron stores and only then will respond, but takes 8 wks +. But effects last for 1-2 yrs if responsive.
o Refractory – give ESA + GCSF, which augments fx of EPO-SAs…
• Immunosuppressive – clonal amplification of T cells suppresses hematopoiesis so give ATG +/- cyclosporine
• Chelation therapy: MDS px at risk for iron overload due to frequent transfusion requirements…(desferoxamine, deferasirox) |
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Term
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Definition
idea that genes can be turned off without destroying them
o Promoter methylation – promoter region of genes can by methylated “off” by cytosine residues
o Methyltransferase – methylates promoter region
o Drug inhibition – azacitidine/decitabine can inhibit methyltransferase turn on genes again |
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Term
| 3 agents for epigenetic therapy...how do they work? what is one of them especially good for!? |
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Definition
• Azacitidine – HYPOMETHYLATING AGENTS - methyltransferase inhibitor, leads to better blood counts & survival and decreased progression to AML in patients with MDS. It’s for transfusion dependent, neutropenic with recurrent infx, systemic sx related to disease, px with high risk of AML hyperprolif…
• Decitabine – same deal as azacitidine…
• Lenalidomide – oral drug, stops MDS clone, sensitizes cells to EPO, decreases apoptotic cytokines
o Inhibits MDS clone – will slow down MDS clone replication, also signal T-cell attack of clone
o Promotes better growth – sensitizes cells to EPO (more RBCs), decreases apoptosis
o QUIZ: Deletion 5q Syndrome – showed immensely positive response to lenalidomide |
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