Flashcards in Bone Marrow Failure/HCST Deck (82):
What is pancytopenia?
Anemia, leukopenia, and thrombocytopenia.
What is the definition of bone marrow failure?
Pancytopenia due to failure of bone marrow to produce blood cells.
What are the symptoms of anemia?
Dyspnea, chest pain, and fatigue.
What are the symptoms of leukopenia/neutropenia?
Fever, infection, and mouth sores.
What are the symptoms of thrombocytopenia?
What is the differential diagnosis of pancytopenia?
1. Increased destruction: immune destruction, sepsis
2. Sequestration: hypersplenism
3. Decreased production: myelodysplasia, marrow infiltrate, B12 def, aplastic anemia, drugs, viruses, radiation
In simplest terms, what are the two causes of bone marrow failure?
Hypercellular or hypocellular marrow.
A hypercellular marrow is the result of what?
What are the 5 causes of bone marrow infiltration?
1. Hematological Malignancies (leukemias, myeloma, lymphoma)
3. Storage disorders
4. Myelodysplastic syndromes
5. B12 or folate def
What is the cause of a hypocellular marrow?
What are the 2 forms of aplastic anemia?
1. Congenital: Fanconi's anemia
2. Acquired: idiopathic, myelodysplastic syndrome, drugs/chemicals, radiation, viruses
Define aplastic anemia.
Severe, life-threatening syndrome in which production of erythrocytes, WBCs, and platelets has failed.
What patient population is anemia most likely to be found in?
All. It may occur in all age groups and both genders.
What is aplastic anemia characterized by?
Peripheral pancytopenia accompanied by a hypocellular marrow.
What is the pathophysiology of aplastic anemia?
Reduction or depletion of hematopoietic precursor stem cells with decreased production of all cell lines.
What are the 3 causes of decreased stem cells in aplastic anemia?
1. Damage to the pluripotential stem cell
2. Defective BM microenvironment
3. Cellular or humoral immunosuppression of hematopoiesis (autoimmune)
What are the 2 congenital causes of aplastic anemia?
1. Fanconi's anemia
2. Familial aplastic anemia (subset of Fanconi's anemia)
Describe Fanconi's anemia.
Progressive BM hypoplasia. Usually becomes symptomatic around 5 years of age. Skin hyperpigmentation and small stature also observed.
Most cases of aplastic anemia are due to what?
Exposure to ionizing radiation can lead to what disease?
Aplastic anemia. Hematopoietic cells especially susceptible to it. Whole body radiation of 300-500 rads can completely wipe out the bone marrow.
What 3 groups of chemical agents can lead to aplastic anemia?
1. Contain a benzene ring
2. Chemotherapeutic agents
3. Certain insecticides
What 2 drugs are known to result in aplastic anemia?
What 5 infections can lead to aplastic anemia?
1. Infectious mononucleosis
2. Infectious hepatitis
5. Miliary TB
T or F. In rare cases, pregnancy can result in aplastic anemia.
PNH can lead to what disease?
Aplastic anemia. PNH is an autoimmune, stem cell disease in which membranes of RBCs, WBCs, and platelets have abnormalities making them susceptible to complement-mediated lysis.
What are the 5 labratory findings in aplastic anemia?
1. Severe pancytopenia with relative lymphocytosis
2. Normochromic, normocytic anemia
3. Mild to moderate anisocytosis and poikilocytosis
4. Decreased retic count
5. Hypocellular marrow (>70% yellow marrow)
Why is a relative lymphocytosis observed in aplastic anemia?
Lymphocytes live much longer than neutrophils.
What 4 things should treatment of aplastic anemia include?
1. Withdrawal of potentially offending agents
2. Supportive care: transfusions, antibiotics, etc.
3. Immunosuppressive regimens
What immunosuppressants can be given to a patient with aplastic anemia?
ATG, cyclosporine, steroids.
What is pure red cell aplasia?
Decreased erythroid precursors. WBCs and platelets unaffected.
What are the 3 causes of acquired pure red cell aplasia?
1. Viral or bacterial infections
2. Hemolytic anemias: may suddenly halt erythropoiesis
3. Thymoma: can produce T cell-mediated response against BM erythroblasts or EPO
What is the treatment for pure red cell aplasia?
Supportive care and immunosuppression.
Myelodysplastic Syndromes (MDS) are characterized by what?
Primary, neoplastic stem cell disorders that tend to terminate in acute leukemia.
The BM in MDS is...
Normocellular or hypercellular with abnormalities in one or more cell lines. Results in ineffective erythropoiesis and/or granulopoiesis and/or megakaryopoiesis.
In MDS, what does the peripheral smear show?
Nucleated RBCs, oval macrocytes, pseudo-Pelger-Huet neutrophils with hyperchromatin clumping, hypogranulated neutrophils, and giant bizarre platelets.
In MDS, what does BM aspirate show?
Ringed sideroblasts and other dysplastic changes.
What are Pelger-Huet neutrophils?
What differentiates MDS from aplastic anemia?
The presence of a neoplastic clone. Aplastic anemia is NOT a neoplastic condition, MDS is.
How is MDS thought to arise?
Mutations in the multipotent BM stem cells. Specific defects not known.
What is wrong with blood precursor cells in MDS?
Impaired differentiation and significant increase in levels of apoptosis in BM cells.
T or F. In MDS, clonal expansion of the abnormal cells results in the production of cells without the ability to differentiate.
How do you know if MDS has progressed to AML?
Overall percentage of BM blasts rises above a cutoff (20% for WHO and 30% for FAB).
What are the goals of therapy in MDS?
Control symptoms, improve quality of life, improve overall survival, and delay progression to AML.
What does the main therapy for MDS involve?
Supportive care with blood product support (transfusions I assume) and hematopoietic growth factors such as EPO.
What 2 agents have been shown to decrease blood transfusion requirements, delay progression to AML, and increase survival in MDS patients?
Both are hypomethylating agents.
What is the 5q- syndrome?
A subset of MDS.
What agent was recently approved in the treatment of 5q- syndrome?
In MDS, what therapy has the potential to be curative? Which patients is it given to?
HSCT. Younger patients (<60) and more severely affected patients.
The transplantation of hematopoietic progenitor cells that have the ability to proliferate and repopulate the marrow spaces.
What is the current procedure for harvesting stem cells for HSCTs?
Patient is given a drug that mobilizes the stem cells out of the marrow and into peripheral blood. They are then harvested via apheresis.
What are the 3 unique characteristics of hematopoietic stem cells that make transplants possible?
1. Ability to regenerate in the marrow
2. Ability to migrate to the marrow following IV infusion
3. Ability to be cryopreserved (frozen) with little or no damage
What is an autologous HSCT?
The stem cells used in the transplant are harvested from the patient. They are then frozen and re-infused after high dose chemotherapy.
What is the purpose of the high dose chemotherapy used in autoSCTs?
It wipes out the patient's faulty bone marrow to allow repopulation by the good stem cells.
Why is there a minimal risk of an adverse reaction with autoSCTs?
The stem cells are from the patient!
AutoSCTs are used mainly in the treatment of what diseases?
Lymphomas and multiple myelomas.
What is an allogeneic HSCT?
Stem cells are harvested from a related or unrelated HLA matched donor.
What is the risk of an alloSCT?
Graft vs. host disease.
What is another source of stem cells in the absence of an HLA matched donor?
Umbilical cord blood.
What are the advantages of an alloSCT compared to an autoSCT?
Can be used when a patient's BM fails (i.e. aplastic anemia and MDS). Or when the recipient has a certain disease such as lymphoma or leukemia, the donor cells can attack the tumor cells (basicaly GVHD but for a good cause).
What are the 3 disadvantages of alloSCTs?
1. Higher risk of chemotherapy-related complications with myeloblative transplant (mucositis, hepatic veno-occlusive disease)
2. Higher risk of infection compared to autoSCT (CMV, EBV, fungal, and parasitic)
What are the 2 types of alloSCTs?
What is the purpose of myeloablation prior to alloSCT?
It wipes out the patients BM to get rid of the disease. Also has an immunosuppressive effect to minimize rejection.
What is the purpose of non-myeloablation prior to allSCT?
Lower doses of chemotherapy and radiation are used and the BM is not completely wiped out. The goal is to prevent rejection of donor cells.
When do you give myeloablative therapy vs. non-myeloablative therapy prior to alloSCT?
Mainly avoid myeloablative therapy in older patients (they can't tolerate it as well). Non-myeloablative therapy allows high-risk patients to receive alloSCTs and potentially be cured.
What agents are used in myeloablation?
Combination of cyclophosphamide with busulfan or total body irradiation.
What are the 5 steps of an alloSCT?
1. Collection: from donor
2. Processing: stem cells isolated, concentrated, and prepared for transplant
4. Chemotherapy: in recipient to destroy cancer cells and induce BM failure
5. Infusion: into recipient
What must be given to patients following alloSCT?
Immunosuppressants. Most transplants require life-long immunosuppression but HSCT recipients can be slowly weaned off them.
What are the 4 complications of alloSCTs?
2. Veno-occlusive disease
Why are alloSCT recipients prone to infection?
1. Recipient's BM was destroyed: no immune cells
2. Immunosuppression: further complicates the myeloablation
3. Recipients lose acquired immunity: must be re-vaccinated with childhood vaccines once they stop immunosuppressants
What is hepatic veno-occlusive disease?
Severe liver injury.
What are the 3 clinical findings of hepatic veno-occlusive disease?
1. Elevated bilirubin
3. Fluid retention
What is mucositis? How is it treated?
Injury of the mucosal lining of the mouth and throat. Not life-threatening but very painful and prevents eating/drinking. Treated with pain meds and IV infusions to prevent dehydration and malnutrition.
What is GVHD?
Inflammatory disease unique to allogeneic transplants. Donor's immune cells attack recipient's tissues.
T or F. GVHD only occurs when there is an HLA haplotype mismatch.
F: GVHD can occur even if donor and recipient are HLA identical (minor histocompatability issues).
Describe acute GVHD.
Occurs in the first 3 months post transplant. Involves skin, intestine, or liver. Often fatal.
How do you prevent acute GVHD?
Treat recipient with cyclosporine and methotrexate to suppress immune response of donor cells.
How do you treat acute GVHD? What is the downside to this treatment?
High dose steroids. Long term steroid use can lead to severe infections.
Describe chronic GVHD.
Occurs 3 months after transplant. Less often results in death than acute GVHD. Inflammation same as acute plus fibrosis can develop in skin, liver, intestine, conjunctiva, mucosa, and lungs.
Chronic GVHD presents the same clinically as what disease?
What cells usually mediate GVHD?
Donor T cells react to minor histocompatability antigens of recipient.
What is graft vs. tumor effect?
Basically, it's the good use of GVHD. Similar mechanism as GVHD but instead of attacking recipient tissues, the donor T cells attacks the cancerous cells in the recipient. Leads to lower risk of cancer relapse.