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define adjuvant therapy and give an example of its use: treatment given to eradicate microscopic amounts of cancer that may remain after removal of a solid tumor (ie. breast CA)
define induction therapy and give an example of its use: treatment to induce remission for a cancer treated primarily with chemotherapy (ie. leukemia, lymphoma)
define consolidation therapy and give an example of its use: treatment given after induction therapy intended to produce sustained remission
define neoadjuvant therapy and give an example of its use: treatment used to shrink a tumor before it is removed or irradiated (ie. shrink a breast cancer to make it more easily resected)
define palliative therapy and give an example of its use: treatment given to attempt to shrink or stabilize an incurable cancer (most common usage of chemo). (ie. CLL or Multiple Myeloma)
define direct local therapy and give an example of its use: treatment given directly into an organ or cavity to deliver higher doses to a specific area (area may be protected from toxic substances - ie. CNS and BBB)(another example is liver)
describe the phases of drug testing: phase I - dose finding
phase II - looking for efficacy
phase III - compare to Gold Standard
phase IV - generic testing
MOA of Alkylating Agents?: impair cell function by forming covalent bonds with biologically important molecules (ie. DNA, RNA, proteins)

*dependant on cell proliferation for activity*
MOA of antimetabolites?: compete with normal metabolites for the catalytic or regulatory site of a key enzyme or by substituting fofr a metabolite that is normally incorporated into DNA or RNA
*works best in S phase*
describe the dose response curve for antimetabolites - what does this mean?: non-linear dose response curve
(beyond a certain dose no more cells are killed despite a higher dose of drug)
MOA of folate analog? name of folate analog drug?: prevents the reduction of folic acid to tetrahydrofolic acid by binding reversibly to dihydrofolate reductase
(methotrexate is prototype)
reversal agent for methotrexate (folate analog)?: folininic acid
when are folate analogs (methotrexate) used? (2): lymphomas
sarcomas
MOA of purine analogs?: block purine/DNA synthesis by inhibiting ribonucleotide reductase
Purine analogs are used in which two disorders??: CLL
Low grade lymphomas
MOA of pyrimidine analogs?: inhibits DNA polymerase - this is incorporated into DNA and causes strand breaks
Pyrimidine analogs are used to treat? (3): AML
Lymphoma
MDS
prototype pyrimidine analog?: cytarabine
MOA of adenosine analogs?: adenosine analog is resistant to metabolic inactivation by the enzyme adenosine deaminase. analog is incorporated into DNA causing strand breaks
adenosine analogs are used to treat? (3): Hairy cell leukemia
Waldenstrom's
CLL
MOA of substituted urea (hydroxyurea)?: blocks DNA by inhibiting ribonucleotide reductase
substituted urea (hydroxyurea) is used to treat? (4): *chronic myeloproliferative disorders*
- CML
-P.vera
-E.T.
- reduction of blasts in AML
General toxicities of antimetabolite therapy?: 1. GI
2. Marrow suppression
3. Neurotoxicity
4. Acute MI (5-FU)
5. nausea (mild xcept MTX)
MOA of anthracyclines (antitumor antibiotic): DNA intercalators insert between DNA base pairs - creates breaks in DNA strands.
- also interferes with topoisomerases (prevents re-litigation of strands during DNA replication)
toxicities of anthracyclines? (3): 1. alopecia
2. cardiotoxic
3. chemical vessicants (tissue burns)
MOA of Bleomycin?: intercalates DNA at G-C and G-T sequences - causes free oxygen radicals that go on to cause strand breakage
Bleomycin is used to treat? (3): 1. Hodgkin's
2. testicular cancer
3. lymphomas
Toxicities of bleomycin? (4): 1. pulmonary fibrosis (O2 administration exascerbates)
2. flu-like rxn
3. anaphylaxis
4. hyperpigmentation
MOA of vinca alkaloids?: M-phase specific alkaloids that bind to tubulin so that microtubules cannot polymerize. this impairs mitotic spindle formation
toxicities of vinica alkaloids? (3): 1. neurotoxicity
2. ileus
3. marrow suppression
MOA of taxanes: promote assembly and stabilization of microtubules
what are the two classes of antimicrotubule agents?: 1. Vinca Alkaloids
2. Taxanes
what are the two classes of antitumor antibiotics?: 1. Anthracyclines
2. Bleomycin
MOA of steroids as chemotherapy?: directly toxic to lymphocytes and malignant lymphoid cells. thought to trigger apoptosis
steroids use to treat which malignancies? (4): 1. CLL
2. ALL
3. Myeloma
4. Lymphoma
MOA of platinum compounds?: (technically considered alkylating agents)
produce DNA crosslinks which inhibit the synthesis of DNA, RNA and protien.
platinum compounds used to treat? (2): 1. many solid tumors (lung, breast, testicular)
2. refractory lymphomas, acute leukemias
toxicities of platinum compounds? (3): 1. nephrotoxic
2. vomiting
3. myelosuppression
MOA of L-Asparaginase?: depletes tumor cells of asparagine (an AA needed for protein synthesis). normal cells can synthesize asp intracellularly and are therefore spared the toxicity.
L-Asparaginase is used to treat? (1): ALL
toxicities of L-Asparaginase? (2): 1. hypersensitivity
2. pancreatitis
MOA of Rituxumab?: anti-CD20 monoclonal antibody that binds compliment - causes compliment and Ab dependant cellular cytotoxicity by directly inducing apoptosis
rituxumab used to treat?: multiple B cell malignancies
- must be CD20 positive
1. the body normall produces IFN-alpha in response to? 2. what cells produce it?: 1. viral infections
2. lymphocytes
MOA of recombinant IFN-alpha used for chemotherapy?: direct anti-viral activity.
- increases expression of MHC and tumor associated antigens.
- also increases NK function
IFN-alpha is used to treat which cancers? (4): 1. chronic phase CML
2. maintain remission in myeloma
3. kidney cancer
4. melanoma
MOA of Imatinib mesylate (Gleevec)?: Tyrosine kinase inhibitor
- Bcr-Abl fusion protein acts as a tyrosine kinase which transforms normal cells to malignant ones. Imatinib stops this by inhibiting this specific tyrosine kinase.
Imatinib is used to treat? (3): 1. chronic and accelerated phases of CML
2. GI stromal tumors
3. Ph positive ALL
MOA of thalidomide?: anti-angiogenesis factor
thalidomide is used to treat? (2): 1. myeloproliferative disorders
2. myeloma
MOA of Bortezomib?: 26S Proteosome inhibitor
- prevents proteolysis
- disrupts signal cascades within cell
Bortezomib is the 2nd line treatment for?: Myeloma
MOA of All-Trans Retinoic Acid?: induces maturation in APL cells (t15;17)
toxicities of All-Trans Retinoic acid? (2): 1. RA-APL Syndrome (25%)
- fever, dyspnea, wt. gain, lung infiltrates
2. leukocytosis (40%)
what is the treatment for RA-APL syndrome?: steroids
what is Neupogen and what is it used for? (4): Neupogen is G-CSF: a recombinant DNA product which contains the G-CSF gene
It is used to:
1. treat chemo induced
myelosuppression
2. supplement BMT
3. assist with stem cell collection
4. treat chronic neutropenia
what is the name for the recombinant GM-CSF and what is it used for?: Leukine
used for AML and allo or auto transplants
What is Neumega and what is it used for?: Megakaryocyte stimulating factor (IL-11)
used to treat post-chemotherapy thrombocytopenia
Cyclophosphamide: What type of drug is it and what is it used to treat? (4): Alkylator
used to treat:
- lymphoma
- breast CA
- CLL
- Lymphoblastic anemia
Nitrogen Mustard: 1. What type of drug is it and 2. what is it used to treat?: 1. Alkylator
2. Hodgkins lymphoma
Azacitadine: 1. What type of drug is it and 2. what is it used to treat? (2): 1. antimetabolite
2. MDS, AML
Chlorambucil: 1. What type of drug is it and 2. what is it used to treat?: 1. alkylator
2. CLL
Mephalan: 1. What type of drug is it and 2. what is it used to treat?: 1. alkylator
2. multiple myeloma
Epirubicin: 1. What type of drug is it and 2. what is it used to treat? (3): 1. antitumor antibiotic
2. breast, AML, esophagus
Capecitabine: 1. What type of drug is it and 2. what is it used to treat? (2): 1. antimetabolite (pyrimidine analog)
2. breast and colon CA
Doxorubicin: 1. What type of drug is it and 2. what is it used to treat? (4) (2): 1. antitumor antibiotic
2. breast, lymphomas, Hodgkin's, bladder
Gemcitabine: 1. What type of drug is it and 2. what is it used to treat? (3): 1. antimetabolite (pyrimidine analog)
2. pancreas, breast, other GI
Ifosfamide: 1. What type of drug is it and 2. what is it used to treat?: 1. alkylator
2. sarcoma, testicular cancers
Danorubicin and Idarubicin: 1. What type of drug is it and 2. what is it used to treat?: 1. antitumor antibiotics
2. AML
Mitoxantrone: 1. What type of drug is it and 2. what is it used to treat? (4): 1. antitumor antibiotic
2. AML, ALL, prostate, lymphomas
5-FU: 1. What type of drug is it and 2. what is it used to treat? (3): 1. antimetabolite (pyrimidine analog)
2. colon, breast, other GI CAs
Vincristine, Vinblastine, Vinorelbine: 1. What type of drug is it and 2. what is it used to treat? (5): 1. Vinca Alkaloids
2. lymphomas, ALL, myeloma, Hodgkin's, other tumors (breast, lung, kidney)
what must developing blood cells "undergo" before they are able to leave the bone marrow?: they must maneuver through the sinusoids
describe the fat content in the bone marrow in a young person vs. an old person?: as a person ages, fat in the bone marrow increases
rule: 100-age= % cellularity)
what is the function of adventitial reticular cells?: promote hemostasis of the bone marrow and line the sinusoids
they determine whether developing blood cells function and can leave the bone marrow.
where are most bone biopsies taken?: posterior iliac crest
what are the four hematopoietic stem cells?: 1. pluripotent
2. multipotent (comitted to either myeloid or lymphoid lineages)
3. progenitor
4. precursor cells ("blasts")
if the % neutrophils is 50%, what is the absolute neutrophil count?: 5,000
(.5 x 10,000)
10,000 is normal WBC count
which type of infections are characteristic of agranulocytosis?: ulcerating necrotizing infections
(bacterial or fungal)
three morphologic changes seen in neutrophilia?: 1. Dohle bodies
2. toxic granulation
3. cytoplasmic granules
why are toxic granulations formed?: cells are released before they are completely mature
why are cytoplasmic vacuoles and Dohle bodies seen in neutrophilia?: characteristic of reactive changes
Dr. Raymond guaranteed Q: very large lymphocytes seen in lymphocytosis of a young female would very likely be?: Infectious mononucleosis
three major causes of eosinophilia?: 1. parasites
2. allergic disorders (MCC)
3. skin disorders
where in the lymph node are B cells found?: in the follicles of the cortex
where in the lymph node are T cells found?: paracortex
what normally passes through the capsule of the lymph node?: afferent and efferent lymph
these 3 disorders are commonly associated with which type of reactive lymph node disorder? 1.prominent germinal centers 2. variation in size and shape of follicles 3. associated with RA, toxoplasmosis, early HIV: Follicular hyperplasia
what three clues upon lymph node examination help us to differentiate lymphadenitis from lymphadenomas?: non-malignant lymph nodes are:
1. tender
2. enlarged
3. mobile
in a malignancy they are nontender and nonmobile
what is the most common cause of sinus histiocytosis thought to be?: thought to be an immune response against a tumor (seen alot in response to breast cancer)
in which type of hyperlasia do T cells undergo transformation to immunoblasts?: paracortical lymphoid hyperplasia
the majority of non-Hodgkins lymphomas (80-85%) are of which origin?: B-cell origin
what is notable about the type of proliferation seen in NHL?: monoclonal proliferation
when in life do most B cell NHLs appear?: 6th or 7th decade
which two lymphomas are the only ones common in children?: 1. Burkitt
2. Large B-cell lymphoma
in NHL: 2/3 present with non-tender nodal enlargement 1/3 present with extranodal involvement. where are these extranodal tissues?: oropharynx
gut
skin
brain
what is the difference in prognosis between an indolent and an agressive lymphoma.: indolent: slow course, generally incurable
aggressive: rapid progression, may be curable
what are two examples of indolent lymphomas?: CLL
follicular lymphoma
what are two examples of aggressive lymphomas?: Burkitt
Large B cell
what are the three classifications that WHO uses for lymphomas?: 1. lymphomas with predominant lymphadenopathy
2. lymphomas with predominant extranodal involvement
3. lymphomas with predominant bone marrow involvement
which type of lymphoma is the most common form of NHL in adults?: follicular lymphomas
describe the morphology/growth pattern seen in follicular lymphoma: nodular growth pattern
no capsules
describe the genetic alterations seen in follicular lymphoma: (14,18) translocation
result is overexpression of BCL-2 protein
BCL-2 is an antagonist of apoptosis
describe the B cell origin seen in follicular lymphoma: CD19+
CD20+
CD10+
(positive for B cell markers)
CD5-
exactly which loci are translocated in follicular lymphoma?: heavy chain (IgH) locus on chromosome 14
BCL-2 locus on chromosome 18
function of BCL-6?: regulates germinal center development
(seen in follicular lymphoma)
in 30-50% of cases, follicular lymphoma transforms to which 2 lymphomas?: 1. diffuse large cell lymphoma
2. Burkitt-like lymphoma
median survival of follicular lymphoma?: 7-9 years
(indolent but not curable)
what is the second most common B cell lymphoma?: Diffuse Large B-cell lymphoma
most common age of diffuse B-cell lymphoma?: middle age or elderly
(also seen in 5% of childhood lymphomas)
genetics of diffuse B-cell lymphomas show which translocation? (3): BCL6 translocation
(14,18) translocation in 10%
mutations in c-myc oncogene
two subtypes of diffuse large cell B-lymphomas?: 1. immundoeficiency associated large B-cell lymphomas
2. Body cavity large cell lymphoma
how does Diffuse Large B-cell lymphoma present?: rapidly enlarging mass at a single nodal or extranodal site
what are the three types of Burkitt's lymphoma?: 1. endemic in Africa
2. non-endemic in US
3. aggressive subset in HIV patients
describe the hallmark morphology seen in Burkitts: high mitotic index
benign macrophages create (STARRY SKY PATTERN)
describe B cell origin of Burkitts lymphoma: idicates origin from germinal centers
CD19+
CD20+
CD10+
BCL-6+
which translocation is associated with Burkitts?: (8,14) translocation
c-MYC oncogene on chr. 8
heavy chain locus on chr. 14
which virus are the majority of African cases associated with?: EBV
regarding Burkits lymphoma: describe the presentation in: 1. African (endemic) 2. US: 1. mandible
2. ileocecum, peritoneum
describe the progression of Burkitt's lymphoma: very aggressive
highly responsive to chemo
most children and young adults cured
what is the other name for Small lymphocytic lymphoma? (SLL): chronic lymphocytic leukemia (CLL)
leukemic form of SLL
how common is CLL?: extremely (25%)
avg. age of CLL/SLL patient?: >50 yrs
describe the cell markers seen in CLL/SLL: CD19+
CD20+
also
CD23+
CD5+
significance of CD5+?: T cell marker
this is used for diagnosis of CLL/SLL
MC chromosomal abnormality SOMETIMES seen in CLL/SLL?: trisomy 12
median survival of CLL pt?: 4-6 yrs
guaranteed Q: older adult male with pancytopenia, hypercellular bone marrow; and splenomegaly - what is it?: Hairy Cell Leukemia
what are hairy cells and where are they found?: malignant B cells
ciculate in peripheral blood, bone marrow and spleen
which test, if positive, is a reliable indicator of hairy cell leukemia?: TRAP
(tartrate-resistant acid phosphatase)
current treatments for HCL?: interferons
chemotherapy
(lasting remission and possible cures)
why is a dry tap commonly seen in HCL?: reticulin fibrosis of bone marrow
what type of neoplasm is characterized by expansion of a single clone of Ig secreting cells?: plasma cell neoplasm
what are Bence-Jones proteins?: light chains of Igs that are small enough to be excreted in the urine
what happens to the heavy chains in a plasma cell neoplasm?: they circulate in the plasma
what is the most common plasma cell neoplasm?: Multiple myeloma
what is multiple myeloma characterized by?: skeletal involvement at multiple sites
which molecules actually mediate the bone destruction seen in MM?: cytokines
which two hallmark lab findings are seen in MM?: Roleaux formation
anemia
most myelomas are disorders of which Ig?: IgG
(then IgA)
why is there hypercalcemia seen in MM?: from breakdown of bone in "punched out" bone lesions
MCC of death in MM pts?: recurrent infections
(due to decrease in all other Ig's besides the one elevated)
renal involvement is multifactorial in MM. what are three causes?: 1. Bence-Jones proteins
2. metastatic calcification (due to hypercalcemia)
3. amyloidosis
median survival of MM?: 3 yrs
two treatments for MM?: chemotherapy
bone marrow transplant
what is significant about solitary myeloma? (plasmacytoma): most bony lesions eventally progress to MM
lymphoplasmacytic lymphoms (Waldenstrom's macroglobulinemia) is characterized by plasma cells that secrete?: monoclonal IgM
lymphoplasmacytic lymphoma (Waldenstrom's) is best viewed as a cross between?: MM and SLL
describe the morphology seen in lymphoplasmacytic lymphoma (waldenstroms): Roleaux formation
lymphoplasmacytic lymphocytes
age of presentation of lymphoplasmacytic lymphoma?: 6th-7th decade
what are two hallmark problems seen in lymphoplasmacytic lymphoma?: 1. bleeding (Igs form complexes with clotting factors)
2. hyperviscosity syndrome (due to large size of IgM)
what is the hallmark of monoclonal gammopathy of undetermined significance?: dysproteinemia without associated disease
(20% progress to MM, waldentrom's or amyloidosis)
what is the most common form of malignancy in young adults (10-30)?: Hodgkin's Lymphoma
what is the distinctive malignant cell seen in Hodgkin's lymphoma?: Reed-Sternberg cell
origin of R-S cell?: germinal center derived B cells
how do clinical features differ from NHL?: most often localized to a group of lymph nodes
(NHL - diffuse)
what are the 5 subtypes of HL?: 1. nodular sclerosis (MC)
2. mixed cellularity
3. lymphocyte rich
4. lymphocyte depletion
5. lymphocyte predominant
describe how lymphocyte predominant HL presents: only type of HL that stains like a B cell lymphoma
CD45+, CD20+ (Bcell markers)
CD15-, CD30- (R-S markers)
CD staining in Nodular sclerosing HL?: CD15+, CD30+
CD45-, CD20-
which R-S variant is seen in nodular sclerosing: lacunar cell
classic test scenario: 20 yr old female presents to clinician with fatigue cervical, supraclavicular lymph nodes enlarged multiple mediastinal lymph nodes on X-ray, R-S cell: nodular sclerosing HL
(only variant in which males are not more common than females)
morphology of R-S cell in mixed cellularity HL?: classic R-S cell
mixed cellularity HL is strongly associated with ?: EBV
rarest form of HL?: lymphocyte depletion
which age patient has a better prognosis when presenting with HL?: younger = better prognosis
older = more systemic involvement
what is the most prognostic variable of HL?: tumor burden (stage)
problem with long term survivors of HL treated with chemotherapy?: increased risk of developing second cancers
in relation to acute leukemia: 1. what describes it? 2. what is the profile of normal hematopoietic stem cells?: 1. clonal expansion of transformed stem cells and failure of maturation
2. normal cells are suppressed
1. ALL is a malignancy involving? 2. AML is a malignancy involving?: 1. transformation of lymphoid series
2. transformation of the myeloid series
describe the onset of acute leukemia?: abrupt onset
for each of the following symptoms, explain the cause: 1. fatigue 2. fever 3. bleeding 4. bone pain: 1. fatigue is due to anemia
2. fever is due to neutropenia
3. bleeding is due to thrombocytopenia
4. bone pain is due to marrow expansion
what is the defining criteria (as far as lab finding go) for acute leukemia?: 20% or greater blasts in the blood or bone marrow
which leukemia accounts for 80% of childhood acute leukemias?: ALL
what age is the peak incidence of ALL?: 4 yrs
which sex is more commonly seen in ALL?: males
which type of ALL has a better prognosis: pre-B cell or pre-T cell ALL?: pre-B cell ALL has a better prognosis
which markers are seen in pre-B cell ALL?: CD19+
CD10+
sIg-
which markers are seen in pre-T cell ALL?: CD2+
CD5+
CD7+
sIg-
precursor T cell ALL closely resembles what lymphoma?: lymphoblastic lymphoma
TdT+ indicates what kind of cell?: very immature cell
(could be T or B cell)
what is the characteristic clinical feature of lymphoblastic lymphoma?: prominent anterior mediastinal mass in 50-70% of pts.
is lymphoblastic lymphoma common?: yes (40% of all childhood lymphomas)
clinical situation: 19 yr. old male with huge mediastinal mass impinging on breathing?: lymphoblastic lymphoma
what separates lymphoblastic lymphoma from pre-T cell ALL?: # of blasts in peripheral blood smear.
(lymphoblastic lymphoma may progress to pre-T cell ALL)
in regards to cytogenetic abnormalities: 1. which one is associated with A GOOD PROGNOSIS? 2. which one is associated with a poorer prognosis?: 1. hyperdiploidy
2. translocations
which translocations are present in ALL? (3): +(9;22)
+(4;11)
+(12;21)
prognosis for ALL?: 90% acheive remission
2/3 considered cured
as far as age goes: which age is associated with a better prognosis? how about a worse one?: better prognosis: 2-10 yrs
worse pronosis: <1 yr, >10 yrs
AML affects primarily what age group?: adults
what is the morphology of the bone marrow seen in AML?: Auer rods!
clinical scenario: red dots on arms (petechiae) kid complains of pain in leg tired 50% blasts in peripheral blood TdT+, CD10+, CD19+ what is the diagnosis?: precursor B cell leukemia
what will a myeloperoxidase stain tell us?: it will show us cytoplasmic granules in AML
tells us we have a myeloid lineage, not a lymphoid lineage (VERY HELPFUL!)
which type of AML is treated differently and therefore "stands out" from all the others? (the one we need to know about?): M3 -> acute promyelocytic Leukemia
what is acute promyelocytic leukemia characterized by as far as cell shape goes?: characterized by a proliferation of abnormal promyelocytes
characteristic translocation seen in acute promyelocytic leukemia? significance?: +(15;17)
produces RARa-PML fusion protein
what are the abnormal promyelocyte cells seen acute promyelocytic cells called?: Faggot cells
(multiple Auer rods)
which stain are the abnormal promyelocytes positive for?: myeloperoxidase stain
what disorder is acute promyelocytic anemia associated with?: DIC
treatment for promyelocytic leukemia?: retinoic acid
(induces maturation of promyelocytes)
ALSO ADD CHEMOTHERAPY
the following translocation is associated with? +(9;22) prognosis?: AML-M1 (also CML)
(this is the Ph chromosome)
poor prognosis
the following translocation is associated with? +(8;21) prognosis?: AML-M2
more favoable prognosis
the following translocation is associated with? +(15;17): acute promyelocytic anemia (AML-M3)
the following translocation is associated with? Inv(16) prognosis?: subtype of M4 with increased eosinophils
longer median survival time than other types of AML
in contrast to AML: what is it called when the blast count in the bone marrow is less than 20%?: myelodysplastic syndrome (MDS)
MDS typically affects which age group?: older individuals
(over age 50-60)
In MDS: what does the peripheral blood and bone marrow show as far as cell count goes?: peripheral blood - pancytopenia
bone marrow - hypercellular
what are Pseudo-Pelger-Huet cells?: unilobed or bilobed neutrophils
(Harry Potter glasses)
what else in notable about the neutrophils seen in MDS?: they are agranular or hypogranular
(vs. hypergranular neurophils - seen in bacterial infx)
refractory anemia (RA) is characterized by?: ineffective erythropoiesis
predominately RBC disorder
what characterizes refractory anemia with ringed sideroblasts? (RARS): ringed sideroblasts (abnormal iron accumulation)
what characterizes refractory cytopenia with multinlineage dysplasia? (RCMD): two or more blood cytopenias and dysplastic changes in two or more major lineages
Auer rods are indicative of which type of MDS?: RAEB (refractory anemia w/ excess blasts)
what percentage of blasts are seen in RAEB?: 5-9%
what would the neutrophils look like in RAEB?: harry potter glasses (pseud-Pelger-Huet cell)
hypogranulation
which is the most aggressive of the MDS?: RAEB
what do cytopenias tell us about the prognosis of MDS?: more pancytopenia - worse diagnosis
RAEB effects which cell lineages?: ALL THREE
(pancytopenia with trilineage dyspoiesis)
what is the name of the new drug used to treat MDS?: azacitidine
what are the four chronic myeloproliferative disorders?: 1. CML
2. Polycythemia vera
3. Primary myelofibrosis
4. Essential Thrombocytopenia
what can we do to easily rule out one of the chronic myeloproliferative disorders?: look for the Ph chromosome
(rule out CML)
why are all the chronic myeloproliferative disorders associated with splenomegaly?: all have extramedullary hematopoiesis
what is the "spent phase" seen in chronic myeloproliferative disorders?: marrow fibrosis
cytopenias
all chronic myeloproliferative disorders can progress to?: acute leukemia
what is the dominant cell line in CML?: granulocytic precursors
where does the Ph chromosome translocation lie?: +(9;22)
chr. 9 has ABL gene
chr. 22 has BCR gene
translocation results in BCR-ABL fusion
function of BCR-ABL fusion gene?: directs synthesis of a fusion protein with tyrosine kinase activity
peak incidence of age seen in CML?: 30-40 yrs
speed of onset of CML?: slow
initial symptoms are nonspecific
what two things cause the symptoms experienced in CML?: anemia
hypermetabolism
(fatigue, weakness, weight loss, anorexia)
what is result in the peripheral blood smear that is a tip-off telling us we have CML?: elevated basophils
what would the leukocyte count be in a pt with CML?: > 100,000 cells per mm cubed
what would the bone marrow look like in a CML patient?: hypercellular
granulocytic hyperlasia
what characteristic test can be used to distinguish CML from a leukemoid rxn?: LAP (leukocyte alkaline phosphatase)
CML - very very low LAP
leukemoid - high
what are the 3 clinical phases of CML?: 1. Chronic
2. Accelerated
3. Blast
characteristics of the chronic phase?: relatively asymptomatic
hypercellular bone marrow
phase lasts 3-4 yrs
characteristics of the accelerated phase?: worsening anemia, thrombocytopenia
progressive myelofibrosis
increase in blasts (<20%)
characteristics of the blast crisis phase?: 20-30% blasts
(50% enter the blast phase immediately following the chronic phase, skipping the accelerated phase)
which drug induces remission in >90% of CML patients? MOA?: Gleevec
inhibits BCR-ABL kinase
which cell line dominates in polycythemia vera?: erythroid precursors
avg. age of onset of polycythemia vera?: 60s
what is the major clinical problem in p.vera?: increased blood volume and viscosity
see:
vascular stasis
thrombotic tendency
hemorrhage
1. blood findings in P. vera? 2. bone marrow findings in P. vera?: 1. increased RBC count, Hgb, Hct.
2. hypercellular, increased erythroid precursors
In P. vera: 1. LAP results? 2. presence of Ph. chromosome?: 1. increased
2. NO (Ph chr. absent)
P. vera patients have an increased risk of?: both hemorrhage and thrombosis
-hemorrhage b/c of abnormal platelet function and blood vessel distention
what is the treatment for P. vera?: phlebotomy
(decrease chance of thrombosis and hemorrhage)
what about P. vera and iron stores?: decreased iron stores
(secondary to chronic bleeding)
primary myelofibrosis involves the formation of abnormal megakaryocytic precursors that release what growth factors?: PDGF
TGF-B
(mitogenic for fibroblasts)
what is the hallmark of primary myelofibrosis?: early progression to marrow fibrosis (similar to "spent phase" but earlier onset)
in primary myelofibrosis: what happens as marrow fibrosis progresses?: get extramedullary hematopoiesis (spleen. liver, lymph nodes)
what are often the first 2 clinical presentations seen in primary myelofibrosis?: anemia
splenomegaly

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