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120 Cards in this Set
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Adjuvant therapy
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therapy after surgery or radiation therapy
for Solid Tumors given to people who do not have detectable cancer but are likely to relapse |
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biological therapy
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therapeutic agents that are not cytotoxic
es) IL-2, retinoids, angiogenesis inhibitors |
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Carcinoma
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epithelial tumors (eg breast, colon, lung)
most common types of human cancer treated by organ of origin there are no carcinomas of the spleen |
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concurrent chemotherapy
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in conjunction with radiotherapy
localized but unresectable cancers |
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consolidation
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chemotherapy given to those in remission to extend disease-free survival
refers to hematopoetic malignancies as opposed to adjuvant therapy for solid cancers |
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epigenetic
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heritable modification of genome that does not change DNA sequence
often permanent silencing of gene or locus through modification of histones or hypermethylation of certain cytosines w/in promotor or regulatory regions Contribute to malignant transformation by: inducing genomic instability by inhibiting DNA repair inactivating tumor suppressor genes in association w/ promoter DNA methylation |
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tumor grade
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based on histological appearance
consideres: nuclear: cytoplasmic ratio, mitotic index, cellular heterogeneity, etc higher grade usually means more aggressive & worse prognosis |
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In Situ cancer
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malignant-looking cells that have not invaded the basement membrane
very high grade dysplasia almost always merits therapy |
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Induction
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high-dose initial chemotherapy used to induce remission
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Leukemia
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malignant cells circulating in blood & bone marrow
most leukemia occurs in adults some cytogenetic lesions are favorable in leukemia |
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epigenetic
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heritable modification of genome that does not change DNA sequence
often permanent silencing of gene or locus through modification of histones or hypermethylation of certain cytosines w/in promotor or regulatory regions |
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tumor grade
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based on histological appearance
consideres: nuclear: cytoplasmic ratio, mitotic index, cellular heterogeneity, etc higher grade usually means more aggressive & worse prognosis |
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In Situ cancer
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malignant-looking cells that have not invaded the basement membrane
very high grade dysplasia almost always merits therapy |
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Induction
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high-dose initial chemotherapy used to induce remission
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Leukemia
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malignant cells circulating in blood & bone marrow
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lymphoma
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malignant lymphoid cells in lymph nodes
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maintenance chemotherapy
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prlonged (can be >18 months) chemotherapy to maintain remission
used for some leukemias, lymphomas & pediatric tumors (not usually in adult solid tumors) |
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Micrometastases
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can't be detected clinically at time of tumor diagnosis (too small for CT scan)
often relapse w/ distant disease later on target of adjuvant therapy |
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Neo-adjuvant therapy
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chemo before surgery or radiation therapy
makes surgery simpler by shrinking tumor can tell if tumor is sensitive to chemotherapy being given |
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Performance status
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most universal predictor fo patient outcomes across wide variety of tumor types
measured by "Karnofsky score" or "ECOG score" PS0: no symptoms, no limits from disease PS1: restricted in strenuous activity but ambulatory 7 able to carry out light work PS2: ambulatory and capable of self-care but unable to carry out work activities; up and about more than 50% of waking hours PS3: limited self-care, confined to bed or chair more than 50% of waking hours PS4: completely disabled |
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partial response
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>50% decrease in tumor mass that last for more than 3 months
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complete response
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complete resolution of disease for more than 3 months
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Response Rate
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partial response + complete response
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Sarcoma
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Mesenchymal tumors of 2 flavors:
soft tissue sarcomas osteosarcomas rarer than carcinomas in adults clinically very heterogeneous histology more important than location (leiomyosarcoma treated similarly no matter the location) |
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staging
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measure of degree of spread
should be done multiple times at different points requires complete history, physical exam, lab, radiographic & pathologic assessment of primary tumor, regional lymph nodes & metastatic sites |
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tumor suppressor gene
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leads to:
modulation of DNA repair senescence or apoptosis |
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estimate tumor burden by
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extrapolate from size of a lesion using radiologic assessment
measuring a marker protein produced by the tumor (eg immunoglobulin in multiple myeloma) |
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refractory cancer
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does not respond to therapy well
ex) pancreatic cancer, melanoma |
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most common sites of metastases
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lungs, liver, bones, brain, adrenals, subcutaneous
however, any solid tumor can spread to anywhere |
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effect of adjuvant therapy on long-term cure rates
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increased in breast, colorectal, osteosarcoma
not increased in lung cancer |
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factors in likelihood of metastasis of a tumor
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tumor motility
angiogenesis patterns of gene expression |
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Principles of Chemotherapy
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single drugs are rarely curative (b/c of resistance)
used for both curative and palliative treatment |
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Principles of Chemotherapy Combo Regimens
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component drugs must be active as single agents
toxicities should be non-overlapping drugs should be used in their optimal dose/schedule combinations should be given at consistent intervals |
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mechanisms of Drug Resistance
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- overexpression of drug metabolizing enzymes
- overexpression of drug targets - drug efflux pumps - increase in DNA repair mechanisms |
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consolidation/intensification
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chemotherapy repeated after a remission is obtained to solidify the remission and increase cure or prolong remission
may be similar to previous regimens (consolidation) or intensified |
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maintenance chemotherapy
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prolonged chemotherapy to maintain a remission
important in some leukemias & pediatric tumors but not in solid tumors |
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What cancers can be treated curatively even at advanced stage?
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testicular, Hodgkin's, non-Hodgenkin's lymphoma
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purpose of surgical oncology
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- reduce or remove bulk
- resect metastatic disease (lung mets in sarcoma, liver mets in colon cancer) - emergencies- spinal cord compression, bowl perforation - palliation - reconstruction |
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Phase I clinical trial
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evidence of toxicity?
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Phase II clinical trial
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are drugs useful for treating the cancer?
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Phase III clinical trials
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how useful is the new drug compared to the gold standard treatment?
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Phase IV clinical trials
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get experience w/ new drug & with combinations of drugs/treatment
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Synthetic Lethality
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2 genes are in a synthetic lethal relationship if a mutation in either gene alone is not lethal but mutations in both lead to cell death
usefulness example) BRCA1 & 2 defects lead to defective base-excision repair when patients are treated w/ PARP (PolyADPRibose polymerase), it disables the homologous recombination repair when both repair mechanisms are disable-->cell dies |
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PARP inhibitors
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cause synthetic lethality in BRCA 1 & 2 related tumors
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Oncogene examples of activation mechanisms
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cyclin D1 - amplification
K-RAS - point mutation c-MYC - translocation akt activation by PTEN loss - loss of inhibitor |
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Tumor Suppressor Gene examples
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p16INK4a (loss of senescence)
RB p53 PTEN BRCA (loss of DNA repair mechanism) |
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malignant cells of ALL
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committed lymphoid progenitor cell (pre-T or -B cell)
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malignant cells of CLL
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mature B-cells
derived from pre or post-germinal center B cells |
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malignant cells of AML
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committed myeloid progenitor
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CML - how is it different from other leukemias?
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- classified as myeloproliferative disorder (like Polycythemia vera, essential thrombocytosis & primary myelofibrosis)
- malignant cells MAINTAIN THE ABILITY TO DIFFERENTIATE - transformation of hematopoietic progenitor cell (HPC) - predilection for myeloid pathway (but does NOT cause Erythrocytosis or usually Anemia) - MORPHOLOGICALLY HETEROGENEOUS - population of cells at all levels of myeloid differentiation - can transform into Acute Myeloid Leukemia or Acute Lymphoblastic Anemia |
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Who gets CML?
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1 to 2 ppl/100,000
median age at diagnosis: 66 yrs male/female ratio: 1.4/4 risk factors: ionizing radiation exposure |
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Unique Clinical Presentation of CML
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usually no adenopathy (like AML)
Leukocytosis - neutrophilia, basophilia, eosinophilia Anemia or normal hemoglobin Thrombocytosis 20-40% detected solely from labs most common symptoms however, are fatigue, weight loss, abdominal fullness, & night sweats splenomegaly (50%), sometimes hepatomegaly |
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Genetics of CML
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Philadelphia Chromosome
t(9;22) required for diagnosis of CML detected cytogenetically in 95% of cases 5% of cases detected by FISH |
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What does the Philadelphia chromosome do?
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t(9;22)
- segment of abl gene coding for non-receptor tyrosine kinase is translocated to bcr gene on chromosome 22 - bcr-abl gene -->abnormal tyrosine kinase that's constitutively active EXCEPTION TO MULTI-STEP MODEL OF NEOPLASIA Philadelphia chromosome is the only mutation that is required for CML |
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How is CML diagnosed?
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Peripheral smear review & bone marrow biopsy
- determine Chronic phase, accelerated phase or blast crisis cytogenetics of blood and marrow -detect most t(9;22) as well as other cytogenetic abnormalities FISH - BEST SCREENING TEST - more sensitive than cytogenetics & can detect cryptic translocations - does not test for other abnormalities Quantitative PCR - most quantitatively sensitive - does not test for other abnormalities, can miss rare mutations |
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Which phase of CML is easiest to treat?
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chronic phase is much easier to treat than accelerated phase or blast crisis
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Prognosis of CML phases
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Chronic phase (most people present at chronic phase)
--- median 3-5 years Accelerated phase (increasingly unresponsive to therapy) --median duration 6-9 months Blast crisis (complications of cytopenias, extramedullary disease) 25-40% of patients skip accelerated phase and go directly to blast phase --- median survival 3-6 months |
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Therapy for CML
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2 options:
Abl tyrosine kinase inhibitors -- Imatinib (Gleevec) -- 2nd generation Abl inhibitors Allgeneic stem cell transplant (only "cure) |
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Imatinib mesylate (Gleevec)
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TYROSINE KINASE INHIBITOR FOR CML
small molecule inhibitor of BCR-ABL avoid moving to Accelerated or Blast phases What about resistance? -->side 3 -----preferentially binds inactive conformation of BCR-ABL can take orally well tolerated excellent efficacy! |
Primary Resistance (VERY UNUSUAL - NOT VERY IMPORTANT)
-- inadequte initial response --- due to Low levels of imatinib (non-compliance, poor absorption, metabolism, reduced influx pump levels) Secondary resistance -- loss of previous response --------overexpression of bcr-abl (10%) -------point mutations within ABL kinase domain - can't bind (50-90%) what to do? use 2nd generation inhibitors |
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Nilotinib (2nd generation ABL kinase inhibitor)
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binds better & more specifically to BCR-ABL than imatinib
still active w/ most BCR-ABL point mutations now FDA approved for initial treatment -- deeper responses than imatinib |
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Stem Cell Transplant in CML
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high dose chemo +/- radiation-->infusion of donor HSCs
Graft vs Host disease is good! -- decreased risk of relapse -- depletion of donor HSC increases risk of relapse can re-induce remission w/ donor lymphocyte infusions Disease free survival after related donor SCT is 45-70% only known cure but substantial morbidity |
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Who gets CLL?
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most common adult leukemia
15,110 US cases in 2008 4,390 deaths median age at diagnosis:72 Risk: family members have 2-7x increased risk Agent Orange UNHEARD OF IN KIDS |
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"smudge cell"
what's it in? |
characteristic of CLL on peripheral smear
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Unique Presentation of CLL
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frequent infections esp respiratory or encapsulated organisms
---- due to hypogammaglobulinemia lymphadenopathy (like ALL) Leukocytosis - SPECIFICALLY LYMPHOCYTOSIS anemia thrombocytopenia (unlike CML) |
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Autoimmunity in CLL
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autoimmune hemolytic anemia in 10-25% of cases
Immune thrombocytopenia in 2% pure red cell aplasia & autoimmune neutropenia (Evans Syndrome) is rare |
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Transformation of CLL
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worse prognosis
evolution of more aggressive lymphoid neoplasim ---- clonally related to CLL in 60% Richter's Transformation ---- CLL-->diffuse large cell lymphoma ----- occurs in 2 to 9% of CLL --- worsening of normal symptoms Prolymphocytic leukemia -----10% of CLL ----- much bigger than CLL cells, much more cytoplasm |
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Dysregulated cell death in CLL
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Bcl-2 is inhibitor of apoptosis
inhibits release of cytochrome c from mitochondria overexpression -->malignant cells |
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Rai Classification used for CLL
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Stage 0: lymphocytosis only -- survival >15 yrs
Stage 1: add lymphadenopathy -- survival 8 yrs Stage 2: add splenomegaly --survival 6 yrs Stage 3: add Anemia -- survival 3 yrs Stage 4: add Thrombocytopenia -- survival 2 yrs |
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Treatment of CLL
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NOT CURABLE
don't treat patients w/out symptoms -- no survival advantage -- early stage long term prognosis is still good Chemotherapy - relieve symptoms - weight loss, fevers, sweats, fatigue - bulky lymphadenopathy, painful splenomegaly - rapidly increases lymphocytosis - autoimmune cytopenias like hemolytic anemia or thrombocytopenia - increased frequency of bacterial infections (due to hypogammaglobulinemia!) Drugs - variety of conventional drugs, now some monoclonal antibodies ---- Rituximab - Anti-CD20 Ab ----Alemtuzumab - anti CD52 Ab |
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Who gets AML?
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13000 cases in US in 2008
8,820 deaths (more fatal than CML & CLL) Median age at diagnosis: 68 Risk factors: Prior radiation Prior chemotherapy --Alkylating agents --Topoisomerase II inhibitors Benzene exposure Prior history of MDS or a myeloproliferative disorder. Familial syndromes --Down syndrome --Fanconi anemia |
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Unique Clinical Features
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Faster onset than CML & CLL (eg 1-2 months)
Severe Anemia Severe Neutropenia-->opportunistic infections (Staph, gram - rods, psuedomonas, invasive fungal infections like Aspergillosis) Severe thrombocytopenia-->petechiae Hyperleukocytosis - stasis of blood flow w/ really high blast count - mental status changes -> lethargy - SOB - diffuse bilateral pulmonary infiltrates - Treatment: Leukophoresis before chemotherapy Acute DIC - most common in acute promyelocytic leukemia (APL) - often have acute DIC right from get go Extramedullary Involvement - CNS, gums - skin - leukemia cutis - leukemic blasts in dermis of patients |
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Pathogenesis of Acute Leukemias
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Class I mutations
- confer survival and/or proliferative advantage ex) FLT-3 Class II mutations - lead to block in hematopoietic cell differentiation ex) PML-RARalpha one of the 2 almost always found in ALL & AML |
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FLT-3
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receptor tyrosine kinase
activating mutations seen in 30% of adult AML cases can be either duplication or point mutation result is deregulated proliferation |
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PML-RARalpha
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retinoic acid receptor-alpha
bound by retinoids-->transcription of genes for differentiation t(15;17) fusion gene PML-RARα central to the pathogenesis of acute promyelocytic leukemia (APL) PML-RARα recruits the nuclear co-repressor (NCoR) complex and histone deacetylases to the RARα response element-->BLOCK TRANSCRIPTION OF GENES FOR DIFFERENTIATION Give ATRA (all-trans retinoic acid) -->release inhibition of gene transcription and promote differentiation |
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Prognosis of AML
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Age - older is worse
history of MDS or myeloproliferative disorder-->bad prior chemo or radiation-->bad -- associated w/ complex cytogenetic abnormalities, inc chromosome 5 & 7 deletion PML-RARalpha - t(15;17) - good - KNOW THIS t(8;21), inv(16) also good deletions of chromosomes 5 or 7 - bad Mixed lineage leukemia - 11q23 - bad |
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AML Treatment
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30-40% cure rates in adults
Induction - reduce level of disease below level of detection -->complete remission & bone marrow works! 7+3 chemotherapy used for induction - less important - 7 days continuous infusion of pyrimidine analog - 3 days of anthracycline Consolidation - several cycles of high dose cytarabine (the pyrimidine analog)-->eradicate minimal residual disease Stem Cell Transplant during 1st complete remission in patients w/ high risk disease |
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APL Treatment
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cure rates 80% or more
induction7+3 chemotherapy + ATRA (all-trans retinoic acid)-->FORCE DIFFERENTIATION then consolidation stem cell transplant only for relapsed/refractory disease |
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ALL
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less common than AML, fewer deaths
5,430 new cases in US in 2008 1460 deaths median age at diagnosis: 11 Most common cancer in children Peak incidence between ages 2 to 5. Risk factors Prior radiation Prior chemotherapy --Alkylating agents --Topoisomerase II inhibitors Familial syndromes --Down syndrome --Neurofibromatosis, etc |
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Unique Clinical Features of ALL
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same symptoms as AML +
lymphadenopathy (like CLL) mediastinal mass - esp w/ precursor T-cell ALL CNS - have to prevent CNS relapse w/ intrathecal chemo or cranial radiation Testicular - strong predictor of CNS involvement/relapse in males Tumor Lysis Syndrome --from high cell turnover-->intracellular electrolyes released (urea, K+, phosphate) --low Calcium --high LDH --acute renal failure due to uric acid in kidneys --more common in ALL than AML --Treatment: aggressive hydration, allopurinol (lower uric acid), rasburicase (break down uric acid) |
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Mutations in ALL
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Type 1:
Bcr-Abl t(9;22): The Philadelphia Chromosome. 33% of adult ALL cases. 4% of pediatric cases. - worse prognosis (remember it was good prognosis in CML) Characterized by the p190 Bcr-Abl product (as opposed to p210 of CML) Constitutive activation of BCR-ABL→ ↑ cell proliferation. Type II: t(12;21): TEL-AML1 The most frequent cytogenetic abnormality in childhood B-cell ALL. Associated with a good prognosis-overwhelming odds of cure Fusion of TEL to AML1 -->abnormal recruitment of NCoR and HDACs → repression of AML1-mediated transcription-->no differentiation! |
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Prognosis for ALL
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adults - 30-40% cure
kids - 80% cure Age <1, ≥10 → bad Cytogenetics Good t(12;21) Hyperdiploidy Bad t(9;22) 11q23 (MLL) translocations, t(4;11) in infant ALL. Hypodiploidy High white blood cell count ≥50x109/L→Bad |
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Treatment of ALL
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very arduous & long
lots of cytotoxic drugs & corticosteroids Induction: prednisone vincristine daunorubicin L-asparaginease imatinib improves outcomes for those with Philadelphia Chromosome Bone Marrow Transplant is treatment of choice for eligible high risk candidates (including Philadelphia Chromosome) |
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Distinguish Leukemias
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Symptom onset over weeks to few months → acute leukemia; months to years → chronic.
Severe cytopenias → acute; less severe → chronic. Blasts → AML or ALL; mature lymphs → CLL; spectrum of myelopoieisis → CML. Remember more disease specific manifestations of the diseases --DIC more likely in AML --blasts and an anterior mediastinal mass in T-cell ALL |
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T-cell immunophenotype
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CD 1, 2, 3, 4, 5, 7, 8
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Granulocyte & Monocyte immunophenotypes
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CD 13 - Granulocyte
CD 14 - Monocytic CD 15 - Granulocyte CD 33 is also myeloid |
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B cell immunophenotype
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Nineteen and Early Twenties: B-cell phenotype
Be all you can “B” in the army at age 19-23 CD 19, 20, 21, 22, 23 |
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Stem cell immunophenotype
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34
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Flow Cytometry
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measure cellular properties as they move in stream past stationary detectors
identify phenotypes by using fluorescently labeled antibodies |
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WHO Classification of Leukemias
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Builds on previous systems (i.e. FAB)
Recently revised (2008) Diagnosed according the prominent cell type involved Two major categories: Acute: rapid onset, aggressive, usually poorly differentiated (blasts) Chronic: insidious onset, usually less aggressive and more mature appearing Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Chronic Lymphoproliferative Disorder Myeloproliferative Disorder Myelodysplastic Syndrome |
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Chronic myeloid Leukemia Peripheral Blood & Bone Marrow Aspirate
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bone marrow
-Hypercellular -Increased M:E -less variety of cell types (not as much trilineage hematopoiesis) but still much less homogenous than AML Peripheral Blood -Numerous immature granulocytes (note they are still differentiated - not blast cells) -Increased basophils, etc |
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CML vs Benign Neutrophilia
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Left shift not as marked as in CML (may see bands but infrequently see
myelocytes and other immature forms) Normal/Increased LAP Neutrophils as opposed to variety |
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Leukocyte Alkaline Phosphatase in CML - increased or decreased?
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decreased
benign process will have a normal or increased LAP |
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What is the CLL equivalent lymphoma?
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small lymphocytic lymphoma
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Other diseases associated with CLL
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Autoimmune Hemolytic Anemia
Immune Thrombocytopenic Purpura |
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CLL Peripheral Smear and Bone Marrow Aspirate
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Peripheral blood: CLL
-usually diagnostic -lymphocytosis Bone Marrow Aspirate: CLL -variable involvement -loss of heterogeneity |
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immature B cell marker
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CD 10
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CD 34
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blast marker
combined with B cell marker-->B lymphocytic leukemia |
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Leukocyte Alkaline Phosphatase - what is it?
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stain for Leukocyte Alkaline Phosphatase - quantitate stain
how do you determine between benign and leukemia? |
leukemia - decreased LAP
reactive neutrophilia - increased |
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What is the best screening test for CML?
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FISH
catch both cryptic and non-cryptic BCR-ABL mutations |
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When does BCR/ABL t(9;22) mutation occur?
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in pluripotent stem cell
most cell lines still have BCR/ABL fusion gene responsible for potential development of AML (80%) or AML (20%) |
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Flow Cytometry of CLL
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CD 19
CD 5 CD 23 either kappa or lambda |
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CD 10
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ALL
Follicular Burkitt |
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CLL Cytogenetics; what to know
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know some are better prognosis, others worse
deletion 11q23/mutation of MLL-->bad prognosis deletion 17p13 (p53) -->bad prognosis |
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Deletion 11q23/mutation of MLL
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bag prognosis in virtually all diseases/cancers
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deletion of 17p13
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includes p53
bad prognosis in CLL |
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AML morphology
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>20% of blood or bone marrow is blasts
Auer rods - polymerized groups of myeloperoxidase granules -- always AML for our purposes |
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Acute Myeloid Leukemia with Multilineage Dysplasia
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follows MDS or MPD or MDS/MPD
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genetics of Acute Promyelocytic Leukemia
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t(15;17)
PML/RARalpha 5-8% of AML Clinically ASSOCIATED WITH DIC up front good prognosis after up front mortality non15;17 translocations don't always respond to ATRA therapy called promyelocytic b/c have technically moved out of blast phase "more mature" |
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t(15;17)
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genetic mutation in ALL-->APL
PML/RARalpha |
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PML/RARalpha
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t(15;17) translocation in ALL-->APL
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Retinoic Acid Receptor alpha
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Normally heterodimerizes with retinoid X receptor (RXR) and interacts with nuclear corepressor complex to transcriptionally block granulocyte differentiation
Retinoic acid releases the complex and allows progression of differentiation past the promyelocyte stage |
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has DIC
suspect/known ALL has no CD34 or HLADR what do they have now? what should you do? |
APL
immediate ATRA treatment |
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cytogenetics of AML
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50% have no clonal cytogenetic abnormality
FLT3 - known mutation - poor prognosis - constitutively active tyrosine kinase - most frequent molecular abnormality in AML NPM1 - also know |
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FLT3
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most common molecular abnormality in AML
contitutively active tyrosine kinase poor prognosis internal tandem duplication (most common) or point mutation |
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is it possible to have "aleukemic" leukemia?
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Yes,
ALL usually has leukocytosis but can be aleukemic bone marrow is packed but they're not circulating cells Usually present with pancytopenia |
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What's more common to see in T-cell ALL?
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mediastinal or soft tissue mass
higher risk, worse prognosis blasts that express T cell markers only |
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What if you suspect acute leukemia? what's the first step?
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Immunohistochemistry
myeloid or lymphoid? TDT & CD34 stain positive - immature cells all cells on bottom left indicate early lymphoid precursor *** check on this - thought granules stained -->myeloid |
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what type of lymphoma is more common with HIV?
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B cell
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favorable prognosis for adult ALL?
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hyperdiploidy
t(12;21) |
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unfavorable prognosis for adult ALL?
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t(9;22) - WORST CYTOGENETIC ABNORMALITY IN ALL
abn(11q23) hypodiploidy |
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