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76 Cards in this Set
- Front
- Back
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Leukemia Pathogenesis
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A genetic alteration occurs in an immature hematopoietic cell resulting in clonality, and excess growth
Usually occurs with myeloid or lymphoid cells but can involve erythroid or megakaryocytic lineage |
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Acute Leukemias
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- Far more aggressive, fast growing
- Excess of immature blood cell - Rapidly the pts come to the hospital - Aggressively treated |
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Chronic Leukemias
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- Slow growing
- Excess of mature blood cell - Takes a longer time for people to come in - Not as aggressively treated as acutes |
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Why do we call them acute?
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Describes which cell is in excess
Describes when people present Describes rate of growth Describes type of treatment |
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Incidence of Acute Leukemia
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3% of all CA
4% of all CA-related deaths incidence increases with age (except for 1-9 y/os with ALL) |
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Synonyms for ALL?
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- Acute Myeloid Leukemia
- Acute Myelogenous Leukemia - Acute Nonlymphocytic Leukemia |
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Which cell is abnormal is AML?
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myeloblast
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What do the myeloblasts do in AML?
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- Grow uncontrollably (grow signal = on, stop growing/die signal = off)
- Maturation (differentiation) is halted - Inhibit growth of normal cells in the marrow |
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AML Risk Factor Categories
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1. Prior chemotherapy
2. Prior ionizing radiation 3. Exposure to benzenes 4. Abnormal genetics |
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Abnormal Genetics
Risk Factors for AML |
1. Down syndrome
2. Neurofibromatosis 3. Schwachman syndrome 4. Bloom syndrome 5. Familial monosomy 7 6. Kostmann syndrome 7. Fanconi anemia |
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Prior Chemotherapy
Risk Factors for AML |
- alkylating agents
- epipodophyllotoxins |
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Prior ionizing radiation
Risk Factors for AML |
- Particularly prenatal (less relevant now)
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What is the Primary Risk Factor for AML?
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UNKNOWN
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How do we recognize AML?
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By the symptoms that develop as a result of not having enough good blood cells
1. fatigue and DOE from anemia 2. petechiae and bleeding from thrombocytopenia 3. persistent infection from neutropenia |
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How do we dx AML?
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Bone marrow aspirate with >=20% blasts
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How do you determine the lineage of the cells causing acute leukemia?
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Flow cytometry to differentiate AML from ALL
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Auer rods
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- little purple rods in cytoplasm = myeloid cells
- coalesced granules |
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What is the most important factor in determining prognosis?
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GENETICS
-perform cytogenetics or FISH with bone marrow aspirate |
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The old AML classification scheme
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French American British (FAB)
- classification based on morphology |
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FAB M0
Common Name? Predominant Cell Type? |
Common Name: Undifferentiated
Predominant Cell Type: Myeloblasts (no differentiation) |
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FAB M1
Common Name? Predominant Cell Type? |
Common Name: Minimally differentiated
Predominant Cell Type: Myeloblasts (minimal differentiation) |
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FAB M2
Common Name? Predominant Cell Type? |
Common Name: Myelocytic (-blastic)
Predominant Cell Type: Myeloblasts (with differentiation) |
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FAB M3
Common Name? Predominant Cell Type? |
Common Name: Promyelocytic
Predominant Cell Type: Hypergranular promyelocytes |
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FAB M4
Common Name? Predominant Cell Type? |
Common Name: Myelomonocytic
Predominant Cell Type: Myelomonoblasts |
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FAB M5
Common Name? Predominant Cell Type? |
Common Name: Monocytic (-blastic)
Predominant Cell Type: Monoblasts |
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FAB M6
Common Name? Predominant Cell Type? |
Common Name: Erthroleukemia
Predominant Cell Type: Erythroblasts and Myeloblasts |
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FAB M7
Common Name? Predominant Cell Type? |
Common Name: Megakaryocytic
Predominant Cell Type: Megakaryoblasts |
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What is the new AML classification scheme?
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WHO (World Health Organization)
- classification based on cytogenetics |
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AML with recurrent genetic abnormalities
(WHO Classification) |
> cytogenetics tell us the prognosis
- AML with t(8;21)(q22;q22), (AML1/ETO) - AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13;q22), (CBFb /MYH11) - Acute promyelocytic leukemia with t(15;17)(q22;q12), PML/RAR-alpha and variants - AML with 11q23 (MLL) abnormalities |
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AML with multilineage dysplasia
(WHO Classification) |
> Less responsive to tx
- Following MDS or MDS/MPD - Without antecedent MDS or MDS/MPD, but with dysplasia in at least 50 percent of cells in two or more myeloid lineages |
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AML and myelodysplastic syndromes, therapy related
(WHO Classification) |
- Alkylating agent/radiation-related type
- Topoisomerase II inhibitor-related type - Other |
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AML, not otherwise categorized*
(WHO Classification) |
- AML, minimally differentiated
- AML without maturation - AML with maturation - Acute myelomonocytic leukemia - Acute monoblastic/acute monocytic leukemia - Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia variants) - Acute megakaryoblastic leukemia - Acute basophilic leukemia - Acute panmyelosis with myelofibrosis - Myeloid sarcoma |
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Which do we use to treat AML: surgery, radiation, chemotherapy?
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- Use Chemotherapy b/c it circulates in the blood like the leukemia cells do
- do NOT use surgery or radiation |
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What to traditional cytotoxic drugs do?
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traditional cytotoxic drugs KILL EVERYTHING (good and bad)
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In AML, what are the circulating blast cells doing?
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Still actively dividing
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What are the phases of treatment?
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1. Baseline Bone Marrow
2. Induction chemotherapy 3. Nadir Bone Marrow (day 14) 4. Recovery Marrow (at DC) 5. Consolidation (intensification) Chemotherapy 6. Post treatment bone marrow |
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During 4 to 6 weeks after induction therapy, what medications do we give patient?
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- Supportive care
- Antibiotics - pRBC transfusions - Platelet transfusions - Preventing and treating tumor lysis syndrome - Monitoring for and treating side effects of the medications |
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What are the side effects for AML Induction Chemotherapy medications?
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- N/V/D
- Mucositis - Cardiotoxicity - Hepatic toxicity - Renal dysfunction/failure |
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Tumor Lysis Syndrome
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- When you have lots of lysis of cells which release cellular components
- Worry about high uric acid -->nephropathy/renal failure - Phosphorus too high - Calcium too low b/c excess calcium released will bind to phosphorous and go to kidney - Potassium released into blood --> cardiac dysrhythmias |
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Induction Chemotherapy
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7 days Cytarabine
3 days Daunorubicin 3 days Etoposide 7+3+-3 trying to induce a remission (first treatment) |
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So if the chemo only takes 7 days to give why do we make patients stay in the hospital for 4 to 6 weeks?
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- To protect them from getting an infection
- Maximal effects of chemo are 2 weeks after treatment - We just destroyed all their good and bad blood cells |
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How do we know if our induction chemotherapy worked?
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Nadir Marrow at day 14 (when chemo has its maximum effect)
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Next step if NOleukemia is visible on nadir marrow?
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- Await count recovery – takes about another two weeks
- Recovery marrow will reveal if patient is in remission |
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Next step if leukemia IS visible on nadir marrow?
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- need additional chemo:
either “5+2+2” or different chemo regimen |
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When is the patient ready to go home after induction therapy?
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When enough good cells have grown back:
- no longer neutropenic - not needing blood or platelets transfusions frequently - no fevers - off antibiotics |
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When will induction chemotherapy not work fast enough?
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Leukostasis
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Leukostasis
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- When patient has too many leukemia cells, which are big and sticky and cause "sludging" (micro infarcts)
- Usually occurs when patients have WBCs >75K with majority being blasts |
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“Sludging” symptoms
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- Chest pain, shortness of breath, headaches, blurry vision
- due to microinfarcts |
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Treatment for Leukostasis
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- EMERGENT LEUKOPHERESIS
- then you must immediately start a chemotherapeutic agent to prevent reestablishment of leukostasis |
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Leukopheresis
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- central line is placed and blasts are filtered out of blood
- WBC can drop from 300K to 150K in a matter of hours |
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If the patient is in remission, and we can’t find any more leukemia cells, then is the patient cured (and therefore not need any more chemotherapy)?
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No - >85% chance the leukemia will come back if no additional treatment is given.
(Remember: Remission= clear recovery marrow) |
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When is consolidation therapy administered?
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after clear recovery marrow when the patient is in remission
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What is consolidation treatment?
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3 Treatments 4 weeks apart:
- high dose ara-C IV q12 hrs on days 1, 3, 5 (6 administrations) - discharge pts on antibiotics and arrange for outpatient transfusions |
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When does consolidation treatment start?
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2 weeks after recovery marrow ... allows patients time at home before more chemotherapy
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What do you do if a patient returns after consolidation therapy with a fever?
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- since the patient is neutropenic, the pt needs IV antibiotics STAT
- this is a medical emergency that happens in 50% of patients |
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When do patients no longer need any more chemotherapy?
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after post-treatment bone marrow is obtained and clear
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Bad Prognostic Factors
AML |
- Increased age
- Secondary AML (toxin-induced) - Certain genetic abnormalities (* most important prognostic factor) - Not obtaining a remission after induction chemotherapy |
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Why is age a bad prognostic factor in AML?
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- Decreased ability to tolerate chemotherapy
- Higher incidence of MDR abnormalities - Higher incidence of antecedent hematologic disorders (MDS, etc.) |
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Which genetic abnormalities are bad prognostic factors in AML?
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-5, -7, 11q23 (MLLgene)
<10% CR rate |
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What are Good Prognostic Factors for AML?
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1. APL: acute promyelocytic leukemia
>80% CR at 5 years 2. Inv(16) or t(16;16) Some AML FAB M4 ~60% CR at 5 years 3. t(8;21) some AML FAB M2 >40% CR at 5 years |
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What does CR stand for?
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complete response
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Are normal cytogenetics a good prognostic factor in AML?
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Considered to be an intermediate risk factor
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When is a transplant considered in AML?
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Complex b/c depends on many variable, like:
>1st CR if pt has poor cytogenetics >At the time of relapse – but need to get them into CR again |
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Acute Promyelocytic Leukemia
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- Comprises ~10% of AMLs
- In > 90% of cases involves t(15;17) – is diagnostic - Pts are younger at dx (~20 y/o) - Associated with risk of DIC |
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What is the incidence of DIC in AML M3 (APL)?
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- High incidence of early fatal hemorrhage (10-20%)
- 7% of patients will die of intracranial hemorrhage |
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APL Treatment
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7 days of cytarabine
4 days of daunorubicin ATRA (all-trans retinoic acid) |
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What is found on Chromosome 15?
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PML gene (promyelocytic leukemia)
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What is found on Chromosome 17?
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RARalpha gene (retinoic acid receptor alpha)
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What is the function of vitamin A in myeloid differentiation?
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retinoic acid is needed to promote differentiation of promyelocytes
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What is the chromosome translocation in APL?
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t(15;17)
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Role of ATRA in APL treatment
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- helps decrease bleeding complications associated with APL and DIC
- improves CR rate - provide supraphysiological doses of retinoic acid |
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What bone marrows do we obtain in a pt treated with ATRA?
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Because ATRA works by a different mechanism, we skip the day 14 marrow and just do a recovery marrow
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Side effects of ATRA
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- Hyperleukocytosis
too many stages of neutrophils differentiating in blood reason why cytotoxic chemo follows ATRA by 2 days - ATRA syndrome |
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ATRA syndrome
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(a.k.a. differentiation syndrome)
- Fever, pulmonary infiltrates, hypotension, dyspnea - Thought to be due to cytokines from granules |
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How do we treat ATRA syndrome?
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2 to 3 day course of decadron (steroid)
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Arsenic trioxide
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- improved overall survival and event-free survival in APL
- treatment is 2 years (much longer than other AML regimens) |
