Malignant hematology, solid tumors & cancer pharm Flashcards
1
Q
Acute vs. chronic leukemia/lymphoma
A
Acute: Cx of precursor/immature cells
Chronic: Cx of mature cells
2
Q
Diff. b/t leukemia and lymphoma
A
- Leuk: Malignant cells circ. in blood –> find on periph smear
- Lymphoma: dz centered in lymphoid tissues (nodes, spleen, MALT/BALT, etc)
3
Q
Key to diagnosing the following:
- Leukemia
- Lymphoma
A
- BM aspiration/biopsy & periph. smear
- Biopsy of enlarged lymph node (or extranodal mass)
4
Q
What are the three mainstream methods used to classify
heme malignancies by specific cell type (in addition to histopathology w/ standard stains)
A
- Histochem (specific cell enzymes)
- Flow cyt (surface Ag’s)
- Xsomal analysis
5
Q
What are the two major types of acute leukemias?
A
AML and ALL
6
Q
Epidem. AML
A
- Older adults (median age = 65 yo)
- 80% adult / 15% peds
7
Q
Epidem. ALL
A
- Median age: 3-5 yrs
- Most common childhood Cx
8
Q
Major classes of R/F’s fro developing heme Cx (w/ example if appropriate) - 5
A
- Genetic disorder (downs)
- Hemetologic disorder
- Rads
- Chems
- Chemo-caused (alkylators)
9
Q
What are the “top two” clinical manif’s of acute leuk?
A
- BM failure
- Leukocytosis (hyperprolif) –> Leukostasis (abnormal intravascular leukocyte aggregation and clumping. It is most often seen in leukemia patients. The brain and lungs are the two most commonly affected organs)
10
Q
Why does leukostasis occur often in acute leuk’s?
What can it lead to?
A
Huge prolif. of immature WBC’s (blasts) –. very viscous blood.
Leads to: cerbral symptoms, pulm. symptoms, depending on where stasis takes place.
AML>ALL (makes sense b/c more WBC’s made in myeloid pathway)
11
Q
What are some of the S/S of ALL outside of BM that you might see on PE?
A
Remember… ALL affects lymphoid tissues… so:
- Lymphadenopathy, splenomeg
- Testes (rarely)
12
Q
Extramed. prez of AML (3)
A
- Leuk. cutis (skin rash)
- Gingival hypertroph.
- Chloroma (blast tumor)
13
Q
What is a renal complication that can take place in ALL? AML?
A
- ALL: tumor lysis syndrome - from chemo - get hyperUric/Phosph/K. Uric acid nephropathy –> renal failure.
- AML: HypoK from renal tubular damage (lysozyme released from blasts)
14
Q
What is the typical morphology of ALL and AML cx cells?
A
- ALL: Increased lymphoblasts that are TdT+
- AML: myeloblasts + Auer rods
15
Q
Key immunohistochemical (IHC) marker (1 each) of ALL cells? AML?
A
- ALL: TdT+
- AML: Myeloperoxidase crystallizes as Auer rod (and also can do IHCstaining for it), MP+
16
Q
Auer rod
A
LInear aggreations of granules, seen only in myeloblasts (AML)
17
Q
What is the FAB classificaton of AML that we have to know? why?
A
- M3 (Acute Promyelocytic Leukemia, APL) promyelocytic, hypergranular
- need to know b/c it has diff’t Rx from the rest of the AML’s
18
Q
What is the “name” of AML:M3?
Defining morph and genetic features?
A
- Promyelocytic leuk.
- Morph: biolobed nuc, large gran’s, Auer rods
- Genetic: t(15;17)
19
Q
FAB classification in ALL is based on _____
A
morphology
20
Q
What is the main WHO category for AML? ALL?
A
- AML: AML w/ recurrent genetic abnorm’s
- ALL: B cell ALL w/ genetic abnorm’s
21
Q
What is the key histochemical + stain for ALL?
A
TdT (terminal deoxynudleotidyl transferase)
22
Q
Key immunohistochenical + stain for AML cells?
A
- Myeloperoxidase (in granules)
- Lysozyme (indicates myeloid diff’tiation)
23
Q
Immunotyping in acute leukemias. Indicate th key immune markers for the following:
- AML
- Precursor B cell (ALL)
- Tc (ALL)
A
- AML: CD 13, 33, 117
- Precursor B cell (ALL): CD 10, 19, 20
- Tc (ALL): CD 2,3,4,5,7,8
24
Q
APML
- Def
- genetic subtype of which cancer?
- favorable or unfavorable risk category?
- First-line Rx?
A
- acute promyelocyte leukemia (APML)
- t(15:17) subtype of AML
- favorable
- ATRA (all-trans retinoic acide, basically vitamin A)
25
Two *unfavorable* cytogenetics in ALL
* **t(9:22)**: phil. xsome (seen also in CML - worse prog. w/ higher recurrence)(
* **t(v;11)**
26
Favorable cytogenetics in ALL?
t(12;21) - ++ in kids
27
Stages of chemo Rx in AML w/ def.
1. **Induction**: initial blast of chemo
2. **Consolidation** (post-remission): prevent replase by killing residual leuk. cells
28
Stagse of chemo Rx in ALL - define each one.
1. Induction: killing!
2. Intensification/consolidation: reduce total body leuk. burden
3. Maintenance: eradicate redidual dz (lo dose)
29
What are the 4 nitrogen mustard drugs to know? What is the prototype?
**\*Cyclophosphamide**
\*Ifosfamide
\*Chlorambucil
\*Melphalan
30
What are the two phases in Gompertzian growth? Which are most effective for chemo + immunotheraphy?
* **Log-linear:** earlier growth - ideal time for chemo and immunotherapy (the latter- specifically in first half of log-linear growth).
* **Plateau**
31
* Best time to kill tumor
* Log-linear growth phase of Gompertzian growth curve
32
When is immunother. of most benefit?
log-linear growth phase of tumor
33
What are the 3 modalities of treating heme Cx's (chemo)?
1. **Induction**: KILL
2. **Consolidation:** Mop up
3. **Maintenance**: low dose, get rid of residual
34
Types of chemo Rx in solid tumors
* **Adjuvant therapy:** Systemic, often post-surgery as in breast Cx - coul be chemo or hormonal.
* **Neoadjuvant ther:** shrink tumor , possibly pre-surg.
* **Palliation:** comfort, quality of life
35
Respnse criteria:
* Complete response (CR)
* Partial (PR)
* Stable Dz (SD)
* Progressive dz (PD)
* **Complete response (CR)**: all tumor gone
* **Partial (PR):** at least 50% dec.
* **Stable Dz (SD)**: b/t a 50% decrease and 25% increase
* **Progressive dz (PD):** incraese of more than 25% in diameter of any lesion
36
Typical chemo cycle
21 days, first three give drugs (single, combo) then 18 days recov.
37
What parts of the cell cycle do diff't cX drugs work on?
* Non-specific
* Mitosis (M)
* Synthesis (S)
38
Explain the general MOA for drugs that work at M and S in cell cycle.
* **M**: these interrupt microtubles needed for proper mitosis.
* **S:** these are _anti-metabolites_, and _pyrimidine analogs_ that act as DNA chain terminators.
39
Most common chemo toxicity?
Nausea & vomiting.
40
What are two NT's that can activate the emetic center?
5-HT and Dopamine
41
**Ondansetron**
* Use
* MOA
* S/E
* antiemetic
* 5-HT antag. (binds serotonin in GI tract & CNS)
* headache
42
**Aprepitant**
* use
* MOA
* Interactions
* Often used in combo with...
* Acute & delayed vomiting - antiemetic (often used with cisplatin)
* NK-1 antagonist
* Many interactions inc. dexamethasone, but dexameth is *not* contraindicated
* (see below)
* Ondansetron + dexameth is a common combo Rx for chemo regimens w/ high N/V profile.
43
What are the two dopamine antagonists we shoudl know?
Discuss:
* Use
* MOA
* 1st line or adjuvant?
* Tox
\*Prochlorperazine
\*Metoclopramide
* Antiemetics
* Dopamine antagonists
* Adjuvant to NK-1 / 5-HT antagonists
* extrapyramidal SE's, sedation
44
What kinds of drugs are **Prochlorperazine** and **Metoclopramide**
Dopamine-antagonist antiemetics (adjuvant to 5-HT and NK-1 antag's)
45
Dexamethasone
* Use
* MOA
* Tox
* Generally a 1st- line antiemetic
* Unknown!
* glucose intol, insomina, agitation
46
What are the two Epo analogs to know about?
procrit and darbepoetin
47
Procrit , Darbepoetin
* Use
* Tox
* Consideration when admistering
* **Rx anemia** (in this context, anemia caused by chemo, rad)
* HTN, rash
* Must have **adequate Fe stores** - perhaps admminister Fe.
48
Why types of drugs are used to treat chemo-induced neutropenia? Give names
Myeloid GF's: **filgrastim** and **pegfilgrastim**
49
Filgrastim, Pegfilgristim
* Use
* SE's
* **Myeloid growth factors to increase neutrophil coun**t (used proph and in establish neutpenia)
* **Fever, bone pain**
50
**Alkylating agents**
* General MOA
* What part of cell cycle they effect
* Cause abnormal covalent linkages/crosslinks which --\> **DNA damage**
* _Not cell-cycle specific!_
51
General toxicities of alkylators (6)
* BM suppression (directly cytotoxic)
* N/V (most chemo drugs do this!)
* diarrhea, anorexia (direct dmg to GI tract cells - rapidly dividing)
* Sterility (cytotoxic)
* 2ndary malignancy
**NB: note how most of these are caused by the killing of rapidly dividing cells!**
52
\*Cisplatin
* use
* MOA
* SE (3)
* Chemo for solid tumors
* Cross-linking via platinum
* Nausea / vomiting, **nephrotoxic, neurotoxic** (axonal degen w/ stocking & glove dist.)
53
What is a major SE/complication of platinum analogues in addition to neurotoxicity & N/V?
Nephrotoxicity
54
Three considerations in management of nephrotoxicity of **cisplatin**?
* avoid renally toxic drugs (NSAIDS, etc)
* Monitor renal fxn
* Monitor for anemia (dec. EPO)
55
How to prevent nephrotoxicity in cisplatin?
* hydration
* hypertonic saline
* mannitol
56
Describe the neurotixicity of cisplatin
* axonal degen w/ periph. neuropathy, **stocking/glove dist.**
* Can also get **audit. impairment**
57
Carboplatin
* Type/Use
* MOA
* SE (2)
* Interaction
* Platinum analogue - 2nd gen. version of cisplatin
* Same as cisplatin - DNA dmg via crosslinks
* **Hypersens in 10%**, **neurotox** but, **\*\*_no nephrotoxicity_** (as in cisplatin)
* must be administered *after* taxane to lower toxicity.
58
Cyclophosphamide
* Class
* Use/MOA
* Cell cycle phase affected
* Toxic metabolite created
* Nitrogen mustard (alkylator)
* Chemo - causes cross-linking
* \*non cell cycle specific!
* **Acrolein**
59
Cyclophosphamide toxicity
* Delayed N/V
* **Hemoragghic cystitis (acrolein)**
* Cardiotoxic
* Immunosupression
* Neutropenia
60
\*Ifosfamide
* Class
* Toxicity
* Clearance considerations
* Nitrogen mustard chemo agent
* Increased renal tox vs. cyclophosphamide (otherwise same as cyclo)
* **P450** - sensitive to inducers and inhibitors.
61
Why is **mesna** used in _ifosfamide_ administration?
Ifosfamide produces higher levels of acrolein. Mesna binds acrolein in bladder to reduce cystic problems.
62
Main uses of glucocort's in Cx Rx (2)?
* Lympholytic (ALL, NHL)
* Also 1st line Rx for N/V (antiemetic)
63
Main use of androgens in cx Rx?
* Myelodysplastic synd
* Other BM failure synd's
\*\*boosts RBC prodn
64
Danazol
* Class
* Use
* Androgen analog
* Boos RBC prod in myelodyspalstic, BM failure synd's
65
**flutamide, bicalutamide**
* class
* use
* tox
* **anti-androgen**
* _Prostate Cx_
* hot flashes, dec. libido, gynecomastia
66
**tamoxifen**
* Use, class
* **\*\*MOA** (including internal signaling molecule)
* Tox
* adjuvant, neoadjuvant, antiestrogen for breast cx
* Competes w/ estrogen at receptor --\> stimulates TGF-B --\> dec. proliferation
* menopausal sx's
67
Raloxifene
* Class
antiestrogen, akin to tamoxifen
68
What are the three aromatase INH's to know?
\*Anastrazole
\*Letrozole
\*Exemestane
69
\*Anastrazole
\*Letrozole
\*Exemestane
* MOA
* Use
* Tox
* ***Aromatase INH's:*** Reduce estrogen by INH of aromatase (testosterone--[*aromatase*]--\>estrogen)
* Same SE's as tamoxifen
70
\*Leuprolide
\*Goserelin
* Class
* MOA
* Use
* Tox
* LH-RH antagonists
* Supress gonadotropins
* Testicular, breast & ovarian Cx's
* hot flashes, gynecomastia
71
What are teh two LH-RH antagonists to know?
\*Leuprolide
\*Goserelin
72
In the scheme of heme malignancies, where does NHL fit in?
* Chronic (mature cells mostly)
* Lymphoma: dz of B,T and NKC's (NHL can affect both B and T cells)
73
def. lymphoma
* Tumor of Lc's w. growth in nodes but may invade other organs
* generally not a lot of circulation in blood in signficant #s
74
What is the most common hematological cx?
NHL (85% are of B cell origin)
75
NHL: clinical pres
* Swollen nodes
* Pain
* Fevers, night sweats, fatigue
76
Two main categories of NHL (w/ most common dz)
* Indolent (**follicular lymphoma - FL**)
* Aggressive (**diffuse large B cell** - **DLBC**)
77
Dx of NHL
* Core needle biopsy (not fine needle asp) of node/extramed/marrow.
78
Staging schematic for NHL
* I: single node
* II: 2+ nodes, same side diaph.
* III: 2+ node groups, both sides diaph.
* IV: extranodal dz
* plus A = asympt, B = symptomatic
79
What is the **IPI** in context of NHL?
Just a more systemic way to index prognosis - don't have to know specifics.
80
What are ther. goals in Rxing indolent vs. aggressive NHL?
* Indolent: sympt. control (not goin for cure)
* Aggressive: cure
81
Rx modalities, NHL
* Rad
* Chemo
* Possible stem cell xplant (aggressive)
* (not surg.)
82
What is an adjuvant drug that has increased overall survival in NHL and CLL?
**Rituximab** (causes cell death) - used w/ success in lymphomas b/c it is a direct CD 20 antibody (Mab). CD 20 is present on Bc's in both NHL and CLL.
83
Epidemiology of Hodgkin's lymphoma
Bimodal dist - peark in early 20's, early 60's
84
Relationship b/t Epstein-Barr Virus (EBV) and Hodgkin's lymphoma?
**50% of cases** have EBV DNA in the Reed-Sternberg cells.
85
What is the diagnostic cell of HL? Describe.
Reed-Sternberg cell :binucleated large cell, represents a malignant B Lc.
86
R/S cell in HL - immuno+ for what CD's?
CD 15 and 30
87
What is the most common classical HL? Non-classical?
Classical: **Nodular sclerosis (NS)**
Non-classical: **Nodular lymphocyte predominance (NLP)**
88
Explain Ann Arbor staging for HL (Stages (I-IV)
I: Single lesion (remember that HL will generally make a chain of involved LN's whereas NHL is more spurious)
II: 2 lesion same side
III: Dz above AND below diaph.
IV: Diffuse non-lymphoid spread, extranodal dz
*plus*
A: **A**bsence of sx's
B: "**B** symptoms" - fever, night sweats
M: Bulky **m**ediastinal mass
E: **E**xtranodal
89
What is the general Rx approach to HL?
Rx as aggressive dz --\> aim for CURE.
90
What is the CD difference b/t nodular sclerosis HL and nodular lymphocyte predominance HL?
**NS**: CD 15,30+
**NLP**: CD 20+
91
What is the advantage of ABVD therapy vs MOPP?
Lowers r/o secondary leukemia or loss of fertility.
92
What are the three antimetabolite drugs we should know? Where do they work in the cell cycle?
\*Methotrexate
\*5-Fluorouracil
\*Hydroxyurea
These work in the S phase of cycle - make problems during DNA synth.
93
MTX
* MOA
* Kinetics consideration (1)
* Elimination
* Inhibits creation of purines
* Tends to accumulate in third spaces due to hi water solubility (ascites, effusions)
* Renal
94
Leucovorin
* Use
* Dosing consideration
* A MTX rescue drug - increased mTHF to nl cells \> cx cells.
* Dosing: timing very important
95
R/F's for developing MTX toxicity (renal)
* Poor hydration
* acidic urine
* low Cr-Cl
* Third spacing
96
In addition to renal tox, what are the other tox's of MTX (3)?
* GI - use anti emetics
* Hepato: monitor liver enzymes
* mucositis: due to increased sloughing, cell death
97
What are two important interactions to consider (with an example) w/ MTX?
* Drugs that affects plasma protein binding (Salicylates)
* Drugs that affect Cr-Cl (NSAIDS)
98
Ara-C (cytaribine)
* Type/MOA
* Clearance
* Tox nl dose (3)
* Tox hi dose (3)
* Type/MOA: antimetabolite, S-phase chemotherapy, **falsely incorporates into DNA (a pyrimidine analog)**
* Clearance: renal
* Tox nl dose (3): myelosuppression, flu-like synd, mucositis
* Tox hi dose (3): cerebellar tox, ocular tox, noncardiogen. pulm. edema
99
5-FU (5-Fluorouracil)
* Use/MOA
* Specific to what phase of cycle?
* Syergistic w/ ??
* Advantage WRT clerance/metab.
* Main toxicities to remember (2)
* Use/MOA: antimetabolite chemo drug
* Specific to what phase of cycle?: S phase
* Syergistic w/ ??: leucovorin
* Advantage WRT clerance/metab.: can be used in pts w/ mild to moderate renal & hepatic failure
* Main toxicities to remember (2): mucositis/diarrh & myelosupression
100
What are the two **pyrimidine analog** drugs used in chemo?
Cytaribine & gemcitibine (notice that these are analogs to pyrimid**INE**s)
101
Gemcitabine
* Type/MOA
* Major toxicity to remember (1)
* Interactions
* Pyrimidine analog chemo drag (S phase specific)
* Myelosupression
* Potent radiosensitizer ('preps' cells for rad Rx); enhances cytotoxicity of **cisplatin**.
102
What part of the cell cycle do anthracyclines affect?
Non-cell-cycle specific
103
**Anthracyclines**
* Ones we need to know
* Class
* Cell-cycle specific?
* MOA
* \***Doxorubicin
\*Daunorubicin**
* Chemo Ab's
* Mess up DNA Topo2 INH
* Not cell-cycle specific
* Intercalates into DNA --\> breaks in DNA --\> poor replication.
104
Anthracyclines
* Elimination
* Tox/ SE's (4)
* Key complications (1)
* **Hepatic**
* Myelosuppression, alopecia, N/V, *cardiotoxic*
* **Extravasation --\> skin necrosis**
105
Discuss acute & chronic cardiotoxicity assoc. w/ anthracyclines
* Acute: acute changes EKG sim. to MI
* Chronic (more common): dec in LVEF akin to LHF/CHF.
106
What is presumed mechanism of cardiotox in anthracyclines?
**Production of reactive O2 species** to which cardiomyocytes are esp. sensitive.
107
What drug is cardioprotective in anthracycline cardiotoxicity? S/E's?
* **dexrazoxane**: an Fe chelator - decreases free rad. formation
* SEs: Very similar to the anthracyclines but no cardiotox. (myelosuppression, alopecia, N/V, mucositis)
108
What mediates anthracycline resistance?
* MDR transporter
109
What are the two antracyclines to know?
Primary uses of each (types of cx)?
* \*Doxorubicin: breast, lymphomas (solid)
\*Daunorubicin: leukemias (liquid)
110
Bleomycin
* Drug class
* Cancer use
* Antitumor antibiotic
* HL
111
camptothecin drugs
* representative
* MOA
* Cell cycle specific?
* SEs (only rep. drug)
* Irinotecan
* Topo I INH
* S phase
* SE's: neutropenia, early & late onset diarrh
112
Irinotecan
* Class
* MOA
* Use
* Camptothecin (plant alkaloid)
* TopoI INH
* Colon & lung xc
113
Why do TopoI INH's work in fighting cx? Example drug?
B/c evidently Cx cells have more TopoI than nl cells. **Irinotecan.**
114
How to Rx the *early* onset diarrh from irinotecan?
**Atropine** (the GI probs though to be due to hypercholinergic syndrome)
115
Vinca alkaloids
* Three representative drugs to know
* Cell cycle specificity?
* MOA
* Three representative drugs to know:
**\*Vincristine
\*Vinblastine
\*Vinorelbine**
* Cell cycle specificity?: M1
* MOA: distrub MT formation
116
Primary toxicities of:
* \*Vincristine
\*Vinblastine
\*Vinorelbine
* **\*Vincristine**: perhiph neuropahty
* **\*Vinblastine:** myelosuppression
* **\*Vinorelbine:** both of above
117
Chronic leukocytic leukemia (CLL)
* Def
* Type of chronic leukemia w/ accum of mature cells, high WBC count.
118
CLL
* Prolif ot what type of cell
* Cell surface marker
* Smear shows?
* Clinical sign
* Prolif of **mature but naive Bc's**
* **CD 20+**
* Smear: Increased leukocytes, **smudge cells**
* LAD
119
Complication of CLL (2)
1. **Autoimmune hemolytic anemia**: can produce Ab against RBC's
2. Can transform to **Diffuse Large B-Cell Lymphoma (DLBC)** - this will be seen via an increasing size of LN's and spleen.
120
CLL
* Epi
* Diagnosis
* Most common leukemia in western world
* Lymphocytosis (increase in # of small, mature Lc's), BM involvement, clonal expansion of Bc's.
121
How does Rai staging (simplified) work in CLL?
Stage 0 = low
I-II: Intermed.
III-IV: Hi
122
What surface proteins, assay proteins and cytogenetics assoc. w/ **worse prognosis** in CLL (1 assay protein, 2 genetic, 1 surface marker)?
ZAP-70
del(17p)
del(11q)
CD 38
123
Unfavorable cell surface marker in CLL?
CD 38 = poor prognosis
124
CLL Rx goals
An indolent dz. Goal: sx control not cure.
125
What is a targeted therapy being used in CLL Rx?
Rituximab - anti-CD20
126
What is a key lab finding (gel) for plasma cell malignancies?
**M-spike** (Mab)
127
What are the parts of an Ig and which xsomes code for them?
* 2 heavy chains (c14)
* 2 light chains - either Kappa (c2) or Lambda (c22)
128
Monoclonal gammopathy of uknown significance (MGUS)
* Def
* Type of what disorder?
* Diagnosis
* Clinical course
* Def: plasma cell disorder w/ abnormally hi levels of serum Ig
* Type of what disorder? as above
* Diagnosis: serum Ig \>- 3g/dL
* Clinical course: progresssion 1%/yr.
129
Multiple Myeloma
* Type of dz
* Epi
* Dx
* S/S
* **Plasma cell neoplasm**
* Epi: rare, adult (65 median age)
* Dx: higher M-spike + can do BM aspirate and skeletal survey also.
* _CRAB_ (hyper**C**a, **R**enal dysfx, **A**nemia**, B**one lesions)
130
What is the cause of the **lytic bone lesions** in multiple myeloma?
The cancer cells (plasma cells) are closely assoc. w/ osteoclasts and boost their activity --\> lesions.
131
What are the 2 components of the ISS prognostic scoring system for Mult. myeloma?
albumin and beta-2
microglobulin
132
In addition to Multiple Myeloma, what are **three** other plasma cell disorders to recognize?
* heavy chain disease
* Waldenstrom’s
* cryoglobulinemia
133
Myelodysplastic syndrome DEF
Cytopenia with hypercellular marrow and dysplastic cells.
134
What is the cause of cytopenias in myelodysplastic synd?
Innefective hematopoeisis of 1+ myeloid lineage caused by defects in the HSC.
135
Myelodysplastic syndrome: greater risk for / can progress to \_\_\_\_
AML
136
Myelodysplastic synd's
* Etiology
* Clinical
* Smear
* BM morphology
* Cytogenetics
* Post-chemo (esp. alkylators, topo INH), post-XRT, benzene, tobacco, Fanconi anemia
* Cytopenias, B symptoms, risk AML progression
* Anemia w/ megalobastic RBC's (large, nucleated), basophilic stippling
* Hypercellular marrow w/ ringed sideroblasts
* Del(5q): good, Monosomy 7/Del(7q): poor, 11q23, poor.
137
Rx of myelodysplastic syndromes
* Support for cytopenias (xfusion, chelation)
* Hypomethylating agents (eg decitabine)
* Allogeneic HSC xplant (curative)
138
What are the distinctive smear cells in myelodys. synd's?
pseudo pelger-huet neutrophil w/ bilobed nucleus
139
How does IPSS scoring work in myelodysp. syndromes?
Based on
* % blasts (BM)
* Marrow karyotype
* # and degree of cytopenias
* age
140
Describe 5q- syndrome (a myelodysplastic synd.)
* Epi
* Smear
* Clinical
* Pt count?
* Clinical course
* F\>M
* Mk's w/ hypolobated nuclei
* refractory macrocytic anemia
* nl or increased Pt's
* favorable
141
BM xplant DEF
Transplant of HSCs (CD34+)
142
Sources of BM for xplant (3)
* BM aspirate
* Periph blood
* Cord blood
143
Autologous BM xplant
refers to source being pt's own marrow or cord blood; allows for pre-xplant myeloabaltive chemo
144
Myeloablative chemo
Agressive chemo performed before an ***autologous BMT*** - used to basically kill all cells in BM including cx cells.
145
Syngeneic BMT
From an ident. twin
146
allogeneic BMT
could be from twin, HLA-matching siblign, or unrelated donor
147
Primary indications of the following:
* Autologous BMT
* Allogeneic BMT
* Autologous BMT: used primarily in lymphoprolif. disorders (mult. myeloma, NHL, HL)
* Allogeneic BMT: used primarily in myelogenous disorders (AML, CML plus ALL, MDS/MPD, aplastic anemia)
148
Graft-vs-tumor effect in BMT
An effect taken advantage of in allogeneic BMT where the graft cells kill the tumor cells. Part of the curative process of the BMT.
149
Haplotype DEF
A set of closely linked DNA sequence variants on a single chromosome - in BMT, used for matching.
150
GvHD
* Def
* Acute vs. chronic
* Def: Graft (BMT) immune system attacks host (takes place in 50%)
* Acute vs. chronic:
- **Acute**: Mucosal disruption in gut lining --\> Tc and cytokine-mediated reaction --\> severe rash, GI sx's, hepatic.
**- Chronic**: Months after BMT w/ autoimmune-like sx's (lots of skin abnl's, GI strictures esp. esophageal)
151
* Short-term risks/complications of autologous & allogeneic BMT (4)
* Which complication has a higher chance of happening in allogeneic?
* Neutropenia (give antibios)
* Anorexia (give TPN)
* Hepatic failure
* GvHD (higher chance in allogeneic)
152
Rituximab
* Use & target
* Type
* Tox (1)
* Syndrome that can result from Rx?
* What dz can reactivate?
* Use: NHL, CLL (anti-CD20)
* Type: Mab
* Toxicities: Immunosuppresive (can reactivate Hepatitis), **tumor lysis syndrome** (HI YIELD: this is from killing of the CD20+ cells, resulting in release of purines which can lead to _uric acid nephropathy_)
153
Cetuximab
* Target
* Uses
* Tox (2)
* Target: **EGFR**
* Uses: solid tumors
* Tox: Acneiform rash (tox-man!)
154
Trastuzumab
* Target
* Use
* Tox (1)
* Target: HER2/neu (an oncoprotein that binds a Tyr kinase)
* Use: breast cx
* Tox: Cardiotoxic
155
**Bevacizumab**
* Target
* Use
* Tox
* Target: **VEGF**
* Use: solid tumors
* Tox: **impaired would healing _(black box)_**, HTN, thrombosis, bleeding
156
Action of the "-nib" drugs, in general
Tyr Kinase INH's
157
Erlotonib
* Target
* Use
* Tox (2)
* Target: EGFR Tyr kinase
* Use:NSCLC
* Tox: Acneiform rash, diarrhea
158
**Imatinib**
* Target
* Use
* Tox (3)
* Target: **INH's Bcr-Abl Tyr Kinase **
* Use: **CML**
* Tox: Edema, cytponeias, cardiotox
159
Thalidomide
* Use
* MOA
* Adverse rxns (4)
* **Multiple myeloma**
* MOA: unknown
* Adverse rxns: **Teratogenic**, **neorotoxic**, sensory sx's, sedative.
160
Lenalidomide
* Advantages over thalidomide?
* **less neurotoxicity** than thalidomide
161
**Azacytidine**
* Use
* MOA
* Tox (3)
* Use: **Myelodysplastic synd.**
* MOA: _hypomethylation_
* Tox: Myelosuppression, N/V, Diarrh
162
Decitabine
see _azacytidne_
163
Bortezomib
* Use:
* MOA:
* Tox (2)
* Use: Mult. myeloma, NHL
* MOA: proteosome INH
* Tox: myelosupression, sensory neuropathy
164
Major tox of interferons?
flu-like syndrome
165
What are the specific immunohistochemical stains for the following cx types?
Carcinomas (2)
Lymphomas
Melanoma
Neuroendocrine tumors (3)
Germ cell tumors (2)
Soft tissue tumors
* Carcinomas – CK, EMA
* Lymphomas – LCA
* Melanoma – S100
* Neuroendocrine tumors – chromogranin, synaptophysin, NSE
* Germ cell tumors – beta-HCG, AFP
* Soft tissue tumors – vimentin
166
5 most common cancers, males:
* Prostate
* Lung
* Colon
* Bladder
* Melanoma (skin)
167
5 most common cx's, females
* breast
* lung
* colon
* uterine
* thyroid
168
What is the avg age dx of breast cx?
60
169
What cx dominates the younger age groups (0-9)?
leukemia
170
Myeloprolif disorder
* DEF
* Major features
* Abnormal (neoplastic) accum. of mature myeloid cell types.
* High WBC, hypercellular BM
171
Complications of myeloprolif disorders (3)
* **Hyperuricemia/gout** (too much cell tunrover --\> cell death --\> more purines)
* **Marrow fibrosis**
* _can xform to acute leukemia_ (if mutation progresses back to HSC's)
172
CML
* Class of dz and Def
* Smear
* Abnormal cytogenetics
CML
* Chronic myelogenous leukemia: a type of myeloprolif. disorder
* Smear: prolife of myeloid cells but **basophils** in particular
* Abnormal cytogenetics: Philadephia xsome, t(9;22) - Bcr-Abl.
173
What is the abnormal cytogenetics in CML?
What is a targeted therapy?
* **t(9;22) - bcr/abl** (an abnormal Tyr kinase)
* **Imatinib** blocks Tyrk kinase activity.
174
CML
* Risks for transformation (to what dz's?)
* Sign of transformation
* 2/3 --\> AML, 1/3 --\> ALL
* **Splenomegaly** incidates increase in pace of dz w/ higher chance of preogression to acute leukemia.
175
How is it possible for CML ( a dz of myeloid lineage) to progress to ALL?
Indicates that mutation started (or got into) the HSC CD34+ cell line and then went into lymphoid lineage.
176
* DEF leukemoid rxn
* How to distinguish b/t that, and CML (3)?
* DEF leukemoid rxn: elevated WBC counts, genearally due to acute medical condition.
* How to distinguish b/t that, and CML?:
1. CML cells are **LAP-** (a normal granuclocyte protein)
2. CML: **increased basophils**
3. cytogenetics - **t(9;22)**
177
Polycythemia vera
* DEF
* Mutation
* Clinical picture
* Rx
* How to distinguish from _reactive polycythemia_?
* DEF: myelodysplastic disorder w/ prolif esp of **RBC's**
* Mutation: **JAK-2** Tyr kinase
* Clinical picture: _hypervisious blood_ --\> blurry vision, headache, inc. risk thrombosis.
* Rx: **Phlebotomy,** **hydroxyurea** (antimetabolite, S phase)
* How to distinguish from r_eactive polycythemia (RP)_?: In RP, Sat will be low and EPO will be HI.
178
Essential Thrombocythemia
* Def
* Smear
* S/S
* Major diff b/t this and polycythemia v., CML?
* Myeloprolif. disorder of mature cells, with especially increased pt's
* Lots of platelets!
* S/S: increase r/o bleeding or thormobsis
* Major diff b/t this and polycythemia v., CML? No increase in gout, _lower_ chance of progressing to marrow fibrosis or acute leuk.
179
Chronic Eosinophilic Leukemia
* Def
* Smear
* Mutation
* Complications
* Def: **myeloprolif. disorder w/ hypereosinophilia**
* Smear: as above - lots of eosins!
* Complications: **thrombosis or pulmonary/ cardiac fibrosis** due to eosinophilic degranulation.
180
Rx of CML
* Imatinib (anti bcr/abl Tyr kinase)
* BM xplant
181
**Myelofibrosis**
* DEF
* Clinical (1)
* Smear (2)
* Complications/risks
* Myekloproliferative disorder (neoplasm) w/ elevated Mk's
* Clincal: (1) splenomeg (increased splenic hematopoeisis)
* Smear: **lots of immature cells** inc. nucleated RBC's due to extramed. h'poeisis, **teardrop RB cells** (fibrosed BM --\> defomration)
* Complications/risks: infection, thromosis, bleeding
182
What is meant by neoadjuvant therapy? Give example of one for breast cx.
* Refers to a Rx to use before the "main treatment"
* Best example is use of **tamoxifen** to reduce size of tumor before surgery.
183
When are benzos used for in chemotherapy?
To treat **anticipatory N/V**
184
Use of **Deferoxamine, Deferasirox**
Fe chelators, used w/ xfusion therapy.
185
Tumor lysis syndrome tends to take place in what dz?
What is a drug that can be used to Rx its main complication?
Tumor lysis synd: lots of cells are destroyed via chemo (in acute leukemias). This frees up lots of purines which can build up and cause uric acid nephropathy, a complication of chemo.
**Allopurinol:** blocks creation of uric acid from purine metabolites.
186
Allopurinol
* Use
* MOA
Allopurinol
* Use: To reduce uric acid production during chemo.
* MOA: prevents purine metabolites from producing uric acid.
187
What are the three Pt analogs to know?
Cisplatin
Oxaliplatin
Carboplatin
188
Primary use of cyclophosphamide?
For **lymphomas** (targets B and T cells)
189
Common combination therapy for HL? Indicate the class of each drug.
* Anthracycline
* Dacarbazine (also an alkylator)
190
what glucocorticoids commonly used as chemo agents?
for what dz's, based on their MOA?
**Prednisone, dexamethasone.**
These are **lympholytic** - so used for lymphocytic leukemias and lymphomas
191
What 2 drugs are mainstay Rx for ALL? Give class/MOA.
* **MTX** (antimetabolite)
* **Cytaribine** (pyr. analog/chain terminator)
192
What enzyme helps to metabolize F-fluorouracil? What is the implicationf for usage/dosing?
DpD (dihydropyrimidine dehydrogenase)
- Pt's with deficient DpD may have increased 5-FU toxicity.
193
Other than risk of hemorrhagic cystitis & nephrotoxicity, what is another SE of ifosfamide? What is given to treat the SE?
* Encephalopathy
* Methylene blue
194
Major SE of irinotecan?
Early and late onset diarrhea.
195
WHat drug is used particularly w/ cisplatin for acute adn delayed n/v?
aprepitant (NK-1 inh)
196
What are two chemo agents (there are more) that can be given intrathecally?
MTX, cytaribine
