Heme Lymph Flashcards
Oncogenes
Ras
Tumor suppressor
P53
Go G1 S and g2 M
M mitosis
Go resting phase of G1
G1has restriction point whihc activation of oncogenes overrides
S synthesis dna replication phase
G2 has dna replication checkpoint which tumor suppressor genes p53 override
Primary chemo
Chemo is the primary treatment in advanced cancer with no alternative treatment
Relieve tumor related symptoms, improve quality of life, prolong time to tumor progression
Curable cancer with primary chemo
Hodgkin and non Hodgkin lymphoma, choriocarcinoma, germ cell cancer, and acute myelogenous leukemia
Kids-burkitts, wilms, embryonal rhabdomyosarcoma, ALL
Neoadjuvant chemotherapy
For localized cancer in adjunct ro other methods whihc are less than completely effective
Reduce size of primary tumor to make surgery easier or spare vital organs
Chemo given for time after surgery as ADJUVAnT therapy
ADJUVAnT chemotherapy
After surgery
Reduce incidence of local adhd systemic recurrence and improve overall survival of patients
Prolong disease free survival and overal survival
What is the log kill hypothesis
Symptoms high number of cancer cells/death -Infrequent treatment, treatment started too late , prolongation of survival with eventual death
Diagnosis pretty high cancer cells- Combination chemotherapy, intensive treatment schedule, therapy continued after clinical evidence of cancer disappears, cure
Surgery lower number-Early surgery combines with intensive adjuvant therapy
Primary/inherent chemotherapeutic resistance
Drug resistance int he absence of prior exposure to available standard agents
Genomic instability of cancer p53
Acquired chemo drug resistance
Develops in response to exposure to a given cancer drug
Genetic change-amplification or suppression fo a particular gene
Increasing heterogeneity over time ->tumor continues to proliferate and is no resistant to treatment x
P-glycoproteins, PGP
On tissues with barrier functions including the kidney, liver and GI tract
Pharmacological barrier sites including the blood brain barrier and the placental blood barrier
High baseline expression of PGP correlates wit hprimary/inherent resistance to natural products
Can be overprexpressed leading to acquired drug resistance
Therapeutic index
TD50/ED50
Chemo therapeutic index
Close ED50 and TD50 when desired is low ED50 and high TD50
High doses are required ot maximize rapid cancer cell death
AE chemo
Non cancerous proliferating cells —bone marrow precursors of blood cells(cytopenias, myelosuppression) —intestinal epithelial cells —oral mucosa —gonadal cells —hair follicles-alopecia
MOA alkylation agents
Transfer of alkyl groups to DNA leading to DNA cross linking
Arrest in late G1, early S phase
Individual drugs vary in how they do this-cisplastin versus cyclophosphamide
What cells are most susceptible to alkalyating agents
Replicating cells
Resistance alkalyating agents
Increased capability to repair DNA lesions through increased expression of activity of DNA repair enzymes
Decreased cellular transport of alkyating drug
Increased expression or activity of glutathione and glutathione associated proteins
—these are needed to conjugate the alkyating agents
Alkylation agents adverse effects
Primarily occur in rapidly growing tissue -bone marrow —myelosuppression -GI tract —diarrhea -reproductive system
N/V
Blistering at the site of administration
Carcinogenic-increased risk of secondary malignancies AML
MOA antimetabolites
Methotrexate-folic acid metabolite
5-FU uracil analog
Cytosine arabinoside-cytosine deoxyriboside
Mimic and/or reduce the essential components needed for the formation of DNA, RNA and proteins
Arrest and/or DNA damage often occurs during S phase
Cells most susceptible to antimetabolites
Replicating
Resistance antimetabolites
Inhibition of metabolism intoactive metabolites-cytarabine and the active metabolite of art-ctp
Decrease drug transport
-methotrexate and the reduced folate carrier or folate receptor
Decreased formation of poly glutamate metabolites by folyl polyglutamate synthase (FPGS)
-important for methotrexate, pemetrexed and pralatrexate
Ae antimetabolites
Myelosuppression
N/v
GI toxicity(5-FU)
Hand foot syndrome
- painful erythema and swelling of the hands and feet
- pemetrxed
Natural products MOA
Tubules polymerization disrupted by vinblastine, vincristine, vinorelbine and enhanced by paclitaxel, docetaxel, and cabazitaxel
Topoisomerase inhibitors
Topoisomerase 1 topotecan, irinotecan
Topoisomerase 2-etoposide
Mechanism of resistance natural products
P-glycoproteins mediated drug efflux
Point mutations ind rug binding (topo 1 and 2)
AE natural products
Myelosuppression N/v Neurotoxicity -vincristine Hypersensitivity -paclitaxel and docetaxel Diarrhea -topotecan and irnotecan
MOA antitumor antibiotics
Inhibition of topoisomerase 2, generation fo free radicals (DNA damage), DNA intercalated
-anthracyclines (doxorubicin)
Induce DNA cross links
-mitomycin
DNA fragmentation and single/double strand breaks due to free radical formation
-bleomycin
Mechanism of resistance antitumor antibiotics
Point mutations in topo2, suppression of apoptotic signaling
-doxorubicin
Increased expression f multidrugresistant efflus pumps
-doxorubicin and mitomycin
Upregulation of bleomycin hydrolase enzyme
-inhibits bleomycin iron binding and limits its cytotoxic effects
Antitumor ae
Myelosuppression N/v Free radical mediated cardiotoxicity -doxorubicin Blue fingernails, sclera, urine -mitoxantrone Pulmonary toxicity -bleomycin
Tyrosine kinase and growth factors receptor inhibitors MOA
Inhibit growth factor receptor signaling
Inhibit tyrosine kinase activity
Resistance tyrosine kinase and growth factors receptor inhibitors
Point mutations in drug binding sites
AE tyrosine kinase and growth factor receptor inhibitos
N/v
Acneform skin rash and hypersensitivity
-cetuximab
Immune checkpoint inhibitors
Nivolumab and pembrolizumab
- PD1 inhibitors
- melanoma, NSCLC, hodgkins
Atezolizumab, avelumab, durvalumab
-PD-L1 inhibitor-bladder cancer, NSCLC, meckel cell skinc ancer
Molecular background immune checkpoint inhibitors
T cell activated by dendritic cells within lymph node
Activated T cell penetrates the tumor microenvironment
-tumor microenvironment includes tumor cells, macrophages, and t regulatory cells
The tumor may possess PD-L1; activated T cells may induce PD-L1 upregulation on tumor cells, macrophages and t reg cells through the release of interferon y
An activated T cell inactivated when it binds PD-L1
-B7.1 and PD-1: receptors on T cell forPD-L1
Mechanism resistance immune checkpoint inhibitors
Primary or acquired
Insufficient generation of anti tumor T cells
Inadequate function of tumor specific T cells
Impaired formation of T cell memory
AE immune checkpoint inhibitors
Fatigue, nausea, loss of appetite, itching
Can allow the immune system to attack normal organs (serious problem)
-lungs, intestines, liver kidneys
Point of immune checkpoint inhibitors
New class of chemo that boosts immune system mediated tumor clearance
The leukemia’s
ALL
AML
CML
CLL
ALL
Acute childhood leukemia
Most common ancer in kids
Discovery of methotrexate increase survival
Treat all
6-merceptopurine, cyclophosphamide, vincristine, and danorubicin
Enter remission with combination prednisone with vincristine
When circulating leukemia cells migrate to sanctuary sites located int he brain and testes
Intrathecal methotrexate to prevent CNS leukemia (prophylaxis)
-major mechanism of relapse
AML
Most common leukemia in adults
Treat AML
Cytarabine most active
Best used in combo with anthracycline
But idarubicin is preferred
Intensive support care during period of induction of chemo with AML
Platelet transfusions to prevent bleeding
G-CSF , filgrastim to shorten periods of neutropenia
Antibiotics to combat infections
How get remission of aml
Allergenic bone marrow transplant
-preceded by high dose chemo and total body irradiation followed by immunosuppression
After remission
Consolidation chemo with high does cytarabine or hematopoietic cell transplant
At what age do ppl respond less to chemo for aml
60 tolerance to aggressive therapy and their resistance to infection are lower
CML
BCG-Abl fusion oncoprotein
-Philadelphia chromosome t9:22
Get constitutive expression of Bcr-Abl fusion oncoprotein
How treat CML
Reduce granulocytes to normal levels, raise hemoglobin concentration to normal, relieve disease related symptoms,
Treat CML
Imatinib first line in previously untreated most exhibit a complete hematologic response
Dasatinib and nilotinib initially approved for patients intolerant to imatinib
Currently each shows clincial activity and now both are indicated as first line treatment of chronic CML
Busulfan and other oral alkyating agents also are effective
CLL
High risk disease or the presence of disease related symptoms means treatment warranted
How treat CLL
Chlorambucil and cyclophosphamide alkylation gets agents
- chlorambucil with prednisone
- COP-cyclophosphamide combined with vincristine and prednisone
- CHOP-cyclophosphamide combined with vincristine, prednisone and doxobrucin
Bendamustine also approved
-monotherapy or combination with prednisone
CLL
Fludarabine is also effective
- monotherapy
- combination with (cyclophosphamide) and with (mitoxantrone and dexamethasone) or it is combined with (rituximab)
Rituximad is an anti-CD20 antibody
-enhances chemotherapy and is effective when resistance to chemopay has emerged
R CHOP
Ofatumumab is fully human IgG1 antibody that binds to different CD20 epitope than rituximab
- maintains activity in rituximab-resistant tumors
- approved for CLL that is refractory to fludarabine therapy
Hodgkin’s lymphoma
A complete staging evaluation is needed before treatment plan can be formulated
Biggest change is int he stage I and stage IIA disease
- combined-modality therapy with a brief course of combination chemotherapy and involved field radiation
- ABVD-doxorubicin , bleomycin, vinblastine, dacrabazine
50-60% of patients with Hodgkin’s lymphoma are cured of disease
Changes in treat for advanced stage II and IV Hodgkin’s lymphoma
MOPP-mechlorethamine, vincristine, procarbazine, and prednisone
—high complete response rates (80-90%); cures in 60% of patients
ABVD-doxorubicin, doxorubicin, bleomycin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone
—alternative regimen, followed by involved radiation therapy
Over 80% of previously untreated patients with advanced disease (stages III and IV) are expected to go into complete remission
-complete remission=disappearance of all disease-related symptoms and objective evidence of disease
Non Hodgkin’s lymphoma- diffuse
Combination chemotherapy is the standard for patients with diffuse non Hodgkin’s lymphoma
CHOP-cyclophosphamide, doxorubicin, vincristine, and prednisone
—best treatment in terms of initial therapy
CHOP+rituximab (R-CHOP)
-clinical studies show increased response rate , disease free survival and overall survival versus CHOP alone
Non hodgkin lymphoma follicular
Initiation of chemotherapy at the onset of symptoms
- watchful waiting
- bendamustine+rituximab
- R-CHOP
Multiple myeloma
Most patients symptomatic at time of initial diagnosis
Requires treatment with cytotoxic chemotherapy
MP protocol-melphalan+prednisone
- standard regimen for 30 years
- 40% of patients respond and the median duration of remission is 2-2.5 years
Stage I breast cancer
Small primary tumor and negative axillary lymph node dissections
Treat with surgery alone
80% chance of a cure
Stage II breast cancer (1-3 nodes node +)
High risk of both local and systemic recurrence (micrometastasis)
Postoperative use of systemic adjuvant combination chemotherapy reduces the relapse rate and prolongs survival
CMF-cyclophosphamide, methotrexate, and 5-FU
FAC-5-FU, doxorubicin, cyclophosphamide
Prostate cancer
Advanced prostate cancer becomes refractory
Mitoxantrone and prednisone
- approved for hormone refractory prostate cancer
- provides palliative int hose experiencing significant. Bone pain
Docetaxel+prednisone has become stand of care for hormone refractory prostate cancer*
Colorectal cancer
High risk stage II and III candidates for adjuvant chemo
- FOLFOX-folinic acid (leucorvin)+5-FU+oxaliplatin
- XELOX-capecitabine+oxalplatin
- used for 6 months following surgical resection
- reduces recurrence rate after surgery by 35%
- improves patient survival compared with surgery alone
Metastatic colorectal cancer
FOLFIRI-folinic acid (leucovorin)+5-FU+irinotecan
-ziv-aflibercept added if progression has been observed with oxaliplatin based chemo
FOLFOX or FOLFIRI+(bevacizumab or cetuximab/panitumumab) results in sig improved clincial efficacy
TAS-102 approved for the chemo refractory disease setting
-limited by significant toxicities ,clincial efficacy and low response rates
Non small cell lung cancer
ADJUVAnT platinum based chemo provides survival benefit in patients with pathological stage IB II and IIIA
Radiation can be used ot relieve pain, airway obstruction or bleeding
-less aggressive , used in patients that cant tolerate more aggressive
Chemo non small cell lung cancer
Bevacizumab
-used in combination with carboplatin and paclitaxel in patients with good performance status and non squamous histology, standard treatment option
Patient not a good candidate for bevacizumab or squamous cell histology present(cisplastin or carboplatin)+ cetuximab
Maintance chemo=pemetrexed used in patients that have stabilized after four cycles of platinum based first line chemo
Erlotinib NSCLC
First line in advanced NSCLC patients with sensitizing EGFR mutations
Afatinib NSCLC
First line of metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 mutations
Osimertinib NSCLC
Approved for the treatment of metastatic EGFR T790M mutant NSCLC following progression on or after EGFR TKI therapy
Overcomes resistance fromt he T790M gatekeeper mutation
-this mutation can happen de novo or after prior TKI therapy
Squamous cell
Platinum based chemo
Cisplastin and gemcitabine combined with necitumumab
Nivolumab-if progressed on or after standard platinum based
Small cell
Initially sensitive to platinum based combination regimes
(Cisplastin+etoposide) or (cisplastin + irinotecan)
Drug resistance develops in nearly all patients with extensive disease
If diagnosed early it is curable using combined chemotherapy and radiation
Topotecan used as a second line monotherapy in patients that have failed based regimen
Ovarian cancer stage I
Whole abdomen radiotherapy
Cisplastin and cyclophosphamide
Ovarian stage III and IV
Carboplatin and paclitaxel
Recurrent ovarian cancer
Topotecan or liposomes doxorubicin
Testicular cancer
PEB-Cisplastin , etoposide, bleomycin
High risk disease-high dose cisplastin+etoposide+bleomycin
Malignant melanoma
Curable with surgical resection when it presents locally
Once metastasis has occurred it is onee of most difficult to treat
Dacarbazine, temozolomide and cisplastin most active -low response rate
Biological agents IFNa and IL2 have greater activity than traditional agents, treat with a high dose IL2
Malignant melanoma
Nivolumab and pembrolizumab
Brain cancer
Nitrosoureas most active
- cross BBB
- carmustine sued as a single agent
- PCV-procarbazine+lomustine+vincristine
Alkyating agent temozolomide
-patients with new glioblastoma multiforme
Oligodendroglioma chemosensitive
-PCV regimen is treatment of choice
Bevacizumab alone or in combination ith chemo has documented clincial activity in adult GBM
Drugs for neutropenia
Filgrastim
Pegfilgrastim
Sargramostim
Plerixafor
Drugs for thrombocytopenia
Oprelvekin
Romiplastin
Eltrombopag
Iron therapy from food
Meat fish poultry well absorbed
Poorly from veggies, grain, milks and eggs
Oral iron 200-400 mg for microcytic anemia
Ferrous in divided doses with only water/juice food inhibits absorption
AE iron therapy
Nausea, constipation, anorexia, heartburn, vomiting, and diarrhea and dark stools
Parenteral iron
For iron malabsorption, intolerance of oral therapy, noncompliance
-iron dextran, sodium ferric gluconate complex and iron sucrose
When get iron effects
Reticulocytosis in a few days and increase Hb in a 2 weeks
Acute iron toxicity
Young kids
Necrotizing gastroenteritis with vomiting, abdominal pain and bloody diarrhea->shock, lethargy, dyspnea
Suggestion of improvementthen severe metabolic acidosis, coma, death
Treat acute iron toxicity
Deferoxamine (potent iron chelating)
Chronic iron toxicity
Hemochromatosis
Deposits in heart, liver, pancrease->organ failure and death
Hereditary hemochromatosis an dpatients who receive many red cell transfusions over a long period of time
B12
Animal products
Fortified breakfast cereals -for vegetarians
Need 2 microgram/day
Body stores 2-5 mg
-takes years to become deficient
Why take years to become b12 deficient
Normal body stores greatly exceed daily requirement
NO inhaled analgesia and B12
Inactivated cyanocobalamin
-normally rapidly replenished from body store
If body store of B12 depleted
Rapid onset neurological dysfunction (paresthesia s, weakness, spasticity) that may not fully reverse
Absorption b12
IF from parietal cells and absorbed in ileum
Pernicious anemia
Elderly
Autoantibody blocks IF-Cbl interaction or IF-Cbl receptors in ileum
Gastrectomy or gastritis
H pylori
Treat b12 defiency
Oral b12 supplementation in pernicious anemia
Parenteral therapy if neurological symptoms are present
Folate what in
Yeast, liver, kidney, green leafy
Usual cause of folate defiency
Inadequate dietar intake or alcoholism
Treat folate defiency
1 mg a day for 4 months
High doses folate
Hypotension, hypoglycemia
Treat megaloblastic anemia
Improve within a few days
Should see reticulocytosis in 2-5 days
HCG up in 2 months
Neurological symptomslonger to improve an dmay be irreversible but not worsen
Folate supplementation for elderly?
Increases risk of masking megaloblastic anemia caused by b12 defiency
Epoetin alfa moa
165 aa erythrpopiesis stimulating glycoproteins
- from recombinant DNA
- identical aa sequence of isolated natural erythropoietin
Effects epoetin Alfa
Stimulated erythropoiesis
Increase reticulocytosis count<10 days
Increase RBC could and hemoglobin and hematocrit
Usually include irona nd folate
Clincial epoetin Alfa
Anemia from chronic kidney disease, cancer chemo, zidovudine treatment for HIV
Reduce allergenic rbc transfusions in patients undergoing elective surgery
Use banned by international Olympic
Pharm epoetin alfa
Administered IV or subcutaneously
Half life of 4-13 horus
AE epoetin alfa
DAP>10 mmHg
Death, MI, stroke, venous thromboembolism,, thrombosis of vascular access and tumor progression or recurrence
-cough HA, muscle pain, spasm, joint or bone pain, spasms, vomiting, insomnia wight loss
Darbepoetin alfa
3x longer HL 21 hours
Hydroxyurea moa
Targets ribonucleotide reductase results in s phase cell cycle arrest
Somehow. Boosts the levels of fetal hemoglobin mechanism unknown
Effects hydroxyurea
Lowers concentration of Hb S within a cell_> less polymerization of the abnormal hemoglobin
Celincal applciation hydroxyurea
Sickle cell!!!!!
Pharmacokinetics sickle cell
Orally
Wide distribution. Concentrates in erythrocytes and leukocytes
Has multiple metabolic pathways also excreted unchanged by kidney
AE hydroxyurea
Cough, hoarseness, fever, chills, low back pain, painful difficult urination
Eculizumab moa
Monoclonal antibody that specifically binds to complement protein C5 with high affinity
Inhibits its cleavage to C5a and C5b
Prevents generation of terminal complement complex C5b-9
Effects eculizumab
Inhibits terminal complement mediated intravascular hemolysis in PNH…RBC lack enough CD59 and CD55 to prevent MAC mediated destruction
Inhibits complement mediated thrombotic miccroangiopathy in patients with atypical HUS
Clincial eculizumab
PNH
Atypical HUS
Pharmacokinetics eculizumab
IV over 35 min
Maintence dose
EXPENSIVE 444,000/yr but so effective
AE eculizumab
Infections herpes influenza like
Meningococcal infections must have menigococcal vaccine Immunogenicity URI MSK pain Anemia, leukopenia HTN HA Insomnia fatigue UTI
Filgrastim moa
G-CSF made by recombinant DNA
Effects filgrastim
G-CSF regulates production neutrophils in bone marrow
Clincial filgrastom
Decrease infection from febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppression anticancer drugs or in those receiving a bone marrow transplant
Mobilize hematopoietic progenitor cells into peripheral blood for collection by leukapheresis
Pharmacokinetics filgrastim
IV infusion continuous wait 24 hours after chemo since dividing cells most vulnerable
AE filgrastom
Well tolerated
Allergic reaction
Bone pain
Splenic rupture
Acute respiratory distress
Pegfilgrastim
Longer lasting version of filgrastim due to conjugation with monomethoxypolyethylene glycol
Sargramostim moa
Recombinant form of granulocytes macrophage
GM-CSF made in year
Effects sargramostim
In bone marrow to increase production of neutrophils, eosinophils and monocytes//macrophages
Clincial sargramostim
Accelerate recovery of myeloid cells after autologous bone marrow transplantation
-allogenic too
Mobilize HSC into peripheral blood for collection via leukapheresis
Induction chemo with AML to shorten time to neutrophil recovery/decreased incidence of severe infections
Pharmacokinetics sargramostim
IV ro SC
AE sargramostim
Benzyl alcohol can cause fatal gasping syndrome in premature infants
Causes fluid retention typically->edema but can cause pleural effusion, pericardial perfusion
Sequesteration fo granulocytes in pulmonary circulation has caused dyspnea
Occasional supraventricular tachycardia
Renal hepatic
Filgrastim vs sargramostim vs cost benefit analysis
Filgrastim fewer ae so filgrastim/pegfilgrastim wine
-filgrastim speed recovery from severe neutropenia but little evidence of impact on clincial outcomes
Plerixafor moa
Partial agonist of the CXCR4 receptos, important for the homing of hematopoietic stem cells to the bone marrow
Effects plerixafor
Mobilizes HSC from the bone to plasma
Clincial plerixafor
Not mobilizing stem cells for autologous transplant with just G CSF
Expensive
Lymphoma, multiple myeloma
Pharmacokinetics plerixafor
Sq
AE plerixafor
Hypersenstivity reaction is main concern
Has potential to mobilize leukemia cells, contaminate apheresis product
Oprelvekin moa
Recombinant for IL-11
Unknown moa
Effects eprelvekin is-11
Increases platelet levels by promoting the formation and maturation of megakaruocytes
Clincial applications oprelvekin is-11
Can be sued to treat thrombocytopenia in patients undergoing myelosuppressive chemotherapy for non myeloid cancers…DOES NO HAVE A MAJOR CLINCIAL USE
Pharmacokinetics is-11
Given sq once/day
AE oprelvekin
Edema from volume expansion cardiac dysrhythmias, severe allergic reactions and bloodshot eyes
Romiplstim moa
Peptibody compose dof two disulfide bonded human IgG1 kappa heavy chain constant regions (an Fc fragment), each of which is covalently bound at residue 228 with two identical peptide sequences linked via polyglycine that bind to the TPO receptor
No TPO homologous
Effects romiplostim
Increased the platelet count in
-health individuals, patients with ITP, patients with myelodysplastic syndrome
Clincial applications romiplostim
Excess platelet destruction due to idiopathic thrombocytopenic purpura
66 ITP cases/1,000,000 per year
Pharmacokinetics romiplostim
Administered weekly as a sq injection
AE romiplostim
Well tolerated most serious is allergic reaction
Eltrombopag moa
Potent, orally available non peptide TPO receptor agonist
Effects eltrombopag
Increases the platelet count in:
Healthy individuals
-patients with ITP
-thrombocytopenia due to hepatitis C
Clincial eltrombopag
Excess platelet destruction due to idiopathic thrombocytopenic purpura
Cirrhosis due to hepatitis C
Pharmacokinetics eltrombopag
Oral once day
AE eltrombopag
Hepatotoxicity if sued with interferon in patients with chronic hepatitis C
Drugs causing hemolytic. Anemia
Cephalosporins-most common cause, espicially ceftriaxone an cefetetan
Penicillin, piperacillin
Drug induced thrombocytopenia
Heparin
Quinidine quinine
Drugs causing aplastic anemia
Cancer chemo (alkylation agents, antimetabolstes, cytotoxic antibiotics
Chloramphenicol-antibiotic
Benzene-aplastic anemia
