Drugs for Heme Malignancies Flashcards
induction therapy
high dose combination chemotherapy
consolidation therapy
repetition of induction therapy during remission - induction therapy only works against cells that are proliferating, consolidation therapy is to catch any cells that may have been in G0 at the time of induction
maintenance therapy
long term, lower dose therapy during remission
Hormesis
CTX designed to kill tumor cells, but the biphasic dosing typical of traditional regimens can cause stimulation of tumor cell proliferation at the low dose phase
metronomic dosing and effect on hormesis
may avoid the effects of hormesis
metronomic dosing definition
daily admin of much lower drug doses (as opposed to dosing intermittently w/ high drug doses - traditional regimens)
metronomic dosing methodology
try to increase the amount of time that the drug is putting pressure on the tumor - help counter continued proliferation of tumor cell population - also has effect on immune system
Metronomic dosing effect on tumor microenvironment
metronomic dosing has effect on immune system as well as some decrease of vasculature - so in addition trying to kill the tumor cells, you make the environment around the tumor shitty so it is hard for the tumor to live
adaptive therapy
gradually decreasing metronomic dosing - induce lifetime-control rather than complete eradication
drugs that have effects on Treg cells
anthracycline, taxanes, cyclophosphamide
what are the effects of these drugs on Treg cells
anthracyclines, taxanes, cyclophosphamide –> decrease numbers and inhibit the suppressive functions of Treg cells
potential problems with metronomic dosing with regards to infancy
angiogenesis - very important to growing infant b/c neovascularization of growing organ is vial fo full development of organ
metronomic dosing - potential problems with long term use (2)
long term use could cause
dose related toxicities
treatment related secondary malignancies
metronomic dosing most common problems
grade 1 N/V, grade 1 and 2 anemia, neutropenia, leukopenia, and lymphopenia
metronomic dosing - 1 unusual problem
subdural hematoma
most common drug regimen for AML (3 part combo)
ARA-C + Daunorubicin + Thioguanine
difference for use indication of doxorubicin vs daunorubicin
doxorubicin - solid tumors
daunorubicin - blood cancers
AML post remission therapy
ARA-C
radiation + autologous transplant - sometimes
Acute Promyelocytic Leukemia indicated treatment
ATRA and/or arsenic
not sure if both together or either or
remission and consolidation therapy for APML
ATRA + anthracycline + cytarabine
common theme of combination chemotherapy
anthracycline (doxo, etc) + cytarabine (can add others)
can complete remission of APML occur w/ ATRA alone?
yup
maintenance therapy for APML
ATRA + 6-mercaptopurine + MTX
arsenic trioxide - adv effects
CV toxicities –> AV block (this is bad.. and unusual side effect for anticancer drugs)
induction therapy for ALL
corticosteroids + vincristine + anthracycline
IT MTX
injecting methotrexate into the CNS compartment
why do you use IT MTX for ALL?
cancer drugs cannot access the CNS compartment (“sanctuary”) –> CNS prophylaxis
consolidation therapy for ALL
MTX + mercaptopurine
Imatinib
tx of ph chromosome 9;22
indications for Imatinib
ALL and CML
MOA of Imatinib
tyrosine kinase inhibitor –> prevents proliferative signaling from this receptor
Imatinib toxicities
GI (nausea), elevation in hepatic enzyme levels, carious cytopenias
Imatinib resistance
mutation in ATP binding site of tyrosine kinase
CML chronic phase - 1st line tx
Imatinib
cute phase
classical CTX agents
2nd generation TKIs
nilotinib, dasatinib
advantage of 2nd generation TKIs
nilotinib, dasatinib - retain activity in mutant clones (TK) that have alterations in ATP binding site
methods of resistance (besides ATP bidning site mutation)
MDR-1 - pushes out small molecular drugs, TKIs can be substrates for this efflux pump
downstream mutation, past receptor (drug won’t work)
Interferon alfa 2
acts on endogenous receptors, MOA of anticancer function not well known,
CLL therapy
fludarabine + cyclophosphamide + rituximab
Bendamustine
antimetabolite and alkylating agent
MOA of Bendamustine
DNA cross linking - single and double strand breaks
Bendamustine advantges
seems less susceptible to resistance
CLL treatment complications (3)
opportunisitic infections, anemia (from hemolysis) and hyperuricemia
tx for opportunistic infections
prophylactic antibiotics
tx for anemia
EPO
tx for hyperuricemia
allopurinol
tx for Hodgkin lymphoma
treated by combinations of drugs - anthracycline (doxo), mitotic spindle inhibitor (vincristine), and alkylating agent (cyclo or bleomycin) and DHFR inhibitor
do you ever use just one drug for Hodgkin?
no - always combos of drugs, more than 2
what rule of combinations does Sweatman love?
diff MOAs from drugs in combo –> decrease likelihood of resistance
Non-Hodgkin lymphoma - low stage disease - tx
COMP - cyclo + vincristine + MTX + prednisone –> admin for 6 mos
adv effects of non-Hodgkin tx (delayed tx effects)
treatment induce secondary malignancy (always a possibility) - others that we didn’t really talk about in class
two other drugs for CD20 targeted theray
Tositumomab, Ibritumomab
additional function of Tositumomab, Ibritumomab
MAbs that carry radioactivity to CD20 positive cells - local delivery
I131 labeled anti-CD20 Ab
Tositumomab
Y90 labeled anti-CD20 antibody
Ibritumomab
Tositumomab
I131 labeled anti-CD20 antibody
Ibritumomab
Y90 labeled anti-CD20 antibody
side effects of Tositumomab
iodine labeled Ab –> thyroid problems
side effects of both Tositumomab, Ibritumomab
generally well tolerated except for expected heme toxic - thrombocytopenia, neutropenia, anemia
Chemo and Pregnancy
in utero drug exposure can have number of consequences - teratogenic - structural malformations or in utero death
chemo fog
decrease CNS functionality following long term chemo –> drugs cause release of cytokines from periphery that produce CNS deficits
Pegasparagase - potential thypersensitivity
product of Erwinia - ppl w/ Erwinia hypersensitivity cannot receive it
Pegasparagase other side effects
affects protein C and protein S - problems with bleeding - secondary adverse effect
corticosteroids
jekyl and hyde drugs - best anti-inflammatory we have, but metabolic problems
corticosteroids metabolic problems
weight gain, water retention, inc blood sugar levels, inc some other blood levels
bleomycin
lung/pulmonary toxicity
platinum drugs
kidney toxicity
chlorambucil
secondary malignancies, aplastic anemia, bone marrow suppression, infertility
Anthracyclines - big red flag
cardiotoxicity - dose limiting
vincas
peripheral neurotoxicity - drugs acting on microtubules - stocking glove
arsenic trioxide
APML differentiation syndrome, AV block, cardiac arrhythmias, leukocytosis
ATRA
APML differentiation syndrome, leukocytosis
busulfan
bone marrow suppression, secondary malignancies
carboplatin
anemia, infection, pregnancy
dacarbazine
hepatic disease, secondary malignancy, pregnancy
all the rubicins (anthracyclines)
heart disease, hepatic disease, extravasational necrosis
Fludarabine
coma, seizures, don’t give w/ pentostatin
Interferon Alfa-2b
dont give with autoimmune disease, cardiac disease; increased suicidal ideation, depression
MTX
ascites, diarrhea, exfoliative dermatitis, pulmonary problems, renal impairment, stomatitis
vincas
extravasation, IT admin = fatal, neuropathic toxicity
nilotinib
contraindicated in hypokalemia and hypomagnesemia; QT prolongation
Ibritumomab,
bone marrow suppression, exfoliate dermatitis, infusion reaction
Tositumomab
iodine hypersensitivity, thrombocytopenia, neutropenia
rituximab
exfoliate dermatitis, infusion rxn, progressive multifocal leukoencephalopathy
