Pharmacology- Hematologic Malignancies II Flashcards
What should you do through out treatment for pts. who are receiving tx for cancer?
support due to myelocuppression and immunosuppression
What governs the design of txments regimens?
Toxicity of “Classical” anit-cancers
What are the governing principles that guide the combination therapies?
- dug MUST show activity against tumor type
- No two drugs should have the same mechanism of action
- Drugs should have different patterns of does-limiting toxicity
What are the stages of chemo?
Induction
Consolidation
Maintenance
What is induction?
high dose cobination chemo
What is consolidation?
repetition of induction therapy during remission
what is maintenance?
long term lower does therapy during remission
What is Neo-adjuvant?
before or during surgery/ radiotherapy
What is adjuvant?
given after surgery/ radiotherapy
What is metronomic dosing?
- giving a lower does everyday, versus high dose every few days or wks.
- showing positive date against many types of cancer but not all tumor types/. pts respond
What is hormesis?
txments designed to kill tumor cells or suppress their proliferation in pts. may have the capacity to enhance tumor growth when the drug is present in certain concentraitons
What may metronomic dosing avoid?
the pro-proliferatice aspect of drug response
Explain metronomic chemotherapy.
exerts both direct and indirect effectos on tumor cells and their microenviorment.
- it can inhibit tumor angiogenesis, stimulate anticancer immune response and may also be able to directly affect tumor cells through a therorectical drug-driven dependency/ deprivation effect,
- the direct effects of metronomic chemo on the differnt compartments of hte tumor micorenviorment and the complex interaction b/n these compartment may lead to additional anticancer effects and potential induction of tumor dormancy
What is an adaptive or evasive resistance?
the ability of a tumor, after an initaila response phase, to adapt so as to evade the therapeutic blockade by inducing or accentuating mechanisms that enable enovascularization despite the therapeutic dlockade, or educe dependence on such growth of new blood vessesls by other means, leading to renewed tumor growth and progression
What is adaptive therapy and why has it come about?
This innovative type of cancer treatment, which can be regarded as a gradually decreasing metronomic chemotherapy regimen, takes into account the complex interactions between resistant and non-resistant cancer clones. Adaptive therapy aims to maintain the equilibrium between these two populations to preserve a certain level of tumor sensitivity to treatment and induce lifetime-long control, rather than complete eradication, of the disease.
What effect does the immune response have on cancer control and how is it being changed by drug therapy to control cancer?
- adaptive immune system has a key role in the development and the control of cancer.
- In addition to the well-characterized adverse effects of chemotherapy on the immune system, such as neutropenia and lymphopenia, various studies suggest that certain cytotoxic drugs, such as anthracyclines, taxanes and cyclophosphamide, display important immunostimulatory properties, amongst which, their effect on regulatory t cells (treG) seem to be quite relevant in the context of metronomic treatments.
- Experimental studies have shown that low doses of cyclophosphamide can increase anti-tumor immune response by selectively decreasing numbers and inhibiting the suppressive functions of treG cells but also by increasing both lymphocyte proliferation and memory t cells. Metronomic cyclophosphamide reduces both the frequency of circulating treG cells and their immunosuppressive functions in advanced cancer patients. nK cell cytotoxic activity and t-cell-receptor induced t cell proliferation were subsequently restored in these patients.
- Some chemotherapeutic drugs—including vinblastine, paclitaxel and etoposide that can be used in metronomic chemotherapy regimens—promote infiltration and maturation of dendritic cells at non-toxic concentrations, thus stimulating anti-tumor immune response.
What are some side effects of metronomic dosing?
-grade 1 nausea and vomiting
-grade 1 and grade 2 anemia
neutropenia, leucopenia and lymphopenia
-associations with secondary diseases *leukemias)
What are the classifications of leukemias?
acute (short natural history)
choronic (long natural history)
Myeloid or lymphoid origin
->1/5– ALL, AML with remainder CLL and CML
What leukemias is seen mostly in childhood?
ALL
What leukmia is seen mostly in elderly?
CLL
What are the drugs approved for acute myeloid leukemia? (AML)
cyclophosphamide Cytarabine, ARA-C Daunorubicin Doxorubicin Idarubicin Gemtuzumab Mitoaxantrone Thioguanine, 6-TG
What is the most effective txment for AML?
a two-drug regime of daunorubicin and cytarabine – 65% response rate
-given with thioguanine, 6-TG is better is able to be done
What is the mechanism of Gemtuzomab?
- recombiant humanized CD33 monoclonacl antibody
- It carries calicheamicin, an antitumor antibiotic that cleaves dsDNA at specific sequences
What is post-remission therapy?
a short-term, relatively intensive chemo
- uses cytratbine-based regimens similar to standard induction clinical trials
- can also do a high-does chemotherapy or chemoradiation therapy with autologous bone marrow resuce (if HLA-identified sib is identified), and high-does marrow-ablative therapy with allogeneic bone marrow rescue
What is Acute Preomyelocytic leukemia?
- PML/RARA fusion gene - drive proliferation
- subtype of AML
What is the mechanism of ATRA?
- overcomes repressive signaling
- differentiation of APL cells and then post-maturation apoptosis
- most pts with APL achieve a complete remission (CR) when txted with aTRA, though single-agent ATRA is not curative
What is the txment of childhood APL?
ATRA+anthracycline+ cytarabine
What is the remission and consolidation therapy for APL?
ATRA+ standard-does cytarabine adn daunorubicin or idarubicin +ATRA w/o cytarabine
What is the maintenance therapy for APL?
ATRA+6mercaptopurine +MTX
What is arsenic trioxide’s mechanism?
not understood, but it degrades PML-RARA fusion protein
What are the ADE’s of arsenic trioxide?
AV block, QT prolongation, Electrolyte imbalance
CARDIOVASCULAR toxicity
What differentiation syndorme are seen with ATRA and arsenic trioxide?
-fever, dyspenea, weight gain, pulomary infiltrates, and pleural or pericardial effusions +/- leukocytosis, and leukocytosis (rapidly increasing counts)
What drugs are sued for ALL? (21)
Asparaginase Pegasparagase L-Asparaginase Betamethasone cortisone Dexamethasone Hydrocortisone Methlypredisolone prednisolone Prednisone Clfarabine Cyclophosphamide cytarabine, ARA-C Dasatinib Daunorubicin Doxorubicin Imatinib Mercaptopurine MTX Teniposide Vincristine
What remission induction thearpy is used with ALL?
- prednisone+ Vincristine + antracycline
- Imatinib mesylate +/- combo chemotherapy (for pts with Ph-1 positive ALL) (9;22)
What consolidation therapy is used with ALL?
MTX+mercaptopurine
What is the mechanism of Imatinib Mesylate? (gleevec)
- oral inhibitor of the BCR-ABL tyrosine kinase, stops the cell from being able to proliferate, by competiviely binding to site for activation
- active as a single agent in Ph-1-positive aLL
- most commonly incorporated in combo chemotherapy
- allogenic transplat no adversly affected by the addition of imatinib to the txment regimen
What are the common drug toxicites of Imatinib?
nausea
^liver enzymes
-may necessitate interruption and or inmatinib dose reduction
What are the drugs used for CML?
Busulfan Cyclophosphamide Cytarabine Dasatinib Hydroxyurea Imatinib Interferon Alpha-2a Mechloretheamine Nilotinib
What is the treatment of CML during acute phase (blast transformation)?
-classical chemotherapy agents like AL are used
What drugs are used during the chronic phase of CML?
- imatinib -1st line txment
- 95% experience a cure (hematologically)
What are the resistance mechanisms of cells for TK I drugs?
-ATP-binding site mutation
How have drugs changed to overcome resistance mechanisms to 1st generation TKIs?
2nd generation TKIs
- Dasatinib and nilotinib
- bind to ATP pocket with a slightly different orientation, making them active in inatinib-resistant cells
What drugs are sued for CLL?
Alemutuxumab Bendamustine Chlorambucil Cyclophosphamide Fludarabine Rituimab
What combination therapies are sued for CLL?
fludarabine/ cyclophosphamide
fludarabine/ Rituximab
fludarabine/ cyclophosphamide/ Rituximab
What does alemtuxumab bind too?
CD52
What does Bendamustine bind too?
It is both an antimetabolite (from its benzimadazole function) and and an alkylating agent (it possesses a 2-chloroethylamine group). It causes DNA cross-linking resulting in very durable single and double-strand breakage, it activates P53 pathways resulting in apoptosis and it inhibits mitotic checkpoints. The last factor causes cells to enter mitosis with DNA damage and mitotic catastrophe ensues. The drug seems to be less susceptible to drug resistance based on alkylguanyl transferase expression that are other alkylating agents.
What is cyclophosphamide?
an alkylating agent
What is rituximab?
a CD-20 antibody
What are the txment complications for CLL and how are they prevented or txed?
- opportunistic infections– prophlactic antibiotics
- Anemia (from hemolysis)– Erythropoietin
- Hyperuricemia– Allopurinol
What drugs are used against Hairy Cel Leukemia?
Cladribine
Interferon Alpha-2b
Pentostain
What are interferon antineoplastics actions?
- direct antiproliferative effect on tumor cells
- -prolong all phases of cell cycle
- induce cellular differentiation (cells enter G0)
- Induce host responses
- -activate cytotoxic T cells and/or NK cells
- -Activate macrophages and monocytes–> increased phagocytic activity and enhanced cytoxicity against tumor cells and other target cells
- -Stimulate production of cytokines suck as IL-1b and IL-1ra, thus IFNs may affect the inflammartor response
What are the 2 types of lymphomas and where are they found?
- Hodgkinlymphoma
- Non-Hodgkin lymphoma
- occur at any site where lymphoid tissue is found
What is the prognosis of lymphomas determined by?
subtype of lymphma
- anatomical extent of diseasze
- buld
What are the main hodgkin lymphoma drugs that are used in combotherapy? / what are most combo therapies made up of?
Doxorubine (anthracyclin)
Vincristine (mitotic spindle inhibitor)
Cycloposphamide or blecomycin (alkylating agent)
Carbazine Drug
Corticosteroids
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
What are the benefits of using drug cocktails with Hodgkin lymphoma?
- generally broadens the spectrum of potential toxicities
- reduces severity of individual drug- or radiation-related toxicities
What drugs therapy is used with Non-Hodgkin Lymphoma (low stage)?
- Low stage
- pulsed chemotherapy with COMP (cyclophosphamide, vincristine, MTX, and prednisone)
What drugs therapy is used with Non-Hodgkin Lymphoma (high stage B-cell)?
- -DLBCL, and Burkitt lymphoma both express high levels of CD20
- rituximab + standard doxorubicin, cyclophosphamide, vincristine, and prdnisone (R-CHOP)
- if remission can be achived in recurrent diseases, SCT may be presued
What are the delayed tratment effects of NHL?
- sterility
- secondary malignacies
- left ventricular dysfunction (doxorubicin)
- myelodysplastic syndrome andAML
What are the CD20+ B-cell targted therapies and how do they work?
Tositumomab, and Ibritumomab
- both anti CD 20 antibodies, that are radiolabed
- apoptosis
- phagocytosis
- radionuclide damage to targe adn adjucet cells
- benifets– not biding to non-lymphoid tissue
What are the toxicites of CD20 radiolabed drugs?
Heatologic: thrombocytopenia, neutropenia, anemia N/V Infections Chills Fever
What is Burkitt Lymphma commonly associated with?
EBV
-rapidly fatal with out therapy (high proliferative index)
What is the drug regimen for Burkitt Lymphoma?
- Cyclical
- -cyclophosphamide+MTX
- -Vincristine + Doxorubicin
- -Possibly cytarabine
- intrathecal chemotherapy used to ensure CNS coverage
