3.24 SWEATMAN Drug Treatment of Hematologic Malignancies Flashcards
Classical Cancer drug administration
- High doses (very toxic; induction therapy)
- Lower doses (less toxic; consolidation therapy during remission)
- Maintenance; long term. lower dose therapy during remission
General Rules for Combo Therapy
- Drugs must show activity against the tumor type
- No two drugs should have the same mechanism of action
- Drugs should have different patterns of dose-limiting toxicity
Neo-Adjuvant
Adjuvent
Neo: before or during surgery/Radiotherapy
Adj: given after surgery/radiotherapy
Metronomic Dosing
Daily administration of much lower doses
- Not all tumors/pts respond
- Hormesis: treatments designed to kill tumor cells or suppress their proliferation in pts may have the capacity to enhance tumor growths when the drug is present in certain concentrations
- May avoid pro-proliferative aspect of drug response
- Thought to avoid the very low drug levels from classic administration suspected to be pro-proliferative (think of anti-biotic levels not high enough and see resistance form, similar concept)
Metronomic Dosing to avoid resistance
Gradually decreasing metronomic chemotherapy regimens aim to maintain the equilibrium b/t resitant and non-resistant tumor populations to reserve a certain level of tumor sensitivity leading to life long control rather than complete eradication.
Ways to Stim Anti-Tumor Immune Response
-Metronomic chemo with some drugs, by decreasing # and activity of Treg and may promote (re)activation of an anticancer immune response with CTLs and NK cells
Ex Cyclophosphamide
Problems with Metronomic Dosing
Nausea, vomitting, anemia, neutropenia, leucopenia and lymphopenia
- -overall well tolerated
- Risk in children
- -angiogenesis important for dev in children
- Secondary malignancies (all chemo agents)
Leukemia
- Acute: short natural history
- Chronic: long natural history
- Myeloid or lymphoid origin
- AML/ALL(children) or CML./CLL (elderly)
Acute Myeloid Leukemia
Treat with combo of: DAUNORUBICIN (free rad, intercalate and topo II) -Tox: BM suppression, CV, Hepatic disease, second malig, extravasational necrosis Cytarabine, ARA-C (pyrimidine analog) Tox: BM suppression THIOGUANINE, 6-TG (purine analog) -Tox: BM supp -Dont always use 6-TG
Post-Remission Therapy
More dose-intensive cytarabine-based treatment
-BM allogenic rescue (transplant)
Gemtuzomab (Mylotarg)
- mAb for CD33
- binds and is internalized, where it has its MOA
- Shows that mAbs can be used as carries and do not only have to work extracellularly
Acute Promyelocytic Leukemia
-PML/RARA fusion drive proliferation
(Retonoic acid receptors alpha)
-All Trans Retinoic Acid (ATRA): leads to differentiation of APL cells and then post-maturation apoptosis
-Tox: Acute Promyelocytic leukemia differentiation syndrome, leukocytosis
-Usually use in combo with other drugs
–anthracycline +/-cytarbine
-Uses ATRA in combo for all stages in different doses
Arsenic Trioxide
-Similar action to ATRA but more toxicity on CV system (black box)
Acute Lymphoblastic Leukemia
- Imatinab does not have actions with acute phase, but does work in chronic phase
- usually use predisone (cortico) +vincristine +antracycline
Imatinib
BCR-ABL tyrosine kinase inhibitor, ppl with 9:22 translocation (Philadelphia chromo)
- usually used with combo therapy
- regular CBC to monitor cytopenias
Chronic Myeloid Leukemia
Imatinib is 1st line of treatment (very effective)
-Dasatinib and Nilotinib are second gen drugs that bind in the ATP pocket with diff orientation than imatinib
Chronic Lymphocytic Leukemia
Bendamustine: antimetabolite and alkylating agent
-DNA cross linking and act of p53 pathway
-inhibits check points and forces cell to enter mitosis with damaged DNA leading to mitotic catastrophy
-Less susceptible to cross drug resistance
can also use Alemtuzumab (CD52) and Rituximab (CD20)
Hairy Cell Leukemia
Use purine analogs: cladribine and Pentostatin
-Can also use IFN-alpha-2b
IFN Antineoplastic Action
-Direct Antiproliferative effect on tumor cell
-prolong all phases of cell cycle and induce cellular differentiation
Induce host responses
-Activate Cytotoxic T cells and/or NK cells and other phagocytes
Lymphomas
Hodgkin and non-Hodgkin Lymphomas
Hodgkin Lymphomas
- Use a lot of combinations, all drug combos have drugs with different MOAs, leads to decreased cross reactivity and decreased general drug toxicity
- Common combos: contain anthracycline (doxorubicin), mitotic spindle inhibitor (vincristine) and alkylating agents (cyclo or bleomycin), a carbazine and sometime a corticosteroid
Bleomycin (toxicity)
Idiosyncratic rxn to bleomycin (fever), pulmonary fibrosis
Busulfan
BM suppression, secondary malignancies
Carboplatin
anemia, infection
Chlorambucil
BM suppression, secondary malignancy, pregnancy, infertility
Cladribine
BM suppression neurotoxicity
Ifosfamide
Coma, hemorrhagic cystitis
Dacarbazine
BM suppression, hepatic disease, pregnancy, secondary malignancy
Daunorubicin, Doxorubicin, and Idarubicin
BM suppression, heart disease, hepatic disease, secondary malignancy, extravasational necrosis
Etoposide
Myelosuppression, bleeding, oppurtunistic Infection
Teniposide
BM suppression
Fludarabine
BM suprression, coma, seizures, dont give with pentostatin
INF-alpha-2b
Contraindicated with autoimmune disease, cardiac disease, increased suicidal ideation, depression
Mechlorethamine
BM suppression, extravasation, pregnancy
Methotrexate
Ascites, diarrhea, exfoliative dermatitis, infection, lymphoma, pulmonary disease, pulmonary fibrosis, renal impairment, stomatitis, tumor lysis syndrome (TLS)
Mitoxantrone
Extravasation, HR failure, intrahecal administration, neutropenia, secondary malignancy
Pentostatin
Hepatic disease, pulmonary edema, renal failure, seizures, use with fludarabine
Vinblastine, Vincristine
Extravasation, intrahecal administration-FATAL, neuropathic toxicity
Alemtuzumab
BM suppression, infection, infusion rxn
Gemtuzumab, Ozogamicin
BM suppression, hepatic and pulmonary disease, infusion rxn
