Drugs for Hematologic Malignancies - Sweatman 03.31.15 Flashcards
1
Q
What are the principles of chemo combo therapy?
A
- Drugs MUST show activity against tumor type
- No two drugs should have the same MOA (to avoid resistance)
- Drugs should have different patterns of dose-limiting toxicity
***This assurest that each drug can contribute to effectiveness when being administered at its max tolerated clinical dose in combo chemo
2
Q
How does dose vary with the stage of treatment?
A
- Induction: high dose combo chemo
- Consolidation: repetition of induction therapy during remission -> without consolidation, you might miss those cells in G0 that weren’t eliminated in 1st round
- Maintenance: long-term lower dose therapy during remission
3
Q
Why is combo treatment better than a single therapy?
A
- Greater effectiveness:
1. Increased max cell kill
2. Heterogeneous cell populations killed
3. Resistance to drug treatment reduced
4
Q
What is metronomic dosing?
A
- Daily administration of much lower drug doses with no drug-free breaks (rather than standard intermittent high doses followed by recovery periods)
- Positive data for: advanced MM, recurrent Non-Hodgkin’s (not all tumor types/patients respond)
5
Q
What is hormesis?
A
- Hormesis: adaptive response of cells and organisms to moderate (usually intermittent stress)
- Tx to kill tumor cells or suppress proliferation in many pts may have capacity to enhance tumor growth when drug is present in certain concentrations
- Metronomic dosing may avoid the pro-proliferative aspect of drug response -> while maintaining cont’d drug “pressure” in countering tumor cell proliferation
6
Q
How does metronomic dosing “work?”
A
- Direct and indirect effects on tumor cells and microenvo -> can:
1) Inhibit tumor angiogenesis,
2) Stimulate anti-cancer immune response, and
3) May also directly affect tumor cells via theoretical drug-driven dependency/deprivation - Direct effects on different compartment of tumor microenvo and complex interaction b/t these compartments might lead to add’l anti-cancer effects and potential re-induction of tumor dormancy
7
Q
What is adaptive therapy?
A
- Aims to maintain the equilibrium b/t resistant and non-resistant cancer clones to preserve certain level of tumor sensitivity to treatment and induce life-long control, rather than complete eradication, of disease
- Important b/c: in tumors, exposure to chemo is a major selective force that drives, at least partially, the capacity of every cancer clone in a tumor to survive and proliferate through genetic and epigenetic modifications
8
Q
What are the apparent immunostimulatory effects of metronomic therapy?
A
- Evidence that innate and adaptive immune system have key role in devo and control of cancer
- Some cytotoxic drugs (anthracyclines, taxanes, cyclo-phosphamide, show immunostimulatory properties, incl a selective inhibition of treGs
- Also INC lymphocyte proliferation and memory t cells -> nK cell cytotoxic activity and TCR-induced t cell proliferation subsequently restored in these patients
- Other drugs promote infiltration and maturation of dendritic cells at non‐toxic concentrations, stimulating anti‐ tumor immune response
9
Q
What are some of the problems associated with metronomic dosing?
A
- Treatment well tolerated
- Most comm toxic effects: N/V, anemia, neutropenia, leukopenia, and lymphopenia
- Potential risks of extended use, esp. in children bc angiogenesis has critical role in growth
- High total doses of anti-cancer agents associated with secondary malignancies
- Unusual problems: subdural hematoma
10
Q
What is the standard tx for AML?
A
- Cytarabine, ARA-C (pyrimidine analog metabolite)
- Daunarubicin (free radical generator, intercalator, and topo II inhibitor) -> dose-related cardiotoxicity
- Thioguanine, 6-TG (purine analog metabolite)
- NOTE: all 3 drugs myelosuppressive, w/possibility of opportunistic infections
11
Q
What does post-remission therapy for AML look like?
A
- ARA-C
- Some patients may also have radio-ablation of bone marrow and autologous transplant
12
Q
What is the standard tx for APL?
A
- ATRA: overcomes repressive signaling -> differentiation of APL cells, post-maturation apoptosis
- Most pts w/APL have complete remission w/ATRA tx, but single-agent ATRA generally not curative
- Childhood APL: ATRA + anthracycline + cytarabine
- Remission/consolidation: ATRA + cytarabine + daunarubicin OR ATRA + idarubicin
- Maintenance: ATRA + 6-MP + methotrexate
13
Q
What is arsenic trioxide used for? Black box warnings?
A
- APL: degrades PML-RARA fusion protein
- Black box: AV block (not conducting from atrium to ventricle), QT prolongation (pro-arrhythmogenic), electrolyte imbalance -> NOT seen with ATRA
- Differentiation syndrome: fever, dyspnea, weight gain, pulmonary infiltrates, pleural/pericardial effusions, luekocytosis -> also seen with ATRA
14
Q
What is the standard tx for ALL?
A
-
Remission induction: vincristine + anthracycline + prednisone
1. Imatinib +/- combo chemo for pts w/9;22 - CNS prophylaxis: IT methotrexate +/- systemic MTX (sometimes w/radiation) -> to “mop up” any cancer that has passed through BBB
- Consolidation: MTX + 6-MP
15
Q
What is Imatinib Mesylate?
A
- Oral inhibitor of BCR-ABL tyrosine kinase
1. Active as single agent in Ph-1+ ALL (9;22)
2. More commonly incorporated in combo chemo - Remissions generally short w/conventional ALL Rx
- Allogeneic transplant not adversely affected by adding imatinib to tx regimen
- Toxicities: nausea, elevated hepatic enzymes, cytopenias -> need routine LFTs and CBCs
16
Q
What is the standard tx for CML?
A
- Acute (blast transformation): bc short durability of response to imatinib, “classical chemo” agents (as for AML) used (busulfan, cyclophosphamide, cytarabine, hydroxyurea, interferon alfa-2, mechlorethamine)
- Chronic: IMATINIB is 1st-line tx (95% w/hematologic cure and 75% w/no detectable BCR-ABL transcripts in blood) -> can be cont’d indefinitely bc mild toxicity
-
NILOTINIB, DASATINIB: 2nd gen TKIs that retain activity in mutant clones (lack long-term data) -> different binding orientation
1. These, and IMATINIB can be substrates for drug efflux, and downstream mut = resistance
17
Q
What is the standard treatment for CLL?
A
- Fludarabine/cyclophosphamide
- Fludarabine/rituximab (OR all 3)
- Major consideration when to tx (30% never require intervention) -> combo regimens SUPERIOR
- Tx complications: opportunistic infections (prophylactic ABs), anemia (from hemolysis) -> EPO, hyperuricemia (allopurinol)
- NOTE: rituximab induces ADCC; bendamustine is an antimetabolite/alkylating agent (causes cell to enter mitosis w/DNA damage -> mitotic catastrophe)
18
Q
What is the standard tx for Hairy Cell?
A
- Cladribine
- Interferon alpha-2
- Pentostatin
- NOTE: probably WILL NOT be on test
19
Q
What is the interferon antineoplastic effect?
A
- Direct antiproliferative effect on tumor cell: prolong all phases of cell cycle, induce cellular differentiation (cells enter G0)
-
Induce host responses: activate CD8 T cells and NK cells, activate macros/monos to cause INC phagocytic activity and enhanced cytotoxicity against tumor cells
1. Stimulate production of cytokines (i.e., IL-1B and IL-1ralpha (IL-1 receptor antagonist) -> may affect inflammatory response
20
Q
What is the standard combo tx for Hodkin lymphoma?
A
- Most combos contain:
1. Mitotic spindle inhibitor (vincristine)
2. Anthracycline (doxorubicin)
3. Alkylating agent (cyclo, bleo)
4. Carbazine drug (or topo inhibitor)
5. Corticosteroid (possibly) - Can be admin in cycles to allow pt blood cell counts to normalize
21
Q
What are the implications of Hodgkin’s tx?
A
- High-dose therapy: raise dose to max level below that at which nonhematopoietic toxicity manifests
-
Recurrent after chemo: potentially very serious (2nd, 3rd remissions w/re-induction chemo)
1. Consolidate remission w/high-dose therapy & peripheral blood cell progenitor rescue (PBPCR); rescue via marrow, or periphery stem cells - About 75% all newly diagnosed adults cured w/combo and/or radiation therapy (national mortality has fallen more for this cancer than any other malignancy over the past 50 yrs)
22
Q
What are the txs for low-stage, high stage, and recurrent NHL?
A
- 70% B, 30% T
- Low-stage: pulsed chemo w/cyclo, vincristine, MTX + prednisone (COMP) admin for 6 mos
- High-stage: diffuse lg B-cell and Burkitt both express high CD20 -> rituximab + CHOP (doxorubicin + cyclo + vincristine + prednisone)
- Recurrent: 10-20% survival due to emergence of chemo resistance -> if remission achieved, high-dose therapy + SCT
23
Q
What are the delayed tx effects associated with NHL?
A
- Sterility: pelvic radiation, high-dose cyclo
- Secondary malignancies: esp. lung, brain, kidney, bladder cancers, melanoma
- Cardio: left ventricular dysfunction (doxorubicin)
- Secondary malignancies: myelodysplastic syndrome and AML are late cx of myeloablative therapy with autologous marrow or peripheral blood stem cell support, as well as conventional chemo-containing alkylating agents
24
Q
What are the two CD20 B-cell targeted chemos?
A
- Tositumomab: I-131 (may affect thyroid function)
- Ibrutumomab: Y-90
- Apoptosis, phagocytosis, radionuclide damage to target and adjacent cells
- No binding in non-lymphoid tissue
- Hematologic toxicity: thrombocytopenia, anemia, neutropenia
- N/V, infections, chills, fever
25
Q
What is the standard tx for Burkitt lymphoma?
A
- Drugs relieve symptoms and potentially curative in high % of cases
- Regimen:
1. Cyclo + MTX
2. Vincristine + Doxo
3. Possibly Cytarabine - IT chemo to ensure CNS coverage
26
Q
What about pregnancy?
A
- Teratogenic drugs: structural malformations or in utero death are possible consequences
- Other drugs: AEs may be more subtle, incl devo dysfunction in brain, heart, and other organs
- Recent report indicates not a certainty that in utero exposure to cytotoxic agents will produce measurable deleterious effects
- In any situation involving the administration of any drug during pregnancy, the clinician and patient should discuss the risks and benefits of proceeding with the planned treatment.
27
Q
What are the black box warnings for Pegaspargase?
A
- Hypersensitivity to product of Erwinia
- Bleeding (decreased fibrinogen, protein C/S activity, and AT)
- Glucose intolerance
28
Q
What are the black box warnings for corticosteroids?
A
- Increased appetite and weight gain, water retention
- Increased risk of infection
- Fluctuation of blood sugar levels
- Changes in mood and behavior, difficulty sleeping
29
Q
What are the black box warnings for Bleomycin?
A
- Idiosyncratic rxn to Bleomycin: fever
- Pulmonary fibrosis
30
Q
What are the black box warnings for platinum drugs?
A
- Platinum hypersenstivity
- Bone marrow suppression
- Anemia, infection
- Kidney
31
Q
What are the black box warnings for the anthracyclines?
A
- Bone marrow suppression
- Heart disease, hepatic disease
- Secondary malignancies
- Extravasational necrosis
32
Q
What are the black box warnings for cytarabine?
A
- Bone marrow suppression
- Opportunistic infection
33
Q
What are the black box warnings for dacarbazine?
A
- Bone marrow suppression
- Hepatic disease
- Pregnancy
- Secondary malignancy
34
Q
What are the black box warnings for Fludarabine?
A
- Bone marrow suppression
- Coma, seizures
- Don’t give with Pentostatin
35
Q
What are the black box warnings for interferon alpha-2b?
A
- Contraindicated with autoimmune disease, cardiac disease
- increased suicidal idiation, depression
36
Q
What are the black box warnings for Methotrexate?
A
- Ascites, diarrhea, exfoliative dermatitis
- Infection, lymphoma
- Pulmonary disease, pulmonary fibrosis
- Renal impairment, stomatitis
- Tumor lysis syndrome
37
Q
What are the black box warnings for the vincas?
A
- Extravasation
- IT admin -> fatal
- Neuropathic toxicity (stocking-glove)
38
Q
What are the black box warnings for Imatinib?
A
- Birth defects
- Bone marrow suppression
39
Q
What are the black box warnings for Dasatinib and Nilotinib?
A
- D: bone marrow suppression and fluid retention
- N: contraindicated in hypokalemia and hypomagnesemia; QT prolongation
40
Q
What are the black box warnings for Ibritumomab and Tositumomab?
A
- I: bone marrow suppression, exfoliate dermatitis, infusion rxn
- T: iodine hypersensitivity, thrombocytopenia, neutropenia
41
Q
What are the black box warnings for Rituximab?
A
- Exfoliate dermatitis
- Infusion reaction
- Progressive multifocal leukoencephalopathy
