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
