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
What is the standard tx for Burkitt lymphoma?
- 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
What about pregnancy?
- _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
What are the black box warnings for Pegaspargase?
- _Hypersensitivity_ to product of Erwinia
- _Bleeding_ (decreased fibrinogen, protein C/S activity, and AT)
- _Glucose intolerance_
28
What are the black box warnings for corticosteroids?
- Increased appetite and weight gain, water retention
- Increased risk of infection
- Fluctuation of blood sugar levels
- Changes in mood and behavior, difficulty sleeping
29
What are the black box warnings for Bleomycin?
- Idiosyncratic rxn to Bleomycin: fever
- Pulmonary fibrosis
30
What are the black box warnings for platinum drugs?
- Platinum hypersenstivity
- Bone marrow suppression
- Anemia, infection
- Kidney
31
What are the black box warnings for the anthracyclines?
- Bone marrow suppression
- Heart disease, hepatic disease
- Secondary malignancies
- Extravasational necrosis
32
What are the black box warnings for cytarabine?
- Bone marrow suppression
- Opportunistic infection
33
What are the black box warnings for dacarbazine?
- Bone marrow suppression
- Hepatic disease
- Pregnancy
- Secondary malignancy
34
What are the black box warnings for Fludarabine?
- Bone marrow suppression
- Coma, seizures
- Don't give with Pentostatin
35
What are the black box warnings for interferon alpha-2b?
- Contraindicated with autoimmune disease, cardiac disease
- increased suicidal idiation, depression
36
What are the black box warnings for Methotrexate?
- Ascites, diarrhea, exfoliative dermatitis
- Infection, lymphoma
- Pulmonary disease, pulmonary fibrosis
- Renal impairment, stomatitis
- Tumor lysis syndrome
37
What are the black box warnings for the vincas?
- Extravasation
- IT admin -\> fatal
- Neuropathic toxicity (stocking-glove)
38
What are the black box warnings for Imatinib?
- Birth defects
- Bone marrow suppression
39
What are the black box warnings for Dasatinib and Nilotinib?
- **D**: bone marrow suppression and fluid retention
- **N**: contraindicated in hypokalemia and hypomagnesemia; QT prolongation
40
What are the black box warnings for Ibritumomab and Tositumomab?
- **I**: bone marrow suppression, exfoliate dermatitis, infusion rxn
- **T**: iodine hypersensitivity, thrombocytopenia, neutropenia
41
What are the black box warnings for Rituximab?
- Exfoliate dermatitis
- Infusion reaction
- Progressive multifocal leukoencephalopathy
