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Drug Trx for Hematologic Malig Flashcards

1
Q

What governs the design of chemo regimens?

A

toxicity

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2
Q

What are the two components of combination chemo?

A
  1. induction therapy (high dose, very toxic)

2. consolidation therapy (lower dose, less toxic; ensures eradication)

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3
Q

What is the criteria for selection of combination of chemo drugs?

A
  1. MUST show activity against tumor type
  2. Drugs should have the same mechanism of action
  3. Drugs should have different patterns of dose-limiting toxicity
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4
Q

What is a neoadjuvant?

A

drug regiment administered before or during surgery/radiotherapy

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5
Q

What is an adjuvant?

A

drug regiment administered after surgery/radiotherapy

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6
Q

How does drug dosage relate to the stage of leukemia treatment?

A
  1. Induction: high dose combination chemo
  2. Consolidation: repetition of induction drugs (given when in remission)
  3. Maintenance: lower dose (long term while in remission)
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7
Q

What are the benefits of combo therapy?

A

More effective than single agent because:

  1. increased maximum cell kill
  2. heterogenous cell populations killed
  3. less resistance to treatment
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8
Q

What is metronomic dosing?

A

continuous, low-dose therapy designed to AVOID enhancing tumor growth (which alternative dosing regimens do)

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9
Q

What is the benefit of metronomic dosing?

A

may avoid the pro-proliferative aspect of drug response

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10
Q

T/F: Metronomic dosing is a better regimen because all tumor types are responsive.

A

F: neither all tumor types nor all patients respond; however it’s looking pretty good for a bunch of cancers

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11
Q

What is hormesis?

A

adaptive response of tumor cells to moderate amounts of intermittent stress (i.e. anti-tumor treatments)

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12
Q

What effects does metronomic chemo have on tumor cells and their microenvironment?

A
  1. inhibit tumor angiogenesis
  2. stimulate an anti-cancer immune response
  3. drug-driven dependency/deprivation effect
  4. collectively, induces tumor dormancy
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13
Q

How do Darwinian principles apply to cancer cells and drugs?

A

In the presence of chemo “drug pressure”, cells are selected on the basis of their survival/fitness (i.e. anti-apoptosis or drug resistance), and produces new phenotypes

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14
Q

What is the long term goal of metronomic treatment, in terms of drug pressure?

A
  1. maintain a certain degree of cancer sensitivity to treatment
  2. induce life-long control via clonal heterogeneity
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15
Q

What is adaptive/evasive resistance?

A

ability of a tumor to overcome a therapeutic blockade and continue to grow by inducing/accentuating mechanisms that:

  1. enable neovascularization despite drug (resistance)
  2. find another way to grow new vessels, such as recruit pro-angiogen cells from BM (indifference)
  3. invade a neighboring tissue (and use their vessels)
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16
Q

What is intrinsic non-responsiveness?

A

absence of ANY beneficial effect of an anti-angiogenic therapy (drug does not shrink tumor or improve quality of life)

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17
Q

What effect does metronomic treatment have on angiogenesis (non-cytotoxic concentration)?

A

anti-angiogenic by:

  1. inhibits endothelial cell proliferation/migration
  2. decreases mobilization and viability of endothelial progenitor cells
  3. increases Thrombospondin-1 expression
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18
Q

How does metronomic treatment effect the anti-cancer immune response (3)?

A
  1. decrease Treg cells
  2. promote dentritic cells to mature
  3. restore NK and cytotoxic T cells
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19
Q

Common side effects of metronomic treatment:

A
  1. nausea/vomiting
  2. anemia, neutropenia, leucopenia, lymphopenia
  3. some toxicity when combined with bevacizumab
  4. treatment-related secondary malignancies

(also mentions “unusual problems”, like subdural hematoma)

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20
Q

Why are there risks associated with giving metronomic treatment to young children?

A

angiogenesis is important for their growth and development

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21
Q

What is the common AML drug-regimen?

A
  1. cytarabine/ARA-C
  2. daunorubicin
  3. thioguanine/6-TG
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22
Q

How did Gemtuzomab [mylotarg] treat AML?

A

CD33 = almost exclusively on myeloid cells

drug was a CD33-antibody linked to calicheamicin, which enters cell to cleave dsDNA at specific sequences

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23
Q

What therapies are typically used post-remission in AML?

A
  1. short-term, dose-intensive cytarabine/ARA-C
  2. chemoradiation
  3. bone marrow rescue (used with either 1 or 2; may be from HLA-match or alogenic)
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24
Q

What drives proliferation of acute promyelocytic leukemia?

A

PML/RARA fusion gene

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25
Q

What drugs are used to treat acute promyelocytic leukemia? By what mechanism?

A

ATRA: overcomes repressive signaling (induces differentiation, then apoptosis once mature)

Arsenic Trioxide: degrades PML-RAR-alpha fusion protein

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26
Q

T/F: Most patients with APL achieve a complete remission with ATRA.

A

T (but not “curative”)

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27
Q

What drugs are used to treat childhood acute promyelocytic leukemia?

A

ATRA + anthracycline +/or cytarabine

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28
Q

What drugs are used for remission/consolidation therapy in acute promyelocytic leukemia?

A

ATRA + cytarabine + daunorubicin
or
idarubicin + ATRA

29
Q

What drugs are used for maintenance therapy in acute promyelocytic leukemia?

A

ATRA + 6-mercaptopurine + methotrexate

30
Q

What are the black box warnings for Arsenic Trioxide [Trisenox]?

A

AV block, QT prolongation, electrolyte imbalance

*not seen with ATRA

31
Q

What is differentiation syndrome?

A
  1. Fever
  2. dyspnea
  3. weight gain
  4. pulmonary infiltrates
  5. pleural or pericardial effusions
  6. leukocytosis
32
Q

What drugs are used in consolidation therapy for acute lymphoblastic leukemia?

A

Methotrexate + mercaptopurine

33
Q

What drugs are used in CNS prophylaxis therapy in acute lymphoblastic leukemia?

A

intrathecal and/or systemic methotrexate

sometimes radiation also

34
Q

What drugs are used in remission induction therapy in acute lymphoblastic leukemia?

A

Prednisone + vincristine + anthracycline

35
Q

What drugs are used in remission induction therapy in Ph1-positive acute lymphoblastic leukemia?

A

Imatinib mesylate and/or combo chemo

36
Q

Common toxicities associated with imatinib?

A
  1. nausea
  2. elevated liver enzymes
  3. leukopenia, thrombocytopenia, neutropenia, anemia, lymphopenia
    (run labs to check)
37
Q

How does imatinib affect allogenic transplants?

A

no adverse effects

38
Q

T/F: Imatinib can be given long term.

A

T: it has very mild toxicities

39
Q

What is the 1st line drug used to treat chronic myeloid leukemia?

A

imatinib (>95% of patients are hematologically cured)

40
Q

What resistance mechanism is associated with the 1st line drug for CML?
What are the alternative treatments?

A

ATP-binding site mutation (tyrosine kinase) prevents imatinib from bind to receptor

dasatinib and nilotinib bind the receptor in a slightly different orientation, so they affect imatinib-resistant cells

41
Q

What is the major consideration related to chronic lymphocytic leukemia?

A

to treat or not (30% patients never need it)

42
Q

What complications are associated with chronic lymphocytic leukemia, and how are they treated?

A
  1. opportunistic infections (prophylactic antibiotics)
  2. hemolytic anemia (EPO)
  3. Hyperuricemia (allopurinol)
43
Q

What are common drug combos used to treat chronic lymphocytic leukemia?

A
  1. Fludarabine
  2. rituximab and/or cyclophosphamine

(the most common combo is all three)

44
Q

How does alemtuzumab treat chronic lymphocytic leukemia?

A

binds to CD52 on lymphocyte, monocyte and dendritic cells–induces cytotoxicity

45
Q

How does bendamustine treat chronic lymphocytic leukemia?

A
  1. causes DNA cross-linking, which results in single/double stranded breaks
  2. cell enters mitosis with damage, which activates p53/apoptosis
46
Q

What drugs are used to treat hairy cell leukemia?

A

Cladribine
Interferon Alfa-2b [Intron A]
Pentostatin

47
Q

What are the effects of purine analog drugs?

A

(such as Pentostatin, Cladribine)

  1. long-lasting CD4 suppression
  2. increased risk of secondary malignancies
48
Q

What are the direct antiproliferative effects of interferon on tumor cells?

A
  1. Prolong all phases of cell cycle

2. Induce cellular differentiation (cells enter G0)

49
Q

What are ways in which interferon induces host responses to effect tumor cells?

A
  1. Activate CTL and/or NK cells
  2. Activate macrophages and monocytes (increases phagocytosis + cytotoxicity against tumor cells)
  3. Stimulate production of cytokines (IL-1β and
    IL-1 receptor antagonist), which may affect
    inflammatory response
50
Q

Which is more common: lymphoma or leukemia?

51
Q

Where does lymphoma occur?

A

anywhere where lymphoid tissue is found

52
Q

How is lymphoma classified?

A

histological appearance:

Hodgkin vs. non-Hodgkin

53
Q

What are the component drugs used in various combinations in Hodgkin lymphoma treatment?

A
  1. anthracyclin (doxorubicin)
  2. carbazine
  3. mitotic spindle inhibitor (vincristine)
  4. alkylating agent (bleomycin/cyclophos)
  5. corticosteroid (prednisone)
54
Q

T/F: Hodgkin lymphoma is treated with a drug “cocktail” and involved-field low-dose radiotherapy.

A

T

broadens the spectrum of potential toxicities and reduces severity of individual drug- or radiation-related toxicities

55
Q

How is remission consolidated in Hodgkin lymphoma?

A

high-dose therapy and peripheral blood cell progenitor rescue

56
Q

Treatment for low stage Non-Hodgkin Lymphoma:

A

6 months of pulsed chemotherapy, COMP

   - cyclophosphamide
    - vincristine, 
    - methotrexate 
    - prednisone
57
Q

Treatment for high stage Non-Hodgkin Lymphoma: (Why?)

A

Rituximab + standard doxorubicin, cyclophosphamide,
vincristine and prednisone (R-CHOP)

large B-cell and Burkitt lymphoma both express high levels of CD20

58
Q

Why are survival rates on 10-20% for recurrent non-Hodgkin?

A

emergence of chemo-resistance

59
Q

Delayed treatment effects associated with Non-Hodgkin Lymphoma:

A
  1. Sterility (pelvic irradiation or high dose cyclophosphamide)
  2. Secondary malignancies (lung, brain, kidney, bladder, skin)
  3. L ventricular dysfunction (doxorubicin)
  4. Myelodysplastic syndrome and acute myelogenous leukemia
60
Q

What are possible causes of myelodysplastic syndrome and acute myelogenous leukemia?

A
  1. myeloablative therapy with autologous BM or peripheral blood stem cell transplant
  2. alkylating agents (chemo)
61
Q

How do Tositumomab [Bexxar] and Ibritumomab [Zevalin] effect B cells?

A

radio-labeled anti-CD20 ab’s that induce:

  1. apoptosis
  2. phagocytosis
  3. radionuclide damage to target/adjacent cells
62
Q

In what tissue are anti-CD20 radio-labeled antibodies able to bind to CD20?

A

ONLY in lymphoid tissue

63
Q

What toxicities are associated with anti-CD20 radio-labeled antibodies?

A
  1. Hematologic
  2. N/V
  3. infections
  4. chills/fever
    * these are due to radiation
64
Q

Why does Burkitt Lymphoma require intrathecal therapy?

A

the BBB protects tumor cells if administered non-thecally

65
Q

What infection is closely associated with Burkitt Lymphoma?

66
Q

T/F: Even without treatment, Burkitt Lymphoma is generally non-fatal.

A

F: High proliferative–very quickly becomes fatal without treatment; which relieves symptoms and is potentially curative

67
Q

What drugs are used to treat Burkitt Lymphoma?

A

Cycles of:

  1. Cyclophosphamide + methotrexate
  2. Vincristine + doxorubicin
  3. Possibly cytarabine
68
Q

T/F: Chemo in pregnant women leads to fetal abnormalities.

A

F:

  • -according to the study in the ppt, no association with CV, CNS, auditory, or growth defects
  • -prematurity appeared to have the strongest effect on impaired cognitive development

Heme (38 decks)

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