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Flashcards in Drug Trx for Hematologic Malig Deck (68):
1

What governs the design of chemo regimens?

toxicity

2

What are the two components of combination chemo?

1. induction therapy (high dose, very toxic)
2. consolidation therapy (lower dose, less toxic; ensures eradication)

3

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

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

4

What is a neoadjuvant?

drug regiment administered before or during surgery/radiotherapy

5

What is an adjuvant?

drug regiment administered after surgery/radiotherapy

6

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

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)

7

What are the benefits of combo therapy?

More effective than single agent because:
1. increased maximum cell kill
2. heterogenous cell populations killed
3. less resistance to treatment

8

What is metronomic dosing?

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

9

What is the benefit of metronomic dosing?

may avoid the pro-proliferative aspect of drug response

10

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

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

11

What is hormesis?

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

12

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

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

13

How do Darwinian principles apply to cancer cells and drugs?

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

14

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

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

15

What is adaptive/evasive resistance?

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)

16

What is intrinsic non-responsiveness?

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

17

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

anti-angiogenic by:
1. inhibits endothelial cell proliferation/migration
2. decreases mobilization and viability of endothelial progenitor cells
3. increases Thrombospondin-1 expression

18

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

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

19

Common side effects of metronomic treatment:

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)

20

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

angiogenesis is important for their growth and development

21

What is the common AML drug-regimen?

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

22

How did Gemtuzomab [mylotarg] treat AML?

CD33 = almost exclusively on myeloid cells

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

23

What therapies are typically used post-remission in AML?

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)

24

What drives proliferation of acute promyelocytic leukemia?

PML/RARA fusion gene

25

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

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

Arsenic Trioxide: degrades PML-RAR-alpha fusion protein

26

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

T (but not "curative")

27

What drugs are used to treat childhood acute promyelocytic leukemia?

ATRA + anthracycline +/or cytarabine

28

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

ATRA + cytarabine + daunorubicin
or
idarubicin + ATRA

29

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

ATRA + 6-mercaptopurine + methotrexate

30

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

AV block, QT prolongation, electrolyte imbalance

*not seen with ATRA

31

What is differentiation syndrome?

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

32

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

Methotrexate + mercaptopurine

33

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

intrathecal and/or systemic methotrexate
(sometimes radiation also)

34

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

Prednisone + vincristine + anthracycline

35

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

Imatinib mesylate and/or combo chemo

36

Common toxicities associated with imatinib?

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

37

How does imatinib affect allogenic transplants?

no adverse effects

38

T/F: Imatinib can be given long term.

T: it has very mild toxicities

39

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

imatinib (>95% of patients are hematologically cured)

40

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

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

What is the major consideration related to chronic lymphocytic leukemia?

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

42

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

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

43

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

1. Fludarabine
2. rituximab and/or cyclophosphamine

(the most common combo is all three)

44

How does alemtuzumab treat chronic lymphocytic leukemia?

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

45

How does bendamustine treat chronic lymphocytic leukemia?

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

46

What drugs are used to treat hairy cell leukemia?

Cladribine
Interferon Alfa-2b [Intron A]
Pentostatin

47

What are the effects of purine analog drugs?

(such as Pentostatin, Cladribine)

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

48

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

1. Prolong all phases of cell cycle
2. Induce cellular differentiation (cells enter G0)

49

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

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

Which is more common: lymphoma or leukemia?

lymphoma

51

Where does lymphoma occur?

anywhere where lymphoid tissue is found

52

How is lymphoma classified?

histological appearance:
Hodgkin vs. non-Hodgkin

53

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

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

54

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

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

55

How is remission consolidated in Hodgkin lymphoma?

high-dose therapy and peripheral blood cell progenitor rescue

56

Treatment for low stage Non-Hodgkin Lymphoma:

6 months of pulsed chemotherapy, COMP
-cyclophosphamide
-vincristine,
-methotrexate
-prednisone

57

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

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

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

58

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

emergence of chemo-resistance

59

Delayed treatment effects associated with Non-Hodgkin Lymphoma:

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

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

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

61

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

radio-labeled anti-CD20 ab's that induce:
1. apoptosis
2. phagocytosis
3. radionuclide damage to target/adjacent cells

62

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

ONLY in lymphoid tissue

63

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

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

64

Why does Burkitt Lymphoma require intrathecal therapy?

the BBB protects tumor cells if administered non-thecally

65

What infection is closely associated with Burkitt Lymphoma?

EBV

66

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

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

67

What drugs are used to treat Burkitt Lymphoma?

Cycles of:
1. Cyclophosphamide + methotrexate
2. Vincristine + doxorubicin
3. Possibly cytarabine

68

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

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