Flashcards in Drug Trx for Hematologic Malig Deck (68):
What governs the design of chemo regimens?
What are the two components of combination chemo?
1. induction therapy (high dose, very toxic)
2. consolidation therapy (lower dose, less toxic; ensures eradication)
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
What is a neoadjuvant?
drug regiment administered before or during surgery/radiotherapy
What is an adjuvant?
drug regiment administered after surgery/radiotherapy
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)
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
What is metronomic dosing?
continuous, low-dose therapy designed to AVOID enhancing tumor growth (which alternative dosing regimens do)
What is the benefit of metronomic dosing?
may avoid the pro-proliferative aspect of drug response
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
What is hormesis?
adaptive response of tumor cells to moderate amounts of intermittent stress (i.e. anti-tumor treatments)
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
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
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
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)
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)
What effect does metronomic treatment have on angiogenesis (non-cytotoxic concentration)?
1. inhibits endothelial cell proliferation/migration
2. decreases mobilization and viability of endothelial progenitor cells
3. increases Thrombospondin-1 expression
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
Common side effects of metronomic treatment:
2. anemia, neutropenia, leucopenia, lymphopenia
3. some toxicity when combined with bevacizumab
4. treatment-related secondary malignancies
(also mentions "unusual problems", like subdural hematoma)
Why are there risks associated with giving metronomic treatment to young children?
angiogenesis is important for their growth and development
What is the common AML drug-regimen?
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
What therapies are typically used post-remission in AML?
1. short-term, dose-intensive cytarabine/ARA-C
3. bone marrow rescue (used with either 1 or 2; may be from HLA-match or alogenic)
What drives proliferation of acute promyelocytic leukemia?
PML/RARA fusion gene
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
T/F: Most patients with APL achieve a complete remission with ATRA.
T (but not "curative")
What drugs are used to treat childhood acute promyelocytic leukemia?
ATRA + anthracycline +/or cytarabine
What drugs are used for remission/consolidation therapy in acute promyelocytic leukemia?
ATRA + cytarabine + daunorubicin
idarubicin + ATRA
What drugs are used for maintenance therapy in acute promyelocytic leukemia?
ATRA + 6-mercaptopurine + methotrexate
What are the black box warnings for Arsenic Trioxide [Trisenox]?
AV block, QT prolongation, electrolyte imbalance
*not seen with ATRA
What is differentiation syndrome?
3. weight gain
4. pulmonary infiltrates
5. pleural or pericardial effusions
What drugs are used in consolidation therapy for acute lymphoblastic leukemia?
Methotrexate + mercaptopurine
What drugs are used in CNS prophylaxis therapy in acute lymphoblastic leukemia?
intrathecal and/or systemic methotrexate
(sometimes radiation also)
What drugs are used in remission induction therapy in acute lymphoblastic leukemia?
Prednisone + vincristine + anthracycline
What drugs are used in remission induction therapy in Ph1-positive acute lymphoblastic leukemia?
Imatinib mesylate and/or combo chemo
Common toxicities associated with imatinib?
2. elevated liver enzymes
3. leukopenia, thrombocytopenia, neutropenia, anemia, lymphopenia
(run labs to check)
How does imatinib affect allogenic transplants?
no adverse effects
T/F: Imatinib can be given long term.
T: it has very mild toxicities
What is the 1st line drug used to treat chronic myeloid leukemia?
imatinib (>95% of patients are hematologically cured)
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
What is the major consideration related to chronic lymphocytic leukemia?
to treat or not (30% patients never need it)
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)
What are common drug combos used to treat chronic lymphocytic leukemia?
2. rituximab and/or cyclophosphamine
(the most common combo is all three)
How does alemtuzumab treat chronic lymphocytic leukemia?
binds to CD52 on lymphocyte, monocyte and dendritic cells--induces cytotoxicity
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
What drugs are used to treat hairy cell leukemia?
Interferon Alfa-2b [Intron A]
What are the effects of purine analog drugs?
(such as Pentostatin, Cladribine)
1. long-lasting CD4 suppression
2. increased risk of secondary malignancies
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)
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
Which is more common: lymphoma or leukemia?
Where does lymphoma occur?
anywhere where lymphoid tissue is found
How is lymphoma classified?
Hodgkin vs. non-Hodgkin
What are the component drugs used in various combinations in Hodgkin lymphoma treatment?
1. anthracyclin (doxorubicin)
3. mitotic spindle inhibitor (vincristine)
4. alkylating agent (bleomycin/cyclophos)
5. corticosteroid (prednisone)
T/F: Hodgkin lymphoma is treated with a drug "cocktail" and involved-field low-dose radiotherapy.
broadens the spectrum of potential toxicities and reduces severity of individual drug- or radiation-related toxicities
How is remission consolidated in Hodgkin lymphoma?
high-dose therapy and peripheral blood cell progenitor rescue
Treatment for low stage Non-Hodgkin Lymphoma:
6 months of pulsed chemotherapy, COMP
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
Why are survival rates on 10-20% for recurrent non-Hodgkin?
emergence of chemo-resistance
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
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)
How do Tositumomab [Bexxar] and Ibritumomab [Zevalin] effect B cells?
radio-labeled anti-CD20 ab's that induce:
3. radionuclide damage to target/adjacent cells
In what tissue are anti-CD20 radio-labeled antibodies able to bind to CD20?
ONLY in lymphoid tissue
What toxicities are associated with anti-CD20 radio-labeled antibodies?
*these are due to radiation
Why does Burkitt Lymphoma require intrathecal therapy?
the BBB protects tumor cells if administered non-thecally
What infection is closely associated with Burkitt Lymphoma?
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
What drugs are used to treat Burkitt Lymphoma?
1. Cyclophosphamide + methotrexate
2. Vincristine + doxorubicin
3. Possibly cytarabine