3.24 SWEATMAN Drug Treatment of Hematologic Malignancies

Question 1

Classical Cancer drug administration

Answer 1

• High doses (very toxic; induction therapy)
• Lower doses (less toxic; consolidation therapy during remission)
• Maintenance; long term. lower dose therapy during remission

Question 2

General Rules for Combo Therapy

Answer 2

• Drugs must show activity against the tumor type
• No two drugs should have the same mechanism of action
• Drugs should have different patterns of dose-limiting toxicity

Question 3

Neo-Adjuvant

Adjuvent

Answer 3

Neo: before or during surgery/Radiotherapy
Adj: given after surgery/radiotherapy

Question 4

Metronomic Dosing

Answer 4

Daily administration of much lower doses

• Not all tumors/pts respond
• Hormesis: treatments designed to kill tumor cells or suppress their proliferation in pts may have the capacity to enhance tumor growths when the drug is present in certain concentrations
• May avoid pro-proliferative aspect of drug response
• Thought to avoid the very low drug levels from classic administration suspected to be pro-proliferative (think of anti-biotic levels not high enough and see resistance form, similar concept)

Question 5

Metronomic Dosing to avoid resistance

Answer 5

Gradually decreasing metronomic chemotherapy regimens aim to maintain the equilibrium b/t resitant and non-resistant tumor populations to reserve a certain level of tumor sensitivity leading to life long control rather than complete eradication.

Question 6

Ways to Stim Anti-Tumor Immune Response

Answer 6

-Metronomic chemo with some drugs, by decreasing # and activity of Treg and may promote (re)activation of an anticancer immune response with CTLs and NK cells
Ex Cyclophosphamide

Question 7

Problems with Metronomic Dosing

Answer 7

Nausea, vomitting, anemia, neutropenia, leucopenia and lymphopenia

• -overall well tolerated
• Risk in children
• -angiogenesis important for dev in children
• Secondary malignancies (all chemo agents)

Question 8

Leukemia

Answer 8

• Acute: short natural history
• Chronic: long natural history
• Myeloid or lymphoid origin
• AML/ALL(children) or CML./CLL (elderly)

Question 9

Acute Myeloid Leukemia

Answer 9

Treat with combo of:
DAUNORUBICIN (free rad, intercalate and topo II)
-Tox: BM suppression, CV, Hepatic disease, second malig, extravasational necrosis
Cytarabine, ARA-C (pyrimidine analog)
Tox: BM suppression
THIOGUANINE, 6-TG (purine analog)
-Tox: BM supp 
-Dont always use 6-TG

Question 10

Post-Remission Therapy

Answer 10

More dose-intensive cytarabine-based treatment

-BM allogenic rescue (transplant)

Question 11

Gemtuzomab (Mylotarg)

Answer 11

• mAb for CD33
• binds and is internalized, where it has its MOA
• Shows that mAbs can be used as carries and do not only have to work extracellularly

Question 12

Acute Promyelocytic Leukemia

Answer 12

-PML/RARA fusion drive proliferation
(Retonoic acid receptors alpha)
-All Trans Retinoic Acid (ATRA): leads to differentiation of APL cells and then post-maturation apoptosis
-Tox: Acute Promyelocytic leukemia differentiation syndrome, leukocytosis
-Usually use in combo with other drugs
–anthracycline +/-cytarbine
-Uses ATRA in combo for all stages in different doses

Question 13

Arsenic Trioxide

Answer 13

-Similar action to ATRA but more toxicity on CV system (black box)

Question 14

Acute Lymphoblastic Leukemia

Answer 14

• Imatinab does not have actions with acute phase, but does work in chronic phase
• usually use predisone (cortico) +vincristine +antracycline

Question 15

Imatinib

Answer 15

BCR-ABL tyrosine kinase inhibitor, ppl with 9:22 translocation (Philadelphia chromo)

• usually used with combo therapy
• regular CBC to monitor cytopenias

Question 16

Chronic Myeloid Leukemia

Answer 16

Imatinib is 1st line of treatment (very effective)

-Dasatinib and Nilotinib are second gen drugs that bind in the ATP pocket with diff orientation than imatinib

Question 17

Chronic Lymphocytic Leukemia

Answer 17

Bendamustine: antimetabolite and alkylating agent
-DNA cross linking and act of p53 pathway
-inhibits check points and forces cell to enter mitosis with damaged DNA leading to mitotic catastrophy
-Less susceptible to cross drug resistance
can also use Alemtuzumab (CD52) and Rituximab (CD20)

Question 18

Hairy Cell Leukemia

Answer 18

Use purine analogs: cladribine and Pentostatin

-Can also use IFN-alpha-2b

Question 19

IFN Antineoplastic Action

Answer 19

-Direct Antiproliferative effect on tumor cell
-prolong all phases of cell cycle and induce cellular differentiation
Induce host responses
-Activate Cytotoxic T cells and/or NK cells and other phagocytes

Question 20

Lymphomas

Answer 20

Hodgkin and non-Hodgkin Lymphomas

Question 21

Hodgkin Lymphomas

Answer 21

• Use a lot of combinations, all drug combos have drugs with different MOAs, leads to decreased cross reactivity and decreased general drug toxicity
• Common combos: contain anthracycline (doxorubicin), mitotic spindle inhibitor (vincristine) and alkylating agents (cyclo or bleomycin), a carbazine and sometime a corticosteroid

Question 22

Bleomycin (toxicity)

Answer 22

Idiosyncratic rxn to bleomycin (fever), pulmonary fibrosis

Question 23

Busulfan

Answer 23

BM suppression, secondary malignancies

Question 24

Carboplatin

Answer 24

anemia, infection

Question 25

Chlorambucil

Answer 25

BM suppression, secondary malignancy, pregnancy, infertility

Question 26

Cladribine

Answer 26

BM suppression neurotoxicity

Question 27

Ifosfamide

Answer 27

Coma, hemorrhagic cystitis

Question 28

Dacarbazine

Answer 28

BM suppression, hepatic disease, pregnancy, secondary malignancy

Question 29

Daunorubicin, Doxorubicin, and Idarubicin

Answer 29

BM suppression, heart disease, hepatic disease, secondary malignancy, extravasational necrosis

Question 30

Etoposide

Answer 30

Myelosuppression, bleeding, oppurtunistic Infection

Question 31

Teniposide

Answer 31

BM suppression

Question 32

Fludarabine

Answer 32

BM suprression, coma, seizures, dont give with pentostatin

Question 33

INF-alpha-2b

Answer 33

Contraindicated with autoimmune disease, cardiac disease, increased suicidal ideation, depression

Question 34

Mechlorethamine

Answer 34

BM suppression, extravasation, pregnancy

Question 35

Methotrexate

Answer 35

Ascites, diarrhea, exfoliative dermatitis, infection, lymphoma, pulmonary disease, pulmonary fibrosis, renal impairment, stomatitis, tumor lysis syndrome (TLS)

Question 36

Mitoxantrone

Answer 36

Extravasation, HR failure, intrahecal administration, neutropenia, secondary malignancy

Question 37

Pentostatin

Answer 37

Hepatic disease, pulmonary edema, renal failure, seizures, use with fludarabine

Question 38

Vinblastine, Vincristine

Answer 38

Extravasation, intrahecal administration-FATAL, neuropathic toxicity

Question 39

Alemtuzumab

Answer 39

BM suppression, infection, infusion rxn

Question 40

Gemtuzumab, Ozogamicin

Answer 40

BM suppression, hepatic and pulmonary disease, infusion rxn