Treatment of Leukemia and Lymphoma Flashcards
1
Q
- covalently bind/modify biological molecules
- DNA is key target
- must be reactive - inherent, or generated by metabolism
- CCNS, but replicating cells are more sensitive
A
alkylating agents
2
Q
- bone marrow, GI tract, spermatogenesis (rapidly growing cells)
- decreased leukocytes and platelets - dose limiting toxic effect
- max suppression 10 days to 4 weeks after therapy
- recovery 3-6 weeks after drug
- monitor patient tolerance - CBC, hematocrit
A
adverse effects of alkylating agents
3
Q
secondary malignancy risk in what class of drugs?
A
alkylating agents
4
Q
- nitrogen mustard, first alkylating agent
- vesicant, caustic to skin/mucus membranes
- IV only, often in arterial supply to tumor
- half life several minutes, rapidly reacts
- adverse: n/v, delayed - decreased blood counts
- primary use for Hodgkin’s lymphoma, part of MOPP
A
mechlorethamine
5
Q
- oral or IV; alkylating agent
- nitrogen mustard pro drug, activated by host metabolism in liver
- widely used, leukemias and lymphomas
- adverse: bone marrow depression, alopecia, sterile hemorrhagic cystitis
A
cyclophosphamide
6
Q
- analog of cyclophosphamide
- IV only
- Hodgkin’s and non-Hodgkins lymphomas; high dose for bone marrow or stem cell rescue; component of ICE
- severe bone marrow depression, peripheral neuropathies, CNS effects maybe due to chloroacetaldehyde
A
ifosfamide
7
Q
- phenylalanine nitrogen mustard
- highly reactive, chemical half life 50 minutes
- IV, renal excretion
- myelosuppression
- Multiple myeloma, myeloablative therapy
A
melphalan
8
Q
- nitrogen mustard, oral, 1X daily dosing
- plasma life 1.5 hours
- CLL, rarely used
A
chlorambucil
9
Q
- alkylsulfonate
- oral administration, IV for high dose
- used to be key drug for CML before imatinib
- profound myelosuppression, high dose –> pulmonary fibrosis, hepatic veno occlusive disease
A
busulfan
10
Q
- nitrogen mustard, IV, plasma half life 30 min
- alkylates DNA, inhibits mitotic checkpoints
- partial cross resistance with other alkylating agents
- CLL, indolent B cell non Hodgkin’s lymphoma
- n/v/myelosuppression/mucositis
A
bendamustine
11
Q
- alkylating agent, IV, activated by host
- n/v/dose limiting myelosuppression
- Hodgkin’s, multiple myeloma
A
dacarbazine
12
Q
- oral
- inhibits DNA/RNA/protein synthesis, causes strand breaks
- high potential for secondary malignancy than with other alkylating agents
- Hodgkin, non-Hodgkin
A
procarbazine
13
Q
- analog of a normal component of the target cells
- enters normal metabolic path, then blocks path
- folate, purine, pyrimidine analogs
A
antimetabolites
14
Q
- DHFR substrate and inhibitor
- tumor cells more sensitive than normal cells, greater accumulation in tumor cells
- blocks production of bases for DNA synthesis
- IV/oral/intrathecal, urine excretion
- high dose, then rescue dose with folinic acid (citrovorin, leucovorin)
- hepatotoxicity, resistance due to altered DHFR or amplified
A
methotrexate
15
Q
- purine analog, oral, well tolerated
- blocks DNA and RNA synthesis (inhibits AMP/GMP; enters RNA)
- resistance due to decrease in hprt activity or increase in alk phosphatase
A
6-mercaptopurine, 6-thioguanine
16
Q
- purine analog, oral or IV as monophosphate
- dephosphorylated in plasma and absorbed by cells
- di: inhibits ribonucleotide reductase; tri: inhibits DNA pol and ligase
- effective mono or combination therapy for CLL
- myelosuppression, n/v
A
fludarabine
17
Q
- purine analog, IV, activated by deoxycytidine kinase
- strand breaks, inhibits ribonucleotide reductase
- hairy cell leukemia, CLL, low grade lymphoma
- resistance, bone marrow suppression
A
cladribine (2-chlorodeoxyadenosine)
18
Q
- pyrimidine analog, IV or intrathecal
- activated by deoxycytidine kinase (polymorphic)
- tri incorporated into DNA, inhibits elongation and repair
- AML, ALL
- more toxic than purines, myelosuppression, GI, stomatitis
A
cytarabine
19
Q
- most produced by microbes
- interact with DNA/RNA, don’t alkylate, block access or function
- all given IV
- unique toxicities
A
antitumor antibiotics
20
Q
- intercalate into DNA, block topoisomerase II, inhibit RNA and DNA synthesis, strand breaks
- generate free radicals, IV, metabolized in liver
- alopecia, cardiotoxicity (function of cumulative), arrhythmias/CHF/cardiomyopathy, free radical mechanism
A
anthracyclines: doxorubicin, daunorubicin, idarubicin
21
Q
least cardiotoxic anthracycline?
A
idarubicin
22
Q
free radical mechanism in anthracyclines reduced by administering?
A
dexrazoxane
23
Q
- mix of glycopeptides
- binds DNA, generates free radicals, causes strand breaks, active in G2 (CCS)
- hypersensitivity, cutaneous reactions
- pulmonary toxicity, fibrosis
A
bleomycin
24
Q
- isolated from periwinkle, inhibits/reverse tubulin polymerization, disrupts mitotic spindles
- causes metaphase arrest
- IV admin, biliary excretion
A
Vina: microtubule poisons
25
- vinca alkaloid
| - n/v, alopecia, bone marrow depression
vinBlastine
26
- vinca alkaloid
- less toxic to bone marrow, no nausea and vomiting
- peripheral neuropathy
vincristine
27
- topoisomerase II inhibitor, double strand breaks, DNA degradation (CCS)
- arrest cells in S-G2 stage
- oral and IV
- n/v/alopecia/bone marrow suppression
etoposide (VP-16)
28
- catalyzes breakdown of asparagine in blood
- inhibits growth of ALL cells, which lack asparagine synthetase
- allergic responses, enhance coagulation
asparaginase
29
- monoclonal antibody, blocks CD20 B cell antigen
- IV, half life 22 days
- used for B cell lymphomas, CLL and non-Hodgkin's
- allergic rxns, hypogammaglobulinemia, autoimmune disorders
rituximab
30
- adrenocorticosteroids, suppress proliferation of immune cells
- oral, for leukemias and lymphomas
- fluid retention, immunosuppression, diabetes
dexamethosone, prednisone
31
- inhibits Bcr-Abl and c-KIT tyrosine kinases
- blocks growth factor signaling in CML
- used in any malignancy with Philadelphia chromosome
- myelosuppressive, edema and fluid retention, hepatotoxicity
Imatinib (Gleevec)
32
- newer broad spectrum TK inhibitors, use in resistance to imatinib
- continue until tumor gains resistance, patient dies, or patient discontinues drug
dasatinib, nilotinib
33
- inhibits Bruton's tyrosine kianse, essential for B cell receptor signaling
- oral, metabolized by CYP3A4, metabolite 15X more potent as BTK inhibitor
- mantle cell lymphoma, refractory CLL (17p deletion)
- GI, thrombocytopenia, neutropenia, infections, fatigue
ibrutinib
34
- oral PI3K inhibitor
- metabolized by aldehyde oxidase and CYP3A4, strong CYP3A4 inhibitor
- relapsed CLL and SLL, relapsed follicular B cell non Hodgkins
- hepatotoxicity, diarrhea/colitis, pneumonitis, intestinal perforation
idelalisib
35
- inhibits 26S proteasome, disrupts multiple signaling cascades, leads to apoptosis
- IV, plasma half life 5.5 hours, half life of inhibition 24 hours
- MM, mantle cell lymphoma
- thrombocytopenia, fatigue, peripheral neuropathy
- hypotension upon infusion
bortezimib
36
- induces terminal differentiation, treats APL
- binds RAR-alpha receptor, promotes differentiation
- degradation of PML-RAR alpha fusion protein
- resistance through enhanced clearance or loss of expression of fusion gene
all trans retinoic acid
37
- inhibits thioredoxin reductase, enhancing oxidative stress
- modification and degradation of APL fusion protein
- cytotoxic, promotes differentiation
arsenic trioxide
38
- thalidomide derivative
- CLL, multiple myeloma
- lacks teratogenic, sedative effects of thalidomide
- inhibits effects of rituximab
lenalidomide
39
Induction: vincristine and prednisone, add an anthracycline, asparaginase for pediatrics, if Philadelphia (+) add dasatinib, if CD20 (+) add rituximab, intrathecal methotrexate and cytarabine
-maintenance 2-3 years: daily 6-mercaptopurine, weekly methotrexate, monthly vincristine and prednisone, imatinib or dasatinib (Ph+)
treatment of Acute Lymphocytic Leukemia (ALL)
