3.28.14* Drug Treatment of Hematologic Malignancies Flashcards
Prestudy* Lecture Notes* In class PPT*
Difference between therapy for solid tumors and hematologic malignancies.
solid tumor treatments have dose-limiting toxicity as myelosuppression. For leukemias, lymphomas and multiple myelomas, the treatment is myelosupression, thus patients are severely immunocompromised and at increased risk of opportunistic infections.
stages of chemo treatment
induction
consolidation
maintenance
ALL (acute lymphoblastic leukemia) is seen mainly in
kids
CLL (chronic lymphocytic leukemia) is seen mainly in
old
Drugs for AML
cytarabine (ara-c)
daunorubicin
thioguanine
Post-remission: cytarabine
cytarabine (ara-c)
AML
pyrimidine analog
daunorubicin
AML
free radical generator, intercalator and topo II inhibitor
thioguanine
AML
purine analog
Acute Promyelocytic Leukemia (acute PML) treatment
(acute PML is caused by constituitively active PML/RARalpha fusion gene)
b. intial treatment all-trans-retinoic acid (ATRA) combined with daunorubicin or idarubicin plus cytarabine
b. alternatively arsenic trioxide is used in patient who cannot tolerate anthracycline
ATRA (retinoid drug,Tretinoin ) MOA in acute PML
disrupts fusion of genes and restores differentiation process.
fusion gene that causes acute promyelocytic leukemia?
PML/RARalpha: results in dedifferentiated proliferaton of promyelocytes
retinoic acid syndrome
fever, dyspnea, weight gain, pulmonary infiltrates, pleural or pericardial effusions
Arsenic trioxide MOA
(to treat acute PML)
also degrates PML-RAR-alpha fusion protein
adverse effect of artsenic trioxide in the treatment of acute PML
Cardiovascular
AB block, QT prologation, electrolyte imbalance (all these are not seen in ATRA
Drugs approved to treat Acute Lymphocytic Leukemia
Imatinib (TKI for BCR-Abl) Pegasparagase Prednisone Vincristine Daunorubicin/Doxorubicin MTX radiation
Most common treatment for ALL
induction: imatinib and combination chemotherapy
consolidation: MTX + Mercaptopurine (two different antimetabolites)
Pegasparagase MOA
a. degrades asparagine and thus blocks protein synthesis. Pegylated.
b. resistance can be due to upregulatin of asparagine synthetase
What is the significance of pegylation?
extends the duration of a drug
What are the adverse effects of pegasparagase?
pancreatitis (necrotic/inflammatory)
immune suppression hyperglycemia (due to no insulin)
clotting abnormalities
hypoalbumineumi
Drugs approved for chronic myeloid leukemia
imatinib
dasatinib/nilotinib (second gen, good for alterations in ATP binding site)
(older: cytarabine + interferon)
MOA of imatinib
TKI that binds to ATP binding site of BCR-ABL fusion gene
what is the only curative treatment for CML >10 years?
allogenic bone marrow or stem cell transplant
Drugs approved for CLL (chronic lymphocytic leukemia)
a. Flydarabine (antimetabolite) + Cyclophosphamide (alkylating) b. Fludarabine + Rituximab c. All three d. Bendamustine (antimetabolite and alkylating agent)
CLL treatment complications
a. oppurtunistic infection
b. AHA and/or thrombocytopenia
c. Hyperuricemia by tumor lysis syndrome (need prophylaxis with allopurinol)
Drugs for Hairy Cell Leukemia
Cladribine/Pentostatin (purine analogs)
Interferon
interferon
direct tumor effect
a. prolongs all phases of cell cycle
b. induce cellular differentiation
induce host responses
a. activates NK, CD8 and macrophages
upregulates antigen presentation to T cells (tumor antigens)
b. keeps cells from being infected by virus
Hodgkin lymphoma chemotherapy
most include: Anthracyclin (doxorubacin) Bleomycin (or cyclophasphamide; alkylating) Vincristine (mitotic spindle inhibitor) Dacarbazine
Regimen is administered in cycles to prevent extremely low blood cell counts. Very good prognosis.
Acute side effects- hair loss, nausea/vomiting/diarrhea/malabsorption, ulceration, increased susceptibility to infections.
Long term side effects- secondary malignancy
Treatment for NHL
high stage: ritixumab and CHOP
what are the two radiolabeled CD20 mABs
Tostiumomab
Ibritumomab
Burkitt Lymphoma
often EBV-associated
very aggressive
Cyclical drug cycle
Drugs for Burkitt lymphoma
cyclophosphamide + MTX
vincristine + doxorubicin
Antracyclines (doxorubucin, daunorubicin) have culmulative toxicity?
cardiopathic; Can cause cardiomyopathy and lead them to die of heart . Interaction with drugs and iron causing free radical damage. Chelating agents may help reduce cardiotoxicity.
Chemotherapy consisted of 8 alternating courses every 21 days or earlier, but at least 14 days apart. What kind of approach is this?
hyperfractionated (to keep the doses low)
- good for toxicity
- good for resistance
- good for fast growing
