28 Pharmacology and Toxicity of Antineoplastic Drugs Flashcards
For bilirubin >1.5 mg/dL reduce initial dose by
50%
For bilirubin >3.0 mg/dL reduce initial dose by
75%
TRUE OR FALSE
Individual agents in a combination should have different mechanisms of action and should have nonoverlapping and should not have overlapping mechanisms of resistance.
TRUE
Individual agents in a combination should have different mechanisms of action and should have nonoverlapping and should not have overlapping mechanisms of resistance.
While most chemotherapy agents have toxicity for marrow and epithelium, certain drugs, such as____________ are particularly valuable because their toxicities do not overlap with cytotoxics, which allows them to be used in combination at full doses.
Bleomycin, prednisone, and antibodies
____________ and __________ are potent radiosensitizers and are often used with radiation therapy to improve local tumor control of the head and neck and gastrointestinal cancers.
5-fluorouracil and cisplatin
The toxicity of radiation therapy to normal tissues such as skin, lung, heart, and brain is markedly enhanced by concurrent administration of _____________________
Anthracyclines, bleomycin, or gemcitabine
Antimetabolites are analogues of normal metabolites kill cells most effectively during the DNA _____________________.
Synthetic phase (S-phase) of the cell cycle
For these agents, a prolonged period of tumor exposure to drug is essential so as to maximize the number of cells exposed during the vulnerable period of the cell cycle.
_______________________ do not require cells to be exposed during a specific phase of the cell cycle, although like the antimetabolites, these drugs are generally more effective against actively proliferating cells as compared to resting cells.
Topoisomerase inhibitors and alkylating agents
_________________ and ____________, are equally toxic to dividing and nondividing cells, and at the same time, deplete marrow stem cells.
Nitrosoureas and busulfan
TRUE OR FALSE
In general, the toxicity of alkylating agents is determined by the total dose of drug, whereas the toxicity of the cell-cycle-specific drugs (such as MTX and cytarabine) depends upon both drug concentration and duration of exposure.
TRUE
In general, the toxicity of alkylating agents is determined by the total dose of drug, whereas the toxicity of the cell-cycle-specific drugs (such as MTX and cytarabine) depends upon both drug concentration and duration of exposure.
For taxanes, which block mitosis, myelosuppression correlates best with the duration of exposure above a threshold plasma concentration, which is approximately _________nM for paclitaxel and_______ nM for docetaxel.
50–100 nM : Paclitaxel
200 nM: Docetaxel
Cells are thus most vulnerable during periods of active DNA synthesis __________, and least affected during quiescent (_______) stages of their life cycle.
S-phase
G0
Enters cells by active uptake process mediated by the reduced folate transporter and is actively effluxed from cells by the MRP class of exporters.
MTX
TRUE OR FALSE
MTX is well absorbed orally at low doses (5–10 mg/m2), but at doses above 30 mg/m2 absorption is variable, requiring the MTX to be orally administered.
FALSE
MTX is well absorbed orally at low doses (5–10 mg/m2), but at doses above 30 mg/m2 absorption is variable, requiring the MTX to be parenterally administered.
MTX is primarily cleared by excretion of unchanged drug through the _______________.
kidney
Patients receiving HD-MTX can be rescued from drug toxicity by administering small doses of ________________, which replenishes the intracellular pool of reduced folates in a competitive manner with MTX.
N-10-formyltetrahydrofolate (leucovorin)
Dose of leucovorin
10–25 mg/m2 at 6-hour intervals, starting 6–24 hours after the infusion of MTX
Leucovorin continues until plasma levels of MTX fall below ______ μM.
1 μM
The primary cause of decreased drug clearance and overwhelming toxicity during HD-MTX treatment.
Drug-induced renal dysfunction
Serious toxicity from MTX can be prevented by vigorous pretreatment hydration of _______L/24 h during drug infusion and by raising the urine pH higher than _______ with intravenous sodium bicarbonate prior to and during therapy.
2.5 L/24 h
higher than 7
A commercially available bacterial enzyme that instantly degrades extracellular antifolates and prevents further toxicity
Glucarpidase
The dose-limiting toxicities of MTX are
Myelosuppression and gastrointestinal toxicity
Most common hematologic side effect
Leukopenia
An early indication of MTX toxicity to the gastrointestinal tract is
Oral mucositis
More severe toxicity may be manifested as diarrhea and gastrointestinal bleeding.
_________ an inhibitor of protein synthesis, blocks cells from entering DNA synthesis and antagonizes the effects of MTX, when used before the antifolate.
L-Asparaginase
- MTX and 6-mercaptopurine (6-MP) are synergistic in their inhibition of purine biosynthesis.
- Nonsteroidal antiinflammatory drugs, which diminish renal blood flow, may reduce MTX clearance, as may proton pump inhibitors, which block the OAT3 MTX transporter in renal tubules
An antimetabolite analogue of 2′-deoxycytidine
An inhibitor of DNA polymerase and is also incorporated into DNA, where it terminates strand elongation.
Mainstay in the induction of remission in patients with AM
CYTARABINE (CYTOSINE ARABINOSIDE, ARABINOSYL CYTOSINE, ARA-C)
Cytratbine is **not orally bioavailable **because of its degradation by ___________________ , which is present in the gastrointestinal epithelium and liver.
Cytidine deaminase
Ara-C confers particular benefit in patients with the ff cytogenetic abnormalities :
- AML: (t[8:21], inv[16], t[9:16], and del[16]) related to the core binding factor that regulates hematopoiesis
- AML: K-RAS mutations
- ALL: mixed lineage leukemia (MLL) gene translocations
TRUE OR FALSE
Single-bolus injections and short infusions (30–60 minutes) at doses as high as 5 g/m2 produce little myelotoxicity because of the drug’s rapid clearance, whereas continuous intravenous infusion of only 1 g/m2 over 48 hours produces severe marrow toxicity.
TRUE
Single-bolus injections and short infusions (30–60 minutes) at doses as high as 5 g/m2 produce little myelotoxicity because of the drug’s rapid clearance, whereas continuous intravenous infusion of only 1 g/m2 over 48 hours produces severe marrow toxicity.
Doseof cytrabine routinely used for consolidation therapy of AML
High-dose ara-C (3 g/m2 q12h for 3 days on days 1, 3, and 5)
Lower doses of 1 g/m2 or less should be used in patients older than 60 years to avoid CNS toxicity
Dose of Ara-C used intrathecally to treat meningeal leukemia.
50–70 mg
Ara-C (50 mg given every 2 weeks) has been impregnated into a gel matrix, in a formulation called DepoCyt, for sustained release into the CSF, thus avoiding the need for repeated spinal taps.
Form of Ara-C that provides a slow release form of drug and has been approved for AML therapy of elderly and high-risk patients.
Liposomal preparation containing a 5:1 ratio of ara-C to daunorubicin
(CPX-351)
The dose-limiting toxicity for conventional dosing regimens of intravenous ara-C
Myelosuppression
The nadir of the white count and platelet count occurs at about days _________ after the last dose of drug.
Days 7 to 10
A 2′-2′-difluoro analogue of 2′-deoxycytidine, has significant activity against Hodgkin lymphoma
It competes with deoxycytidine triphosphate (dCTP) for incorporation into the elongating DNA strand
It inhibits ribonucleotide reductase, the rate-limiting enzyme that converts ribonucleotides into deoxyribonucleotides
GEMCITABINE
Drug that upon incorporation into DNA, covalently inactivates DNA methyltransferase
AZACITIDINE AND DECITABINE
Block the de novo synthesis of purines
6-MP and thioguanine (6-TG)
TRUE OR FALSE
MTX and 6-MP are highly synergistic, possibly because MTX blocks the de novo synthesis of purines and enhances the activation of 6-MP from purine salvage pathways.
TRUE
MTX and 6-MP are highly synergistic, possibly because MTX blocks the de novo synthesis of purines and enhances the activation of 6-MP from purine salvage pathways.
6-MP blocks warfarin anticoagulation in some patients, leading to a requirement for higher doses of warfarin in patients receiving chronic 6-MP therapy for immunosuppression.
Dose of both 6-TG and 6-MP
Given orally at doses of 50–100 mg/m2 per day
Oral absorption of 6-MP is erratic, as only 16% to 50% of an oral dose is systemically available.
Drug that inhibits the metabolic inactivation of 6-MP, but not of 6-TG
Allopurinol
Therefore, it is recommended that dosages of orally administered 6-MP be reduced by 75% in patients receiving allopurinol.
Both 6-TG and 6-MP are myelotoxic, producing nadirs of white blood cells and platelets at ________ days after treatment.
7–10 days
TRUE OR FALSE
Patients may experience mild but rapidly reversible hepatotoxicity after treatment with either compound.
TRUE
Patients may experience mild but rapidly reversible hepatotoxicity after treatment with either compound.
TPMT (thiopurine- S-methyltransferase), which inactivates 6-thiopurines, is found in polymorphic forms that fail to metabolize the analogues.
An an inhibitor of DNA synthesis and ribonucleotide reductase
Has outstanding activity in chronic lymphocytic leukemia (CLL)
Strongly immunosuppressive, like the other purine analogues, and is frequently used for this purpose in low-intensity allogeneic marrow transplantation, and for preparation for chimeric antigen-receptor T-cell (CAR-T) therapy
FLUDARABINE PHOSPHATE
Fludarabine
Intravenous dose:
Oral dose:
Intravenous dose: 25 mg/m2 daily for 5 days
Oral dose: 40 mg/m2 daily for 5 days
Drug that was originally identified as an adenosine deaminase (ADA) inhibitor
Has potent activity in hairy cell leukemia
CLADRIBINE (2-CHLORODEOXYADENOSINE, 2-CDA)
Dose of Cladribine
IV:
SQ:
IV: 0.1 mg/kg per day for 7 days
SQ: 3.4 mg/m2 per day × 7 days, or by 2-hour intravenous infusion of 0.12 mg/kg daily for 5 days
A guanine nucleoside analogue that has useful activity as a secondary agent for T-cell lymphoblastic lymphoma and acute T-cell leukemias.
NELARABINE (6-METHOXY-ARABINOSYLGUANINE)
A ribonucleotide reductase inhibitor that quenches the free radical action of RNR by chelating iron, an essential cofactor in the reduction of the ribose to a deoxyribose
Hydroxyurea (HU)
Uses of HU:
- Polycythemia vera (PV)
- Essential thrombocythemia (ET)
- Lowering the myeloblast count in patients presenting with AML or blastic crisis of CML
- Preventing painful crisis and reducing hospitalization in patients with sickle cell disease
- Thalassemia patients with hemoglobin (Hb) C/SS
- Its antisickling activity results from induction of HbF through its activation of a specific promoter for the γ-globin gene.
- It may also prevent occlusion of small vessels in sickle cell patients through its generation of nitric oxide, a vasodilator, and through decreased expression of adhesion molecules such as L-selectin, on neutrophils
The major toxicities of HU
Leukopenia and thrombocytopenia
The leukocyte nadir occurs 3–5 days after a single dose of drug, and the leukocyte count recovers rapidly.
Mitotic inhibitors that derived from extracts of the vinca rosea or periwinkle plant
Bind to tubulin, a structural protein found in the cytoplasm of cells, and interrupt the formation of tubulin polymers (microtubules), the spindle along which the chromosomes migrate during mitosis
Vinblastine
Vincristine
Vinblastine: testicular cancer and Hodgkin lymphomas
Vincristine:non- Hodgkin lymphomas and ALL and in pediatric sarcomas
The average single dose of:
Vinblastine
Vincristine
Vinblastine: 8 to 9 mg/m2
Vincristine: 1.4 mg/m2
Sequential doses of the drugs are usually given at 1–2-week intervals.
Vinca drugs have long half-lives of 20–85 hours in plasma, as they undergo metabolism by the cytochrome P450 (CYP) system in the liver.
*Both drugs cause severe pain and local toxicity if extravasated.
Do not give either drug intrathecally. *
The dose-limiting side effect of vincristine
Neurotoxicity
- Usually occurs when the total dose received exceeds 6 mg/m2.
- The initial signs of neurotoxicity are paresthesia of the fingers and lower extremities and loss of deep tendon reflexes.
TRUE OR FALSE
While marrow suppression is not common with vincristine administration, myelosuppression may be noted in patients with impaired marrow function as a consequence of prior treatment with other drugs. Platelet counts are relatively unaffected.
TRUE
While marrow suppression is not common with vincristine administration, myelosuppression may be noted in patients with impaired marrow function as a consequence of prior treatment with other drugs. Platelet counts are relatively unaffected.
The primary toxicity of vinblastine
Leukopenia
The white count reaches a nadir at day 5–7 and reverses rapidly.
A unique class of natural products that intercalate the DNA double helix and inhibit topoisomerase II (Topo II), an enzyme important in DNA strand passage allowing the untangling of DNA prior to replication or repair
ANTHRACYCLINE ANTIBIOTICS
Doxorubicin, daunorubicin, idarubicin, and epirubicin
Mitoxantrone
The anthracyclines are produced by a Streptomyces species, whereas mitoxantrone is a synthetic compound.
Uses of Antracyclines:
Doxorubicin:
Daunorubicin, idarubicin, and mitoxantrone:
Epirubicin:
Doxorubicin: Hodgkin lymphoma (doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]) and aggressive non-Hodgkin lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
Daunorubicin, idarubicin, and mitoxantrone: AML
Epirubicin: solid tumors
Liposome-encapsulated doxorubicin (Doxil) is employed primarily for relapsed ovarian cancer and Kaposi sarcoma
Vyxeos, a liposome incorporating both ara-C and daunorubicin in fixed dose ratios, is approved for treatment of therapy-related AML.
The only anthracycline amenable to oral administration
Idarubicin
Has a bioavailability of 20% for the parent drug and 40% for the parent drug plus idarubicinol, the primary active metabolite
Unlike other anthracycline, eliminated primarily by renal excretion. No dose adjustment for hepatic dysfunction is indicated.
The anthracycline of choice in the treatment of adult AML
Daunorubicin
- The daunorubicin dosage (45–60 mg/m2 for adults younger than 60 years) is given daily for 3 days
- In people older than 65 years, a lower dose of 30 mg/m2 daily for 3 days is typically used in combination therapy.
The primary acute toxicity of anthracycline
Myelosuppression
Nadir occurring 7–10 days after single-dose administration and recovery by 2 weeks.
The major late toxic effect of anthracyclines, resulting from free radical formation catalyzed by the anthracycline’s quinone moiety.
Cardiotoxicity
Monitoring ejection fraction is required during anthracycline treatment and discloses reductions of 15% or greater from baseline, or an absolute ejection fraction less than 40%
Clinical risk factors include age younger than 4 years, prior chest irradiation, patients of African descent, female gender, and a history of cardiac disease.
In patients with normal cardiac function prior to treatment, the subsequent rate of doxorubicin-induced CHF reaches less than 1% at total doses of 400 mg/m2, but climbs steeply thereafter to 7% to 20% at total doses of 550 mg/m2.
Early institution of angiotensin-converting enzyme inhibitors and β blockers appears to forestall the development of CHF, and cardiac resynchronization may add benefit.
The incidence of cardiotoxicity is decreased by coadministering _________________, an iron chelator, during chemotherapy.
Dexrazoxane
Fortunately, dexrazoxane does not cause any apparent diminution of antitumor activity.
Should be added only in patients who have received a total dose of at least 300 mg/m2 doxorubicin.
Dexrazoxane injected subcutaneously lessens tissue damage after extravasation.
Treatment with Topo II inhibitors, including anthracyclines, mitoxantrone, and the epipodophyllotoxins , increases the risk of AML.
Usually can give rise to balanced chromosomal translocations involving the _______________________ genes, which contain apparent “hot spots” for Topo II breaks
MLL or PML (promyelocytic leukemia) genes
Major toxicities of Alkylating agents:
- Myelosuppression and mucositis- primary acute toxicities
- Delayed pulmonary fibrosis (busulfan and the nitrosoureas)
- Late secondary leukemias
These secondary leukemias often arise after a period of myelodysplasia, are usually highly drug-resistant AML, and carry defects in chromosome 5 or 7.
Busulfan, bischloroethylnitrosourea (BCNU), or cyclophosphamide are most likely to cause vascular endothelial damage (hepatic venoocclusive disease) when used in high doses.
TRUE OR FALSE
Platinum analogues are not true alkylating agents in that they form metal adducts rather than carbon adducts with DNA, RNA, and protein
TRUE
Platinum analogues are not true alkylating agents in that they form metal adducts rather than carbon adducts with DNA, RNA, and protein
Their range of toxicities and mechanisms of resistance have much in common with the classical alkylators.
They have few indications in hematologic malignancy, aside from carboplatin and its role in high-dose chemotherapy for lymphomas.
The oxic metabolite of cyclophosphamide and ifosfamide
Acrolein
To counteract toxicity of acrolein to kidneys and bladder, the mercaptoethane sulfonate (mesna) disulfide becomes a sulfhydryl in acid urine and inactivates acrolein.
A structural congener of DTIC, spontaneously activates to a methylating intermediate, and has become the preferred drug for treating glioblastomas
Temozolomide
A highly reactive compound in its parent form, and thus can be administered topically for treatment of skin cancers and cutaneous lymphoma
Nitrogen mustard (mechlorethamine)
The dose-limiting toxicity of DTIC is _______________ rather than marrow suppression.
Nausea and vomiting
Other adverse effects:
* Carboplatin causes an acute thrombocytopenia, neutropenia, and a more chronic sensory neuropathy.
* Nitrosoureas cause nephrotoxicity
* Cyclophosphamide and ifosfamide cause chronic bladder toxicity, hematuria, and, in rare cases, bladder carcinomas
The most frequently used conditioning regimen for autologous stem transplantation for lymphomas
(BEAM) includes BCNU, etoposide, ara-C, and melphalan
Dose-Limiting Extramedullary Toxicities of Single-Agent High-Dose Chemotherapy:
- Cyclophosphamide
- Ifosfamide
- Thiotepa
- Melphalan
- Busulfan
- BCNU
- Cisplatin
- Carboplatin
- Etoposide
- Cytarabine
- Cyclophosphamide:Cardiac
- Ifosfamide: Renal, CNS
- Thiotepa: GI, CNS
- Melphalan: GI
- Busulfan: GI, hepatic
- BCNU: Lung, hepatic
- Cisplatin: Renal, neuropathy
- Carboplatin: Hepatic, renal
- Etoposide: GI
- Cytarabine: Neurologic, mucositis
Primary toxicities of Bleomycin
Pulmonary fibrosis and skin changes
The clinical risk of pulmonary toxicity is related to the cumulative dose of BIP administered, with the risk increasing to 10% in patients given more than 450 mg over the patient’s lifetime.
Early symptoms of BIP include cough and dyspnea.
Baseline pulmonary function tests are not recommended, except for patients with known pulmonary disease.
Catalyzes the hydrolysis of asparagine to aspartic acid and ammonia, rapidly depletes l-asparagine from plasma and induces an asparagine deficiency in lymphoid malignant cells
L-Asparaginase
TRUE OR FALSE
Hyperdiploid ALL cells are particularly sensitive to l-asparaginase, whereas lymphoid leukemia cells containing the BCR-ABL translocation are more resistant
TRUE
Hyperdiploid ALL cells are particularly sensitive to l-asparaginase, whereas lymphoid leukemia cells containing the BCR-ABL translocation are more resistant
Preparations that have long plasma half-lives, are less likely to cause hypersensitivity, and are used for first-time therapy and for patients hypersensitive to the unmodified enzyme
Pegaspargase and calaspargase
DOSE:
* E. coli enzyme-derived: 6000–10,000 IU intramuscularly every third day for 3–4 weeks
* Pegaspargase: 2500 IU/m2 intramuscularly every 2 weeks
* Calaspargase: 2500 IU doses every 3 weeks
TRUE OR FALSE
Anaphylaxis is less likely when E. coli l-asparaginase is given intramuscularly than when it is administered intravenously.
TRUE
Anaphylaxis is less likely when E. coli l-asparaginase is given intramuscularly than when it is administered intravenously.
The other major toxic effects of l-asparaginase are a consequence of the ability of this drug to inhibit protein synthesis in normal tissues, resulting in hypoalbuminemia, a decrease in clotting factors, a decrease in serum lipoproteins, and a marked increase in plasma triglycerides, which predisposes to pancreatitis.
Induces myeloid differentiation physiologically through binding to dimers formed by the retinoic acid receptor-α (RARα) and various partners such as the retinoid X receptor
ALL-TRANS RETINOIC ACID
For induction of remission, ATRA is administered to APL patients in oral doses of 25–45 mg/m2 per day until complete remission is achieved.
ATRA side effects that causes hyperleukocytosis, fever, altered mental status, pleural and pericardial effusions, and respiratory failure.
Differentiation syndrome
Glucocorticoids and HU are effective in reversing this syndrome.
It promotes ubiquitination and degradation of the PML-RARα fusion protein, and upregulates p53 and proapoptotic proteins.
Part of the preferred all-oral regimen for induction and consolidation therapy of low-risk and intermediate-risk APL
ARSENIC TRIOXIDE
For induction, patients typically receive ATRA orally and a 2-hour intravenous infusion of ATO, 0.15 mg/kg day for up to 60 days, or until marrow remission is achieved, with further ATRA/ATO consolidation therapy beginning 3 weeks after remission
To avoid the inconvenience of daily infusions of ATO, oral formulations of both micronized ATO (15 mg/day) and arsenic Realgar-Indigo naturalis formula (RIF) (0.15 mg/kg per day) have been employed
Side effects of ATO:
- Hyperglycemia
- Elevated liver enzymes
- Depletes serum potassium and magnesium
- Prolongs the cardiac QT interval
- Atrial or ventricular arrhythmias (uncommon)
It is important to monitor the QT (< 500 msec), adjust serum potassium to above 4 mEq/L, and serum Mg2+ above 1.8 mEq/L prior to drug administration, and to avoid other drugs that prolong the QT interval (macrolide antibiotics, methadone, or quinidine).
Demythelating agents that incorporated into DNA, substituting for cytosine bases, and form a suicide covalent bond with DNMT
Azacitidine and decitabine
- Decitabine is phosphorylated by dCK whereas azacitidine is activated by cytidine kinase.
- Decitabine nucleotide is incorporated only into DNA, whereas azacitidine is found in both RNA and DNA.
TRUE OR FALSE
A metaanalysis showed a significant overall survival benefit versus supportive care only for azacitidine.
TRUE
A metaanalysis showed a significant overall survival benefit versus supportive care only for azacitidine.
A retrospective review found no significant difference in efficacy for MDS treatment between the 2 compounds except in patients older than 65 years, for whom azacitidine resulted in improved survival and a more favorable toxicity profile.
Dosing
Azacitidine:
Decitabine:
Azacitidine: 75 mg/m2/day for 7 days every 28 days
Decitabine: 20 mg/m2 intravenously daily for 5 days every 4 weeks
Azacitidine is initially phosphorylated by a different kinase (uridine-cytidine kinase) than decitabine; thus, decitabine may benefit patients unresponsive to azacytidine.
Directly deacetylate and activate many nonhistone proteins, including p53 and members of the DNA repair complex
Effective in relapsed or refractory multiple myeloma, T-cell lymphomas
HISTONE DEACETYLASE INHIBITORS
The most potent pan-HDAC inhibitor, is approved in combination with bortezomib and dexamethasone, for relapsed or refractory multiple myeloma.
Panobinostat
t has notable, but preliminary activity in angioimmunoblastic T-cell lymphoma, either alone or in combination with oral 21 day azacitidine.
Other HDACs (disease targeted)
Vorinostat and romidepsin:
Romidepsin and belinostat:
Vorinostat and romidepsin: Cutaneous T-cell lymphoma
Romidepsin and belinostat Peripheral T-cell lymphoma
An inhibitor of ABL tyrosine kinase activity and is particularly efficacious against the mutant ABL characteristic of the BCR-ABL fusion protein
BCR-ABL TYROSINE KINASE INHIBITORS
Other gene targets of TKI:
- c-KIT kinase: gastrointestinal stromal tumor and mastocytosis
- PDGFR: hypereosinophilia syndrome,chronic monomyelocytic leukemia, MDS with PDGFR rearrangement, and dermatofibrosarcoma protuberans
Dasatinib and ponatinib also inhibit the Src family kinases, an important secondary target in CML.
The only agent with significant activity against the most common resistance mutation T315I
Ponatinib
All BCR-ABL inhibitors can promote fluid retention resulting in peripheral edema and pleural effusions; ____________ being the most significant offender
Dasatinib
Example of JAK inhibitors
Ruxolitinib (Jakafi)
Fedratinib (Inrebic)
- Ruxolitinib inhibits all JAK kinases independent of their mutational status and to similar degree independent from the disease subtype
- Fedratinib is a selective JAK2 inhibitor with activity against wild-type and mutant JAK2 as well as FLT3, but significantly less activity against JAK1, JAK3, and TYK2.
TRUE OR FALSE
Ruxolitinib improves constitutional symptoms and splenomegaly, but does not have disease-modifying activity.
TRUE
Ruxolitinib improves constitutional symptoms and splenomegaly, but does not have disease-modifying activity.
Fedratinib carries this boxed warning
Fatal Wernicke encephalopathy
Thiamine levels should be checked before and throughout fedratinib treatment
The most common activating FLT3 mutation
Internal tandem duplication (ITD) variant,
- Found in approximately 25% of patients with AML
- Confer an adverse overall prognosis
Type of FLT3 inhibitors
- Sorafenib- only FLT3-ITD
- Midostaurin
- Gilteritinib
Isocitrate Dehydrogenase Inhibitor Therapies
IDH1:
IDH2:
IDH1: Ivosidenib
IDH2:Enasidenib
BTK inhibitors
- Ibrutinib
- Acalabrutinib
- Zanubrutinib
Uses: CLL, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and chronic graft-versus-host disease
Ibrutinib is administered orally once daily, while acalabrutinib and zanubrutinib are administered orally twice daily.
Blocks the binding and inactivation of BH3 proapoptotic peptides to BCL-2
Venetoclax
Venetoclax is given in a dose escalation of 100 mg on day 1, increasing to 200 mg on day 2, 400 mg on days 3–28, with further increase in dose to 600 mg on day 4 when given with low-dose ara-C.
Antifungal drugs (posaconazole and voriconazole) strongly inhibit its clearance and necessitate a 75% reduction in dose.
PHOSPHOINOSITOL 3 KINASE DELTA INHIBITORS:
- IDELALISIB
- COPANLISIB
- DUVELISIB
- UMBRALISIB
Idelalisib and duvelisib are isoform-selective, whereas copanlisib is a multitargeted pan-class I PI3K inhibitor.
Umbralisib, in addition to having selective PIK3δ inhibition, inhibits casein-kinase-1ε, an important new target for therapy of inflammatory bowel disease.
Approved for approved for R/R CLL/SLL or follicular lymphoma
- Idelalisib : 150 mg orally twice daily
- Duvelisib: 25 mg orally twice daily
THERAPEUTIC MONOCLONAL ANTIBODIES
- Rituximab - anti CD-20
- Ofatumumab - anti CD-20
- Obinutuzumab- anti CD-20
- Alemtuzumab - anti CD-52
- Brentuximab Vedotin - anti-CD30
The main toxicity of Brentuximab Vedotin
Peripheral neuropathy
ANTILEUKEMIC ANTIBODIES:
- Gemtuzumab Ozogamicin - anti-CD33
- Inotuzumab Ozogamicin - anti-CD22
- Blinatumomab - concurrently binding CD3 on T cells and CD-19 on leukemic cells
Hepatic damage with Gemtuzumab Ozogamicin likely results from calicheamicin injury to sinusoidal cells causes
Hepatic sinusoidal obstructive syndrome (SOS)
Also with Inotuzumab ozogamicin
Defibrotide may play a therapeutic role in preventing severe hepatic injury in patients receiving a stem cell transplantation following GO.
ANTIMYELOMA ANTIBODIES
- Daratumumab - anti-CD38
- Isatuximab- anti-CD38
- Elotuzumab- anti-SLAMF7
IMMUNOTOXINS
Immunotoxins combine immune proteins such as antibodies, antibody Fab fragments, or interleukins with toxins
- Moxetumomab Pasudotox : Pseudomonas exotoxin A+ CD22 (hairy cell leukemia)
- Denileukin diftitox: diphtheria toxin + IL-2 (non-Hodgkin lymphoma)
- Tagraxofusp: diphtheria toxin + CD123 (IL-3 receptor α) (blastic plasmacytoid dendritic cell neoplasm)
The most common side effects of Moxetumomab Pasudotox :
Capillary leak syndrome and hemolytic uremic syndrome
PROTEASOME INHIBITORS
Targets the ubiquitin–proteasome pathway
- Bortezomib
- Carfilzomib
- Ixazomib
- Marizomib
- Oprozomib
The novel beta-lactone proteasome inhibitor, marizomib, has emerged as the most potent inhibitor, blocking the β1, β2, and β5 subunits of the proteosome, and displaying synergy with IMiDs preclinically.
Bortezomib has potent clinical activity against myeloma, and other plasma cell dyscrasias, including amyloidosis and Waldenström macroglobulinemia, and is also active in mantle cell lymphoma
Main dose-limiting toxicity of Bortezomib
Sensory peripheral neuropathy
SELECTIVE INHIBITOR OF NUCLEAR PROTEIN EXPORT
Selinexor
Selinexor is FDA approved in combination with dexamethasone for adult patients with R/R multiple myeloma who have received at least 4 prior therapies and have become refractory to at least 2 proteasome inhibitors, at least 2 IMiDs, and an anti-CD38 monoclonal antibody
IMMUNOMODULATORY DRUGS
- THALIDOMIDE
- LENALIDOMIDE
- POMALIDOMIDE
Pomalidomide, the newest IMiD, is the most potent and least toxic
IMID highly active in first-line combination therapy with dexamethasone, and also with bortezomib for myeloma, and is approved for the treatment of myelodysplasia in patients with the 5q− variant of this syndrome.
Lenalidomide
Lenalidomide produces a dramatic tumor swelling (tumor flare reaction) and tumor lysis in patients with CLL, a potentially fatal complication, even in patients with disease refractory to conventional agents.
In CLL, it is equally effective in patients with poor prognostic cytogenetics (chromosomes 11 and 17 deletions).
