Pharmacology of Hematologic Malignancies
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What are the 6 classes of alkylating agents?
- Nitrogen Mustards
- Alkyl Sulfonates
- Platinum Analogues
What are the 6 Nitrogen Mustards?
- Mechlorethamine hydrochloride
What are the 4 Nitrosoureas?
What is the Alkyl Sulfonate?
What are the 2 Ethylenimines?
What is the Triazene?
What are the three Platinum Analogues?
This drug is indicated for the treatment of patients with CLL and NHL. It is compared to Chlorambucil.
100 mg/m2 IV over 30 min on Days 1 and 2 of a 28-day cycle.
Myelosuppression is DLT
Do not use if CrCL is <40 mL/min
What agents have the following mechanism of action?
One 2-chloroethyl side chain undergoes a first-order intramolecular cyclization
Results in the release of Cl- and the formation of a highly reactive ethyleniminium intermediate (aziridinium ion)
Unstable aziridine ring can undergo nucleophilic attach by an electron donor (drug is an electrophile)
Reaction with guanine at N-7 occurs to the greatest extent
Other sites on guanine, other bases, and phosphate oxygens also can be alkylated
In the mechanism of action of alkylating agents, the reaction with guanine at ______ occurs to the greatest extent.
What are the four Topoisomerase Agents?
This class of drugs work by inhibiting topoisomerase II. This prevents the religation of DNA during DNA replication causing DNA strand breaks.
Dose reductions are required in patients with hepatic impairment. Decrease dose by 50% if bilirubin levels 1.2-3.0 mg/dL and by 75% for bilirubin > 3.0; generally omitted if bilirubin >5.0
Toxicities: potent vesicants; dose limiting myelosuppression, chronic cardiomyopathies; dose dependent nausea and vomiting; alopecia; radiation recall.
The mechanism of action of this drug is as a Topoisomerase II Inhibitor.
Dosage and Administration: 50 to 200 mg/m2 per day IV for 3-5 days every 3 weeks; IV infusion should be infused over 30-60 minutes to avoid hypotension; oral dose is 2x greater than the IV
Toxicities: dose limiting myelosuppression -- primarily leukopenia; additional toxicities include nausea and vomiting (with oral dosing); alopecia
What are the two types of antimicrotubules?
This class of drugs requires dose reductions in patients with hepatic impairment. Decrease dose by 50% if bilirubin levels 1.5-3.0, and by 75% for bilirubin >3.0; generally omitted if bilirubin >5.0.
All drugs in this class are potent vesicants.
Which drug within this class has the following additional toxicities?: a dose-limiting leukopenia and thrombocytopenia; neurologic toxicity; constipation; abdominal cramps
Which drug within this class has the following additional toxicities?: dose-limiting neurologic toxicity; constipation; and paralytic ileus. Rarely causes bone marrow suppression and SIADH
- Vinca Alkaloids
Often drugs that inhibit cell growth are used to combat cancer. Many of these compounds are analogues of purine and pyrimidine bases or nucleotides. Many of these drugs must be activated by cellular enzymes. They affect nucleic acid synthesis and tumor cells tend to be more susceptible since they are dividing more rapidly. What drug class does this describe?
This drug is a dihydrofolate reductase inhibitor that prevents the conversion of dihydrofolate to tetrahydrofolate. Therefore, tetrahydrofolate is not formed. This causes a decrease in thymidylate (a pyrimidine) due to a lack of N5-10 methylene FH4 cofactor for thymidylate synthase. There is a decrease in purine synthesis because synthesis requires one-carbon transfer reactions, which are dependent on FH4. The end result is decreased RNA, DNA, and protein synthesis.
Toxicities of this drug include: dose-limiting leukopenia and thrombocytopenia. Renal tubular necrosis seen with high dose therapy. Vigorous hydration and alkylation of the kidney necessary to decrease risk of kidney damage. Additional toxicities include: pulmonary pneumonitis, alopecia, and stomatitis and mucositis.
This provides a source of reduced folate.
These two purine analogues are converted in the body to the ribonucleotide form, which incorporate in the DNA to prevent purine synthesis
The triphosphate form of this purine analogue inhibits ribonucleotide reductase and DNA polymerase
These two purine analogues inhibit ribonucleotide reductase
What is the main adverse effect of the purine analogues?
Increase risk of infection
These two pyrimidine analogues are triphosphorylated to the active drug which inhibits DNA polymerase
This drug, which is an analogue of CTP, is incorporated into DNA and inhibits chain synthesis. It is used extensively in the acute leukemias.
Cytosine Arabinose (araC)
This is a prodrug that undergoes conversion to the triphosphate nucleotide, ara-cytosinetriphosphate (ara-CTP) and difluorodeoxycytidine triphosphate, respectively. The triphosphate forms then act as competitive inhibitors of DNA polymerase halting chain elongation.
Toxicities include: dose-limiting leukopenia and thrombocytopenia; N&V; mucositis; diarrhea; flu-like syndrome; rash
High doses are often given with allopurinol to prevent tumor lysis syndrome
This drug is a novel purine nucleoside analog. It is less susceptible to metabolic inactivation by adenosine deaminase. It inhibits DNA replication and repair, and disrupts mitochondrial integrity leading to apoptosis. It is active in both dividing and non-dividing cells, and is used in biochemical modulation strategies with other nucleoside analogues (Ara-C)
What are the two types of Targeted Therapies?
- Monoclonal Antibodies
- Tyrosine Kinase Inhibitors
The biologic response to these include: direct tumor effects -- induce apoptosis; interfere with ligand-receptor binding; modulate cytotoxic effects of a second agent; prevent protein expression; Complement-dependent cytotoxicity (CDCC); and Antibody-dependent cellular cytotoxicity (ADCC)
Biologic Response to Antibody
A drug name ending in -mab refers to what type?
The indication for this drug is for relapsed or refractory low-grade or follicular CD20 + B-cell NHL (>90% of B cell lymphomas are CD20+)
Mechanism of action includes ADCC, CDCC, and apoptosis.
This is used as a single drug or in combination in low-grade lymphoma; as combination therapy in higher grades (CHOP-R); and in CLL and autoimmune disorders.
Toxicities include: infusion related reactions (fever, chills, rigors, hypotension, nausea); tumor lysis syndrome; mucocutaneous reactions; Hep B reactivation; and PML
The main indication for this drug is in patients with B-cell CLL who were treated with alkylating agents and have not responded to fludarabine (targets the CD52 antigen). The MOA is cellular lysis
In therapy it is used as a single agent salvage therapy
Toxicity includes: infusion reactions; hematologic; and opportunistic infections (pneumocystis carinii; herpes virus)
Which drug targets CD-52 on lymphocytes
MOA: CDC & ADCC
Which 2 drugs target CD-20 on B-cells
MOA: ADCC, CDC, & apoptosis
Which 2 drugs target CD-20 on B-cells
MOA: ADCC, CDC, apoptosis, & radiation
Which drug targets CD-33 on myeloid cells
MOA: double stranded DNA breaks
What tyroine kinase inhibitor targets the Bcr-Abl on the Ph Chromosome [t(9;22)] Translocation?
This drug is used for initial or salvage therapy for CML and in treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST)
MOA: inhibits the tyrosine kinase activity of Bcr-Abl; inhibits the c-Kit and platelet-derived growth factor receptor
Place in Therapy: CML; GIST
Inhibitor of substrate of CYP3A4
This drug is a proteasome inhibitor.
Toxicities: GI -- N&V, diarrhea; General -- fatigue, weakness, malaise; Hematologic: thrombocytopenia; Peripheral Neuopathy
In APL t(15;17), part of RAR-alpha gene on 17q, is translocated to 15q and fused to another gene, PML. The fusion-gene product (pml-rar alpha) causes failure of promyelocytes to differentiate and blocks apoptosis.
The drug used in APL allows for differentiation of the leukemic cell. What is it?
Toxicities include: headache, dryness of the skin and mucous membranes, nausea, vomiting, and moderate bone and joint pain are also seen. "Retinoic Acid Syndrome"
Response: complete remissions in 64-100% of patients with duratiosn of 2 to 13+ months
All-trans-Retinoic Acid (Tretinoin)
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